Gary Null Anti-Aging Protocol For Nursing Homes - Studies

Gary Nulls Anti-Aging Protocol for Nursing Homes: Nutrients Scientifically Proven to be Beneficial to Cognition and the Overall
Body
Prepared by: Gary Null, Ph.D., and Doug Henderson, Esq.
Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved
PROTOCOL DISCLAIMER:
The attached protocol is not in any way to be construed as a prescription to cure the condition, but as a suggested nutritional component only. This protocol was initially requested by a physician from Gary Null & Associates for a specific patient, for whose condition this protocol is to be employed under the physicians directions. Firstly, patients diagnosis, treatment, and medications must be considered in determining if any of the suggested vitamins, minerals, foods, and herbs in contraindicated. Special considerations should be given to pregnant and nursing mothers. Secondly, the attached protocol must be implemented in gradual steps. Begin with low doses of one or two items of the protocols suggested items to determine the patients acceptance and tolerance. Once it is determined that the patient has adapted, the dosage should be increased in gradual steps.
Gary Nulls Anti-Aging Protocol for Nursing Homes: Nutrients Scientifically Proven to be Beneficial to Cognition and the Overall Body............................................................... 1 PROTOCOL DISCLAIMER:......................................................................................... 2 Nursing Home Intervention Study: Introduction ............................................................ 5 NURSING HOMES, DYING FROM NEGLECT 16 References .............................. 6 INFECTION 76 Studies............................................................................................. 10 ANTIDEPRESSANTS 109 Studies........................................................................... 32 THE HIGH COST OF MEDICAL CARE 49 Studies............................................... 65 MALNUTRITION 30 Studies ................................................................................... 80 MEDICAL ERRORS & ADVERSE DRUG REACTIONS 76 Studies.................... 89 NURSING HOME PROTOCOL................................................................................ 112 Vitamin B1 120 Studies........................................................................................... 202 Vitamin B12 64 Studies........................................................................................... 217 Pantothenic Acid (B5) 47 Studies............................................................................ 222 Calcium Carbonate - 86 Studies ................................................................................. 226 Magnesium 68 Studies........................................................................................... 233 Ginkgo Biloba 33 Studies ........................................................................................ 237 L-Phenylalanine 33 Studies ..................................................................................... 240 L-Glutathione 67 Studies ......................................................................................... 243 L-Taurine 94 Studies ............................................................................................... 249 Choline Bitartrate 63 Studies................................................................................... 265 Inositol 56 Studies ................................................................................................... 273 L- Carnitine 93 Studies ............................................................................................ 277 L-Cysteine 50 Studies.............................................................................................. 287 Blue Cohosh Root 2 Studies .................................................................................... 292 Siberian Ginseng Root 40 Studies ........................................................................... 292 Rosemary Leaves 17 Studies ................................................................................... 295 Apsartic Acid 21 Studies ......................................................................................... 296 L-Glutamine 58 Studies ........................................................................................... 298 L-Tyrosine 53 Studies.............................................................................................. 302 Linoleic Acid 56 Studies.......................................................................................... 306 Linolenic Acid 10 Studies........................................................................................ 311 Caprylic Acid - 9 Studies............................................................................................ 312 Glycerophosphorylcholine 11 Studies ..................................................................... 312 Phosphatidylserine 13 Studies ................................................................................. 314 Pregenolone -23 Studies ............................................................................................. 315 Benfotiamine 32 Studies.......................................................................................... 317 SUPER ANTIOXIDANTS ......................................................................................... 320 Vitamin A 41 STUDIES .......................................................................................... 320 Vitamin C 51 STUDIES ......................................................................................... 323 Vitamin E - 78 Studies............................................................................................ 327 Vitamin B6 - 28 STUDIES........................................................................................ 335 Magnesium - 86 Studies .......................................................................................... 338 Zinc 50 STUDIES.................................................................................................... 349 Selenium 50 STUDIES............................................................................................ 356 Copper 60 Studies.................................................................................................... 362 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 3
Quercetin 20 STUDIES ........................................................................................... 368 Astaxanthin 20 STUDIES........................................................................................ 370 L-Carnosine - 28 Studies ......................................................................................... 374 Lycopene 50 Studies........................................................................................... 377 Rosemary Leaf Powder - 20 STUDIES...................................................................... 380 Tocotrienols 40 STUDIES....................................................................................... 383 Raspberry Leaf Powder - 10 Studies ......................................................................... 388 Citrus Bioflavonoids 11 STUDIES.......................................................................... 389 Rutin 16 STUDIES .................................................................................................. 391 Billberry - 17 Studies............................................................................................... 392 Red Wine Concentrate 14 STUDIES....................................................................... 396 Grape Skin Extract 48 STUDIES ............................................................................ 398 China Green Tea Leaf Powder - 100 Studies ............................................................ 402 Reduced L-Glutathione - 13 CITATIONS ................................................................. 423 L-Cysteine 22 STUDIES ......................................................................................... 425 Coenzyme Q10 43 STUDIES .................................................................................. 429 N-Acetylcysteine (NAC) - 40 STUDIES.................................................................... 434 Alpha Lipoic Acid 20 STUDIES ............................................................................. 443 Superroxide Dismutase 51 STUDIES...................................................................... 446 Taurine ........................................................................................................................ 450 Pycnogenol 20 STUDIES ........................................................................................ 454 Licorice Root 21 STUDIES..................................................................................... 458 BroccolI Stem - 26 STUDIES .................................................................................. 460 Lutein - 21 STUDIES ................................................................................................ 462 Cabbage Leaf 10 STUDIES..................................................................................... 464 Carrot Root - 11 STUDIES......................................................................................... 466 Milk Thistle Leaf - 27 STUDIES ............................................................................... 467 Bromelain 49 STUDIES .......................................................................................... 473 Nutrients That Have Demonstrated The Ability To Slow Down the Rate at Which We Age.............................................................................................................................. 477 Acetyl-L-Carnitine - 49 ABSTRACTS ..................................................................... 477 Alpha Lipoic Acid - 70 ABSTRACTS ....................................................................... 503 Mixed Tocopherols - 398 Studies............................................................................... 547 Glycerylphosphorylcholine 4 Studies...................................................................... 596 Carnosine - 47 ABSTRACTS................................................................................... 598 Magnesium - 570 CITATIONS .................................................................................. 621 Quercetin - 30 ABSTRACTS ..................................................................................... 718 L-Carnosine - 15 Studies ........................................................................................... 737 Cayenne 267 Studies................................................................................................ 739 Phosphatidylserine 19 Studies ................................................................................. 741 Ginkgo Biloba Leaf Powder 25 Studies .................................................................. 743 Linoleic Acid 29 Studies.......................................................................................... 745 Inositol 6 Studies ..................................................................................................... 748
Nursing Home Intervention Study: Introduction
The current health status of many of the individuals living in nursing homes is directly related to their nutritional intake. Numerous studies have concluded that these individuals suffer from multiple nutritional deficiencies. From the Clinton Administration Report on the Quality of Nursing Homes: "The report concludes that the private Joint Commission on accreditation of Healthcare Organizations (JCAHO) survey process was not effective in protecting the health and safety of nursing home residents". Also, the office of the Health Care Financing Administration stated that "Five and a half years seems a long time for Clinton to discover that hundreds of people are still dying from malnutrition, dehydration, sepsis from bedsores and even physical abuse while in nursing homes". The problems of malnutrition and dehydration are due in particular to the institutional food provided by vendors who have used RDAs which have been shown to be, A) both insufficient and, B) grossly inadequate for people who have compromised immune systems and multiple nutritional deficiencies. This proposal carefully examines the scientific literature which cites the actual therapeutic dosages in relation to the category of illnesses that the majority of people in nursing homes fall into. We conclude, after reviewing thousands of scientific articles and using data from test groups of 300 individuals, most of whom are in senior citizen age groups, that nutrition and exercise, as presented in this proposed protocol, played a key role in the health and well-being of the senior citizens. In January of 1997 I enrolled 300 people into a "Reverse the Aging Process Study" whicCreated by dhendersonh would last for 18 months. 18 months later 65 people completed the study. 235 people became controls. This was not a double blind study. It was an observation of changes in their blood chemistry, weight, physical dimensions, physical appearance, memory, energy levels, sleep patterns, bowel movements, night time urination, muscle strength, digestion, olfactory senses, visual senses, tactile senses, skin texture, hair texture and stress levels. This was a lifestyle modification study. 52% of participants had lower cholesterol and tryglyceride levels. 68% of participants had increased DHEA levels. 78% of participants had a significant improvement in their fat / muscle ratio. 90% of participants had an increase in bowel movements. 92% of participants had a decreased need for sleep. 95% of participants had increased energy levels, and stress levels were lowered by 97%. In addition, numerical diaries had been kept by the participants reflecting subjective data. This data cited improvements that affected the participants in their overall quality of life.
We can also conclude that this protocol would benefit the vast majority of people in nursing homes and hospices. The following is not a theoretical model, it is an actual model. Harry Biele, a 90 year old man who just 10 years ago had chronic sinusitis, asthma, arthritis, enlarged prostate, a pre-cancerous lower bowel and main coronary artery blockage is now a marathoner living life to its fullest. His cardiologist has taken away all medication like beta blockers, and his general practitioner has taken away his inhalers for asthma. He is not an exception. Harry is the example of someone who has taken positive action toward his own health. He improved his nutrition by applying a protocol similar to this one. Exercise became part of Harrys daily ritual. He now appears to be closer to 70 than 90. All senior citizens and baby boomers can improve their health. This is the scientific literature that justifies the use of recommended supplements in this protocol. Applying this protocol can play an important role in anyones life. Gary Null Ph.D.
NURSING HOMES, DYING FROM NEGLECT 16 References

The term nursing home implies two things: one, that nurses are taking care of the elderly and, two, that, instead of an institution, people are living in a home. Three separate reports that took over ten years to complete show us that neither assumption is correct. During President Clintons term in office, The Clinton Administration Report on the Quality of Nursing Homes was prepared. The five and one-half year report concluded that "The private Joint Commission on accreditation of Healthcare Organizations (JCAHO) survey process was not effective in protecting the health and safety of nursing home residents." Also, the office of the Health Care Financing Administration analyzed the report and stated that "Five and a half years seems a long time to discover that hundreds of people are still dying from malnutrition, dehydration, sepsis from bedsores and even physical abuse while in nursing homes". (1) Congressman Waxman sponsored a report published in 2001 called "Abuse of Residents is a Major Problem in U.S. Nursing Homes." The report found that one third - 5,283 of the nations 17,000 nursing homes - were cited for an abuse violation in the two-year period studied, January 1999 - January 2001. (2) The major findings of the report were: 1. There were more than 9,000 abuse violations during the two-year period. 2. Ten-percent of nursing homes had physical harm violations to residents. 3. Over 40-percent, or 3,800 abuse violations, were only discovered after a formal complaint was filed, usually by concerned family members. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 6
4. Many verbal abuse violations were reported. 5. There were reports of sexual abuse. The third report was an exhaustive study of nurse-to-patient ratios in nursing homes. Although mandated by Congress in 1990, the study was not begun until 1998. (3) The report found that dangerously understaffed nursing homes lead to neglect, abuse, overuse of medications, and overuse of physical restraints. About the report, a spokesperson for The National Citizens Coalition for Nursing Home Reform said, "They compiled two reports of three volumes each thoroughly documenting the number of hours of care residents must receive from nurses and nursing assistants to avoid painful, even dangerous, conditions such as bedsores and infections. Yet it took the Department of Health and Human Services and Secretary Tommy Thompson only four months to dismiss the report as insufficient." (4) The main categories of abuse in nursing homes that cause harm in the elderly are: 1. Overuse of medication and side effects of medication 2. Overuse of physical restraints 3. Malnutrition, dehydration, and nutrient deficiency 1. OVERUSE OF MEDICATION AND SIDE EFFECTS OF MEDICATION A 2003 study surveyed drug use in the elderly population. Dr. Robert Epstein, chief medical officer of Medco Health Solutions Inc. (a unit of Merck & Co.), conducted the study on drug trends. (5) Medco oversees drug benefit plans for more than 60 million Americans, including 6.3 million senior citizens who received more than 160 million prescriptions. Data analysis showed that the average senior receives 25 prescriptions annually. A total of 7.9 million medication alerts were triggered in the group of 6.3 seniors. When compared with 1999 statistics, twice as many medication alerts occurred in 2003. About 2.2 million of those alerts indicated excessive dosages unsuitable for senior citizens and about 2.4 million indicated clinically inappropriate drugs for the elderly. In a "snapshot" survey of 818 residents of residential care facilities for the elderly, 94% were receiving at least one medication at the time of the interview. The average intake of medications was five per resident; the authors noted that many of these drugs were given without a documented diagnosis justifying their use. (6) Lets also look at the irony of lack of proper pain medication for patients that really need it. In one study, the authors concluded that older patients suffering pain were more likely to go untreated. In this study pain management was evaluated in a group of 13,625 cancer patients aged 65 or over living in nursing homes. Overall, almost 30% or 4,003 patients reported pain. More than 25% or (1,000) patients with pain received absolutely no pain relief medication. Another 16% received a World Health Organization (WHO) level one drug (mild pain reliever); 32% received a WHO level two drug (moderate pain reliever); and only 26% received adequate pain-relieving morphine for their cancer pain. (7)
2. OVERUSE OF RESTRAINTS Study after study concludes that physical restraints are a preventable cause of death. (8,9) Nursing home administrators argue that they must use physical restraints to prevent falls. In fact, they cause more injury and death because people naturally fight against such imprisonment. Studies show that the use of restraints carries a higher mortality rate and economic burden than no restraints. (10,11,12) In one study a mortality rate of 1 in every 1,000 nursing home deaths was found to be due to physical restraints, including bedrails. (13) In these studies, descriptions of frail, elderly people suffocated between the mattress and bed rails, being hung by bed restraints, and with heads crushed between bed rails gives graphic testament to their dangers. It appears that drugs are used to "restrain" nursing home residents as much as physical restraints. Sarah Green-Burger, in her 2000 review, reminds us that nursing home resident-rights include freedom from physical and chemical restraints. She says drug "restraints" are known to decrease appetite and impede eating. There is also provision for reasonable accommodation of individual needs, which should assure a healthy diet and a suitable environment conducive to eating. 3. MALNUTRITION, DEHYDRATION, AND NUTRIENT DEFICIENCY According to Green-Burger studies on nursing home populations, conducted over the last ten years, show that from 35% to 85% of U.S. nursing home residents are malnourished. (14) This can be directly measured by a simple weight scale; 30% to 50% of residents are substandard in bodyweight. These findings directly contravene specific components of The Nursing Home Reform Act of 1987 (NHRA) to prevent both malnutrition and dehydration. They also mean that nursing homes are failing our elderly on many levels. In order for such abuse to exist there is no proper assessment of residents, no individualized care, improper physician supervision, insufficient nursing staff, and little attention to quality of life care and service. The law specifically mandates that nursing homes must meet residents nutrition and hydration needs. But according to GreenBurger " the level of malnutrition and dehydration in some American nursing homes is similar to that found in many poverty-stricken developing countries where inadequate food intake is compounded by repeated infections." The Green-Burger study goes on to emphasize the seriousness of malnutrition and dehydration, which can result in repeated infections (including urinary tract infections and pneumonia), pressure ulcers, anemia, hypotension, confusion and impaired cognition, decreased wound healing, and hip fractures. Beyond physical signs and symptoms nutritionally-impaired residents become weak, fatigued, bedridden, apathetic, and depressed. Often residents are transferred to hospital for acute illness, and if malnourished or dehydrated, we know that they suffer increased morbidity and require longer lengths of stay. Green Burger states that compared with well-nourished hospitalized nursing home residents, they have a five-fold increase in mortality in the hospital.
Green-Burger identifies four key issues that need to be addressed for the prevention and treatment of malnutrition and dehydration: 1) inadequate staffing, 2) poor environment, 3) insufficient data collection, and 4) lack of enforcement. We would add a fifth: improved nutritional intake in the form of healthier diets and nutrient supplements. TIP OF THE ICEBERG While conditions in many nursing homes appear very serious, there is evidence that what we know is only the tip of the iceberg. In fact, deaths caused by malnutrition, dehydration, and physical restraints are rarely recorded on death certificates. Even though 1 in 5 people die in nursing homes, the autopsy rate is only 0.8%. (15) Thus, we have no way of knowing the true causes of death. Dr. Steven Miles, professor of Geriatric Medicine at the University of Minnesota, in an in-depth study found many barriers to researching accidental deaths in nursing homes. (16) He found that adverse drug reactions or the late consequences of falls may go unrecognized as the cause of death. A substantial barrier was found to be nursing home staff who conceal some accidental deaths. Dr. Miles reports on one anecdotal series where attempts were made to cover up four out of eight lethal accidents. Miles says, obviously, "The success of these efforts cannot be known since successful efforts will not be countable." In a review of 17 nursing home deaths, Dr. Miles found that in 8 of 17 there was an effort to conceal the fact that a death was caused by asphyxiation by bedrails or physical vest restraints. REFERENCES: 1. http://www.hhs.gov/asl/testify/t980728b.html 2. CNN Washington senate briefing, Abuse of Residents is a Major Problem in U.S. Nursing Homes - live coverage July 30, 2001. 3. Report to Congress: Appropriateness of Minimum Nurse Staffing Ratios In Nursing Homes. Phase II Final Report. December 24, 2001. 4. Press Release. Consumer Group Criticizes Thompson Letter Dismissing Report on Dangerous Staffing Levels in Nursing Homes. The National Citizens Coalition for Nursing Home Reform. March 22, 2002. 5. Overmedication of U.S. Seniors. Reuters Health, May 21, 2003. 6. Williams BR, et al. Medication use in residential care facilities for the elderly. Ann Pharmacother. 1999 Feb;33(2):149-55. 7. Bernabei R, et al. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology. JAMA 1998 Jun 17;279(23):1877-82. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 9
8. Miles SH, Irvine P. Deaths caused by physical restraints. Gerontologist. 1992 Dec;32(6):762-6. 9. Annas GJ. The Last Resort: The Use of Physical Restraints in Medical Emergencies. N Engl J Med. 1999 Oct 28;341(18):1408-12. 10. Robinson BE. Death by destruction of will. Lest we forget. Arch Intern Med. 1995 Nov.13;155(20):2250-1. 11. Capezuti E. et al. The relationship between physical restraint removal and falls and injuries among nursing home residents. J Gerontol A Biol Sci Med Sci. 1998 Jan;53(1):M47-52. 12. Phillips CD, Hawes C, Fries BE. Reducing the use of physical restraints in nursing homes: will it increase costs? Am J Public Health. 1993 Mar;83(3):342-8. 13. Parker K., et al. Deaths caused by bedrails. J Am Geriatr Soc. 1997 Jul;45(7):797802. 14. Green-Burger S, Kayser-Jones J, Prince-Bell J. Malnutrition and Dehydration in Nursing Homes: Key Issues in Prevention and Treatment. National Citizens' Coalition for Nursing Home Reform. June 2000. http://www.cmwf.org/programs/elders/burger_mal_386.asp 15. Katz PR, Seidel G. Nursing home autopsies. Survey of physician attitudes and practice patterns. Arch Pathol Lab Med. 1990 Feb;114(2):145-7. 16. Miles SH. Concealing accidental nursing home deaths. HEC Forum. 2002 Sep;14(3):224-34.
INFECTION 76 Studies
1. Notice to Readers: Fourth Decennial International Conference on Nosocomial and Healthcare-Associated Infections.
MMWR, February 25, 2000 / 49(07);138.
This article reports that every year in the U.S., approximately 2,000,000 patients develop hospital-acquired infections and 88,000 die from them. The cost of hospital-acquired infections has been estimated at $4.6 billion. These estimates are conservative, because
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they do not take into account nosocomial infections occurring in patients in nursing homes, outpatient clinics, dialysis centers and other health care centers.
2. Mortality associated with nosocomial infections: analysis of multiple causeof-death data.

White MC. J Clin Epidemiol 1993 Jan;46(1):95-100. This article emphasizes that hospital-acquired infections are among the 10 leading cause of death in the U.S.
3. The nationwide nosocomial infection rate. A new need for vital statistics.
Haley RW, Culver DH, White JW, Morgan WM, Emori TG. Am J Epidemiol 1985 Feb;121(2):159-67. The results of this study indicate that in 1985, the incidence of hospital-acquired infections in the U.S. was 5.7 per 100 patients. Extrapolation of these data to the 6,449 acute-care hospitals revealed that every year, in the U.S., approximately 2 million infections occur in hospitalized patients. However, after adjustment for accuracy of detection methods, trend toward a nationwide increase in infection rates, and number of infections in nursing home patients, the estimated number of yearly nosocomial infections increased to 4 millions. The authors emphasizes that these data greatly exceed previous evaluations, and call for correct statistics to properly address the problem.
4. Trends in infectious disease hospitalizations in the United States, 1980-1994. Simonsen L, Conn LA, Pinner RW, Teutsch S. Arch Intern Med 1998 Sep 28;158(17):1923-8. The results of this study show that from 1980 to 1994, mortality rates in individuals hospitalized for infectious disease doubled, from 1.9% to 4.0%.
5. Trends in infectious diseases mortality in the Unites States. Pinner RW, et al. JAMA 1996 Jan 17;275(3):189-93. The results of this study show that from 1980 to 1992, death due to infectious diseases in the U.S. increased 58%, from 41 to 65 deaths per 100,000 population. Of note, death due to infectious diseases increased 6.3 times in individuals aged 25- to 44-years-old, from 6 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 11
to 38 deaths per 100,000 population. These data indicate that despite previsions of a decline in rates of infectious diseases in the U.S., mortality rates from infectious diseases have actually been progressively increasing in recent years.
6. Nosocomial bloodstream infections. Secular trends in rates, mortality, and contribution to total hospital deaths. Pittet D, Wenzel RP. Arch Intern Med 1995 Jun 12;155(11):1177-84. The results of this study show that the incidence of hospital-acquired bloodstream infections increased threefold in the period from 1980 to 1992, from a rate of 6.7 to 18.4 infections per 1,000 discharges. Population-attributable risk of death from this complication also rose during this period, from 3.55 to 6.22 deaths per 1,000 discharges.
7. Nosocomial enterococci resistant to vancomycin--United States, 1989-1993. MMWR Morb Mortal Wkly Rep 1993 Aug 6;42(30):597-9. This article reports that from 1989 to 1993, the rate of enterococci responsible for hospital-acquired infections that acquired resistance to the antibiotic vancomycin increased by more than 20 folds. The majority of these bacteria are resistant to all available antibiotics. In the intensive care units, the percentage of vancomycin-resistant enterococci strains increased from 0.4% in 1989 to 13.6% in 1993.
8. Emerging and reemerging microbial threats. Nosocomial fungal infections. Henderson VJ, Hirvela ER. Arch Surg 1996 Mar;131(3):330-7. This article shows that the rate of fungal hospital-acquired infections increased steadily in the past 25 years, from a rate of 2.0 infections per 1000 discharges to as high as 6.6 infections per 1000 discharges.
9. Hospital-acquired candidemia. The attributable mortality and excess length of stay. Wey SB, Mori M, Pfaller MA, Woolson RF, Wenzel RP. Arch Intern Med 1988 Dec;148(12):2642-5. The results of this study show that from 1977 to 1984, the incidence of hospital-acquired bloodstream infections caused by Candida species in the U.S. tripled. Patients with fungemia have a 3-fold increased risk of dying, compared to uninfected, closely matched Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 12
patients. Hospital length of stay in patients who survived the bloodstream infection was 70 days, as compared to 40 days in matched controls. Candida infections were responsible for 10% of all bloodstream infections.
10. Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance System. Beck-Sague C, Jarvis WR. J Infect Dis 1993 May;167(5):1247-51. This article reports on the increase in the incidence of hospital-acquired fungal infections in U.S. hospitals, as determined by evaluation of data submitted to the National Nosocomial Infections Surveillance System. The rate of this complication increased from 2.0 per 1000 discharges in 1980 to 3.8 per 1000 discharges in 1990, an almost two-fold increase. Candida species accounted for three-quarters of infections. Patients with a central intravascular catheter had a 3-fold increased risk of developing a fungal bloodstream infection, compared to those without it. Thirty percent of patients with hospital-acquired fungemia died, compared to 17% of those with bloodstream infections due to other microorganisms.
11. Accuracy of reporting nosocomial infections in intensive-care-unit patients to the National Nosocomial Infections Surveillance System: a pilot study. Emori TG, et al. Infect Control Hosp Epidemiol 1998 May;19(5):308-16. The results of this study indicate that the National Nosocomial Infections Surveillance (NNIS) System is not a reliable indicator of the true incidence of nosocomial infections in hospital settings. This system was instituted under the sponsorship of the Centers for Disease Control (CDC) to monitor rates of hospital-acquired infections through voluntarily reporting of this complication by participating hospitals. The accuracy of the system in reflecting the rate of nosocomial infections was evaluated by reviewing the charts of 1,136 patients admitted to the intensive care units of 9 hospitals. There were 611 reports of hospital-acquired infections submitted to the NNIS system for this cohort. However, when some trained epidemiologists evaluated retrospectively the charts of the patients, they identified 340 extra infections that had not been previously reported. These data indicate that the voluntary system of reporting of hospital-acquired infections is significantly underestimating the true incidence of nosocomial infections in U.S. hospitals, and, as a consequence, all studies that utilize data from the NNIS system are misrepresenting the real magnitude of the problem.
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Influence of nosocomial infection on mortality rate in an intensive care unit. Bueno-Cavanillas A, et al. Crit Care Med 1994 Jan;22(1):55-60. The results of this study show that patients who develop hospital-acquired infections have a twofold increased risk of death, compared to uninfected patients. The increased risk of death persists even after adjustment for several confounding factors, and is particularly high in younger patients with less severe disease.
12. A survey of nosocomial infections and their influence on hospital mortality rates. Dinkel RH, Lebok U. J Hosp Infect 1994 Dec;28(4):297-304. The results of this study show that even after controlling for possible confounders, patients who develop a hospital-acquired infection have a two-fold increased risk of death, compared to patients without this complication. The risk of death increases by three-folds in patients hospitalized for trauma who develop a hospital-acquired infection.
13. Nosocomial infections in elderly patients in the United States, 1986-1990. National Nosocomial Infections Surveillance System. Emori TG, et al. Am J Med 1991 Sep 16;91(3B):289S-293S. This study reports that from 1986 to 1990, 89 hospitals submitted to the National Nosocomial Infections Surveillance (NNIS) system a total of 101,479 reports of hospitalacquired infections occurring in 75,398 adult patients. In 12% of the infections the patients died. In 54% of elderly patients that died an in 59% of younger patients that died the infection was judged to be related to their death. Bloodstream infections and pneumonias were associated with the highest mortality rates.
14. The impact of surgical-site infections in the 1990s: attributable mortality, excess length of hospitalization, and extra costs. Kirkland KB, Briggs JP, Trivette SL, Wilkinson WE, Sexton DJ. Infect Control Hosp Epidemiol 1999 Nov;20(11):725-30. The results of this study, conducted on 255 pairs of matched surgical patients with and without surgical site infection, indicate that infected patients have a 2.2-fold increased risk of dying, a 60% increased risk of being admitted to an intensive care unit, and a twofold increased hospital length of stay, compared to uninfected patients. In addition, patients who survive a surgical site infection are approximately 6 times more likely to be Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 14
readmitted to the hospital in the 30-days following discharge, compared to uninfected patients. The study estimated that, after the inclusion of the second hospital admission, each surgical site infection was associated with an excess hospital stay of 12 days and with an excess cost of $5,038 per patient. The authors highlight that the implementation of measures designed to reduce the rates of surgical site infections will likely result in a significant reduction of infection-related morbidity, mortality and health care costs.
15. Nosocomial infections in surgical patients in the United States, January 1986-June 1992. National Nosocomial Infections Surveillance (NNIS) System. Horan TC, Culver DH, Gaynes RP, Jarvis WR, Edwards JR, Reid CR. Infect Control Hosp Epidemiol 1993 Feb;14(2):73-80. This study reports that from 1986 to 1992, 106 hospitals reported to the National Nosocomial Infections Surveillance System a total of 59,351 hospital-acquired infections occurring in 48,168 surgical patients. The probability that these infections were related to the death of the patients ranged from 22% for urinary tract infections, to 90% for organ/space surgical site infections.
16. Infection in surgical patients: effects on mortality, hospitalization, and postdischarge care. DiPiro JT, Martindale RG, Bakst A, Vacani PF, Watson P, Miller MT. Am J Health Syst Pharm 1998 Apr 15;55(8):777-81. The results of this study show that 12% of patients who undergo moderate to high-risk surgical procedures develop hospital-acquired infections. Mortality rates in infected patients are 14.5%, as compared to 1.8% in uninfected patients. In addition, hospital length of stay more than triples in infected versus uninfected patients (14 days vs. 4 days), and so does the number of patients who require health care assistance after hospital discharge (24% of infected patients versus 7% of uninfected ones).
17. Nosocomial infection, indices of intrinsic infection risk, and in-hospital mortality in general surgery. Delgado-Rodriguez M, et al. J Hosp Infect 1999 Mar;41(3):203-11. The results of this study show that patients who develop a surgical site infection or a bloodstream infection have a 4.5-fold and 17.3-fold increased risk of dying, respectively, compared to uninfected patients.
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18. Nosocomial infection in surgery wards: a controlled study of increased duration of hospital stays and direct cost of hospitalization. Vegas AA, Jodra VM, Garcia ML. Eur J Epidemiol 1993 Sep;9(5):504-10. The results of this study show that hospital-length of stay increases by an average of 14 days in patients who develop hospital-acquired wound infections. The study was conducted on a sample of patients from a general and digestive surgical ward, to assess the effect that hospital-acquired infections had on the length of their hospital stay. Infected and uninfected patients were matched for age, diagnosis, surgical procedure, and, when possible, underlying conditions, elective or emergency surgery, and invasive devises. Length of hospital stay increased by l2.6 days in patients who developed superficial wound infection, compared to those without infection. Wound infections, either superficial or deep, and other infections were associated with an extra 14.3 and 7.3 days of hospital stay, respectively.
19. Selected aspects of the socioeconomic impact of nosocomial infections: morbidity, mortality, cost, and prevention. Jarvis WR. Infect Control Hosp Epidemiol 1996 Aug;17(8):552-7. This study shows that in the U.S., every year, approximately 2 million infections occur in hospital patients, leading to substantial increase in morbidity, mortality, and health care costs. Hospital length of stay increases by 1 to 4 days in patients who contract urinary tract infections, by 7-8 days in those with surgical site infections, by 7 to 21 days in those with bloodstream infections, and by 7 to 30 days in those with pneumonia. Costs associated with these infections have been estimated at $550-$600 for each urinary tract infection, $2,700 for each surgical site infection, $3,000 to $40,000 for each bloodstream infection, and $5,000 for each pneumonia.
20. Nosocomial pneumonia and mortality among patients in intensive care units. Fagon JY, Chastre J, Vuagnat A, Trouillet JL, Novara A, Gibert C. JAMA 1996 Mar 20;275(11):866-9. The results of this study show that 16.6% of patients admitted to an intensive care unit in France develop hospital-acquired pneumonia. The study, conducted on 1978 consecutive patients, also showed that patients who developed pneumonia while in the hospital had a twofold increased rate of death, compared to those without pneumonia, and this increase was unrelated to the severity of underlying diseases.
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21. Hospital-acquired pneumonia. Attributable mortality and morbidity. Leu HS, Kaiser DL, Mori M, Woolson RF, Wenzel RP. Am J Epidemiol 1989 Jun;129(6):1258-67. The results of this study show that 30% of patients who develop hospital-acquired pneumonia die. In one third of patients the infection is judged to be directly responsible for the death of the patient.
22. Nosocomial pneumonia in ventilated patients: a cohort study evaluating attributable mortality and hospital stay. Fagon JY, Chastre J, Hance AJ, Montravers P, Novara A, Gibert C. Am J Med 1993 Mar;94(3):281-8. The results of this study show that the development of hospital-acquired pneumonia is associated with a two-fold increased risk of death in mechanically ventilated patients, and with a significant prolongation of hospital length of stay, from a median of 21 days to a median of 34 days. The increase in death rates is independent from underlying diseases.
23. Guidelines for Prevention of Nosocomial Pneumonia. MMWR January 03, 1997 / 46(RR-1);1-79. This article reports that pneumonia accounts for 15% of all hospital-acquired infections (HAIs), and is the second most frequent HAI after urinary tract infections. The incidence of nosocomial pneumonia has been estimated at approximately 6 per 1000 hospitalized patients, and is significantly higher in university hospitals, compared to non-teaching hospitals. Reported mortality rates range from 20% to 50%, and in 30% to 33% of cases the death is directly attributed to the infection contracted in the hospital. Conservative estimates place the total costs of this complication at $1.2 billion per year. Bacteria responsible for the infections are found everywhere in the hospital and are frequently spread from patient to patient through contaminated hands of health care workers. The risk of spreading the infection could be considerably reduced by adhesion to simple handwashing practices. However, doctors rarely comply with this practice, and as a consequence the use of gloves has been promoted in order to reduce cross-contamination. Unfortunately, transmission of infection has been reported even with use of gloves, and is attributable to either breaks in the glove, or to the omission by health care workers to change their gloves between contacts with different patients.
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24. Hand washing. A modest measure with big effects. Handwashing Liaison Group. BMJ 1999;318:686-686 ( 13 March ). This article highlights that hand washing, a simple preventive measure effective in reducing the spread of in-hospital infections, is frequently disregarded as such by health care workers, who often fail to perform it. The incidence of in-hospital infections is significantly high, with an estimated 9% of patients acquiring an infection while being in the hospital. Hands are an important vehicle of transfer of pathogenic bacteria from one patient to the other. The majority of physicians, however, fail to decontaminate their hands after contact with patients. One study documented hand washing in only 9% of physicians, and another documented senior physicians washing their hands only twice during a 21-hour ward shift. Failure of physicians to recognize the risks associated with non-compliance reflects a system of belief that is deeply ingrained and of difficult solution. The authors emphasize how physicians need to recognize that hand contamination is an important mean of transfer of pathogenic bacteria before hand washing practices can be integrated as part of normal duty care.
25. Current guidelines for the treatment and prevention of nosocomial infections. Bergogne-Berezin E. Drugs 1999 Jul;58(1):51-67. This article highlights that in the U.S., 5% to 10% of patients admitted to the hospital develop a hospital-acquired infection. The incidence of this complication is particularly high in the intensive care units, where it occurs in as many as 28% of patients. There are preventive measures that could reduce the incidence of hospital-acquired infections, and they include improvement in nursing practices, decreased rates of antibiotic prescribing, and shortened hospital stay. These measures could significantly lower health care costs and infection-related morbidity and mortality.
26. Nosocomial Hepatitis B Virus Infection Associated with Reusable Fingerstick Blood Sampling Devices -- Ohio and New York City, 1996. MMWR. March 14, 1997 / 46(10);217-221. This article reports on two outbreaks of hepatitis B virus infection that occurred in diabetic patients from an Ohio nursing home and a New York City hospital. In both instances, an epidemiologic investigation revealed that patients became infected because the health-care personnel did not change fingerstick devices for blood-glucose monitoring between patients.
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27. Nosocomial transmission of hepatitis B virus associated with the use of a springloaded finger-stick device. Polish LB, et al. N Engl J Med 1992 Mar 12;326(11):721-5. This article reports on the case of 26 diabetic patients who developed hepatitis B virus infection in a California hospital. Epidemiologic investigation revealed that the virus was spread from one infected patient to the others due to nursing practices of utilizing the same blood glucose monitoring fingerstick device for several patients.
28. Hospital infection rates in England out of control. News. Kmietowicz, Z. BMJ 2000;320:534 ( 26 February ). This letter explains that in England, every year, at least 100,000 patients develop hospital-acquired infections and 5,000 of them die from the complication. Hospitalacquired infections affect approximately 1 every 10 hospitalized patients, for an annual cost of 1bn ($1.6 billion). Very little effort is put in the prevention of infections, as shown by the scant participation of clinicians and hospital chief executives to the problem. In some areas, for example, 1 infection control nurse is in charge of 1,000 beds, and only 1 of 5 hospitals surveyed has the minimum number of infection control doctors recommended by the Royal College of Pathologists -1 physician per 1,000 beds. These resources are obviously insufficient to guarantee an effective control of the spread of pathogens among hospitalized patients, a negligence that results not only in excess length of hospital stay and health care costs, but also in significant morbidity and mortality.
29. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs, and attributable mortality. Pittet D, Tarara D, Wenzel RP. JAMA 1994 May 25;271(20):1598-601. The results of this study show that patients who develop hospital-acquired bloodstream infections have an over three-fold increased risk of dying and an almost two-fold increase in hospital length of stay, compared to uninfected ones. The study was conducted on 86 pairs of patients from a surgical intensive care unit (SICU), with and without bloodstream infection, who were matched for age, sex, length of hospital stay and number of discharge diagnoses. Fifty percent of patients with bloodstream infection died, compared to 15% of those without this complication. In addition, patients who survived the infection spent an additional 24 days in the hospital and an additional 8 days in the SICU, compared to controls (54 vs. 30 days and 15 vs. 7 days, respectively). Health care costs attributable to the bloodstream infection were estimated at $40,000 per patient.
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30. Microbiological factors influencing the outcome of nosocomial bloodstream infections: a 6-year validated, population-based model. Pittet D, Li N, Woolson RF, Wenzel RP. Clin Infect Dis 1997 Jun;24(6):1068-78. This study reports that, between 1986 and 1991, a total of 1745 patients developed hospital-acquired bloodstream infections in a 900-bed tertiary care hospital, and 35% of them died from this complication.
31. Incidence, risk factors, and outcome of severe sepsis and septic shock in adults. A multicenter prospective study in intensive care units. French ICU Group for Severe Sepsis. Brun-Buisson C, et al. JAMA 1995 Sep 27;274(12):968-74. The results of this study, conducted on 11,828 consecutive patients admitted during a two-month period to 170 intensive care units in France, show that overall, 9.0% of patients developed signs of severe bloodstream infection and 56% of them died in the 4 weeks following the infection.
32. The Second National Prevalence Survey of infection in hospitals--overview of the results. Emmerson AM, Enstone JE, Griffin M, Kelsey MC, Smyth ET. J Hosp Infect 1996 Mar;32(3):175-90. The results of this study, conducted on over 37,000 patients from 157 hospitals in the UK and Ireland, show that nosocomial infections (infections acquired in the hospital) occur in 9% of patients, and are more frequent in teaching hospital, compared to non-teaching ones.
33. Epidemiology of infection in ICUs. Spencer RC. Intensive Care Med 1994 Nov;20 Suppl 4:S2-6. This study reports the results of the European Prevalence of Infection in Intensive Care Study (EPIC), the largest study on Intensive Care Unit (ICU)-related infections in Western Europe, that was conducted on a cohort of 10,038 patients admitted to 1417 adult ICUs from 17 countries. Overall, 21% of ICU patients developed a minimum of one Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 20
hospital-acquired infection. Pneumonia was the most frequent infection (47% of cases), followed by other lower respiratory tract infections (18%), urinary tract infections (18%), and bloodstream infections (12%).
34. The impact of nosocomial infections on patient outcomes following cardiac surgery. Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D, Fraser VJ. Chest 1997 Sep;112(3):666-75. This study evaluated the frequency of hospital-acquired infections in a cohort of 605 consecutive patients admitted for cardiac surgery. After the surgery, 22% of patients developed at least one hospital-acquired infection. The risk of this complication was associated with the duration of mechanical ventilation and urinary tract catheterization, and with the initiation of empiric antibiotic therapy after surgery. Infected patients had a two-fold increased risk of dying, compared to uninfected ones.
35. The impact of nosocomial infections on patient outcomes following cardiac surgery. Kollef MH, Sharpless L, Vlasnik J, Pasque C, Murphy D, Fraser VJ. Chest 1997 Sep;112(3):666-75. The results of this study, conducted on a sample population of 605 patients who underwent cardiac surgery in an U.S. hospital, show that approximately 22% of patients developed at least one hospital-acquired infection. Infected patients had a 4-fold increased risk of dying, compared to uninfected ones. In addition, hospital length of stay in patients who survived was two times greater in infected versus uninfected patients (20 days versus 9.7 days). These data indicate that hospital-acquired infections are associated with significant mortality, increased length of stay, and health care costs.
36. Epidemiology of Nosocomial Infection and Resistant Organisms in Patients Admitted for the First Time to an Acute Rehabilitation Unit. Mylotte JM, Graham R, Kahler L, Young L, Goodnough S. Clin Infect Dis 2000 Mar;30(3):425-432. The results of this study indicate that 16.5% of patients admitted to an acute rehabilitation center develop at least one hospital-acquired infection. Urinary tract infections, surgical site infections, Clostridrium difficile diarrhea and bloodstream infections accounted for 30%, 17%, 15% and 13% of the infections, respectively.
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37. Incidence of hospital-acquired infections associated with caesarean section. Henderson E, Love EJ. J Hosp Infect 1995 Apr;29(4):245-55. This study, conducted on a cohort of 1335 women who underwent caesarean section in a Canadian teaching hospital, shows that the rate of hospital-acquired infections in women delivered by primary and secondary caesarean section, was 42.1% and 46.1%, respectively. Women delivered by primary section had significantly higher incidence of deep wound infections, endometritis and bacteraemia, compared to those delivered by secondary section. Hospital-acquired infections resulted in increased length of hospital stay.
38. Post-discharge surveillance and infection rates in obstetric patients. Couto RC, Pedrosa TM, Nogueira JM, Gomes DL, Neto MF, Rezende NA. Int J Gynaecol Obstet 1998 Jun;61(3):227-31. The results of this study show that women who deliver by Cesarean section have an almost 50-fold increased risk of developing hospital-acquired surgical site infections, compared to women who deliver by the vaginal route. The study evaluated the incidence of this complication in 2431 women who delivered vaginally and 2032 women who delivered by Cesarean section, by monitoring patients during their hospital stay and up to 30 days after hospital discharge. While the incidence of hospital-acquired surgical site infections detected during hospital stay was 1.6% in women who underwent Cesarean section, this rate increased to 9.6% when cases detected by post-discharge surveillance were included. By comparison, rates of infections in women who delivered by the vaginal route were significantly lower, occurring in only 0.2% of cases. These findings indicate that unless data collected after hospital discharge are included in the estimates of the incidence of surgical site infections after Cesarean delivery, the true prevalence of this complication can be substantially underestimated.
39. Occurrence of nosocomial bloodstream infections in six neonatal intensive care units. Brodie SB, et al. Pediatr Infect Dis J 2000 Jan;19(1):56-65. This study evaluated prospectively the incidence of hospital-acquired bloodstream infections in neonates weighing less than 1,500 g admitted to six neonatal intensive care units (NICUs). Almost 20% of neonates developed a hospital-acquired bloodstream infection, and the risk of this complication was significantly associated with use of Broviac catheters and intravenous nutrition supplements. Since these infections are associated with substantial morbidity and mortality, preventive measures are urgently needed.
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40. Nosocomial infections in pediatric intensive care units in the United States. National Nosocomial Infections Surveillance System. Richards MJ, Edwards JR, Culver DH, Gaynes RP. Pediatrics 1999 Apr;103(4):e39. The results of this study show that approximately 6% of children admitted to a pediatric intensive care unit (ICU) develop hospital-acquired infections. In the study, 6290 infections occurred in a cohort of 110,709 patients admitted to 61 pediatric ICUs, according to data collected through the National Nosocomial Infections Surveillance System -a voluntary system of reporting of hospital-acquired infections. The most common type of infection was bloodstream infection (28%), followed by pneumonia (21%), and urinary tract infection (15%). These complications were almost always associated with use of invasive devices.
41. Nosocomial infections among neonates in high-risk nurseries in the United States. National Nosocomial Infections Surveillance System. Gaynes RP, Edwards JR, Jarvis WR, Culver DH, Tolson JS, Martone WJ. Pediatrics 1996 Sep;98(3 Pt 1):357-61. This study reports data submitted by 99 hospitals participating in the National Nosocomial Infections Surveillance system, a voluntary, hospital-based, reporting system established to monitor rates of hospital-acquired infections, indicating that from 1986 to 1994, a minimum of 13,179 neonates in high-risk nurseries developed this complication. The most common hospital-acquired infections were bloodstream infections, followed by pneumonias and gastrointestinal infections.
42. Hospital-acquired morbidity on a neurology service. Shafer SQ, Brust JC, Healton EB, Mayo JB. J Natl Med Assoc 1993 Jan;85(1):31-5. This study evaluated prospectively the charts of 1317 consecutive patients admitted over a 3-year period to the neurology department of a city hospital, to determine the incidence of hospital-acquired infections in this sample population. Overall, 6.8% of patients developed at least one hospital-acquired infection, which consisted of a bloodstream infection in almost half of the cases. The authors emphasize that these data greatly exceed previously reported estimates.
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43. Surveillance of nosocomial infections in geriatric patients. Beaujean DJ, et al. J Hosp Infect 1997 Aug;36(4):275-84. The results of this study, conducted on 300 geriatric patients admitted to a medical ward of a hospital in the Netherlands, show that one third of patients developed at least one hospital-acquired infection (126 infections in 100 patients). Fifty-nine percent of the infections were urinary tract infections, and 20% were infections of the gastrointestinal tract. Seventy percent of patients with asymptomatic urinary tract infection received antibiotics. Age, dehydration, and the presence of a urinary catheter were all significant risk factors for the development of hospital-acquired infections. Hospital length of stays increased by twofold in infected versus uninfected patients.
44. Hospital-acquired pressure ulcers: risk factors and use of preventive devices. Perneger TV, Heliot C, Rae AC, Borst F, Gaspoz JM. Arch Intern Med 1998 Sep 28;158(17):1940-5. The results of this study, conducted on 2373 patients who did not have pressure ulcers upon admission to a university hospital, show that 10% of them developed this complication during their hospital stay. The study detected suboptimal use of special devices (such as mattresses, cushions, and beds) for the prevention of this complication.
45. Pressure ulcers, hospital complications, and disease severity: impact on hospital costs and length of stay. Allman RM, Goode PS, Burst N, Bartolucci AA, Thomas DR. Adv Wound Care 1999 Jan-Feb;12(1):22-30. The results of this study, conducted on a sample population of 286 patients aged 55 and older, show that those who developed pressure ulcers had, after controlling for several confounders, increased length of hospital stay (21 vs. 13 days) and increased incidence of hospital-acquired infections (46% vs. 20%) and other complications (86% vs. 43%), compared to those who did not. Hospital costs for patients with incident pressure ulcers were estimated at $29,048 compared to 13,819 in those without this ailment.
46. Epidemiology of infectious and iatrogenic nosocomial diarrhea in a cohort of general medicine patients. McFarland LV. Am J Infect Control 1995 Oct;23(5):295-305.
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The results of this study, conducted on 382 patients admitted over an 11-month period to the general medicine ward of a county hospital, show that the incidence of hospitalacquired diarrhea in this cohort was 33%. The risk of developing this complication increased with increasing patient age, length of stay, number of antibiotics and nasogastric tube feeding. Patients with hospital-acquired diarrhea had an increased risk of developing a second infection, of having a prolonged hospital length of stay, and of dying, than patients without this condition.
47. Risk factors for Clostridium difficile carriage and C. difficile-associated diarrhea in a cohort of hospitalized patients. McFarland LV, Surawicz CM, Stamm WE. J Infect Dis 1990 Sep;162(3):678-84. The results of this study show that the incidence of hospital-acquired diarrhea caused by Clostidrium difficile, as evaluated in a cohort of 399 patients, was 7.8 per 100 patients. C. difficile accounted for one fifth of all hospital-acquired diarrhea, and the risk of developing C. difficile-associated diarrhea increased by 2-3 folds in individuals using cephalosporin, penicillin, enemas, gastrointestinal stimulants, or stool softeners.
48. Nosocomial infections in the ICU: the growing importance of antibiotic-resistant pathogens. Weber DJ, Raasch R, Rutala WA. Chest 1999 Mar;115(3 Suppl):34S-41S. This study indicates that patients in intensive care units have a 5-10 fold increased risk of developing a hospital-acquired infection, compared to those admitted to other hospital units. A major contributor to the morbidity and mortality associated with this complication is the antibiotic-resistance of the pathogens involved in the infection. Measures of prevention include proper handwashing, patient isolation, proper disinfection and sterilization techniques, and judicious use of antibiotics, as demonstrated by the fact that hospitals with the highest rates of hospital-acquired infections also have the highest rates of antibiotic use.
49. Inadequate antimicrobial treatment of infections: a risk factor for hospital mortality among critically ill patients. Kollef MH, Sherman G, Ward S, Fraser VJ. Chest 1999 Feb;115(2):462-74. The results of this study, conducted on 2000 patients admitted to a medical or surgical intensive care unit, show that 25% of hospitalized patients with community- or hospitalCopyright Gary Null & Associates, Inc., 2005 All Rights Reserved 25
acquired infections receive inappropriate antibiotic treatment. Mortality rates in patients receiving inadequate antibiotic treatment are 42%, compared to 17.7% in patients appropriately treated. After logistic regression analyses it was shown that inappropriate antibiotic treatment was the strongest determinant of hospital mortality for the entire (infected and uninfected) patient cohort, and resulted in a 4.3-fold increased risk of death.
50. Appropriateness of antibiotic therapy in long-term care facilities. Jones SR, Parker DF, Liebow ES, Kimbrough RC 3d, Frear RS. Am J Med 1987 Sep;83(3):499-502. This study evaluated the appropriateness of antibiotic therapy in patients of two nursing homes in Portland, Oregon, over a 3-month period. One hundred twenty infections occurred during the study period. Antibiotic treatment was judged appropriate only in 49% of cases, and inappropriate and unjustified in 42% and 9% of cases, respectively.
51. Method of physician remuneration and rates of antibiotic prescription. Hutchinson JM, Foley RN. CMAJ 1999 Apr 6;160(7):1013-7. The results of this study, conducted on 476 Canadian doctors, show that physicians who are paid for fee-for-service and those with greater volume of patients are much more likely to prescribe antibiotics, compared to doctors paid by salary and with smaller patient volume. These findings indicate that factors unrelated to medical conditions play an important role in physicians' attitude toward antibiotic prescribing.
52. Antimicrobial use for pediatric upper respiratory infections: reported practice, actual practice, and parent beliefs. Watson RL, Dowell SF, Jayaraman M, Keyserling H, Kolczak M, Schwartz B. Pediatrics 1999 Dec;104(6):1251-7. This study was conducted on a sample of 366 pediatricians and family physicians from Georgia to determine their antibiotic prescribing practices in pediatric patients with upper respiratory tract infections (URTIs). While 97% of them reported that widespread use of antibiotics was a major contributor to the development of antibiotic resistant bacterial strains, they nevertheless prescribed antibiotics in 72% of visits for URTIs. In addition, contrary to published guidelines for the management of pediatric patients with these conditions, 86% of physicians prescribed antibiotics in patients with bronchitis regardless of the duration of cough, and 42% prescribed antibiotics for the common cold. Interestingly, physicians who prescribed the most antibiotics also had the highest rates of return office visits (up to 30% more). The authors conclude that antibiotic prescribing Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 26
practices in pediatric patients with URIs often are in disagreement with published guidelines, in spite of physicians' knowledge of the role of injudicious use of antibiotics in the development of antibiotic resistance.
53. Antibiotic prescribing for children with colds, upper respiratory tract infections, and bronchitis. Nyquist AC, Gonzales R, Steiner JF, Sande M. JAMA. 1998 Mar 18;279(11):875-7. This study evaluated the rates of antibiotic prescribing in 531 children younger than 18 years diagnosed with common cold, upper respiratory tract infections (URTIs) or bronchitis. Forty-four percent of children with common cold, 46% of those with URTIs, and 75% of those with brochitis received an antibiotic prescription. Extrapolation of these data to the entire U.S. population revealed that in 1992, physicians wrote 6.5 million prescriptions for children with URTIs or common cold and 4.7 million prescriptions for children with bronchitis, despite the fact that, as emphasized in the article, antibiotic treatment is typically ineffective in these conditions. These data indicate that 21% of all antibiotic prescriptions written for children younger than 18 in 1992 (over 11 million prescriptions) are unnecessary.
64. Systematic review of the treatment of upper respiratory tract infection. Fahey T, Stocks N, and Thomas T. Arch Dis Child 1998;79:225-230 ( September ). The results of this meta-analysis, conducted on 6 randomized, placebo-controlled studies involving 1,699 children, show that antibiotic treatment does not improve clinical outcome or reduce rates of complications in children with upper respiratory tract infections. The authors conclude that there is no evidence from randomized trials supporting the use of antibiotics in the management of children with upper respiratory tract infections.
65. Outcomes After Judicious Antibiotic Use for Respiratory Tract Infections Seen in a Private Pediatric Practice. Pichichero, ME. et al. Pediatrics 2000 Apr;105(4):753-759. The results of this study show that antibiotic treatment is not routinely recommended in the management of children with respiratory tract infections without a concomitant bacterial infection. The study was conducted on a sample of 383 infants and children younger than 12 with respiratory tract infections, to evaluate the effects of a reduction of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 27
antibiotic prescribing rates on the incidence of return office visits or subsequent bacterial infections. In the study, physicians prescribed antibiotics only when a bacterial infection was confirmed or presumed, resulting in only 23% of children receiving a prescription. Of note, more than half of the antibiotic prescriptions were written for children who were diagnosed with middle ear infections, even though current evidence (presented later in this text) indicates that antibiotics are no better than placebo in the management of this condition. Evaluation of the frequency of subsequent unscheduled return visits revealed that only 29% of children who did not receive antibiotics returned for an additional visit, compared to 44% of those treated with antibiotics. These data further support judicious use of antibiotics in children and infants with respiratory tract infections, i.e. avoidance of antibiotic treatment when there are no signs of bacterial infection. Less than 1 every 5 infants or children who present with respiratory tract infections require antibiotic treatment. Untreated children had lower rates of subsequent return office visits or bacterial infections, compared to treated children. Physicians should comply with current evidence demonstrating the safety and effectiveness of judicious antibiotic use, especially in consideration of the worldwide increase in antibiotic resistant bacteria, leading to a staggering increase in morbidity, mortality and health care costs due to untreatable infections.
66. Decreasing Antibiotic Use in Ambulatory Practice. Impact of a Multidimensional Intervention on the Treatment of Uncomplicated Acute Bronchitis in Adults. Gonzales, R. et al. JAMA 1999;281:1512-1519. The results of this study show that an intervention program consisting of office-based patient educational materials and clinician educational meetings resulted in a decline in antibiotic prescribing rates from 74% to 48% in patients with uncomplicated bronchitis. No differences in office return visits were observed in the month following the first visit, between the institutions with reduced antibiotic prescribing and those with rates of antibiotic prescribing of 80%, indicating that use of these drugs is unnecessary in the routine management of patients with uncomplicated bronchitis.
67. Antibiotic prescribing for adults with colds, upper respiratory tract infections, and bronchitis by ambulatory care physicians. Gonzales R, Steiner JF, Sande MA. JAMA 1997 Sep 17;278(11):901-4. The results of this study show that although antibiotics have been shown to be largely ineffective in treating colds, upper respiratory tract infections and bronchitis, they are nevertheless prescribed to 51%-66% of patients diagnosed with these conditions. This study demonstrates that in 1992, an estimated 12 million antibiotic prescriptions, or one fifth of all antibiotics prescriptions filled during that year, were written for patients with Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 28
colds, upper respiratory tract infections or bronchitis, despite lack of evidence of their effectiveness in the management of these ailments (more than 90% of upper respiratory infections -including bronchitis and colds- note the authors, are caused by a virus and are therefore impervious to antibiotics.) This practice has contributed to the spread of antibiotic-resistant bacteria and consequent infections in community settings.
68. Antibiotics and upper respiratory infection: do some folks think there is a cure for the common cold. Mainous AG 3d, Hueston WJ, Clark JR. J Fam Pract 1996 Apr;42(4):357-61. The results of this study show that 60% of patients who present with a complaint of common cold receive an antibiotic prescription. This practice leads to an estimated annual cost of $37.5 millions for unnecessary treatment of a condition that is not improved by antibiotic treatment.
69. Trends in antimicrobial drug prescribing among office-based physicians in the United States. McCaig LF, Hughes JM. JAMA 1995 Jan 18;273(3):214-9. The results of this study indicate that from 1980 to 1992, rates of prescribing of more expensive antibiotics with a broader antibacterial spectrum have been increasing, while prescribing of cheaper antibiotics with a narrower spectrum have been decreasing. The authors emphasize that this trend leads to an increase use of health care resources and has a potential deleterious effect on the insurgence of antibiotic resistance.
70. Factors associated with antibiotic use for acute bronchitis. Gonzales R, Barrett PH Jr, Crane LA, Steiner JF. J Gen Intern Med 1998 Aug;13(8):541-8. The results of this study show that physicians in primary care office practices prescribe antibiotics to 85% of patients with acute bronchitis. The authors could not identify clinical factors that explained the high rates of antibiotic prescribing and conclude that it seems feasible that a diagnosis of acute bronchitis is interpreted by physicians as an indication for antibiotic treatment, despite available evidence indicating the contrary.
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71. Treatment of acute bronchitis in adults. A national survey of family physicians. Oeffinger KC, Snell LM, Foster BM, Panico KG, Archer RK. J Fam Pract 1998 Jun;46(6):469-75. The results of this study show that family physicians prescribe antibiotics to 75% of nonsmoking and otherwise healthy adult patients with acute bronchitis and to 90% of smoking and otherwise healthy adult patients with acute bronchitis, despite evidence from clinical trials indicating that antibiotics are largely ineffective in the management of this condition. The authors emphasize how the increasing prevalence of antibiotic resistance calls for a change in the management of patients with acute bronchitis.
72. Antimicrobials for acute otitis media? A review from the international primary care network. Froom, J. et al. BMJ 1997;315:98-102 (12 July). This article highlights that even though there is no scientific evidence demonstrating that antibiotics are effective in the treatment of middle ear infections, this condition represent the most frequent reason for prescribing antibiotics in outpatient settings in the U.S. The seven randomized studies that evaluated the effectiveness of antibiotics in children with middle ear infection showed little or no benefits compared to placebo. The authors conclude that there is no convincing evidence in support of the use of these drugs in children with middle ear infections, and the management of this condition should therefore be reevaluated. Changing treatment practices is especially important since injudicious use of antibiotics is a major factor implicated in the development of antibiotic resistance and the consequent increase in morbidity, mortality, and health care costs associated with untreatable infections.
73. Primary care based randomised, double blind trial of amoxicillin versus placebo for acute otitis media in children aged under 2 years. Damoiseaux, Roger A M J et al. BMJ 2000;320:350-354 ( 5 February ). The results of this randomized study indicate that use of antibiotics is inappropriate not only in older children with middle ear infections but also in those aged 6 months to 2 years. In the study, 240 children under 2 years diagnosed with middle ear infection were randomly assigned to receive antibiotics or placebo. Signs of inflammation, pain and crying were no different in the group receiving antibiotics, compared to that receiving placebo. One every 7 or 8 treated children showed symptomatic improvement at day 4 of infection, but there were no improvements at day 11 or 42. The small benefits observed in a 13% of children do not justify routine antibiotic use in children of this age group with middle ear infection. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 30
74. Quantitative systematic review of randomised controlled trials comparing antibiotic with placebo for acute cough in adults. Fahey T, Stocks N, Thomas T. BMJ 1998 Mar 21;316(7135):906-10. This study is a meta-analysis of 9 randomized, placebo-controlled trials evaluating the efficacy of antibiotics in the treatment of individuals with acute cough. The results of the analysis revealed that antibiotics neither improve symptoms nor speed up recovery time in individuals with acute cough, while causing significantly more side effects compared to placebo. These data indicate that antibiotic treatment is inappropriate in individuals with acute cough.
75. National trends in the use of antibiotics by primary care physicians for adult patients with cough. Metlay JP, Stafford RS, Singer DE. Arch Intern Med 1998 Sep 14;158(16):1813-8. The results of this study show that primary care physicians' rates of antibiotic prescribing for adult patients presenting with cough increased significantly from 1980 to 1994. In particular, in 1980 an estimated 59% of patients who went to their doctor with a complaint of cough received an antibiotic prescription, as compared to 70% of patients who presented with cough in 1994. These data indicate an increasing trend of antibiotic prescribing for patients with cough, despite increasing evidence of the lack of efficacy of antibiotic treatment in this condition.
76. Outpatient visits for infectious diseases in the United States, 1980 through 1996. Armstrong GL, Pinner RW. Arch Intern Med 1999 Nov 22;159(21):2531-6. The results of this study show that every year 129 million outpatient visits, or approximately 20% of all outpatient visits to physicians are for infectious diseases. Of these, the majority (38%), are for upper respiratory tract infections, followed by middle ear infections (15.1%) and lower respiratory tract infections. These data indicate that over half of all visits for infectious diseases (approximately 68.5 million annual visits) are for upper respiratory tract infections or otitis, conditions that are typically not improved by antibiotics and for which antibiotics are first choice treatment.
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ANTIDEPRESSANTS 109 Studies
1. Trends in the prescribing of antidepressant pharmacotherapy: office-based visits, 19901995. Sclar DA. et al. Clin Ther 1998 Jul-Aug;20(4):871-84; 870. The results of this study show that the number of office visits resulting in prescription of an antidepressant drug increased from 16,534,268 in 1990 to 28,664,796 in 1995, a 73.4% increase. A diagnosis of depression was documented in 6.7% of the U.S. population in 1990, and in 7.1% in 1995, a 16.4% increase. The large increase in number of prescriptions, not matched by a similar increase in the prevalence of depression, suggests that the criteria for prescribing antidepressant medications have loosened during the study period. A variation in rates of prescribing of different class of drugs was also noticed, with a decline in use of tricyclic antidepressants (from 42% to 25%), and an increase in use of selective serotonin reuptake inhibitors (from 37% to 65%).
2. Association between selective serotonin reuptake inhibitors & upper gastrointestinal bleeding population based case-control study. de Abajo, FJ, Garca Rodrguez LA, Montero D. BMJ 1999;319:1106-1109 ( 23 October ). The results of this study show that users of the antidepressants selective serotonin reuptake inhibitors (SSRIs) have a significantly increased risk of upper gastrointestinal (GI) bleeding, compared to nonusers. The study was conducted on 1651 patients hospitalized with upper GI bleeding, and 10,000 matched controls. Use of SSRIs was associated with a 3-fold increased risk of bleeding, compared to nonuse. The incidence of this complication was estimated at 1every 8,000 prescriptions. Combined use of SSRIs and aspirin was associated with a 7-fold increased risk of GI hemorrhage, and combined use of SSRIs and non-steroidal anti-inflammatory drugs resulted in a 15.6-fold increased risk. The authors emphasize that the large increase in risk of GI hemorrhage observed in their study could have important public health implications due to the frequent use of both classes of drugs in industrialized countries.
3. Hemorrhagic syndromes related to selective serotonin reuptake inhibitor (SSRI) antidepressants. Seven case reports and review of the literature. French. Nelva A, Guy C, Tardy-Poncet B, Beyens MN, Ratrema M, Benedetti C, Ollagnier M. Rev Med Interne 2000 Feb;21(2):152-60. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 32
The results of this study suggest that intake of the antidepressants selective serotonin reuptake inhibitors is associated with an increased risk of developing hemorrhagic syndromes. This adverse effect is under-recognized and under-reported, and may be due to a decrease in concentration of platelet serotonin, leading to platelet dysfunction.
4. Antidepressant Medication Use and Breast Cancer Risk. Cotterchio M, Kreiger N, Darlington G, and Steingart A. Am J Epidemiol 2000;151:951-57. The results of this study indicate that women who take antidepressants are at significantly higher risk of developing breast cancer, compared to the general population. The association between antidepressant drugs and breast cancer first emerged from animal and epidemiological data. This case-control study, conducted to further test the hypothesis, found that users of selective serotonin reuptake inhibitors (SSRIs) and tryciclic antidepressants have a 7- and 2-fold increased risk of breast cancer, respectively, compared to nonusers. The finding of a large increase in risk of breast cancer in users of SSRIs may have public health implications owing to the high prevalence of use of this class of drugs.
5. Comparative study of fluoxetine, sibutramine, sertraline and dexfenfluramine on the morphology of serotonergic nerve terminals using serotonin immunohistochemistry. Kalia M, et al. Brain Res 2000 Mar 6;858(1):92-105. The results of this study indicate that short-term exposure to selective serotonin reuptake inhibitors (SSRIs) results in changes of rat brain cells, which resemble those induced by the recreational drug Ecstasy. SSRIs work by increasing the concentration of serotonin in the brain through inhibition of their re-uptake by brain cells. Their mode of action is similar to that of the recreational drug Ecstasy, which also increases the concentration of serotonin at the receptor site through a double action of inhibited reuptake and stimulated secretion from brain cells. While Ecstasy-induced brain damage has been well demonstrated in both animal and human studies, there are no data on the effects of SSRIs on brain cells. This study documented that, after only 4 days of intake of SSRIs, rat brain cells underwent morphological changes characterized by swelling and acquisition of a corkscrew shape, indicative of occurred damage. These findings indicate that SSRIs, the most commonly prescribed class of antidepressant drugs, cause damage in animal brain cells, after only 4 days of exposure. More studies on humans are needed, before these drugs can be considered safe.
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6. Discontinuation symptoms and psychotropic drugs Young, A. and Haddad P. Lancet 2000; 355: 1181 - 1190. This letter emphasizes that 35% to 78% of individuals who take the antidepressants selective reuptake inhibitors (SSRIs) for several months, experience, upon abrupt treatment interruption, physical and psychological symptoms such as: changes in mood, affect, appetite and sleep, dizziness, fatigue, anxiety, agitation, nausea, headache, and sensory disturbance. The symptoms are so typical that the clinical entity "SSRI discontinuation syndrome" is now widely accepted, after its existence had been negated for several years following the introduction of SSRIs on the market. Symptoms are usually mild and short-term, but occasionally can be severe and long lasting. They have often been interpreted as a sign of relapse into depression, leading to re-institution of treatment. The authors propose that all new psychotropic drugs be tested in double-blind placebo-controlled studies lasting several weeks beyond the actual drug trial, in order to properly monitor adverse reactions that may occur only upon discontinuation of treatment.
7. Hormonal markers of stress response following interruption of selective serotonin reuptake inhibitor treatment. Michelson D, et al. Psychoneuroendocrinology 2000 Feb;25(2):169-77. The results of this study show that following abrupt interruption of treatment with selective serotonin reuptake inhibitors patients develop signs of activation of a stress response, as shown by significantly increased plasma levels of IGF-1 and heart rate.
8. Antidepressant discontinuation reactions. Haddad P, Lejoyeux M, and Young A. BMJ 1998;316:1105-1106 ( 11 April ). This article reports on the frequency and nature of adverse reactions occurring upon discontinuation of antidepressant treatment. It explains that the existence of discontinuation reactions is often unrecognized by clinicians and that the extent of their occurrence is largely unknown because very few studies have ever addressed this issue. Discontinuation reactions usually start after few days of interruption of antidepressant treatment, and may consist of nausea, diarrhea, abdominal pain, insomnia, nightmares, headaches, lethargy, anxiety, and irritability. With selective serotonin-reuptake inhibitors, withdrawal is more commonly associated with symptoms such as dizziness, paraesthesia, numbness, and electric shock-like sensations. Results of a double blind placebo controlled study have shown that adverse reactions occur in 35% of patients after discontinuation of a 12-week treatment with the serotonin reuptake inhibitor paroxetine. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 34
Such reactions usually resolve within one day to three weeks, but occasionally they can be more severe and persist chronically, causing substantial morbidity.
9. Discontinuation symptoms after treatment with serotonin reuptake inhibitors a literature review. Zajecka J, et al. J Clin Psychiatry 1997 Jul;58(7):291-7. The results of this study indicate that discontinuation of selective serotonin-reuptake inhibitor therapy is associated with the development of a cluster of symptoms including dizziness, light-headedness, insomnia, fatigue, anxiety, nausea, headache, and sensory disturbance. These symptoms may last up to three weeks after interruption of treatment, and may be relieved by restarting antidepressant therapy (!).
10. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM. J Clin Psychiatry 2000 Apr;61(4):276-81. The results of this study indicate that 30%-70% of patients who take the selective serotonin reuptake inhibitors (SSRIs) paroxetine and sertraline experience sexual dysfunction as a side effect of treatment. Impairment in drive and/or desire occurs more frequently in men than women, while impairment in level of arousal and orgasm is experienced at similar rates by both sexes. These data indicate that the majority of patients treated with SSRIs experience sexual dysfunction. The low rates of this complication reported in previous studies were due to underreporting and was not confirmed in subsequent trials.
11. Sexual dysfunction induced by serotonin reuptake antidepressants. Labbate LA, Grimes J, Hines A, Oleshansky MA, Arana GW. J Sex Marital Ther 1998 Jan-Mar;24(1):3-12. The results of this study show that the antidepressants selective serotonin reuptake inhibitors negatively affect sexual functios. The study was conducted on 61 individuals who took these drugs for at least two months. Both men and women experienced a significant worsening of quality of orgasm after 1 and 2 months of treatment, compared to baseline. Women reported failure to achieve an orgasm significantly more often than men, while both sexes experienced prolongation of time to orgasm induction after 1, 2, and 3 months of treatment, compared to baseline.
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12. Incidence of sexual dysfunction in healthy volunteers on fluvoxamine therapy. Nafziger AN, et al. J Clin Psychiatry 1999 Mar;60(3):187-90. The results of this study show that 35% of healthy volunteer who took the antidepressant fluvoxamine developed, after 4 weeks of treatment, sexual dysfunction.
13. Adverse reactions of selective serotonin reuptake inhibitors reports from a spontaneous reporting system. Spigset O. Drug Saf 1999 Mar;20(3):277-87. This study evaluated 1202 spontaneous reports on 1861 adverse reactions to selective serotonin reuptake inhibitors (SSRIs), and found that 22.4% of such reports consisted of neurological disturbances, 20% of psychiatric disorders, and 18% of gastrointestinal symptoms. The elderly were particularly susceptible to Parkinsonism, confusion, hallucinations, and hypotension, while younger patients experienced more frequently hematological, endocrine, and sexual dysfunction. Akathisia and aggression occurred more frequently in men than women.
14. A survey of antidepressant drug use in Parkinson's disease. Parkinson Study Group. Richard IH, et al. Neurology 1997 Oct;49(4):1168-70. The results of this study indicate that approximately 26% of patients with Parkinson's disease (PD) are given antidepressant medications, which consist, in over half of the cases, of serotonin reuptake inhibitors (SSRIs). Forty-three percent of physicians of the Parkinson Study Group showed concern that use of SSRIs might induce worsening of motor function in PD patients, and 37% of physicians had at least one patient in which they believed such aggravation occurred.
15. Prenatal exposure to fluoxetine (Prozac) produces site-specific & age-dependent alterations in brain serotonin transporters in rat progeny Evidence from autoradiographic studies. Cabrera-Vera TM, Battaglia G. J Pharmacol Exp Ther 1998 Sep;286(3):1474-81.
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The results of this study show that prenatal exposure to the selective serotonin reuptake inhibitor fluoxetine (Prozac) induces changes in the density of brain serotonin transporters in rats, which are particularly evident in regions of the limbic system, such as the hypothalamus, hippocampus and amygdala. These data indicate that fluoxetine alters brain function in rats exposed to the drug while in uterus.
16. Pregnancy outcome following first-trimester exposure to fluoxetine. Pastuszak A, Schick-Boschetto B, Zuber C, Feldkamp M, Pinelli M, Sihn S, et al. JAMA 1993 May 5;269(17):2246-8. The results of this study show that women who use the antidepressant fluoxetine (Prozac) in the first trimester of pregnancy have approximately a 2-fold increased risk of miscarriage, compared to nonusers.
17. Birth outcomes in pregnant women taking fluoxetine. Chambers CD, et al. N Engl J Med, 335(14):1010-5 1996 Oct 3. This study evaluated pregnancy outcome of women who took the antidepressant fluoxetine (a serotonin uptake inhibitor) while expecting, and compared it to that of women who did not take the drug. In infants exposed to the drug, the incidence of three or more minor anomalies was 15.5% vs. 6.5% in controls. Infants exposed to fluoxetine during the third trimester had, compared to those exposed only during the first and second trimester, reduced birth weight and length, an almost 5-fold increased risk of premature delivery, a 2.6-fold increased risk of being admitted to special-care nurseries, and an almost 9-fold increased risk of experiencing respiratory difficulties, cyanosis on feeding, and jitteriness.
18. Antidepressants and suicidal risk. Muller-Oerlinghausen B, Berghofer A. J Clin Psychiatry 1999;60 Suppl 2:94-9; discussion 111-6. This article emphasizes that selective serotonin reuptake inhibitors and other non-lithium antidepressants may increase the risk of suicide in certain patients by inducing akathisia (a condition characterized by restlessness and psychomotor agitation and associated with self-destructive impulses) and by liberating suppressed energies that may be used to act upon suicidal thoughts.
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Reexposure to fluoxetine after serious suicide attempts by three patients: the role of akathisia. Rothschild AJ. et al. J Clin Psychiatry, 52(12):491-3 1991 Dec. This article describes three cases of attempt suicide after induction of akathisia in patients on fluoxetine therapy. When re-exposed to the drug, all three patients re-developed akathisia and precipitated in suicidal thoughts, strongly suggesting a relation of causality between drug exposure and suicidal impulse.
19. Selective serotonin reuptake inhibitors: meta-analysis of efficacy and acceptability. Song F. et al. BMJ 1993 Mar 13;306(6879):683-7. This study presents the results of a meta-analysis of 63 randomized controlled studies comparing the efficacy of selective serotonin reuptake inhibitors (SSRIs) to that of tricyclic antidepressants as first line treatment for depression. The analysis revealed that SSRIs are no more effective than tryciclics in the management of depression. Dropouts rate were similar for both class of drugs, but slightly more patients reported side effects as a reason for dropping out in the tryciclic group compared to those in the SSRI group (18.8% v 15.4%). The authors concluded that "Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit". This study is important since it shows that SSRIs are not significantly better than classic antidepressant drugs, in spite of advertising campaigns claiming the superiority of SSRIs in the treatment of depression due to their excellent safety records. The underreporting of SSRI-related adverse reactions is also partly responsible for the vast increase in prescribing rates of these drugs.
20. Double-blind, multicenter comparison of sertraline and amitriptyline in elderly depressed patients. Cohn CK. et al. J Clin Psychiatry, 51 Suppl B():28-33 1990 Dec. In this study, 241 elderly individuals suffering from depression were randomized to receive an 8-week treatment with either amitriptyline (a tricyclic antidepressant) or sertraline (a serotonin uptake inhibitor). Over 30% of patients in the sertraline group and 35% in the amitriptyline group withdrew from the study because of drug-related side effects or laboratory abnormalities.
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The cost of antidepressant drug therapy failure: a study of antidepressant use patterns in a Medicaid population. McCombs JS, et al. J Clin Psychiatry, 51 Suppl():60-9; discussion 70-1 1990 Jun. The results of this study, conducted on a cohort of 2344 patients with major depressive disorders on antidepressant medications, show that only in 3.5% of patients the pattern of use of antidepressant was indicative of successful treatment. In 12.6 of patients, pattern of antidepressant use suggested treatment failure. In the remaining 84% of cases the efficacy of treatment could not be clearly classified.
21. The adequacy of reporting randomized, controlled trials in the evaluation of antidepressants. Streiner DL, et al. Can J Psychiatry, 43(10):1026-30 1998 Dec. This study examined the statistical and methodological validity of 69 randomized control trials that compared the efficacy of two antidepressant drugs with that of placebo. Criteria scores were defined as minimal and ideal. Zero percent of the studies met all of the ideal criteria for reporting clinical trials. Only 9 of 69 articles met the minimal criteria to be included in metaanalytical studies. These data indicate that the quality of the majority of studies on antidepressant drugs is extremely poor.
22. Hyponatremia in relation to treatment with antidepressants: A survey of reports in the World Health Organization database for spontaneous reporting of adverse drug reactions. Spigset O, et al. Pharmacotherapy 1997 Mar-Apr;17(2):348-52. The results of this study show that from 1968 to 1993, 668 cases of antidepressant-related hyponatremia were spontaneously reported to the World Health Organization. In over half of the patients, the reaction occurred within two weeks of starting antidepressant treatment.
23. Relative mortality from overdose of antidepressants. Henry JA, et al. BMJ, 310(6974):221-4 1995 Jan 28.
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This study reports on the case of 1606 deaths from antidepressant toxicity, occurring in the period from 1987 to1992. Over 80% of these deaths were associated to amitriptyline and dothiepin use.
24. Antidepressant-treated patients in ambulatory care. Mortality during a nine-year period after first treatment. Bingefors K. et al. Br J Psychiatry, 169(5):647-54 1996 Nov. The results of this study show that, in individuals over 65 years of age, treatment with antidepressant is significantly associated with increased risk of long-term mortality, especially from cardiovascular causes.
25. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients. Reilly, J G. et al. Lancet 2000; 355: 1048 - 1052. The results of this study show that use of psychotropic drugs is associated with a significantly increased risk of heart arrhythmias. The study was conducted on 495 psychiatric patients and 101 healthy individuals who served as control. As a marker for increased risk of arrhythmias the authors used the lengthening of the QT interval on the electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, compared to non-users. The risk increased with increasing doses of drugs, and was increased by more than 8 times in users of very high doses. These findings may explain some cases of sudden unexplained death occurring in patients taking psychotropic drugs, as this type of death has been linked to cardiac rhythm abnormalities.
26. Relative mortality from overdose of antidepressants Henry JA, et al. BMJ 1995;310:221-224 (28 January). The results of this study show that for every million prescriptions written for antidepressant drugs, approximately 30 people die from overdose. Tricyclic drugs are associated with the highest incidence of death (34 deaths per million prescriptions), and selective serotonin reuptake inhibitors with the lowest (2 deaths per million prescription).
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27. Imipramine overdose complicated by toxic megacolon. Ross JP, et al. Am Surg, 64(3):242-4 1998 Mar. This article emphasizes that tricyclic antidepressants are responsible for approximately 20 to 25% of drug overdoses leading to hospitalization. Death occurs primarily from cardiovascular complications. Respiratory disturbances, urinary retention, constipation, and intestinal obstruction are common signs of toxicity. Less frequent complications include: pancreatitis, intestinal perforation, and gangrene of the large intestine.
28. Cardiotoxic side effects associated with tricyclic antidepressant overdose. Keis NA. AACN Clin Issues Crit Care Nurs, 3(1):226-32 1992 Feb. This article emphasizes that intake of excessive doses of tricyclic antidepressants is associated with a significant risk of cardiotoxicity, especially during the first 24 hours from the overdose.
PSYCHOTROPIC DRUGS
"Psychotropic drugs" is a term that refers to drugs that have an effect on the psychological function, including antidepressants, antipsychotics or neuroleptics, antianxiety drugs, and hallucinogens.
29. QTc-interval abnormalities and psychotropic drug therapy in psychiatric patients Reilly JG. et al. Lancet 2000; 355: 1048 - 1052. The results of this study show that use of psychotropic drugs is associated with a significantly increased risk of heart arrhythmias. The study was conducted on 495 psychiatric patients and 101 healthy individuals who served as control. As a marker for increased risk of arrhythmias the authors used the lengthening of the QT interval on the electrocardiogram. Eight percent of patients receiving psychiatric drugs had prolonged QT interval, which poses them at risk of cardiac arrhythmias. The risk of having an abnormal QT interval in patients taking tricyclic antidepressants and the antipsychotic drugs thioridazine, and droperidol was increased by 4.4-, 5.5-, and 6.7-folds, respectively, compared to non-users. The risk increased with increasing doses of drugs, and was increased by more than 8 times in users of very high doses. These findings may explain Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 41
some cases of sudden unexplained death occurring in patients taking psychotropic drugs, as this type of death has been linked to cardiac rhythm abnormalities.
30. Dopamine-antagonistic, anticholinergic, and GABAergic effects on declarative and procedural memory functions. Rammsayer TH, Rodewald S, Groh D Brain Res Cogn Brain Res. 2000 Jan;9(1):61-71. The results of this study show that the psychotropic drugs haloperidol and midazolam (a benzodiazepine used for sedation) significantly impair memory functions in healthy individuals. The study was conducted on 80 healthy volunteers who were randomly assigned to receive haloperidol, midazolam, scopolamine, or placebo. Adverse effects on immediate and delayed word recall tests were observed with all three drugs, but were more pronounced in individuals taking midazolam. All drugs provoked severe impairment on object recognition tests, and these effects were particularly strong in individuals receiving midazolam. The results of this study indicate that use of these drugs is associated with significant memory-related problems in healthy individuals.
31. A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers. Beuzen JN, Taylor N, Wesnes K, Wood A. J Psychopharmacol (Oxf) 1999;13(2):152-8. The results of this study show that the antipsychotic drug haloperidol produces significant cognitive and psychomotor impairment in elderly individuals, and these effects don't seem to improve with treatment. The study was conducted on 14 healthy elderly individuals who were randomly assigned to receive haloperidol, olanzapine (a new antipsuchotic drug), or placebo for 4 days. On day 1 of treatment, significant impairment in attention, memory, and motor control was observed in both groups receiving antipshycotic drugs. On day 4 of treatment, the cognitive and psychomotor deficits were attenuated in patients who took olanzapine, (indicating adaptation to these side effects), but had worsened in patients taking haloperidol. These data indicate that patients taking haloperidol may be experiencing significant deterioration of cognitive and motor skills from the drug. These powerful adverse effects must be taken in consideration when prescribing haloperidol to elderly individuals, as the drug may precipitate their overall health status and may render them unsuitable for independent living. Since other antipsychotic drugs don't share the same persistency of effects, haloperidol use should be replaced with safer alternatives.
32. Effects of haloperidol and amisulpride on motor and cognitive skill learning in healthy volunteers. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 42
Peretti CS, Danion JM, Kauffmann-Muller F, Grange D, Patat A, Rosenzweig P. Psychopharmacology (Berl). 1997 Jun;131(4):329-38. The results of this study show that intake of haloperidol is associated with impaired cognitive functions in healthy individuals. The study was conducted on 60 healthy individuals who were randomized to receive haloperidol, amisulpride (a drug used in the treatment of depression and dysthymia), or placebo. Those who received haloperidol showed the greatest deficits in higher cognitive functions as evaluated through a battery of tests performed immediately after and some time after drug administration, while those who received amisulpride demonstrated cognitive slowing only at tests performed at distance from drug intake.
33. Psychomotor, Cognitive, extrapyramidal, and affective functions of healthy volunteers during treatment with an atypical (amisulpride) and a classic (haloperidol) antipsychotic. Ramaekers JG, et al. J Clin Psychopharmacol 1999 Jun;19(3):209-21. The results of this study show that haloperidol significantly impairs cognitive and motor performance in healthy individuals. The study was conducted on 21 healthy volunteer who were randomly assigned to receive the atypical neuroleptic amisulpride, the classic neuroleptic haloperidol, or placebo, for 5 consecutive days. Significant cognitive and psychomotor deficits were observed at day 5 of treatment in individuals taking amisulpride and haloperidol. Additionally, practically every individual who took haloperidol exhibited extrapiramidal symptoms ranging from akatisia (restlessness of movements, an urge to move about constantly, often associated with anxiety and agitation) to acute dystonia (sustained abnormal postures or muscle spasms), and mental disturbances. These data indicate a high rate of severe adverse effects associated with neuroleptic intake. Interestingly, several of the adverse effects of haloperidol resemble symptoms found in schizophrenic patients, thus raising the question of whether they are due to the disease or to the treatment.
34. Managing antipsychotic-induced acute and chronic akathisia. Miller CH, Fleischhacker WW. Drug Saf 2000 Jan;22(1):73-81. This article emphasizes that 5% to 37% of patients treated with antipsychotic drugs develops akathisia, a condition characterized by a feeling of restlessness accompanied by anxiety, agitation, and an urge to move about that leads patients to continuously rock while sitting or standing, to lift their feet as if marching on the spot and to cross and uncross their legs while sitting. Since currently there is no satisfactory treatment for this
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complication, the only remedy is to prevent its occurrence by reducing the intake of drugs, or switching to safer antipsychotic drugs.
35. Antipsychotic-induced life-threatening 'esophageal dyskinesia'. Horiguchi J et al. Int Clin Psychopharmacol 1999 Mar;14(2):123-7. This article describes a potentially fatal adverse reaction to antipsychotic drugs, esophageal dyskinesia, consisting of abnormal movements affecting the lower portion of the pharynx and the upper portion of the esophagus. A case of a patient who died from asphyxiation of food is reported.
36. Effects of the clozapine national registry system on incidence of deaths related to agranulocytosis. Honigfeld G. Psychiatr Serv, 47(1):52-6 1996 Jan. Clozapine is an antipsychotic drug with a high potential of inducing white blood cell suppression, and is administered only to patients whose weekly blood tests show no evidence of toxicity. From its release in 1990 until December 1994, 382 cases of agranulocytosis and 12 related deaths have been identified through a national patient registry maintained by the drug manufacturer. From results of clinical research performed prior to the release of the drug in the market, the expected number of cases of agranulocytosis and death was 995 and 149, respectively, raising the question of whether such a drug should have been approved in the first place.
37. A survey of sudden death associated with the use of antipsychotic or antidepressant drugs: 49 cases in Finland. Mehtonen OP; Aranko K; Malkonen L; Vapaatalo H. Acta Psychiatr Scand, 84(1):58-64 1991 Jul. The antipsychotic class of drugs phenothiazines causes disturbances of the cardiac rhythm, and while their use has been associated with the occurrence of sudden death, a causal link has not been clearly demonstrated. This study shows that in 46 of 49 cases of sudden death reported in users of antipsychotic or antidepressant drugs, individuals were taking therapeutic doses of phenothiazines, which consisted of the drug thioridazine in over half the cases. The high representation of this class of drugs in individuals with sudden death is indicative of a causal association.
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38. Assessment of EPS and tardive dyskinesia in clinical trials. Collaborative Working Group on Clinical Trial Evaluations. J Clin Psychiatry 1998;59 Suppl 12:23-7. This article explains that approximately 50%-75% of individuals who take conventional antipshycotic drugs develop acute extrapyramidal symptoms (EPS) such as akathisia, dystonia and parkinsonism. Although the incidence of such symptoms is less frequent with the new antipsychotic drugs, the authors still caution to use them at doses below the EPS-producing levels until more data on their long-term effects are available.
39. Extrapyramidal syndromes in neuroleptic-treated patients: prevalence, risk factors, and association with tardive dyskinesia. Muscettola G, et al. J Clin Psychopharmacol 1999 Jun;19(3):203-8. This study evaluated the prevalence of signs of extrapyramidal syndrome (EPS) (akathisia, dystonia and parkinsonism) in a cohort of 1,559 patients treated with antipsychotic drugs. EPS was present in approximately 30% of patients, with 65% of these patients presenting with signs of parkinsonism such as rigidity, tremors and slowness of movements. These data indicate a high rate of severe and disabling adverse reactions associated with neuroleptic use.
40. Intermittent neuroleptic treatment and risk for tardive dyskinesia: Curacao Extrapyramidal Syndromes Study III. van Harten PN, et al. Am J Psychiatry 1998 Apr;155(4):565-7. The results of this study, conducted on a cohort of patients with a history of antipsychotic drug use of more than 3 months, show that the incidence of tardive diskinesia increases by 3-folds in patients who had 3 or more treatment interruptions, compared to those who had 2 or less breaks in drug therapy.
41. Incidence of tardive dyskinesia in early stages of low-dose treatment with typical neuroleptics in older patients. Jeste DV, et al. Am J Psychiatry 1999 Feb;156(2):309-11. This study evaluated the incidence of tardive dyskinesia (a syndrome characterized by potentially irreversible, involuntary abnormal movements usually of the trunk and face, associated with use of antipsychotic drugs) in a cohort of 307 outpatients over 45 year of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 45
age treated with low-dose antipsychotic drugs. In patients who had not used this type of drugs in the past, the incidence of tardive dyskinesia was 3.4% after 1 month and 6% after 2 months of use. After 1 year, the syndrome developed approximately in 25% of patients, and in 37% of those who had a history of antipsychotic drug use of over 30 days.
42. Prospective study of tardive dyskinesia in the elderly: rates and risk factors. Woerner MG, et al. Am J Psychiatry 1998 Nov;155(11):1521-8. The results of this study, conducted on a cohort of 261 patients on antipsychotic drugs, show that after 1, 2, and 3 years of cumulative treatment, 25%, 34%, and 53% of patients who started taking the drugs at age 55 or above developed tardive dyskinesia.
43. Incidence and risk factors for severe tardive dyskinesia in older patients. Caligiuri MP, et al. Br J Psychiatry 1997 Aug;171:148-53. The results of this study show that after 1, 2, and 3 years of treatment with antipsychotic drugs, the incidence of severe tardive diskinesia in middle-aged and elderly individuals is 2.5%, 12% and 23%, respectively. The authors concluded affirming, "Conventional neuroleptics may be prescribed to older patients only when necessary and at the lowest effective dosage".
44. Transient and intermittent oral dyskinesia appearing in a young woman ten days after neuroleptic treatment. Tawara Y, et al. Clin Neuropharmacol 1997 Apr;20(2):175-8. This article reports on the case of a 22-year-old woman initiated on antipsychotic drugs who developed severe extrapiramidal signs and tardive diskinesia lasting for 6 days, after only 9 days of treatment.
45. Neuroleptic drug exposure and treatment of parkinsonism in the elderly a case-control study. Avorn J, Bohn RL, Mogun H, Gurwitz JH, Monane M, Everitt D, Walker A. Am J Med 1995 Jul;99(1):48-54.
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The results of this study show that elderly patients who take antipsychotic drugs have a significant increased risk of developing symptoms of Parkinson's disease requiring initiation of pharmacological treatment. The study was conducted on a cohort of 3,512 patients aged 65 and older who received a new prescription for the treatment of Parkinson's disease and a similar number of controls without symptoms of parkinsonism. Users of neuroleptic drugs had a 5.4-fold increased risk of being treated for parkinsonism, compared to nonusers. Of note, users of neuroleptic drugs also had an over two-fold increased risk of receiving a drug with indications for idiopathic Parkinson's disease and not appropriate in individuals with drug-induced parkinsonism. The authors estimated that 37% of all prescriptions for the treatment of Parkinson's disease are due to neuroleptic drug use. In 71% of patients neuroleptic treatment was not discontinued in spite of the occurrence of parkinsonian symptoms. These data indicate that extrapyramidal symptoms of parkinsonism are a frequent complication of neuroleptic treatment. Physicians however, often fail to recognize that these symptoms are drugrelated, as shown by the high rate of inappropriate prescribing of drugs that are not indicated for drug-induced parkinsonism, resulting in inappropriate management of the condition and failure of optimization of treatment regimens.
46. Drug-induced cognition disorders in the elderly: incidence, prevention and management. Gray SL, Lai KV, Larson EB. Drug Saf 1999 Aug;21(2):101-22. This article highlights that elderly individuals are particularly at risk of developing drugrelated delirium and dementia. Although practically every drug has the potential of worsening cognitive function in the elderly, those more commonly implicated are benzodiazepines, opioids, anticholinergics, and tricyclic antidepressants. The risk is particularly high in elderly frail individuals who are taking several medications at once, such that a careful evaluation should always be conducted to exclude the possibility of drug-related cognitive impairment in this age group.
47. Increased morbidity and mortality related to asthma among asthmatic patients who use major tranquillisers. Joseph KS, et al. BMJ 1996;312:79-81 (13 January). The results of this study show that use of neuroleptic drugs in asthmatic patients with psychosis is associated with a 3.2-fold increased risk of death or near-death from asthma, compared to nonuse.
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48. Association of venous thromboembolism and clozapine. Staffan Hgg, Olav Spigset, Torbjrn G Sderstrm. Lancet 2000; 355: 1155 - 1156. The results of this study show that the antipsychotic drug clozapine is associated with a significantly increased risk of death from venous thromboembolism. The researchers evaluated cases of deep venous thrombosis and pulmonary embolism that occurred in individuals treated with clozapine, reported to the Swedish Adverse Reactions Advisory Committee from April 1989 through March 2000. Of the 12 patients who experienced venous thromboembolism, 5 died (42%). Median age of patients was 38 years. Only one had known risk factors for thromboembolism (contraceptive use). Sixty-seven percent of the cases occurred during the first 3 months of clozapine treatment. Overall, from 20,000 to 70,000 Swedish patients take clozapine, indicating that the risk of this complication is at least 1 per 2-6,000 treated patients. The actual risk, however, is likely to be higher, in view of the fact that reporting of adverse events is spontaneous (not mandatory), such that a substantial number of cases may be missed due to under-reporting.
49. Myocarditis and cardiomyopathy associated with clozapine. Jens G Kilian, Kristin Kerr, Christopher Lawrence, David S Celermajer. Lancet 1999; 354: 1841-45. The results of this study show that individuals taking the anti-psychotic drug clozapine have a 1,000-2,000-fold increased risk of death from myocarditis, compared to non-users. The study was conducted after two young, physically healthy patients died unexpectedly soon after initiation of treatment. The authors investigated the risk of adverse cardiovascular effects by searching for cases of myocarditis and cardiomyopathy in the Australian Adverse Reaction Committee register, a voluntary reporting system. They found 15 reports of myocarditis and 8 of cardiomyopathy. Six patients died, 5 from myocarditis, and 1 from cardiomyopathy. All cases of myocarditis occurred within 3 weeks of initiation of treatment, whether cardiomyopathy occurred up to 3 years after initiation of treatment. From 1993 to 1999, 8,000 patients were started on clozapine in Australia. Among these 8,000 patients, a minimum of 23 cases of myocarditis and cardiomyopathy occurred, including 6 deaths. The number of patients who suffered these complications may, however be higher, since reporting of adverse events is not mandatory. Extrapolation of this data indicates that approximately 1 in 500 young individuals who are treated with clozapine for schizophrenia will have fatal and nonfatal myocarditis in the first month of treatment. These estimates are conservative, due to likely underreporting. Since myocarditis is a very rare cause of death worldwide (approximately 4 deaths per 1,000,000 individuals), these figures represent a 1000-2000 increased risk of death from the disease in patients taking clozapine, compared to the general population. In addition, users of clozapine have a 5-fold increased risk of cardiomyopathy, compared to non-users. This article further highlights the risks associated with use of this drug, which has been found to cause potentially fatal agranulocytosis (marked decrease in the number of white blood cells) in one every 100 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 48
treated patients, and deep venous thrombosis in at least 1 in 2-6-000 patients (based on spontaneous reporting), the latter complication being fatal in over 40% of cases.
PSYCHOTROPIC DRUGS USED FOR ADULTS AND THE ELDERLY
50. Prescribing trends in psychotropic medications: primary care, psychiatry, and other medical specialties. Pincus HA, Tanielian TL, Marcus SC, Olfson M, Zarin DA, Thompson J, Magno Zito J. JAMA 1998 Feb 18;279(7):526-31. The results of this study show that in 1985, in the U.S., 32.73 million visits to officebased primary care physicians resulted in prescription of psychotropic drugs. In 1994, the number of such visits increased to 45.64 million. Psychiatrists and primary care physicians' visits for depression doubled from 1988 to 1994, and visits for stimulants more than quadrupled. In addition, of the visits for depression, those paid to psychiatrists in 1994 resulted in a higher rate of drug prescribing, compared to 1988.
51. Expenditures for psychotropic medications in the United States in 1985. Zorc JJ. et al. Am J Psychiatry 1991 May;148(5):644-7. This study shows that, in 1985, the U.S. spent $1.45 billion in psychotropic drugs for outpatients. Sixty percent of this sum ($868 million) was spent for antianxiety and sedative-hypnotic medications, 18% for antipsychotics, and 17% for antidepressants.
52. The direct economic costs of insomnia in the United States for 1995. Walsh JK, Engelhardt CL. Sleep 1999 May 1;22 Suppl 2:S386-93. The results of this study show that in 1995, the U.S. spent $13.9 billion for the treatment of insomnia.
53. Psychotropic prescribing for the elderly in office-based practice. Aparasu RR, Mort JR, Sitzman S. Clin Ther 1998 May-Jun;20(3):603-16. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 49
The results of this study show that 17% of visits by the elderly to office-based physicians result in the prescription of at least one inappropriate psychotropic drug. According to the study, in 1995, approximately 12 million visits by the elderly to their doctors resulted in prescription of a psychotropic drugs, primarily antidepressants and antianxiety drugs. In over 2 million visits, patients received a minimum of one potentially inappropriate psychotropic medication. The high rates of inappropriate prescribing, coupled with the particular susceptibility of elderly patients to experiencing drug-related adverse effects, raises concerns on the quality of care offered by physicians in ambulatory settings.
54. Determinants of psychotropic drug usage in a general intensive care unit. Stolker J. et al. Gen Hosp Psychiatry 1998 Nov;20(6):371-6. The results of this study show that 36% and 17.5% of patients admitted to a Dutch general intensive care unit receive benzodiazepines and antipsychotics, respectively.
55. Psychotropic drug use and polypharmacy in a general hospital. Salzman C. Gen Hosp Psychiatry, 3(1):1-9 1981 Mar. The results of this study show that approximately 43% of patients admitted to a general Boston teaching hospital received psychotropic drugs. Drugs were given mainly for sleep problems or to reduce anxiety. The authors found high rates of inappropriate prescribing of antipsychotic drugs, which were given to control symptoms such as nausea, pain, or agitation rather than psychosis, and of antidepressant drugs, which were given irrespective of signs of depression, or below therapeutic doses in patients with depression.
56. Psychotropic use among older residents of board and care facilities. Spore D. et al. J Am Geriatr Soc, 43(12):1403-9 1995 Dec. The results of this study, conducted on 2054 elderly residents from 410 board and care facilities in 10 states, indicate that approximately 35% of them were receiving a minimum of one psychotropic drug. Simultaneous use of 2 or more psychotropic drugs occurred in 30% of psychotropic drug users.
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57. Regulatory environment and psychotropic use in board-and-care facilities: results of a 10-state study. Spore D. et al. J Gerontol A Biol Sci Med Sci, 51(3):M131-41 1996 May. The results of this study, conducted on a sample population of 2,949 residents from 493 board-and-care facilities in 10 states, show that 41% of them were primarily or routinely being prescribed a minimum of one psychotropic drug. Twenty-one percent of residents were on antipsychotic drugs. About half of the individuals currently on psychotropic drugs did not have any psychiatric diagnosis in the previous year.
58. Psychotropic drug intake in residents newly admitted to nursing homes. Wancata J. et al. Psychopharmacology (Berl) 1997 Nov;134(2):115-20. The results of this study indicate that prescribing of psychotropic drugs to nursing home residents occurs irrespective of prior history of psychiatric conditions. The study, conducted on a cohort of 262 individuals admitted to nursing homes in Austria, show that the prevalence of use of psychotropic drugs rose from 45.5% in the 3 months before admission, to 72% in the 2 weeks after admission, to 79% during the first six months of stay.
59. Psychotropic drug use in Sydney nursing homes. Snowdon J. et al. Med J Aust, 163(2):70-2 1995 Jul 17. The results of this study, conducted on all residents of 46 nursing homes in Sydney, show that 59% of them were regularly receiving psychotropic drugs, and 7% of them were receiving them on an "as required" basis. Benzodiazepines, antipsychotics, hypnotics, antidepressants and anxiolytics were taken regularly by 32.3%, 27.4%, 26.6%, 15.6% and 8.6% of individuals, respectively.
60. A follow-up survey of psychotropic drug use in Sydney nursing homes. Snowdon J. Med J Aust 1999 Apr 5;170(7):299-301. The results of this study show that 48.5% of Sidney nursing home residents receive at least one psychotropic drug regularly, and another 4.5% "as required". Antipshychotic drugs were taken by 27.6% of residents. Anticonvulsants, who were not considered in this study as psychotropic drugs, were given to 13% of residents. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 51
61. Use of psychotropic medications for persons with mental retardation who live in Oklahoma nursing homes. Spreat S. et al. Psychiatr Serv, 49(4):510-2 1998 Apr. The results of this study, conducted on a cohort of 1,056 individuals with mental retardation living in Oklahoma nursing homes, show that 32% of them were taking antipsychotic medications, 16% were taking anxiolytic drugs, and 6% were taking antidepressants. Use of antipsychotics, a class of drugs associated with a high risk of severe complications, was not always justified by patients' clinical history. The high rates of prescribing of antipsychotic drugs make the authors question the appropriateness of placing individuals with mental retardation in nursing homes.
62. Use of psychotropic medication in Oklahoma: a statewide survey. Spreat S. et al. Am J Ment Retard, 102(1):80-5 1997 Jul. The results of this study indicate that 22.5%, 9.3%, and 5.9% of mentally retarded individuals are prescribed antipsychotic drugs, anxiolytics and antidepressant medications, respectively. Rates of prescribing for mentally retarded individuals living in institutions or intermediate care facilities are significantly higher.
63. Frequency of and determinants for psychotropic drug use in an institution for the mentally retarded. Linaker OM. Br J Psychiatry 1990 Apr;156:525-30. The results of this study, conducted on a cohort of 168 mentally retarded individuals institutionalized in Norway, show that 49% of them were receiving antipsychotic drugs. Only in a small percentage of cases the prescription of these drugs could be justified by a psychiatric diagnosis.
64. Prevalence and prediction of psychotropic drug use in California developmental centers. Stone RK. et al. Am J Ment Retard, 93(6):627-32 1989 May.
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The results of this study show that, on average, 35.4% of developmentally disabled individuals institutionalized in California are treated with psychotropic drugs, with 26.8% of them receiving antipsychotic medications. Rates of prescription of psychotropic drugs varied greatly among institutions, ranging from 13.7% to 63.6% of the individuals.
65. Withdrawal of haloperidol, thioridazine, and lorazepam in the nursing home: a controlled, double-blind study. Cohen-Mansfield J, et al. Arch Intern Med 1999 Aug 9-23;159(15):1733-40. This double-blind placebo controlled study evaluated the effect of discontinuation of treatment with haloperidol, thioridazine, and lorazepam, three psychotropic drugs commonly used to control patient behavior, in residents of a nursing home. The behavior of patients who were slowly switched to placebo did not differ from that of patients who continued taking the drugs, questioning the efficacy of these medications in managing patient agitation. The authors conclude that an attempt to discontinue the use of such drugs should be routinely performed in nursing home settings.
66. Long-stay patients with long-stay drugs. A case review; a cause for concern. Fottrell E, et al. Lancet 1976 Jan 10;1(7950):81-2. The results of this study, conducted on a cohort of 200 long-term psychiatric patients, show that approximately half of them were being prescribed unnecessary or excessive medications.
67. Clonidine impairs sustained attention and memory in Alzheimer's disease. Riekkinen Jr P, Laakso MP, Jakala P, Riekkinen P Jr. Neuroscience 1999;92(3):975-82. The results of this study indicate that clonidine at doses of 2 microg/kg significantly disrupts attention and short-term memory in approximately one-third of Alzheimer patients. The negative effects of clonidine on attention were observed only in tests that were demanding for the patients, while those requiring simpler processing remained unaffected.
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68. Psychotropic drug use and cognitive decline among older men and women. Dealberto MJ. et al. Int J Geriatr Psychiatry, 12(5):567-74 1997 May. The results of this study, conducted on a cohort of 1200 individuals without cognitive impairment at baseline, show that users of non-benzodiazepine psychotropic drugs have a 5-fold increased risk of cognitive decline compared to nonusers.
69. Benzodiazepine use and cognitive function among community-dwelling elderly. Hanlon JT, et al. Clin Pharmacol Ther 1998 Dec;64(6):684-92. The results of this study, conducted on 2765 elderly individuals living in the community and followed up for 3 years, show that current users of benzodiazepines experience significant worsening of memory function, compared to non-users. The association between benzodiazepine use and memory decline is dose-dependent, and exists with both short- and long-acting drugs.
70. Cognitive impairment in long-term benzodiazepine users. Golombok S, Moodley P, Lader M. Psychol Med 1988 May;18(2):365-74. The results of this study indicate that long-term use of benzodiazepines is associated with significant cognitive impairment, particularly for tasks involving sustained attention and visual-spatial ability.
71. Anterograde amnesia linked to benzodiazepines. Mejo SL. Nurse Pract 1992 Oct;17(10):44, 49-50. This article highlights that use of benzodiazepines is associated with disruption of longterm memory, a symptom that is often unrecognized by patients who take the drugs. The author concludes that is important that patients be fully informed on the side effects of treatment, and that the minimum possible dose be prescribed for the shortest period of time, in order to reduce the occurrence of treatment-induced adverse events.
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72. Benzodiazepine use as a cause of cognitive impairment in elderly hospital inpatients. Foy A, O'Connell D, Henry D, Kelly J, Cocking S, Halliday J. J Gerontol A Biol Sci Med Sci 1995 Mar;50(2):M99-106. The results of this study show that use of benzodiazepines significantly increases the risk of cognitive impairment in elderly individuals. The study was conducted on 418 individuals aged 59-88, with normal cognitive function upon admission to the hospital. During hospitalization, 10.8% of patients developed cognitive impairment. Patients who reported use of benzodiazepines were 3.5 times more likely to develop cognitive impairment, compared to nonusers. Overall, benzodiazepine use accounted for 30% of all cases of cognitive disruption.
73. Fatal myocardial infarction and use of psychotropic drugs in young women. Thorogood M. et al. Lancet, 340(8827):1067-8 1992 Oct 31. The results of this study show that current use of psychotropic drugs in women aged 16 to 39 is associated with a 17-fold higher incidence of fatal myocardial infarction, compared to nonuse.
74. Use of psychotropic drugs and risk of myocardial infarction: a case-control study in Finnish farmers. Penttinen J. et al. Int J Epidemiol, 25(4):760-2 1996 Aug. The results of this study, conducted on a cohort of 3172 male farmers, show that users of psychotropic drugs have a 2.5-fold increased risk of myocardial infarction, compared to nonusers. The risk of heart attack increased by 5.4-folds in users of antidepressants.
75. Psychotropic medication use and risk of epithelial ovarian cancer. Harlow BL; et al. Cancer Epidemiol Biomarkers Prev, 7(8):697-702 1998 Aug. The results of this study, conducted on cohort of 563 women with ovarian cancer and 523 controls, show that users of psychotropic drugs for 6 or more months had a 60% increased risk of invasive ovarian cancer, compared to nonusers. In women who first used psychotropic drugs before menopause for more than two years, the risk increased by almost three times.
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PSYCHOTROPIC DRUGS IN PREGNANCY
76. Psychotropic drug use during pregnancy: weighing the risks. Cohen LS. et al. J Clin Psychiatry, 59 Suppl 2():18-28 1998. This article discusses some of the risks associated with use of psychotropic drugs by pregnant women, which include malformations, neonatal toxicity, and neurological and behavioral impairment. Additionally, it emphasizes that since the safety and efficacy of these drugs in the expecting mother has never been tested, nor their use has been approved by the FDA, a careful evaluation of the risks and benefits of treatment should be conducted before psychotropic drugs are taken during pregnancy.
77. Psychotropic drug use in pregnancy and perinatal death. Laegreid L. et al. Acta Obstet Gynecol Scand, 71(6):451-7 1992 Aug. This study analyzed psychotropic drug use in a sample population of 73 mothers of dead infants and in a control cohort of mothers of surviving infants, and found that psychotropic drug use was significantly associated with perinatal death.
78. Use of psychotropic drugs and pregnancy outcome. Larivaara P; et al. J Clin Epidemiol, 49(11):1309-13 1996 Nov. The results of this study, conducted on a cohort of 7933 pregnant women and their 8030 babies, show that use of psychotropic drugs during pregnancy is significantly associated with an increased need for hospital observation. In particular, 80.8%, and 38.3% of regular and occasional psychotropic drug users required hospital observation, compared to 27.4% of nonusers. In addition, bleeding was significantly more frequent in users vs. nonusers (23% vs. 13%), and infant mean birth weight was significantly lower among regular users.
79. Neurodevelopment in late infancy after prenatal exposure to benzodiazepines--a prospective study. Laegreid L. et al. Neuropediatrics, 23(2):60-7 1992 Apr.
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This study evaluated neurodevelopment and growth in 17 children of mothers who used therapeutic doses of benzodiazepines (BZD) throughout pregnancy. Follow up was performed at 6, 10, and 18 months of age. Children exposed to BZD had slightly reduced head circumference at birth and throughout follow up, compared to children of women who were not exposed to BZD. Craniofacial abnormalities were present in 5 infants. Gross motor development was impaired at 6 and 10 months while fine motor development was impaired throughout follow up. Deviating muscle tone and movements were found more frequently in children exposed to BZD compared to controls. These data indicate that exposure to therapeutic levels of BZD during pregnancy is associated with a significantly higher risk of abnormal development in the offspring.
80. Mental development in late infancy after prenatal exposure to benzodiazepines--a prospective study. Viggedal G, Hagberg BS, Laegreid L, Aronsson M. J Child Psychol Psychiatry 1993 Mar;34(3):295-305. The results of this study show that continuous use of benzodiazepines during pregnancy is associated with significant impairment of mental development in the offspring.
81. Benzodiazepine use in pregnancy and major malformations or oral cleft: metaanalysis of cohort and case-control studies. Dolovich LR, et al. BMJ 1998;317:839-843 ( 26 September ). This article presents the results of a meta-analysis of 23 selected studies investigating whether use of benzodiazepine during the first trimester of pregnancy increases the risk of major malformations or oral cleft in the offspring. While cohort studies did not detect an increased incidence of major malformations or oral cleft, analysis of case-control studies revealed a 3-fold increase in incidence of major malformations and an 80% increase in incidence of oral cleft alone in the offspring of benzodiazepine users, compared to controls.
DRUGS, FALLS AND HIP FRACTURES
82. Injurious falls in nonambulatory nursing home residents: a comparative study of circumstances, incidence, and risk factors. Thapa PB. et al. J Am Geriatr Soc 1996 Mar;44(3):273-8. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 57
The results of this study show that ambulatory nursing home residents who take psychotropic drugs have a 2.5-fold increased risk of falls resulting in injuries, compared to those not on these drugs.
83. Psychotropic drugs and risk of recurrent falls in ambulatory nursing home residents. Thapa PB. et al. Am J Epidemiol 1995 Jul 15;142(2):202-11. The results of this study show that 36% of all recurrent falls in ambulatory nursing home residents can be attributed to psychotropic drug use.
84. Relationship between the administration of selected medications and falls in hospitalized elderly patients. Gales BJ. et al. Ann Pharmacother, 29(4):354-8 1995 Apr. The results of this study, conducted on a sample group of 100 patients aged 70 and older who fell and 100 control subjects of the same age, show that benzodiazepine use in fallers was 2.7 times more frequent that in non users. Sixty-five percent of patients who fell while taking long-acting benzodiazepines, were taking higher than recommended doses of the drug. Congestive heart failure, treatment with digoxin and use of 3 or more psychotropic drugs were all factors positively associated with an increased risk of falls.
85. Falls, injuries due to falls, and the risk of admission to a nursing home. Tinetti ME, et al. N Engl J Med 1997 Oct 30;337(18):1279-84. The results of this study, conducted on a sample group of 1103 elderly individuals living in the community, show that those who fall are at significantly increased risk of being admitted to a nursing home, compared to the remaining population. In particular, the risk of being admitted to a nursing home increases by 3 times in those with one noninjurious fall, by 5.5-times in those with multiple noninjurious falls, and by more than 10 times in those with one or more injurious fall. These data suggest that interventions aiming at reducing the incidence of falls can substantially reduce the number of admission to nursing homes.
86. Potential adverse outcomes of psychotropic and narcotic drug use in Canadian seniors. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 58
Ebly EM. et al. J Clin Epidemiol 1997 Jul;50(7):857-63. The results of this study, conducted on a large population of elderly individuals with intact cognition, show that the incidence of falls is 3 times greater in users of two or more psychotropic drugs, compared to nonuser (42.6% versus 13.9%). These data indicate that psychotropic drug-related adverse effects may significantly increase the risk of falls in elderly individuals.
87. Effects of central nervous system polypharmacy on falls liability in communitydwelling elderly. Weiner DK. et al. Gerontology 1998;44(4):217-21. The results of this study, conducted on a cohort of 305 community-dwelling elderly individuals, show that use of one psychotropic drug is associated with a 54% increased risk of falls, while use of two or more psychotropic drugs is associated with a 137% increased risk of falls. The authors conclude that the dose-response effect is indicative of a relation of causality between use of psychotropic drugs and falls.
88. Antidepressants and the risk of falls among nursing home residents. Thapa PB. et al. N Engl J Med 1998 Sep 24;339(13):875-82. The results of this study, conducted on a sample population of 2428 nursing home residents, show that use of the antidepressants tricyclics, serotonin-reuptake-inhibitors and trazodone, is associated with a 2.0-, 1.8- and 1.2-fold increased risk of falls, respectively.
89. Risk factors for falls as a cause of hip fracture in women. The Northeast Hip Fracture Study Group. Grisso JA. et al. N Engl J Med 1991 May 9;324(19):1326-31. The results of this study show that use of long-acting barbiturates in the elderly is associated with a 5.2-fold increased risk of hip fractures.
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90. Opioid analgesics and the risk of hip fracture in the elderly: codeine and propoxyphene. Shorr RI. et al. J Gerontol 1992 Jul;47(4):M111-5. The results of this study, conducted on a cohort of 4,500 elderly individuals and 24,041 matched controls, show that users of the commonly prescribed anti-pain medications codeine or propoxyphene have a 60% increased risk of hip fractures, compared to nonusers. The risk of hip fractures increases by 2.2-times in new users of the drugs, and by 2.6 times in those who take them in combination with a psychotropic drug. These findings are important, especially in consideration of the widespread prescribing of antipain medications to elderly individuals.
91. Cognitive impairment, drug use, and the risk of hip fracture in persons over 75 years old: a community-based prospective study. Guo Z. et al. Am J Epidemiol 1998 Nov 1;148(9):887-92. The results of this study, conducted on a sample group of 1,608 individuals aged 75 and older, show that those using the opioid analgesic propoxyphene have a two-fold increased risk of hip fractures, compared to nonusers. In addition, use of potassium supplements was associated with a 45% reduction in hip fracture risk.
92. Cyclic antidepressants and the risk of hip fracture. Ray WA, et al. Arch Intern Med 1991 Apr;151(4):754-6. The results of this study show that elderly individuals using tricyclic antidepressants have a 60% increased risk of hip fractures, compared to nonusers.
93. Use of selective serotonin-reuptake inhibitors of tricyclic antidepressants and risk of hip fractures in elderly people. Liu B, et al. Lancet 1998 May 2;351(9112):1303-7. The results of this study, performed on a sample group of 8,239 elderly individuals with hip fracture and five controls matched to each subject, show that use of the antidepressants selective serotonin-reuptake inhibitors, secondary-amine tricyclics and tertiary-amine tricyclics, was associated with a 2.4-, 2.2-, and 1.5-fold increased risk of
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hip fractures, respectively, compared to nonuse. New use of each class of drugs resulted in a further increase in the risk of hip fractures.
94. Benzodiazepines of long and short elimination half-life and the risk of hip fracture. Ray WA, et al. JAMA 1989 Dec 15;262(23):3303-7. The results of this study, conducted on a cohort of 4501 elderly individuals with hip fracture and 24,041 controls, show that use of long-acting benzodiazepines is associated with a 70% increased risk of hip fractures.
95. Effect of a single dose of diazepam on balance measures in older people. Cutson TM, Gray SL, Hughes MA, Carson SW, Hanlon JT. J Am Geriatr Soc 1997 Apr;45(4):435-40. The results of this study show that diazepam adversely affects balance control in elderly individuals. The researchers evaluated the effects of a single dose of diazepam on balance in 12 healthy individuals aged 65 and older. Administration of the drug was associated with prolongation of the latency time of the muscle of the lower leg in response to a sudden perturbation, and with impaired performance at neuropsychological tests of attention. These findings seem to confirm the epidemiological finding of an increased risk of falls associated with use of benzodiazepines.
96. Psychotropic drug use and the risk of hip fracture. Ray WA; Griffin MR; Schaffner W; Baugh DK; Melton LJ 3d. N Engl J Med, 316(7):363-9 1987 Feb 12. The results of this study, conducted on a cohort of 1021 elderly patients with hip fracture and 5606 controls, show that use of long-acting hypnotics-anxiolytics, tricyclic antidepressants, and antipsychotics drugs is associated with an 80%, 90%, and 2-fold increased risk of hip fractures, respectively, compared to nonuse. The risk of fractures increases with increasing doses of these drugs, thus suggesting a relation of causality between drug use and injurious falls.
97. Diuretic drug use and the risk for hip fracture. Heidrich FE, et al. Ann Intern Med 1991 Jul 1;115(1):1-6.
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The results of this study, conducted on a cohort of 462 elderly patients hospitalized for hip fractures and 462 matched controls, show that current use of thiazide diuretics is associated with a 60% increased risk of hip fractures, compared to nonuse. Use of the diuretic furosemide was associated with an almost 4-fold increased risk of fracture.
98. Psychotropics, thiazide diuretics and hip fractures in the elderly. Cumming RG. et al. Med J Aust 1993 Mar 15;158(6):414-7. The results of this study, conducted on a sample group of 209 individuals with hip fracture and 207 controls, show that use of the benzodiazepine temazepan is associated with a 3.5-fold increased risk of hip fractures, compared to nonuse. Intake of thiazide diuretics in this study was not associated with a higher risk of fractures.
99. Rheumatoid arthritis, corticosteroid therapy and hip fracture. Cooper C, et al. Ann Rheum Dis 1995 Jan;54(1):49-52. The results of this study show that patients with rheumatoid arthritis and those taking corticosteroids have a 2.0- and 2.7-fold increased risk of hip fractures, respectively, compared to patients without this condition and not using these drugs. After adjusting for functional impairment, the risk decreased in patients with RA, but remained high in those taking corticosteroids.
100. Hip fractures and fluoridation in Utah's elderly population. Danielson C, et al. JAMA 1992 Aug 12;268(6):746-8. The results of this large ecological study, conducted on all elderly individuals from three communities in Utah who presented with hip fractures over a 7-year period, show that men and women living in fluoridated areas had a 41% and 27% increased risk of hip fractures, respectively, compared to those living in areas without fluoridated water.
101. Quality of life related to fear of falling and hip fracture in older women: a time trade off study. Salkeld, G. et al. BMJ 2000;320:341-346 ( 5 February ).
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The results of this study, conducted on a sample group of 194 women aged 75 and older, show that 80% of them would rather die than lose their independence and be admitted to a nursing home after a bad hip fracture.
PSYCHOTROPIC DRUGS AND MOTOR VEHICLE ACCIDENTS
102. Psychoactive drugs and the risk of injurious motor vehicle crashes in elderly drivers. Ray WA. et al. Am J Epidemiol, 136(7):873-83 1992 Oct 1. The results of this study, conducted on a cohort of 16,262 individuals aged 65 and older, show that users of benzodiazepines have a 50% increased risk of motor vehicle crashes, compared to nonusers. Use of tricyclic antidepressants was associated with an over twofold increased risk of crashes, and the risk increased with increasing drug dosage, being 5.5-times higher in users of 125 mg or more of amitriptyline, compared to nousers.
103. Association of road-traffic accidents with benzodiazepine use. Barbone F, et al. Lancet 1998 Oct 24;352(9137):1331-6. The results of this study show that use of long half-life benzodiazepines (used to treat anxiety) and of short half-life hypnotics (zopiclone) is associated with an increased risk of motor vehicle crash in individuals aged 18 and older. The risk increases with increasing doses of benzodiazepine.
104. Benzodiazepine use among the elderly in the community. Kirby M, et al. Int J Geriatr Psychiatry 1999 Apr;14(4):280-4. The results of this study show that 17% of community-dwelling elderly individuals in Ireland take benzodiazepines, which are, in over 50% of cases, of the long-acting form. The high rate of prescription of long-acting benzodiazepines causes concern, since these drugs have been associated with an increased risk of hip fractures and motor vehicle crashes in the elderly.
ANTIPSYCHOTICS Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 63
105. Growth patterns in the developing brain detected by using continuum mechanical tensor maps. Thompson PM, Giedd JN, Woods RP, MacDonald D, Evans AC, Toga AW. Nature 2000 Mar 9;404(6774):190-3. The results of this study show that brain cells continue to grow and organize at least into puberty. The researchers scanned the brain of children at intervals of up to 4 years, from the age of 3 to 15 years. They observed waves of growth at the fiber system that relays information between the right and left side of the brain, throughout the follow-up period, with growth occurring predominantly in the frontal regions, associated with the planning of new actions, earlier in age, and subsequently in the mid- and posterior regions of the brain, where associative thinking and language are regulated. These data indicate that brain development can be affected throughout puberty, contradicting previous theories which viewed the brain as essentially organized by the time a child reach the age of 6. The effects of psychotropic drugs on the evolving brain must be carefully evaluated, since these drugs have the potential of interfering with its development.
106. A comparison of prazepam, diazepam, lorazepam and placebo in anxious outpatients in non-psychiatric private practices. Zung WW; et al. J Clin Psychiatry, 42(7):280-4 1981 Jul. The results of this double-blind, randomized, placebo controlled study, show that the anxiolytics prazepam, diazepam, lorazepam, or placebo were all effective in relieving anxiety and depression in patients predominantly depressed with anxiety, while only placebo and prazepam reduced both symptoms in patients predominantly anxious with depression. These data suggest that anxyolytics are no better than placebo in the management of patients with anxiety and depression.
107. Benzodiazepines for depression? A review of the literature. Birkenhager TK; et al. Int Clin Psychopharmacol, 10(3):181-95 1995 Sep This study shows that combination therapy with benzodiazepines and tricyclic antidepressants (TCA) for treatment of depression is not superior, beyond the first few weeks of treatment, to monotherapy with TCAs.
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108. Worsening of symptoms of multiple sclerosis associated with carbamazepine. Letter. Ramsaransing G, Zwanikken C, De Keyser J. BMJ 2000;320:1113 ( 22 April ). This article reports on the worsening of symptoms of multiple sclerosis associated with use of carbamazepine, a tricyclic drug used to treat some forms of pain, convulsions, epilepsy, and manic episodes. The case of five patients with severe aggravation of disease following initiation of treatment and with symptoms resolution after carbamazepine discontinuation is presented. In one case, the onset of new symptoms (loss of the ability to walk) was interpreted as progression of disease and the patient, rather than having carbamazepine treatment interrupted, was aggressively treated with intravenous corticosteroids without improvement. Only after being discharged from the hospital, carbamazepine was stopped and the patient resumed her ability of walking.
109. Hypericum extract versus imipramine or placebo in patients with moderate depression: randomised multicentre study of treatment for eight weeks. Philipp M. et al. BMJ 1999;319:1534-1539 ( 11 Dec ). This double blind, placebo controlled study shows that the herbal supplement hypericum extract (St. John's Wort) (1050 mg per day) is as effective as the antidepressant imipramine (100 mg per day) in alleviating symptoms in moderately depressed patients. Furthermore while patients in the hypericum arm reported improvement in the physical scale of a quality of life questionnaire, patients in the imipramine arm did not. Patients taking hypericum experienced the same rate of adverse reactions of patients taking placebo, and less than half the rate of those taking imipramine.
THE HIGH COST OF MEDICAL CARE 49 Studies
1. Hospital expenditures in the United States and Canada. Redelmeier DA, et al. N Engl J Med 1993 Mar 18;328(11):772-8.
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The results of this study indicate that hospital costs in the U.S. are considerably higher than in Canada. In 1987, the cost of each patient' admission to an acute care hospital was 24% higher in the U.S. than in Canada, and 46% higher in California than in Ontario. Total hospital expenditures were significantly lower in Canada even though Canadian hospitals had more hospital beds (5.4 vs. 3.9 per 1000 individuals) more admissions (142 vs. 129 per 1000 individuals) and longer stays (11.2 vs. 7.2 days) than U.S hospitals. Higher administrative costs were partly responsible for the increase in hospital expenses observed in the U.S. Applying the same spending patterns of Canada would have saved to the U.S. over $30 billion in 1985 alone.
2. The cost of inappropriate admissions: a study of health benefits and resource utilization in a department of internal medicine. Eriksen BO, Kristiansen IS, Nord E, Pape JF, Almdahl SM, Hensrud A, Jaeger S. J Intern Med 1999 Oct;246(4):379-87. The results of this study show that approximately 1 every 4 patients are inappropriately admitted to the hospital. The study was conducted on 422 consecutive patients who were admitted to a teaching hospital over a 6-week period. In 102 of them (24%), the admission was judged to be inappropriate. The average cost of each inappropriate admission was estimated at $2532, significantly lower than that of appropriate admissions ($5800). Overall, unnecessary admissions accounted for 12% of the total hospital costs.
3. The costs of adverse drug events in hospitalized patients. Adverse Drug Events Prevention Study Group. Bates DW; et al. JAMA, 277(4):307-11 1997 Jan 22-29. The results of this study indicate that over a 6-month period, 190 of the 4108 admissions to a tertiary hospital occurred as a consequence of an adverse drug event (ADE). Of these, 60 were preventable. The authors estimated at $5.6 million the annual cost of all admissions for ADEs in a 700-bed teaching hospital, and at $2.8 million the cost of preventable ADEs. These data indicate that ADEs account for a substantial fraction of total hospital costs. Implementation of measures aimed at reducing the occurrence of these events would translate in significant health care savings and in reduction of patients' morbidity and mortality.
4. Involvement of HMO-based pharmacists in clinical rounds at contract hospitals. Yee DK; Veal JH; Trinh B; Bauer S; Freeman CH. Am J Health Syst Pharm, 54(6):670-3 1997 Mar 15.
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The results of this study indicate that the recommendations of a managed care pharmacist participating to clinical rounds saved, over a 14-month period, an estimated $523,907 to the hospital. These data indicate that inappropriate drug treatment is an important source of extra health care expenses in hospital settings.
5. Pharmacist participation on physician rounds and adverse drug events in the intensive care unit. Leape LL, et al. JAMA 1999 Jul 21;282(3):267-70. The results of this study, conducted in the intensive care unit of a teaching hospital, show that participation of a senior pharmacist to clinical rounds decreased the rate of preventable adverse events caused by prescription errors by 66%.
6. Impact of a pharmacist on medication discontinuation in a hospital-based geriatric clinic. Phillips SL; Carr-Lopez SM. Am J Hosp Pharm, 47(5):1075-9 1990 May. This study evaluated the effect of a pharmacist on doctors' drug prescription practices in a geriatric ambulatory care clinic. Before pharmacist intervention, 72 patients received 414 prescriptions, 246 of which were for drugs associated with adverse drug reactions in the elderly. After intervention, there was a 32% reduction in total number of prescription with a direct overall cost saving of $3872 over a six-month period.
7. Drug-related emergency department visits and hospital admissions. Prince BS; Goetz CM; Rihn TL; Olsky M. Am J Hosp Pharm, 49(7):1696-700 1992 Jul. The results of this study show that 2.9% of visits to the emergency department of a tertiary care hospital are due to drug-related problems. Twenty-four percent of these visits result in hospital admission, and the average cost of each admission is $8888.
8. Adverse drug events in hospitalized patients. Excess length of stay, extra costs, and attributable mortality. Classen DC; Pestotnik SL; Evans RS; Lloyd JF; Burke JP. JAMA, 277(4):301-6 1997 Jan 22-29.
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The results of this study indicate that 2.43% of hospital admissions are complicated by adverse drug events (ADEs). ADEs are associated with a prolonged length of stay of 1.91 days, an increased cost of $2262 per event, and an almost doubled risk of death.
9. Medication errors: 1977 to 1988. Experience in medical malpractice claims. Kuehm SL; Doyle MJ. N J Med, 87(1):27-34 1990 Jan. This article shows that from 1977 to 1988, MIIENJ paid US$30,144,636 in indemnity from medical malpractice suits due to medication errors.
10. Pressure ulcers, hospital complications, and disease severity: impact on hospital costs and length of stay. Allman RM, Goode PS, Burst N, Bartolucci AA, Thomas DR. Adv Wound Care 1999 Jan-Feb;12(1):22-30. The results of this study, conducted on a sample population of 286 patients aged 55 and over, show that those who developed pressure ulcers had significantly increased length of hospital stay (21 vs. 13 days) and incidence of hospital-related infections (46% vs. 20%) and other complications (86% vs. 43%), compared to those who did not. Hospital costs for patients with incident pressure ulcers were estimated at $29,048, more than two-fold higher than the costs for patients without this ailment ($13,819).
11. Sedative-hypnotic use and increased hospital stay and costs in older people. Zisselman MH, Rovner BW, Yuen EJ, Louis DZ. J Am Geriatr Soc 1996 Nov;44(11):1371-4. The results of this study, conducted on a cohort of 856 consecutive elderly patients admitted to a tertiary care teaching hospital, show that those with sedative-hypnotic (S/H) use exceeding the Health Care Financing Administration (HCFA) guidelines had, compared to patients with S/H use within recommended values or not on these drugs, longer hospital stay (21.5 days vs 12.3 days vs 6.7 days), increased hospital costs ($29,245 vs $15,219 vs $7,516), and greater severity of illness. These data indicate that appropriate use of sedative-hypnotic drugs could reduce morbidity and substantially cut health care costs.
12. Expenditures for psychotropic medications in the United States in 1985. Zorc JJ. et al. Am J Psychiatry 1991 May;148(5):644-7. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 68
This study shows that, in 1985, the U.S. spent $1.45 billion in psychotropic drugs for outpatients. Sixty percent of this sum ($868 million) was spent for antianxiety and sedative-hypnotic medications, 18% for antipsychotics, and 17% for antidepressants.
13. The direct economic costs of insomnia in the United States for 1995. Walsh JK, Engelhardt CL. Sleep 1999 May 1;22 Suppl 2:S386-93. The results of this study show that in 1995, the U.S. spent $13.9 billion for the treatment of insomnia.
14. Reevaluation of continuous oxygen therapy after initial prescription in patients with chronic obstructive pulmonary disease. Oba Y, Salzman GA, Willsie SK. Respir Care 2000 Apr;45(4):401-6. The results of this study show that lack of reevaluation of the need of home oxygen therapy in patients with chronic obstructive pulmonary disease (COPD) costs the nation an estimated extra $106-$153 million per year. In the study, 57 patients with COPD were prescribed home oxygen therapy. Of the 55 that returned for follow-up, only 19 (35%) were properly evaluated as to the need for continuous oxygen therapy, and in approximately 60% of them, oxygen treatment was discontinued. These data indicate that the majority of patients with COPD assigned to home oxygen therapy are needlessly kept on treatment. The lack of reevaluation of patients' need for oxygen treatment goes against recommended guidelines issued by the Third Oxygen Therapy Consensus Conference, which recommend patients' reassessment within 1 to 3 months after initiation of oxygen therapy. This omission results in unnecessary discomfort for the patient and in an estimated extra health care expenses of $106 to $153 million per year in the U.S. alone.
15. Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. Wolfe MM, et al. N Engl J Med. 1999 Jun 17;340(24):1888-99. Review. This article emphasizes that every year in the U.S., at least 103,000 individuals are hospitalized for serious gastrointestinal toxicity from nonsteroidal antiinflammatory drugs (NSAID) use, and an estimated 16,500 will not survive the complication. Based on these estimates, death from gastrointestinal complications of NSAIDs represents the 15th cause of death in the U.S. Unfortunately these figures are conservative since they do not take in account users of over-the-counter NSAIDs. The cost of NSAID gastrointestinal
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toxicity has been estimated at approximately $15,000 to $20,000 per hospitalization, leading to total annual health care expenses exceeding $2 billion.
16. Cost of medication-related problems at a university hospital. Schneider PJ, Gift MG, Lee YP, Rothermich EA, Sill BE. Am J Health Syst Pharm 1995 Nov 1;52(21):2415-8. This study estimated at $1.5 million the costs associated with drug-related complications in a medical center hospital during the year 1994.
17. Cost implications of malpractice and adverse events. Korin J. Hosp Formul 1993 Jan;28 Suppl 1:59-61. This study shows that each year approximately 5% of hospitalized patients develop hospital-acquired infections, for a total annual cost of $10 billion. Over three-quarters of these expenses are due to increased length of hospital stay for intravenous antibiotic therapy.
18. Notice to Readers: Fourth Decennial International Conference on Nosocomial and Healthcare-Associated Infections. MMWR, February 25, 2000 / 49(07);138. This article reports that every year in the U.S., approximately 2,000,000 patients develop hospital-acquired infections and 88,000 die from them. The cost of hospital-acquired infections has been estimated at $4.6 billion. These estimates are conservative, since they do not take into account infections occurring in patients in nursing homes, outpatient clinics, dialysis centers and other health care centers.
19. Selected aspects of the socioeconomic impact of nosocomial infections: morbidity, mortality, cost, and prevention. Jarvis WR. Infect Control Hosp Epidemiol, 17(8):552-7 1996 Aug. The results of this study indicate that every year in the U.S., approximately 2 million patients develop hospital-acquired infections (HAIs). Overall, 23.8 % to 50% of patients with hospital-acquired bloodstream infections and 14.8% to 71% of patients with hospital-acquired pneumonia die. The cost associated with each HAI is: $558 to $593 for Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 70
each urinary tract infection, $2,734 for each surgical site infection, $3,061 to $40,000 for each bloodstream infection, and $4,947 for each pneumonia.
20. Nosocomial bloodstream infection in critically ill patients. Excess length of stay, extra costs, and attributable mortality. Pittet D, Tarara D, Wenzel RP. JAMA 1994 May 25;271(20):1598-601. The results of this study show that the incidence of hospital-related bloodstream infections in the Surgical Intensive Care Unit (SICU) of a tertiary hospital is 2.67%. Mortality rates in patients with this complication are 50% versus 15% in matched controls. Length of stay in the hospital and in the SICU increases significantly in patients with bloodstream infection compared to controls (54 vs. 30 days and 15 days vs. 7 days, respectively). The cost attributable to this complication was estimated at approximately $40,000 per survivor.
21. Prolongation of hospital stay and extra costs due to hospital-acquired infection in a neonatal unit. Leroyer A, et al. J Hosp Infect 1997 Jan;35(1):37-45. The results of this study indicate that the incidence of hospital-acquired infections (HAIs) in a neonatology unit ias 5.5%. For each HAI, the mean extra length of stay per patient is 5.2 days and the mean extra cost per patient $10,440.
22. Costs of treating simple nosocomial urinary tract infection. Rutledge KA, McDonald HP Jr. Urology 1985 Jul;26(1 Suppl):24-6. The results of this study show that the annual national cost of hospital-acquired urinary tract infections is $1.8 billion (1985 values).
23. Infections in the hospitalized elderly. Gingrich D. Hosp Physician 1990 Jan;26(1):35-8. The results of this study show that hospital-acquired infections in the elderly are associated with high mortality rates and with health care costs of $4 billion per year (1990 values). Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 71
24. Otitis media-related antibiotic prescribing patterns, outcomes, and expenditures in a pediatric medicaid population Berman S; Byrns PJ; Bondy J; Smith PJ; Lezotte D. Pediatrics, 100(4):585-92 1997 Oct. This study evaluated the pattern of antibiotic prescribing in a sample population of 12,381 children with middle ear infection. This condition is the most frequent reason for prescribing antibiotics to children in the U.S., even though several studies have shown that they are no better than placebo in the management of children and infants with middle ear infections. The results of the study show that in 1991 and 1992, low-cost antibiotics accounted for 67% of the total antibiotic fills and for 21% of the total costs. High-cost antibiotics, on the other hand, accounted for 30% of the fills and for 77% of the total costs. The more expensive antibiotics had the same efficacy and were associated with a slightly higher incidence of adverse reactions compared to the less expensive ones. These data indicate that just switching choice of antibiotic in patients with middle ear infection could save almost two-thirds of the cost of antibiotic treatment without interfering with patient outcome.
25. Errors in the treatment of tuberculosis in Baltimore. Rao SN, Mookerjee AL, Obasanjo OO, Chaisson RE. Chest 2000 Mar;117(3):734-7. The results of this study show that private physicians often treat tuberculosis (TB) incorrectly, favoring the development of acquired drug resistance and multidrug resistant TB. The study was conducted on 110 patients diagnosed with TB in the city of Baltimore between 1994 and 1995. Almost 40% of patients treated by a private physician were prescribed the wrong treatment regimen, compared to 5% of those treated at the Baltimore City Health Department's Tuberculosis Clinic. Inappropriate management consisting of low-doses antibiotics and short treatment courses is an important cause of treatment failure and acquired antibiotic resistance. The authors estimated the costs of salvage of inadequate treatment at $180,000 per patient.
26. "Routine" preoperative studies. Which studies in which patients? Marcello PW, Roberts PL. Surg Clin North Am 1996 Feb;76(1):11-23 This article highlights that 60% of routine tests conducted on patients in preparation of their surgery are unnecessary and add an extra $18 billion to the annual health care bill. In addition, unnecessary tests cause harm resulting from complications associated with
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the testing procedure, or with the unnecessary treatment of patients who receive a false positive test result.
27. Unnecessary preoperative investigations: evaluation and cost analysis. Allison JG; Bromley HR. Am Surg, 62(8):686-9 1996 Aug. The results of this study indicate that two-thirds of the tests patients undergo in preparation of their surgery are unnecessary. The study evaluated prospectively the appropriateness of pre-operative testing in 60 randomly selected ambulatory surgery patients. Only one-third of tests had clinical indications and was therefore deemed appropriate. The cost of inappropriate tests was estimated at $47 to $80 per patient. The authors emphasize the need of changing obsolete practices.
28. Extraimmunization Among US Children. Feikema SM et al. JAMA 2000;283:1311-1317. The results of this study show that in the U.S., every year approximately 900,000 children aged 19-36 months (one fifth of all U.S. children in that age group) receive at least an extra immunization, leading to an excess cost of $26.5 billion. The investigators surveyed parents of 32,742 children and obtained information from 22,806 of them through their health care provider. They found that 21% of them had received at least one extra vaccination. Extra doses of vaccine, in addition to adding discomfort and stress to the baby, are associated with an increased risk of adverse reactions. The risk of adverse reactions is particularly high with extra doses of the diphtheria-tetanus vaccine, and there is evidence showing that extra doses of these vaccines can cause serious side effects. In addition extra immunizations add extra costs and labor to the health care system. This study estimated this excess cost at $26.5 billions. This estimate, however, is conservative, since it does not take in account the costs associated with vaccine handling and distribution, parent's travel time, treatment for adverse effects, or other indirect costs.
29. Cost-Utility Analysis of Screening Intervals for Diabetic Retinopathy in Patients With Type 2 Diabetes Mellitus. Vijan S; Hofer TP; Hayward RA. JAMA 2000;283:889-896. The results of this study show that screening for eye disease every other year or every three years can be as effective as screening annually to prevent blindness in patients with type 2 diabetes and no signs of eye deterioration. Current guidelines recommend yearly eye examination for diabetic patients on the basis of cost-effectiveness analyses Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 73
demonstrating an economic benefit associated with this practice. The authors of the study used a computer model to assess the costs and effectiveness of yearly versus extended screening intervals. The results of the study indicate that a high-risk diabetic patient aged 45 years with poor glycemic control is expected to gain 21 days of sight by attending screening visits annually, rather than every third year. On the other hand, a 65-year old low-risk diabetic patient with moderately well glycemic control is expected to gain 3 days of sight by undergoing screening annually, rather than every third year. Screening low-risk patients annually rather than every other year results in an additional cost of $123,580 for each year of quality life gained. These estimates show that annual eye screening produces little benefits in low-risk diabetic patients, while substantially increasing health care costs. The authors emphasize that current guidelines calling for yearly screening in patients with type 2 diabetes should be re-evaluated, and recommendations should be tailored to patients clinical status.
30. Costs of poison-related hospitalizations at an urban teaching hospital for children. Woolf A; Wieler J; Greenes D. Arch Pediatr Adolesc Med, 151(7):719-23 1997 Jul. The results of this study show that poison-related admissions to a single pediatric facility account for 0.9% of all pediatric hospital admissions and are associated with an estimated annual cost of $1 million. Acetaminophen, lead and antidepressants are the substances most frequently involved in poisoning.
31. Economic outcomes of a targeted intervention program: the costs of treating allergic rhinitis patients. Santos R, Cifaldi M, Gregory C, Seitz P. Am J Manag Care 1999 Apr;5(4 Suppl):S225-34. The results of this study, conducted on a cohort of 7,936 patients with symptoms of allergic rhinitis, show that each year one managed care provider (Lovelace Health Systems) spends approximately $2 million for the symptomatic treatment of this condition.
32. Cost effectiveness of low-molecular weight heparin versus warfarin following hip replacement surgery. Saunders ME; Grant RE. J Natl Med Assoc, 90(11):677-80 1998 Nov. This study compared the cost-efficacy of low-molecular-weight (LMW) heparin versus warfarin use for the prophylaxis of deep vein thrombosis and pulmonary embolism Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 74
following hip-replacement surgery. Use of LMW heparin was associated with a saving of $1,253 per patient and with a 0% versus 3% incidence of thrombo-embolic events, compared to warfarin. These data indicate that switching to LMW heparin could significantly cut health care costs and improve patient outcome.
33. Cost-effectiveness of routine radiation therapy following conservative surgery for early-stage breast cancer. Hayman JA; Hillner BE; Harris JR; Weeks JC. J Clin Oncol, 16(3):1022-9 1998 Mar. The results of this study show that in women aged 60 and older, radiation therapy after conservative surgery for early stage breast cancer adds nothing in terms of life expectancy while increasing the cost of therapy by $9,800 per patient.
34. Escalating costs for cancer chemotherapy. Nyman JV; Dorr RT; Hall GR. Am J Hosp Pharm, 38(8):1151-4 1981 Aug. The results of this study indicate that the annual cost of antineoplastic drugs for one hospital rose from $10,156 in 1973-1974 to $296,914 in 1979-1980, these amounts consisting of 5.74% and 16.74% of the hospital total drug budget, respectively. This increase was not justified by patient load, inflation, or amount of medication prescribed.
35. The costs of cancer care in the United States: implications for action. Schuette HL; Tucker TC; Brown ML; Potosky AL; Samuel T. Oncology (Huntingt), 9(11 Suppl):19-22 1995 Nov. This article emphasizes that the annual direct and indirect costs of cancer care are in the range of $100 billion, indicating the need to shift the costs toward more effective measures such as prevention.
36. Comprehensive discharge planning and home follow-up of hospitalized elders: a randomized clinical trial. Naylor MD, Brooten D, Campbell R, Jacobsen BS, Mezey MD, Pauly MV, Schwartz JS. JAMA 1999 Feb 17;281(7):613-20. This randomized study evaluated the outcome of a comprehensive discharge planning and home follow-up intervention program conducted by nurses from two urban hospitals Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 75
on a cohort of elderly patients at risk for hospital readmissions. Twenty-four weeks after discharge, patients in the intervention group, compared to those in the control group, showed decreased rate of hospital admissions (37% vs. 20%), decreased rate of multiple hospital readmissions (6.2% vs. 14.5%) and reduced length of hospital stay when readmitted (1.5 days vs. 4 days). Total Medicare reimbursement costs were about $0.6 million in the intervention group versus $1.2 million in the control group. These data indicate that preventive intervention in high-risk patients results in a 50% reduction in health care costs and in improved patient outcome.
37. Cost-effectiveness of colon cancer screening. Lieberman D. Am J Gastroenterol, 86(12):1789-94 1991 Dec. This study evaluated the cost-effectiveness of two different methods of colon cancer screening: sigmoidoscopy from age 50 with yearly testing for fecal occult blood (as recommended by the American Cancer Society) and colonoscopy. The cost of preventing one death from colon cancer was estimated to be $444,133 with sigmoidoscopy and $347,214 with colonoscopy.
38. Clinical and economic impact of oral ciprofloxacin as follow-up to parenteral antibiotics. Grasela TH Jr; et al. DICP, 25(7-8):857-62 1991 Jul-Aug. This study, conducted on a sample population of 766 patients initially treated with parenteral antibiotics for respiratory tract (RTI), skin or skin structure (SSS), bone or joint (BJI), and urinary tract infections (UTI) for a median of 4, 6, 6, and 7.5 days, respectively, shows that switching to oral antibiotic therapy shortened hospital stay and saved in drugs and hospitalization costs a total of $980,246.
39. Cost and morbidity associated with antibiotic prophylaxis in the ICU. Namias N; Harvill S; Ball S; McKenney MG; Salomone JP; Civetta JM. J Am Coll Surg, 188(3):225-30 1999 Mar. This study evaluated prospectively data on prophylactic antibiotic (PA) treatment in patients admitted to the Surgical Intensive Care Unit of a teaching hospital over a 19month period, to determine physicians' compliance to current guidelines recommending cessation of PA at 24 hours. In 61% of patients, PA therapy was continued beyond 24 hours. Patients receiving PA for more than 4 days had higher rates of bacteremias and
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line infections, compared to those with shorter antibiotic course. The cost of inappropriate antibiotic treatment in this patient population was estimated at $44,893.
40. Antimicrobial prophylaxis in surgical patients. Crossley K, Gardner LC. JAMA 1981 Feb 20;245(7):722-6. This study evaluated use of prophylactic antibiotics (PA) in a cohort of 1,021 surgical patients from 27 different hospitals. Only 41% of patients received PA in the four hours before surgery, and in one-third of patients PA continued for more than 72 hours. Reducing the time of PA treatment would save 18% to 50% of the total cost of perioperative antibiotic prophylaxis.
41. Surveillance of the use of antibiotic prophylaxis in surgery. Finkelstein R, Reinhertz G, Embom A. Isr J Med Sci 1996 Nov;32(11):1093-7. This study evaluated implementation of prophylactic antibiotic (PA) treatment two years after updated recommendations on its use were made available throughout the surgical wards of an Israeli hospital. In certain types of surgery, PA was prescribed systematically without indications for its use. In almost 50% of patients the first dose of PA therapy was not given at the appropriate timing; PA administration extended over the recommended 24 hours in 21% of cases and frequently consisted of unstandardized regimens. These data indicate high rates of inappropriate PA treatment. This phenomenon results in extra health care costs and contributes to the worldwide increase in antibiotic resistance.
42. Surgical infections and prophylactic antibiotics: 341 consecutive cases of gallbladder surgery in the era of laparoscopic surgery. Garcia N, Kapur S, McClane J, Davis JM. J Laparoendosc Adv Surg Tech A 1997 Jun;7(3):157-62. This study evaluated the appropriateness of prophylactic antibiotic (PA) treatment in a cohort of 341 consecutive patients admitted to the hospital for laparoscopic and open cholecystectomy. In 63.2% of cases PA was administered inappropriately. Seventy-three percent of patients received a large-spectrum antibiotic when a cheaper and narrower spectrum agent would have been adequate.
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43. Oral versus intravenous antibiotics for community acquired lower respiratory tract infection in a general hospital: open, randomised controlled trial. Chan R; Hemeryck L; O'Regan M; Clancy L; Feely J. BMJ, 310(6991):1360-2 1995 May 27. The results of this study, conducted on a cohort of 541 patients admitted to the hospital over a 1-year period for lower respiratory tract infections who had no immune system depression or severe infection, show that treatment with oral antibiotics is equally effective to intravenous antibiotic therapy as to patient clinical outcome and mortality, and is associated with reduced hospital length of stay. The authors estimated that if the 800 patients admitted every year to the hospital would be treated routinely with oral rather than intravenous antibiotics, the hospital could save approximately 176,000 pounds per year, and patients would benefit from early discharge.
44. Early transition to oral antibiotic therapy for community-acquired pneumonia: duration of therapy, clinical outcomes, and cost analysis. Omidvari K; de Boisblanc BP; Karam G; Nelson S; Haponik E; Summer W. Respir Med, 92(8):1032-9 1998 Aug. This randomized study evaluated the therapeutic efficacy and costs of conventional 7-day treatment with intravenous (IV) antibiotics for community-acquired pneumonia versus abbreviated 2-day course of IV antibiotics followed by oral antibiotics. Clinical course, cure rates and survival were similar in the two treatment groups. Oral therapy was associated with shorter hospital stay (7.3 versus 9.71 days) and reduced overall costs of care ($2953 vs. $5002 per patient).
45. Oral versus initial intravenous therapy for urinary tract infections in young febrile children. Hoberman A, Wald ER, Hickey RW, Baskin M, Charron M, Majd M, et al. Pediatrics 1999 Jul;104(1 Pt 1):79-86. This randomized study evaluated the cost and efficacy of outpatient oral versus inpatient intravenous antibiotic therapy in the treatment of children 1 to 24 months old with febrile urinary tract infection. Oral therapy was judged to be as safe and effective as intravenous therapy, and its use was associated with an over 50% reduction in overall costs ($1473 per patient for oral therapy versus $3577 for intravenous therapy).
46. The cost of antibiotics in treating upper respiratory tract infections in a medicaid population.
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Mainous AG 3rd; Hueston WJ. Arch Fam Med, 7(1):45-9 1998 Jan-Feb. Antibiotic therapy for nonspecific upper respiratory tract infections (URIs) is nonindicated and ineffective, and increases the occurrence of antibiotic-resistant pathogens. This study evaluated antibiotic prescribing practices for URIs in a sample population of 50,000 Medicaid recipients. Antibiotics were prescribed in 60% of outpatient visits and in 48% of emergency department episodes. In 23% and 9% of the outpatient and emergency department visits, respectively, a prescription for antihistamines was filled. These data indicate that contrary to published guidelines, physicians routinely prescribe antibiotics in over 50% of patients with upper respiratory infections, resulting in significant extra health care costs and in the favoring of the spread of antibiotic-resistant bacterial strains.
47. Antibiotic administration in patients undergoing common surgical procedures in a community teaching hospital: the chaos continues. Gorecki P, Schein M, Rucinski JC, Wise L. World J Surg. 1999 May;23(5):429-32. This study evaluated the appropriateness of antibiotic treatment in a randomly selected sample of 211 patients undergoing elective (132 patients) or emergency (79 patients) surgery in a teaching hospital during 1996. Seventy-four percent of patients received inappropriate antibiotic treatment. The total cost of prolonged antibiotic treatment for this cohort was estimated at $18,533.
48. Decrease in expenditures and selected nosocomial infections following implementation of an antimicrobial-prescribing improvement program. Frank MO, Batteiger BE, Sorensen SJ, Hartstein AI, Carr JA, McComb JS, et al. Clin Perform Qual Health Care 1997 Oct-Dec;5(4):180-8 The results of this study show that implementation of an antimicrobial-prescribing improvement program in an academic medical center was associated with a substantial reduction in antibiotic use, which translated in cost savings of $390,000 in 1994 alone, compared to the costs prior to program implementation. In addition, decreased use of antimicrobial agents was associated with an over 50% reduction in the rate of several hospital-acquired infections.
49. Government orders inquiry as price of generic drugs soars. Jones, J. BMJ 1999;319:1151 ( 30 October ). Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 79
This article reports on the recent sharp increase in the price of generic drugs in UK. In 1999 for example, the price of common drugs such as amoxicillin, furosemide, and thyroxine, was 4-8 times higher than in 1998. This rise could result in extra annual health care expenses of $320 million.
MALNUTRITION 30 Studies
1. Prevalence of malnutrition in general medical patients. Bistrian BR, Blackburn GL, Vitale J, Cochran D, Naylor J. JAMA 1976 Apr 12;235(15):1567-70. This study shows that in 1976, the prevalence of malnutrition in hospitalized patients of the general wards of an urban teaching hospital, was 44% or greater. Thirty-four percent of patients had levels of lymphopenia likely to be associated with reduced cellular immunity.
2. Incidence and recognition of malnutrition in hospital. McWhirter JP, Pennington CR. BMJ 1994 Apr 9;308(6934):945-8. This 1994 study shows that 40% of patients admitted to an acute teaching hospital were malnourished, and in 78% of them nutritional status further deteriorated during hospital stay. In addition, two thirds of all patients lost weight during hospital stay.
3. In 1995 a correlation between malnutrition and poor outcome in critically ill patients still exists. Giner M, Laviano A, Meguid MM, Gleason JR. Nutrition 1996 Jan;12(1):23-9. This study shows that 43% of 129 patients admitted to the intensive care unit of a hospital, were malnourished. Length of hospital stay, complications and number of deaths were greater in malnourished compared to well-nourished patients, and malnourished patients with less severe illnesses had worse clinical outcomes than sicker, wellnourished patients. The study also showed that malnutrition in patients who underwent surgery developed mainly during their preoperative stay in general medicine wards.
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4. In-hospital malnutrition: indications of postoperative evolution. Farre Rovira R, Frasquet Pons I, Ibor Pica JF. Nutr Hosp, 13(3):130-7 1998 May-Jun. This study shows that, after admission to the hospital, the number of patients with belownormal levels of serum albumin doubles, and the number of those with below-normal levels of body weight and body mass index, triplicates. Nutritional status worsens as length of hospital stay increases.
5. Protein-energy undernutrition among elderly hospitalized patients: a prospective study. Sullivan DH, Sun S, Walls RC. JAMA 1999 Jun 2;281(21):2013-9. This study evaluated whether hospitalized patients receive adequate nutritional intake during hospital stay and whether eventual nutritional deficits translate in increased mortality rates. The results of the study, conducted on 497 elderly patients during a 4year period, showed that 21% of patients consumed less than 50% of their estimated maintenance energy requirements, and this was partly due to the fact that patients were frequently ordered to eat nothing by mouth but did not receive nutritional supplementation by other routes. Patients with low energy intake were 8 times more likely to die while being in the hospital and 3 times more likely to die within 90 days, compared to patients with normal energy intake. These findings indicate that during their hospital stay, elderly patients often receive largely inadequate nutrient intake -a practice that seems associated with a significant negative impact on their overall survival.
6. Malnutrition and clinical outcomes: the case for medical nutrition therapy. Gallagher-Allred CR, Voss AC, Finn SC, McCamish MA. J Am Diet Assoc 1996 Apr;96(4):361-6, 369. This article reports on the results of several studies conducted on over 1,327 patients, indicating that 40% to 55% of hospitalized patients are either malnourished or at risk for malnutrition, and 12% of them are severely malnourished. Postoperative complications and mortality occur 2-3 times more often, and hospital costs are 35% to 75% higher, in malnourished compared to well-nourished patients.
7. Prevalence of malnutrition in nonsurgical hospitalized patients and its association with disease complications. Naber TH, et al. Am J Clin Nutr 1997 Nov;66(5):1232-9.
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The results of this study, conducted on 155 patients admitted to the internal medicine ward of a hospital, show that the prevalence of malnutrition in this cohort, according to the Maastricht Index (which evaluates ideal weight together with prealbumin, albumin, and lymphocytes levels) was 62%. Rates of complications were 3 times higher in malnourished versus well-nourished patients.
8. The relationship between clinical assessments of nutritional status and adverse outcomes in older hospitalized medical patients. Covinsky KE, Martin GE, Beyth RJ, Justice AC, Sehgal AR, Landefeld CS. J Am Geriatr Soc 1999 May;47(5):532-8. This study evaluated the nutritional status of 369 patients aged 70 years or more admitted to a general ward of a tertiary care hospital, and found that 60% of them were well nourished, 25% were moderately malnourished, and 16% were severely malnourished. After controlling for severity of disease, presence of coexisting diseases, and functional status on admission, the researchers showed that severely malnourished patients were 2.8 times more likely to die and 3.2 times more likely to be admitted to a nursing home within a year of discharge, compared to well nourished patients.
9. Protein-energy undernutrition and the risk of mortality within six years of hospital discharge. Sullivan DH, Walls RC. J Am Coll Nutr 1998 Dec;17(6):571-8. The results of this study show that protein-energy malnutrition is the single strongest predictor of long-term mortality in elderly individuals discharged from the hospital. In the study, 322 elderly patients were followed for 6 years after being discharged from the hospital to evaluate the effects that nutritional status had on their long-term survival. Patients were defined as being at risk for malnutrition if they had serum albumin levels below 3.0 g/dL or body mass index below 19. Being at risk for malnutrition was the strongest predictor of death in the following 6 years. A diagnosis of congestive heart failure, being discharged to a health care facility, age and marital status were not as strongly associated with mortality as protein-energy malnutrition.
10. Economic impact of malnutrition: a model system for hospitalized patients. Reilly JJ Jr, Hull SF, Albert N, Waller A, Bringardener S. JPEN J Parenter Enteral Nutr 1988 Jul-Aug;12(4):371-6. This retrospective study, conducted on 771 individuals admitted to two acute care hospitals, shows that the rate of likelihood of malnutrition was 59% in medical wards and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 82
48% in surgical wards. Rates of minor and major complications were 2.6 and 3.4 times higher, respectively, in patients with likelihood of malnutrition compared to those without it. Likelihood of malnutrition was associated with a 3.8-fold increased risk of death. Suspected malnutrition was also associated with increased length of hospital stay and increased excess average costs of $1738 to $3557 per patient. The impact of a nutritional intervention program could not be assessed, because too few patients had received it.
11. High-quality nutritional interventions reduce costs. Smith PE, Smith AE. Healthc Financ Manage 1997 Aug;51(8):66-9. This article reports on the results of a survey of 19 hospitals indicating that length of hospital stay decreases by approximately 2 days in patients who receive optimal nutritional care. The survey also revealed that only 7.5% of patients at risk for malnutrition receive optimal nutritional intervention, and this omission results in an increased cost of $1.064 per patient at risk of malnutrition.
12. Relationship of nutritional status to length of stay, hospital costs, and discharge status of patients hospitalized in the medicine service. Chima CS, Barco K, Dewitt ML, Maeda M, Teran JC, Mullen KD. J Am Diet Assoc 1997 Sep;97(9):975-8. This study, conducted on all 173 individuals admitted to three medicine units during a 1month period, shows that those who, upon admission, were classified as being at risk for malnutrition, had, compared to patients not a risk of malnutrition, higher hospital length of stay (6 days vs. 4 days), higher hospitalization costs ($6,196 vs. $4,563), and higher home health care needs, even if 91% of them received nutrition intervention during hospitalization.
13. The five-year evolution of a malnutrition treatment program in a community hospital. Brugler L, DiPrinzio MJ, Bernstein L. Jt Comm J Qual Improv 1999 Apr;25(4):191-206. This study shows that implementation of a malnutrition treatment program in a 395-bed community hospital in Delaware, resulted in reduction of average patient length of stay from 10.8 to 8.2 days, in decrease of incidence of major complications from 75.3% to 17.5%, and in reduction of 30-day hospital re-admission rates from 16.5% to 7.15.
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14. Effect of malnutrition after acute stroke on clinical outcome. Davalos A, et al. Stroke, 27(6):1028-32 1996 Jun. This study, conducted on a cohort of 104 patients with acute stroke, shows that the number of individuals with malnutrition increased from 16.3% at admission to 26.4% after a week in the hospital. Malnourished patients had increased incidence of infections and bedsores. In addition, patients with malnutrition after a week of hospitalization had a 3.5-fold increased risk of poor outcome, regardless of their age and nutritional status at admission.
15. Influence of nutritional status on clinical outcome after acute stroke. Gariballa SE, Parker SG, Taub N, Castleden CM. Am J Clin Nutr 1998 Aug;68(2):275-81. This study shows that the nutritional status of patients admitted to the hospital over a 15month study period for acute stroke, deteriorated significantly during hospital stay. Malnutrition was significantly associated with increased risk of infections and poor functional outcome, and was a strong predictor of mortality in the 3 months after the stroke.
16. Clinical significance of preoperative nutritional status in 215 noncancer patients. Warnold I, Lundholm K. Ann Surg 1984 Mar;199(3):299-305. The results of this study, conducted on 215 patients hospitalized for surgery, show that those with low nutritional status had a two-fold increase in rates of post-operative complications and in length of hospital stay, compared to those with normal nutritional status. The difference in rate of complications was particularly evident for major complications, which occurred in 31% of undernourished patients, compared to 9% of well-nourished subjects.
17. Outcomes of undernutrition in patients in the community with cancer or cardiovascular disease. Edington J, Winter PD, Coles SJ, Gale CR, Martyn CN. Proc Nutr Soc 1999 Aug;58(3):655-61. The results of this study indicate that even low levels of malnutrition are associated with significantly increased rates of morbidity and mortality in individuals with cancer or cardiovascular diseases. In the study, conducted on 10,128 individuals aged 18 and older Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 84
with a diagnosis of cancer or cardiovascular disease, those with body mass index (BMI) levels below 20 kg/m2 had higher rates of physician consultations and higher rates of death, compared to those with higher levels of BMI. Poor nutritional status was strongly associated with increased risk of hospitalization in patients with cardiovascular disease.
18. Impact of body mass index and albumin on morbidity and mortality after cardiac surgery. Engelman DT, et al. J Thorac Cardiovasc Surg 1999 Nov;118(5):866-73. The results of this study indicate that patients with albumin levels below 2.5 g/dL and body mass index below 20 kg/m2 undergoing cardiac bypass surgery have significantly higher rates of post-operative morbidity and mortality, compared to those with normal values of both parameters.
19. Nutritional status is a prognostic factor for survival in ALS patients. Desport JC, Preux PM, Truong TC, Vallat JM, Sautereau D, Couratier P. Neurology 1999 Sep 22;53(5):1059-63. The results of this study show that patients with amyotrophic lateral sclerosis (ALS) with malnutrition have a 7.7-fold increased risk of death, compared to well-nourished patients, independently of neurological scores and type of ALS. The authors recommend increased surveillance of nutritional status in patients with this disease.
20. The impact of nutritional status on the outcome of lung volume reduction surgery: a prospective study. Mazolewski P, Turner JF, Baker M, Kurtz T, Little AG. Chest 1999 Sep;116(3):693-6. The results of this study indicate that patients with end stage emphysema and with belownormal levels of body mass index (BMI) undergoing lung surgery have significantly increased post-operative morbidity and length of hospital stay, compared to patients with normal levels of BMI. This study shows that body mass index value is a good indicator of nutritional status and a simple way to screen individuals at risk of nutritional deficiencies. The authors suggest that correction of nutritional deficiencies may translate in lower rates of hospital morbidity, length of stay, and health care costs in this group of patients.
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21. Malnutrition in childhood lymphoblastic leukemia: a predictor of early mortality during the induction-to-remission phase of the treatment. Mejia-Arangure JM, et al. Arch Med Res 1999 Mar-Apr;30(2):150-3. The results of this study show that malnourished children undergoing chemotherapy for acute lymphoblastic leukemia (ALL) have a 2.6-fold increased risk of death, compared to well-nourished children. The risk of mortality increases with increased severity of nutritional deficit.
22. Disability is associated with malnutrition in institutionalized elderly people. The I.R.A. Study. Istituto di Riposo per Anziani. Romagnoni F, et al. Aging (Milano) 1999 Jun;11(3):194-9. The results of this study indicate that disability in elderly patients is strongly associated with the presence of anthropometric and plasma measurements indicative of malnutrition. This association exists independently of age, gender, and presence of coexisting illness or other confounding factors. The authors highlight the importance of correcting nutritional imbalances in the management of elderly disabled patients.
23. Body mass index and mortality among older people living in the community. Landi F, et al. J Am Geriatr Soc 1999 Sep;47(9):1072-6. The results of this study show that elderly individuals living in the community who have body mass index (BMI) levels below 22 Kg/m2 (a sign of malnutrition) have a 20% increased risk of being dependent in one or more Activities of Daily Living and a 15% increased risk of death, compared to individuals with normal BMI levels.
FOLLOWING IS A SERIES OF STUDY SHOWING THE EFFECTS OF NUTRITIONAL SUPPLEMENTATION ON MORBIDITY AND MORTALITY.
24. Dietary supplementation in elderly patients with fractured neck of the femur. Delmi M, Rapin CH, Bengoa JM, Delmas PD, Vasey H, Bonjour JP. Lancet 1990 Apr 28;335(8696):1013-6.
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The results of this study show that elderly patients hospitalized with a fracture of the neck of the femur who underwent nutritional supplementation had approximately half the rates of complications and death, compared to those who did not receive dietary supplementation. The study was conducted on 59 elderly patients who were randomly assigned to receive daily for an average of 32 days an oral nutritional supplement (27 patients), or no supplementation (32 patients). Most patients had nutritional deficiencies upon admission. Outcome was favorable in 56% of supplemented patients, compared to 13% of those not supplemented. In the supplemented group, 44% of patients experienced complications or death, compared to 87% of patients in the non-supplemented group. These differences persisted 6 months after the occurrence of the fracture. Average length of hospital stay was 24 days in the supplemented group, and 40 days in the nonsupplemented group. These findings indicate that daily oral supplementation cuts length of hospital stay and rates of complications and death by half, in elderly patients with fractured neck of the femur.
25. Effect of vitamin and trace-element supplementation on immune responses and infection in elderly subjects. Chandra RK. Lancet 1992 Nov 7;340(8828):1124-7. The results of this study show that supplementation with modest physiological amounts of nutrients improves immune status and significantly reduces rates of infections in elderly individuals. The study was conducted on 96 healthy elderly subjects who were randomized to receive a nutritional supplement containing vitamins and trace elements or a placebo pill. After 12 months, immune function was improved, compared to baseline values, in individuals who had received nutritional supplementation, but not in those receiving placebo. In addition, those who received the supplement, spent considerable less time being ill from infectious diseases, compared to control subjects who received placebo (23 days versus 48 day per year). These findings indicate that a simple nutritional supplement is efficacious in improving immune status and significantly decreasing rates of infections in elderly individuals.
26. Vitamin C depletion and pressure sores in elderly patients with femoral neck fracture. Goode HF, Burns E, Walker BE. BMJ 1992 Oct 17;305(6859):925-7. The results of this study show that vitamin C concentration in elderly patients hospitalized with fractured neck of the femur who developed pressure ulcers is approximately half that of patients who did not develop this complication, indicating that vitamin C depletion may be an important factor in the etiology of pressure ulcers in the elderly.
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27. Impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. MIN. VIT. AOX. geriatric network. Girodon F, et al. Arch Intern Med 1999 Apr 12;159(7):748-54. The results of this double-blind, placebo-controlled study conducted on 725 institutionalized patients aged 65 and older, show that supplementation with zinc and selenium is associated with a significant reduction of the incidence of respiratory tract infections.
28. The clinical effects of vitamin C supplementation in elderly hospitalised patients with acute respiratory infections. Hunt C, Chakravorty NK, Annan G, Habibzadeh N, Schorah CJ. Int J Vitam Nutr Res 1994;64(3):212-9. The results of this randomized, double-blind, placebo controlled trial show that elderly patients admitted to the hospital for acute respiratory infections who receive daily supplementation of 200 mg of vitamin C, had significantly improved disease course, compared to those who received placebo. The positive effects of vitamin C supplementation were particularly evident in patients who were most severely ill, and who often had very low levels of the vitamin on admission.
29. Routine protein energy supplementation in adults: systematic review. Potter, J et al. BMJ 1998;317:495-501. This study reviewed 30 randomized trial conducted on 2,062 patients, evaluating the impact of routine oral and enteral nutritional supplementation on survival in adult hospitalized patients. Patients who received nutritional supplementation showed significant improvements in body weight and mid-arm muscle circumference, and had an overall 36% increased rate of survival, compared to untreated patients. These findings indicate that protein calorie supplementation improves nutritional status in adults and significantly lowers fatality rates.
30. Care of dying patients in hospital. Mills M, Davies HT, Macrae WA. BMJ 1994 Sep 3;309(6954):583-6. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 88
This study assessed the level of care received by dying patients in 13 wards of four large university hospitals in Scotland and concluded that patients basic needs before dying were left unmet: thirst remained unquenched, oral hygiene was poor, eating was not encouraged. Contact with patients by nurses and doctors was minimal and patient isolation increased as death advanced. Over half of the patients remained conscious until shortly before death.
MEDICAL ERRORS & ADVERSE DRUG REACTIONS 76 Studies

1. Epidemiology of medical error. Weingart, SN. et al. BMJ 2000;320:774-777 ( 18 March ). This article presents a review of current available information on the incidence and nature of medical errors in U.S. hospitals. Medical errors have been estimated to kill 48,00098,000 Americans each year, and to injure an additional 1 million. These data, however, are likely to significantly underestimate the real extent of the problem, since they only refer to hospital patients, and are not inclusive of errors occurring in nursing homes and other health care settings. In addition, the methods used by investigators to identify adverse medical events can significantly affect the estimates of their prevalence. In a landmark study conducted by the University of Harvard, for example, where the researchers used a stringent definition of error, it was calculated that 3.7% of hospitalized patients experienced an adverse event, which was caused by errors -and was therefore preventable- in two-thirds of cases. In another study, where errors were detected through a computerized model, the incidence of adverse drug reactions in hospitalized patients was estimated to be 1.7%. On the other hand, when Bates and colleagues determined the incidence of adverse drug reactions by reviewing patients' medical charts and by conducting interviews with physicians, they found that 6.5% of hospitalized patients developed an adverse drug reaction, and another 5.5% developed a potential adverse drug reaction; these events were found to be caused by errors in 28% of cases. Furthermore, when trained observers who visited a general surgery unit where asked to evaluate the rate of adverse events, they reported that almost 50% of patients experienced an adverse event, which was serious in 18% of cases. Little research has been conducted on the extent of medical error outside hospital settings. One study revealed that drug-related complications occur in 18% of outpatients. Another study calculated that every year treatment-related complications result in 116 million additional physicians visits, 76 million prescriptions, 17 million emergency department visits, 8 million hospital admissions, 3 million long-term care facility admissions, and 200,000 additional deaths, for a cost of $76.6 billion. These data indicate that the extent of injury caused by preventable errors occurring in health care settings is enormous, and the real dimension of the problem is largely unknown.
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2. Reporting and preventing medical mishaps: lessons from non-medical near miss reporting systems. Barach, P. and Small S. BMJ 2000;320:759-763 ( 18 March ). This article reports on some of the data that emerged from the results of two studies conducted by the Institute of Medicine showing that, every year, approximately 100,000 patients die needlessly in the hospital as a result of errors in medical management, and many more are injured. These data, already alarming, become even more preoccupying when considering that, as the article highlights, 50%-96% of adverse events are not reported. These data indicate that preventable deaths from errors in medical management have reached endemic proportions, and that the extent of the injury is largely underestimated.
3. To Err Is Human: Building a Safer Health System. Kohn L., Corrigan J., and Donaldson M., Editors; Committee on Quality of Health Care in America, Institute of Medicine. http://www.iom.edu The Institute of Medicine (IOM) committee released a report on November 29, 1999 on medical errors in U.S. hospitals. A medical error was defined as "the failure to complete a planned action as intended or the use of a wrong plan to achieve an aim". The report presented the results from two large studies revealing that medical errors occurring in the hospital kill an estimated 44,000 (based on one study) or 98,000 (based on the second study) Americans each year. These estimates do not include errors that may arise in settings other than the hospital such as outpatient clinics, retail pharmacies, nursing homes, home care, and day-surgery clinics. Even considering only the most conservative figure (44,000 deaths per year), medical errors would be the eight leading cause of death, killing more people than breast cancer, AIDS or traffic accidents. The yearly cost resulting from such errors has been estimated at approximately $9 billion. Many of these errors are avoidable, and the IOM called for a 50% reduction in errors over the next 5 years. According to the report, systems designed to ensure public safety are over a decade behind in the health care industry compared to other high-risk industries.
4. Reducing errors in medicine. Leape LL. BMJ 1999;319:136-137 ( 17 July ). This article reports on previous studies demonstrating that injuries from medical care occur in 3.7% to 6.7% of hospital admissions, and are fatal in 13.6% of cases. Over half of these injuries are preventable. From these data it is deduced that, in the U.S., more than 120,000 individuals die each year while in the hospital from errors that are Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 90
avoidable. The cost of a preventable medication error has been estimated at approximately $4,700 per event.
5. Medication-prescribing errors in a teaching hospital. A 9-year experience. Lesar TS, Lomaestro BM, Pohl H. Arch Intern Med, 157(14):1569-76 1997 Jul 28. In this study 11,186 medication-prescribing errors with a potential for adverse patient outcome were detected and averted by a staff pharmacist of a teaching hospital over a 9year period. The number of detected errors increased from 522 in the year 1987 to 2115 in 1995, with a significant increased rate of errors per order written, per admission and per patient/day.
6. Factors related to errors in medication prescribing. Lesar TS, Briceland L, Stein DS. JAMA, 277(4):312-7 1997 Jan 22-29. In this study, conducted on a 631-bed tertiary care teaching hospital, 2103 errors with a potential for adverse patient consequences were detected and averted over a 1-year period. Overall, the rate of errors was 3.99 per 1000 written orders.
7. Medication prescribing errors in a teaching hospital. Lesar TS, Briceland LL, Delcoure K, Parmalee JC, Masta-Gornic V, Pohl H. JAMA, 263(17):2329-34 1990 May 2. In this study, conducted in a tertiary care teaching hospital, researchers detected and averted a rate of 3.13 medication-prescribing errors per 1000 physicians' written orders. In 58% of cases, the errors had a potential for adverse patient consequences.
8. A look into the nature and causes of human errors in the intensive care unit. Donchin Y, Gopher D, Olin M, Badihi Y, Biesky M, Sprung CL, Pizov R, Cotev S. Crit Care Med, 23(2):294-300 1995 Feb. In this study, an estimated 1.7 errors per patient per day were detected in the intensive care unit (ICU) of a teaching hospital. For the whole ICU, an average of two severe or potentially detrimental errors occurred each day.
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9. Relationship between medication errors and adverse drug events. Bates DW, Boyle DL, Vander Vliet MB, Schneider J, Leape L. J Gen Intern Med 1995 Apr;10(4):199-205. This study evaluated the frequency of medication errors in a sample population of 379 consecutive patients admitted to an urban tertiary care hospital. On average, 0.3 medication errors per patient occurred each day, with half of these errors consisting of missing doses. About 1% of the medication errors resulted in adverse drug events.
10. A computer alert system to prevent injury from adverse drug events: development and evaluation in a community teaching hospital. Raschke RA, et al. JAMA 1998 Oct 21;280(15):1317-20. In this study, a computer alert system was used in a 650-bed university hospital to identify prescription errors with the potential of causing adverse drug events. Errors with such potential were detected at a rate of 64 per 1000 admissions and were unrecognized by physicians prior to notification in 44% of cases.
11. Improving prescribing patterns for the elderly through an online drug utilization review intervention: a system linking the physician, pharmacist, and computer. Monane M, Matthias DM, Nagle BA, Kelly MA. JAMA 1998 Oct 14;280(14):1249-52. In this study, a computer alert system was used to evaluate the appropriateness of medications prescribing in a cohort of 23,269 elderly patients. Overall, the system fired 43,007 alerts for suboptimal medication. In 56% of cases, a pharmacist was able to notify the alert to a physician. Of the notified alerts, 24% resulted in change to a more appropriate drug.
12. Inappropriate medication is a major cause of adverse drug reactions in elderly patients. Lindley CM, et al. Age Ageing 1992 Jul;21(4):294-300. This study evaluated the rate of prescribing of drugs with absolute contraindications or unnecessary, in a sample population of 416 elderly patients consecutively admitted to a teaching hospital. On admission, 11.5% of patients were receiving drugs with absolute contraindications, and 27% were receiving drugs that were unnecessary. Adverse drug reactions (ADRs) occurred in 27% of patients on medication, and half of these reactions Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 92
were due to drugs with absolute contraindications or unnecessary. ADRs were the cause of hospital admission in 6.3% of patients, and were due to inappropriate prescribing (and were therefore avoidable) in half of the cases.
13. Inappropriate medication prescribing for the elderly by office-based physicians. Aparasu RR, Fliginger SE. Ann Pharmacother 1997 Jul-Aug;31(7-8):823-9. The results of this study show that in 1992, 7.6% of individuals aged 65 and greater received at least 1 of 20 medications that should never be prescribed to the elderly, by their office-based doctor. The authors emphasize how the high rates of inappropriate prescribing by office-based doctor raises concerns on the quality of care they deliver.
14. Inappropriate drug prescriptions for elderly residents of board and care facilities. Spore DL, Mor V, Larrat P, Hawes C, Hiris J. Am J Public Health 1997 Mar;87(3):404-9. The results of this study indicate that a minimum of 20% to 25% of elderly individuals living in board and care facilities receive at least one inappropriate medication (a drug that should be entirely avoided in this age group).
15. Prescription of contraindicated and interacting drugs in elderly patients admitted to hospital. Gosney M, et al. Lancet 1984 Sep 8;2(8402):564-7. The results of this study, conducted on 573 elderly patients admitted to a teaching hospital, show that overall, 3.2% of the prescriptions they received before, during, or after hospital stay, were for drugs that were either contraindicated or that interacted adversely with other drugs. Overall, almost 24% of patients received a contraindicated or interacting drug. Approximately 84% of the inappropriate prescriptions were either preventable or probably preventable.
16. Do too many cooks spoil the broth? Multiple physician involvement in medical management of elderly patients and potentially inappropriate drug combinations. Tamblyn RM; McLeod PJ; Abrahamowicz M; Laprise R. CMAJ, 154(8):1177-84 1996 Apr 15.
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This study shows that the prevalence of a potentially inappropriate drug combination (PIDC) in a population of elderly Medicare patients ranged from 4% to 20.3%. The greater the number of physician involved in patient care, the higher the risk of PIDC.
17. A database analysis of potentially inappropriate drug use in an elderly medicaid population. Piecoro LT, Browning SR, Prince TS, Ranz TT, Scutchfield FD. Pharmacotherapy 2000 Feb;20(2):221-8. The results of this study, conducted on 64,832 elderly individuals, show that 27% of them had been prescribed at least one inappropriate medication. The rate of irrational prescribing was higher in nursing home residents (33%) than in outpatients (24%).
ADVERSE DRUG REACTIONS AND ADVERSE EVENTS
18. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis of prospective studies. Lazarou J, Pomeranz BH, Corey PN. JAMA 1998 Apr 15;279(15):1200-5. This study analyzed 39 prospective U.S. studies to determine the incidence of serious and fatal adverse drug reactions (ADRs). Serious ADRs were defined as those requiring hospitalization or resulting in permanent damage. Only ADRs requiring hospital admission or occurring in the hospital were included in the analysis. Overall, the incidence of serious ADRs was 6.7 per 100 patients and that of fatal ADRs was 0.32 per 100 patients. Extrapolation of these data to the entire U.S. population revealed that in 1994 alone, over 2.2 million patients experienced a serious ADR and 106,000 died from this complication. These figures place ADRs between the fourth and sixth leading cause of death in the U.S. These are conservative estimates, since they don't take in consideration possible ADRs, errors in drug administration, patient non-compliance, overdose, drug abuse, therapeutic failures and injuries and deaths occurring in nursing home patients.
19. Drug-related emergency department visits and hospital admissions. Prince BS, Goetz CM, Rihn TL, Olsky M. Am J Hosp Pharm 1992 Jul;49(7):1696-700.
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This study evaluated the prevalence of different drug-related illnesses in patients visiting the emergency department or admitted to the hospital at one institution during a 4-month period. Drug-related illnesses were found to account for 3% of emergency visits and resulted in hospital admission in approximately 1/4 of cases. Of interest, adverse drug reactions were not the most common type of drug-related illnesses. Overdose or abuse accounted for 35% of drug-related complications, followed by noncompliance (28%), adverse drug reactions (28%), toxicity (8%), and drug interaction (1%).
20. The role of medication noncompliance and adverse drug reactions in hospitalizations of the elderly. Col N; Fanale JE; Kronholm P. Arch Intern Med, 150(4):841-5 1990 Apr. The results of this study, conducted on 315 elderly patients consecutively admitted to the hospital, show that in 28.2% of them, the cause of hospitalization was related to the medication they were taking, and was due to noncompliance with treatment in 11.4% of cases, and to adverse drug reactions in another 16.8%.
21. Drug-related hospital admissions. Nelson KM, et al. Pharmacotherapy 1996 Jul-Aug;16(4):701-7. The results of this study indicate that 73 (16%) of 452 consecutive admissions to a hospital were for drug-related problems. Approximately 55% were due to drug failure, 33% to adverse drug reactions and 12% to drug overdose. About half of the drug-related admissions were preventable.
22. Recent considerations in nonsteroidal anti-inflammatory drug gastropathy. Singh G. Am J Med, 105(1B):31S-38S 1998 Jul 27. This study shows that each year, approximately 107,000 individuals are hospitalized for gastrointestinal (GI) complications derived from nonsteroidal anti-inflammatory drug (NSAID) use and that, among arthritis patients alone, at least 16,500 die as a consequence of NSAID use. These are conservative estimates, since they don't take into account gastrointestinal complications occurring in patients taking over-the-counter NSAIDs. If we consider that every year, in the U.S., there are over 70 million prescriptions written for NSAIDs, and over 30 billion tablets are sold over-the-counter, the number of injuries and death caused by only one type of adverse event related to NSAID use -gastrointestinal complications- reaches staggering figures. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 95
23. Incidence and types of preventable adverse events in elderly patients: population based review of medical records. Thomas, EJ. and Brennan TA. BMJ 2000;320:741-744 ( 18 March ). The results of this study show that hospitalized elderly patients have almost twice the risk of developing preventable adverse reactions, compared to younger patients. The study, conducted on 13 Utah' and 15 Colorado' hospitals, found that the incidence of adverse events leading to prolongation of hospital stay, disability or death in patients younger than 64 years of age is 2.8%, while that of patients aged 65 years or more is 5.3%. The incidence of preventable adverse events is 1.6% in younger patients and 3.0% in older ones, indicating that almost half of the adverse events that occur in hospitalized patients are preventable. Elderly patients, compared to younger ones, experience significantly higher rates of preventable adverse drug reactions, adverse events due to medical procedures, and falls. These data are likely to significantly underestimate the real incidence of adverse events in hospitalized patients, since adverse events were evaluated through medical chart documentation (where the occurrence of an adverse event is often not documented), the evaluation was performed by nurses and general practitioners (and not by specialists), their judgment of an adverse event was not always consistent, the study evaluated only adverse events that prolonged hospital stay or resulted in disability or death, and was conducted on hospitals that were not randomly selected. With this said, death due to preventable adverse events in hospitalized patients, still ranks at least as the 8th cause of mortality in the U.S.
24. Medication-related visits to the emergency department: a prospective study. Tafreshi MJ, Melby MJ, Kaback KR, Nord TC. Ann Pharmacother 1999 Dec;33(12):1252-7. The results of this study show that 28% of visits to the emergency room are related to medications. In the study, one physician and pharmacists evaluated prospectively the percentage of visits to the emergency room that were due to medications in a sample of 253 consecutive patients. In 71 patients (28.1%) the cause of the visit was due to medications, either in the form of adverse drug reaction, or of overprescribing. Over twothirds of the reactions were judged to be preventable. Cardiovascular medications were the most frequent class of drugs implicated. The cost for each preventable drug-related visit was estimated at $1444. The article emphasizes that the high rate of drug-related visits found in the study is accounted for by the study design (prospective, observational study) and by the presence of drug experts in determining the presence of treatmentcomplications.
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25. Drug Complications in Outpatients. Gandhi TK, Burstin HR, Cook EF, Puopolo AL, Haas JS, Brennan TA, Bates DW. J Gen Intern Med. 2000 Mar;15(3):149-154. The results of this study show that almost 1 out of 5 patients who take prescription drugs experience a treatment-related complication. The study was conducted on 2,248 randomly chosen patients from 11 ambulatory clinics in Massachusetts. Patient interviews and medical chart reviews were conducted to determine the frequency of drugrelated adverse reactions. Eighteen percent of patients reported complications from treatment, but only one-sixth of these adverse reactions were reported in the medical chart. Approximately 50% of patients who experienced an adverse reaction sought medical attention as a consequence of it, and 5% of them were hospitalized. These figures show that drug-related complications occur significantly more often than reported in patients' medical charts, leading to extensive utilization of the health care resources and patients' dissatisfaction with quality of care. This study is particularly important because presents rates of adverse drug reactions in outpatient settings, where most of the medications are given, and because reveals how the vast majority of adverse reactions are unreported.
26. Adverse drug events in elderly patients receiving home health services following hospital discharge. Gray SL, Mahoney JE, Blough DK. Ann Pharmacother 1999 Nov;33(11):1147-53. The results of this study show that 20% of elderly individuals who are discharged after hospitalization on medications, experience drug-related adverse effects. The study was conducted on 256 individuals aged 65 or more, who were hospitalized for medical illness and who received, upon discharge, home health nursing services. Twenty-percent of them reported at least one adverse effect from treatment, which involved the gastrointestinal system in approximately one third of cases and the central nervous system in another third. Women and individuals with low cognition were particularly at risk of experiencing treatment-related adverse events.
27. Incidence of adverse events and negligence in hospitalized patients. Results of the Harvard Medical Practice Study I. Brennan TA, et al. N Engl J Med 1991 Feb 7;324(6):370-6. This study evaluated the extent of injuries caused by medical management in a random population of over 30,000 patients hospitalized in the state of New York. Treatmentrelated injuries occurred in 3.7% of patients and were due to negligence in over a quarter of them. They led to disability lasting less than 6 months in 70% of patients, to permanent Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 97
disability in 2.6% of cases, and to death in 13.6% of cases. Extrapolation of these data for the whole state of New York showed that in 1984, medical management in the state of New York alone injured approximately 100,000 patients, with 27,000 of these injuries being due to negligence. Elderly patients were particularly at risk of adverse reactions due to negligent care. When these data were later further analyzed (Leape et al. Qual Rev Bull 1993 May;19(5):144-9.), it was shown that two-thirds of the injuries was due to errors, and was therefore potentially preventable.
28. Computerized surveillance of adverse drug reactions in hospital: implementation. Levy M, et al. Eur J Clin Pharmacol 1999 Jan;54(11):887-92. The results of this study, conducted on a sample population of 199 consecutive patients admitted to the medical ward of a hospital, indicate that adverse drug reactions (ADRs) were present in 32% of patients and were the cause of hospitalization in 9% of cases. Twenty-seven percent of ADRs were defined as serious.
29. Incidence of adverse drug events and potential adverse drug events. Implications for prevention. ADE Prevention Study Group. Bates DW, et al. JAMA 1995 Jul 5;274(1):29-34. The results of this study, conducted on 4031 hospitalized patients from 11 different units of two tertiary care hospitals, show that the incidence of adverse drug events (ADEs) and potential ADEs in this cohort was 6.5% and 5.5%, respectively. One percent of all ADE were fatal, 12% life-threatening, 30% serious, and 57% significant. Forty-two percent of the serious and life-threatening ADEs were preventable.
30. Incidence of adverse drug reactions in adult medical inpatients. Bowman L, Carlstedt BC, and Black CD. Can J Hosp Pharm 1994 Oct;47(5):209-16. This study estimated that 23.1% of patients admitted to the internal medicine ward of a hospital experience an adverse drug reaction (ADR). Length of hospital stay doubled in patients with ADR, compared to those without this complication. The severity of ADRs in this study was less than previously reported, with 10% of all ADRs judged to be severe, 53% moderate, and 36% mild.
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31. Adverse drug reaction-related hospitalizations of nursing facility patients: a 4-year study. Cooper JW. South Med J 1999 May;92(5):485-90. The results of this study indicate that one every 6-7 nursing home residents is hospitalized for adverse drug reactions (ADRs). The drugs more commonly involved in ADR-related hospitalizations are NSAIDs, psychotropic drugs (for inducing falls), digoxin and insulin. In the sample population evaluated in this study, 10% of patients experienced recurrent hospitalization for the same problem. The risk of being hospitalized increased with the number of medications that nursing home patients received.
32. Iatrogenic complications in high-risk, elderly patients. Lefevre F, Feinglass J, Potts S, Soglin L, Yarnold P, Martin GJ, Webster JR. Arch Intern Med 1992 Oct;152(10):2074-80. This study evaluated the medical records of 120 elderly patients admitted to a large university hospital for congestive heart failure, acute myocardial infarction, or pneumonia, and found that in 58.3% of them, a minimum of one iatrogenic complication occurred. The complication was judged to be potentially preventable in 35.8% of patients.
33. Adverse drug events in high risk older outpatients. Hanlon JT, et al. J Am Geriatr Soc 1997 Aug;45(8):945-8. This study evaluated the frequency of adverse drug events (ADEs) in a cohort of 167 elderly ambulatory patients taking more than 5 scheduled medications. Fifty-eight patients (35%) reported 80 ADEs that were textbook confirmed, of which 95% were predictable. Eleven percent of patients with ADEs were hospitalized, 10% required an emergency room visit and 63% a physician consultation.
34. Adverse drug events in hospitalized elderly. Gray SL, Sager M, Lestico MR, Jalaluddin M. J Gerontol A Biol Sci Med Sci 1998 Jan;53(1):M59-63. The results of this study, conducted on a cohort of 157 patients aged 70 and over consecutively admitted to the hospital, show that 14.6% of them experienced adverse drug reactions (ADRs), that were potentially preventable in half the cases. Upon Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 99
discharge, 50% of patients with ADRs experienced a decline in one or more activities of daily living, compared to 24% of patients without ADRs.
35. Adverse drug reactions in an elderly outpatient population. Schneider JK, Mion LC, Frengley JD. Am J Hosp Pharm 1992 Jan;49(1):90-6. This study, conducted on a cohort of 463 elderly outpatients, documented 107 adverse drug reactions (ADRs) that occurred in 97 (21%) individuals and caused the hospitalization of 12 of them. Attendance to a geriatric clinic, use of potentially dangerous drug combinations, and use of drugs requiring laboratory monitoring were all associated with an increased risk of experiencing ADRs.
36. Hospital characteristics associated with adverse events and substandard care. Brennan TA, et al. JAMA 1991 Jun 26;265(24):3265-9. This study evaluated 31,000 medical charts from 51 randomly selected NY hospitals, and found that the incidence of patient injuries due to medical treatment varied from 0.2% to 7.9% (mean 3.2%). Rates of adverse events were significantly higher in primary teaching hospitals (4.1%) compared to rural hospitals (1%). The percentage of adverse events due to negligence varied from 1 to 60% (mean 25%) and was significantly lower in teaching hospitals (10.7%) and significantly higher in hospital with a predominance of minority patients.
37. Physician characteristics and prescribing for elderly people in New Brunswick: relation to patient outcomes. Davidson W; Molloy DW; Bedard M. CMAJ, 152(8):1227-34 1995 Apr 15. This study examined whether mortality and morbidity rates in a community of elderly patients in New Brunswick could be associated with any physician' personal, professional, or practice characteristic. The results of the study revealed that general practitioners with higher patients' mortality rates were more likely to be males, prescribed more drugs, had larger practices, saw more patients and billed more per year compared to doctors with lower mortality rates. In addition, the study found higher rates of hip fractures in patients of doctors who prescribed more frequently antihypertensives, bronchodilators, cholesterol-lowering agents, gastrointestinal drugs and non-steroidal antiinflammatory drugs, who had larger practices, and who billed more per year.
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38. An alternative strategy for studying adverse events in medical care. Andrews LB, Stocking C, Krizek T, Gottlieb L, Krizek C, Vargish T, Siegler M. Lancet 1997 Feb 1;349(9048):309-13. This study shows that the frequency of adverse drug reactions (ADRs) reported in medical records may not be a real representation of the actual rate at which these events occur. When trained observers recorded all ADRs discussed at clinical meetings, the actual incidence of serious ADRs among a study group of 1047 patients was 17.7%. With each day of hospital stay, the risk of experiencing an adverse event increased by 6%.
39. The incident reporting system does not detect adverse drug events: a problem for quality improvement. Cullen DJ, Bates DW, Small SD, Cooper JB, Nemeskal AR, Leape LL. Jt Comm J Qual Improv 1995 Oct;21(10):541-8. The results of this study show that adverse drug events (ADEs) occurring in hospitalized patients are rarely reported to the hospital's quality assurance program. In particular, of the 55 ADEs that were detected during the study period, only 3 (6%) had been reported to the incident reporting system, even though 26 of them were serious or life threatening. Fifteen of the ADEs detected were considered preventable. These findings indicate that studies based on data gathered from voluntary reporting of adverse events may be underestimating the incidence of these complications by as much as 94%.
40. Reporting of adverse drug reactions by hospital doctors and the response to intervention. McGettigan P, Golden J, Conroy RM, Arthur N, Feely J. Br J Clin Pharmacol 1997 Jul;44(1):98-100. The results of this study indicate that in Ireland only 45% of doctors from 118 hospitals had ever reported adverse drug reactions (ADRs). When reporting cards were made readily available by placing them inside the patient admission chart and doctors were regularly reminded to report ADRs, the frequency of reports increased by 5 times over a 3-month period. However, the rate of reports declined rapidly after discontinuation of verbal reminders.
41. Underreporting of suspected adverse drug reactions to newly marketed ("black triangle") drugs in general practice: observational study.
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Martin,M, et al. BMJ 1998;317:119-120 ( 11 July ). The results of this study show that physicians report only 9% of suspected adverse reactions to newly marketed drugs to the Committee on safety of Medicines. Although the highest rate of reporting was for serious adverse drug reactions, still only 32% of serious unlabelled reactions (those that are not listed in the accompanying drug information sheet) and 11% of serious labeled reactions were submitted to the Committee. These data indicate that the large majority of serious adverse drug reactions go unreported.
42. Adverse drug reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicines. Smith CC, et al. Br J Clin Pharmacol 1996 Oct;42(4):423-9. The results of this study show that suspected adverse drug reactions (ADRs) occur in 6.8% of patients admitted to the hospital and are responsible for the hospitalization in 3/4 of cases. Only 6.3% of adverse drug reactions that, according to current guidelines, should have been notified to the Committee on Safety of Medicines had been actually submitted. The majority of unreported ADRs were for those that caused hospital admissions and involved mostly well-known complications to commonly used drugs.
43. Differences in perceived and presented adverse drug reactions in general practice. Ottervanger JP, Valkenburg HA, Grobbee DE, Stricker BH. J Clin Epidemiol 1998 Sep;51(9):795-9. This study indicates that patients experience significantly more adverse drug reactions (ADRs) than what their physicians are aware of. ADRs to sumatriptan were evaluated through a questionnaire sent to physicians and their patients. To avoid bias, no specific reactions were listed in the questionnaire. The most frequent ADRs reported by patients' physicians were: dizziness (1.7%), nausea or vomiting (1.5%) drowsiness or sedation (1.4%) and chest pain (1.3%). Patients on the other hand reported dizziness (8.1%), chest pain (7.9%), paraesthesia (11.7%), and feeling of heaviness (8%). The authors conclude that post-marketing studies that utilize data from physicians could significantly underestimate the real incidence of adverse drug reactions.
44. Postmarketing surveillance and adverse drug reactions: current perspectives and future needs.
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Brewer T, Colditz GA. JAMA 1999 Mar 3;281(9):824-9. This article illustrates how spontaneous reporting of adverse drug reactions (ADRs) is not a reliable indicator of the true occurrence of these events. Spontaneous reporting leaves potentially important ADRs undetected, since it cannot adequately assess the incidence of events occurring separated in time from treatment initiation, or consisting of symptoms occurring also in individuals not exposed to the drug.
45. Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies. Martin RM, Biswas PN, Freemantle SN, Pearce GL, Mann RD. Br J Clin Pharmacol 1998 Nov;46(5):505-11. The results of this study, conducted on a cohort of over 510,000 patients, show that women have a 60% increased risk of developing an adverse drug reactions compared to men. Interestingly, the majority of clinical trials are conducted on men.
46. Adverse drug events in hospitalized patients. A comparison of doctors, nurses and patients as sources of reports. van den Bemt PM, et al. Eur J Clin Pharmacol 1999 Apr;55(2):155-8. The results of this study, conducted on a sample population of 620 hospitalized patients, indicate that adverse drug events (ADEs) occur in 29% of patients. Serious ADEs comprised 26% of all ADEs reported by doctors, and were detected three-times as frequently by doctors than by their patients. Adverse reactions to new drugs, on the other hand, were reported more frequently by patients than by their doctors.
47. Retrospective analysis of the frequency and recognition of adverse drug reactions by means of automatically recorded laboratory signals. Tegeder I, et al. Br J Clin Pharmacol 1999 May;47(5):557-564. This study evaluated retrospectively the incidence of adverse drug reactions in hospitalized patients through an automatic system (ALS) that fired signals every time laboratory results revealed abnormalities potentially indicative of an adverse drug reaction (ADR). Eighteen of 98 signals that were alerted were considered as probable ADRs after reviewing laboratory results and patients' charts. In two-thirds of the cases,
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the attending physician was not aware that an adverse drug reaction had occurred, even though 80% of the reactions were considered predictable.
48. The nosocomial component of medical care. A prospective study on the amount, spectrum and costs of medical disturbances in a department of infectious diseases. Jorup-Ronstrom C, Britton S. Scand J Infect Dis Suppl 1982;36:150-6. The results of this study, conducted on a cohort of 1271 patients admitted to the infectious disease department of a hospital, show that 11% of the admissions were due to complications to previous medical treatment while 27% of patients developed adverse reactions during hospitalization. Overall, the cost for medical care-related adverse events accounted for 17% of the total department costs.
49. Visits to office-based physicians in the United States for medication-related morbidity. Aparasu RR. J Am Pharm Assoc (Wash) 1999 May-Jun;39(3):332-7. This study indicates that in 1995, approximately 2 million outpatients visits occurred because of medication side effects, and the majority of these visits resulted in a scheduled follow-up visit. The drugs most frequently involved were hormones and synthetic substitutes (13%), followed by antibiotics (11.5%) and cardiovascular drugs (9%). These data indicate that adverse drug reactions leading to consultation of an office-based physician result in significant utilization of health care resources.
50. Adverse reactions to antibiotic drugs: the present scope of the problem in outpatient care and possibilities for improvement. Hemminki E. Int J Health Serv 1981;11(2):283-301. This article shows that in 1974, in the U.S., physicians wrote an average of 1 antibiotic prescription for each inhabitant. Antibiotic-related adverse drug reactions (ADRs) and serious ADRs, occurred in 7.6% and 1.4% of the population, respectively. If antibiotics had been prescribed only when necessary, two-thirds of ADRs would have been prevented; if the drug of choice had been prescribed, 37% of ADRs would have been prevented. If the antibiotic of choice had been prescribed only when necessary, four fifth of all ADRs would have been avoided.
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51. Errors in the treatment of tuberculosis in Baltimore. Rao SN, Mookerjee AL, Obasanjo OO, Chaisson RE. Chest 2000 Mar;117(3):734-7. The results of this study show that private physicians often treat tuberculosis (TB) incorrectly, favoring the development of acquired drug resistance and multidrug resistant TB. The study was conducted on 110 patients diagnosed with TB in the city of Baltimore between 1994 and 1995. Almost 40% of patients treated by private physicians were prescribed the wrong treatment regimen, compared to 5% of those treated at the Baltimore City Health Department's Tuberculosis Clinic. Inappropriate management consisting of low-doses antibiotics and short treatment courses is an important cause of treatment failure and acquired antibiotic resistance. The authors estimated the costs of salvage of inadequate treatment at $180,000 per patient.
52. Complications of care in a medical intensive care unit. Rubins HB, Moskowitz MA. J Gen Intern Med 1990 Mar-Apr;5(2):104-9. The results of this study indicate that 14% of patients admitted to a medical intensive care unit of a teaching hospital develop a complication from treatment. Patients with complications tend to be older and more severely ill, and have longer hospital stay and higher mortality rates, compared to those with uncomplicated course (67% vs. 27%). The authors conclude that since mortality rates in these patients exceeded significantly the expected mortality rate of 46%, it is conceivable that complications of care in the MICU independently contribute to in-hospital mortality.
53. Acute renal failure: clinical outcome and causes of death. Barretti P; Soares VA. Ren Fail, 19(2):253-7 1997 Mar. This study shows that the incidence of acute renal failure (ARF) in hospitalized patients is 4.9/1000 patients. Over 46% of patients who develop ARF die. Nephrotoxic drugs are the main cause of ARF in 21% of cases.
54. Incidence and characteristics of preventable iatrogenic cardiac arrests. Bedell SE, et al. JAMA 1991 Jun 5;265(21):2815-20.
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The results of this study, conducted on all patients hospitalized during a one-year period at Boston's Beth Israel Hospital, show that 28 (14%) of the 203 cardiac arrests suffered by patients had a iatrogenic cause (e.g. medications, medical procedures, or failure to detect warning signs). Sixty-one percent of patients with iatrogenic cardiac arrest died. Approximately 10% of all arrests were due to preventable physicians' errors (lack of attention to patients' history, to findings of physical examination, and to laboratory results).
55. Iatrogenic congestive heart failure in older adults: clinical course and prognosis. Rich MW, et al. J Am Geriatr Soc 1996 Jun;44(6):638-43. This study shows that in 7% of patients aged 70 years or older hospitalized with heart failure the cause is iatrogenic, e.g. the heart failure is induced by medications, by excessive administration of fluids or by a complication of a medical procedure. In this study, in-hospital and one-year mortality rates in patients with iatrogenic heart failure were 32% and 68%, respectively, compared to 9% and 39% in noniatrogenic patients. Iatrogenic vs. noniatrogenic heart failure was associated with a 2.5-fold higher risk of death.
56. Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem. Page J, Henry D. Arch Intern Med 2000 Mar 27;160(6):777-84. The results of this study indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) are an important cause of hospitalization for congestive heart failure (CHF) in individuals with or without a history of heart disease. The study was conducted on 365 patients hospitalized for heart failure and 658 controls. Individuals who used NSAIDs in the previous week had a 2-fold increased risk of hospitalization for CHF, compared to nonusers. In patients with a history of heart disease, use of NSAIDs was associated with a 10-fold increased risk of hospitalization for CHF. The risk increased with increasing doses of NSAIDs taken in the previous week, and was greater with NSAIDs of long versus short half-life. The authors concluded that NSAIDs could account for approximately 20% of hospitalizations for congestive heart failure. Heart failure affects approximately 4.6 million Americans and this condition represent the most common hospital discharge diagnosis among patients older than 65 years. If this association is casual, as the dose-response relation suggests, cardiovascular morbidity due to NSAIDs would surpass gastro-intestinal NSAID-related morbidity, which alone is responsible for a minimum of 105,000 hospitalizations and 16,500 deaths occurring each year in the U.S. The economic and health consequences of these findings are staggering.
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57. Hospitalizations with adverse events caused by digitalis therapy among elderly Medicare beneficiaries. Warren JL, McBean AM, Hass SL, Babish JD. Arch Intern Med 1994 Jul 11;154(13):1482-7. This study indicates that in 1987, more than 3 million Medicare recipients were taking digitalis. During a seven-year study period, among this cohort, 202,011 patients were hospitalized because of adverse reactions to digitalis. This means that, every year, for every 1,000 individuals taking digitalis, 8.53 are hospitalized for adverse drug reactions to the drug.
58. Contribution of adverse drug reaction to admission rates in an acute psychiatric ward. Hermesh H, et al. Acta Psychiatr Scand 1985 Jul;72(1):104-10. The results of this study show that 7.5% of all admission to an acute psychiatric ward, are due to adverse drug reactions. The elderly are particularly at risk of experiencing drugrelated complications.
59. Adverse drug reactions (ADRs) in patients with HIV infection. A prospective study. Gonzalez-Martin G, et al. Int J Clin Pharmacol Ther 1999 Jan;37(1):34-40. In this study, the frequency of adverse drug reactions (ADRs) evaluated in a cohort of 50 ambulatory patients with HIV infection was 32%. In 18.5% of patients ADRs were severe and in 70.4% moderate. Trimethroprim-sulfamethoxazole and zidovudine were the most frequent cause of ADRs. Withdrawal of the responsible drug was required in 50% of cases.
60. Survey of drug-related deaths in Victoria. Coleridge J; Cameron PA; Drummer OH; McNeil JJ. Med J Aust, 157(7):459-62 1992 Oct 5. This study evaluated the cause of death in a sample of 231 drug-related deaths reported in Victoria. The primary cause of death was attributed to heroin and morphine in 35% of cases and to prescription drugs in 47% of cases. Tricyclic antidepressants and benzodiazepines were responsible for 14% and 6.5% of deaths, respectively. The mode of death was unclear in most cases and could have been other than suicide. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 107
61. The manner of death among fatalities where dextropropoxyphene caused or contributed to death. Jonasson B; Jonasson U; Saldeen T. Forensic Sci Int, 96(2-3):181-7 1998 Sep 28. In this study, blood sample analyses from 23,691 deceased individuals were evaluated for presence of dextropropoxyphene (DXP), one of the most frequently prescribed painmedication in Sweden. DXP was found in 1782 samples (7.5%) and was the cause of death in 54% of these cases.
62. Deaths related to iodinated contrast media reported spontaneously to the U.S. Food and Drug Administration, 1978-1994 Effect of the availability of low-osmolality contrast media. Spring DB; Bettmann MA; Barkan HE. Radiology, 204(2):333-7 1997 Aug. This study evaluated the number of iodinated contrast medium-related deaths reported to the U.S. Food and Drug Administration Spontaneous Reporting System from 1967 to 1994. Over a thousand deaths were reported during that period, 855 of which occurred after 1978. There was a 42% increase in deaths each year from 1987 to 1994 mostly associated with use of nonionic contrast media.
63. Reports of 355 transfusion-associated deaths: 1976 through 1985. Sazama K. Transfusion, 30(7):583-90 1990 Sep. This study describes 256 blood transfusion-related deaths reported to the Food and Drug Administration from 1976 to 1985. Fifty-one percent of these deaths were due to transfusion of incompatible blood products.
64. Autologous donation error rates in Canada. Goldman M, Remy-Prince S, Trepanier A, Decary F. Transfusion 1997 May;37(5):523-7. This study shows that although use of autologous blood transfusions should eliminate certain risks associated with transfusions, the possibility of errors, mainly clerical, is still high, with a detected rate of 1 error for every 149 units transfused.
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65. Wristband identification error reporting in 712 hospitals. A College of American Pathologists' Q-Probes study of quality issues in transfusion practice. Renner SW, Howanitz PJ, Bachner P. Arch Pathol Lab Med 1993 Jun;117(6):573-7. Wristband identification of patients is essential to prevent incompatible blood transfusions. This study detected wristband identification errors in 2.2% of patients from 712 hospitals. Absent wristband was the error most frequently encountered, followed by multiple wristbands with different information, incomplete, erroneous and illegible data, and patient wearing another patient' wristband.
ADVERSE DRUG REACTIONS AND ERRORS IN CHILDREN
66. Drug utilization and reported adverse reactions in hospitalized children. Mitchell AA, Goldman P, Shapiro S, Slone D. Am J Epidemiol 1979 Aug;110(2):196-204. This study estimated the frequency of adverse clinical events in a cohort of 1669 hospitalized children at 45.7%. Approximately 17% of the adverse events were drugrelated.
67. A prospective study of adverse drug reactions as a cause of admission to a paediatric hospital. Martinez-Mir I, et al. Br J Clin Pharmacol 1996 Sep;42(3):319-24. The results of this study indicate that 4.3% of 512 consecutive hospital admissions of children 1 to 24 months old were probably drug-related. Respiratory drugs, antibiotics, drugs active on the central nervous system and dermatological drugs were the agents most frequently involved.
68. A prospective study of adverse drug reactions in hospitalized children. Martinez-Mir I, Garcia-Lopez M, Palop V, Ferrer JM, Rubio E, Morales-Olivas FJ. Br J Clin Pharmacol 1999 Jun;47(6):681-8.
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The results of this study, conducted on a cohort of 512 consecutive pediatric patients 1 to 24 months old admitted to the medical ward of a hospital, show that the incidence of adverse drug reactions (ADRs) in this study group was 16.6%. Girls had a 66% higher risk of ADRs. Antibiotics and vaccines were the most frequent cause of ADRs (41.5%).
69. Adverse drug reactions (ADRs) in hospitalized pediatric patients. A prospective study. Gonzalez-Martin G, Caroca CM, Paris E.Int J Clin Pharmacol Ther 1998 Oct;36(10):530-3. The results of this study show that 13.7% of children admitted to the hospital develop an adverse drug reaction (ADR). Ninety-three percent of the ADRs were dose-dependent. Twenty-eight percent were severe and 51% were moderate. Causality assessment determined that 54% of ADRs were probable and 32% possible.
70. Medication errors in paediatric practice: insights from a continuous quality improvement approach. Wilson DG; et al. Eur J Pediatr, 157(9):769-74 1998 Sep. In this prospective study, a multidisciplinary committee evaluated over a 2-year period the incidence of medication errors in pediatric patients. The committee detected 411 errors that occurred in 682 children. Sixty-eight percent of errors were averted prior to drug administration, 24 errors with potential for serious patient adverse reactions were not detected in advance and caused overt clinical consequences in 4 cases.
71. Errors by paediatric residents in calculating drug doses. Rowe C; Koren T; Koren G. Arch Dis Child, 79(1):56-8 1998 Jul. This article shows that a significant number of physicians specializing in childcare prescribe the wrong dose of medication to infants and children. This finding is important, since inappropriate dosage in this age group may be associated with significant morbidity and mortality. Approximately 10% of residents who participated in this study committed a 10-fold dosage error, which may be life threatening.
72. Prevalence of feeding tube placement errors & associated risk factors in children. Ellett ML; Maahs J; Forsee S. MCN Am J Matern Child Nurs, 23(5):234-9 1998 Sep-Oct. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 110
The results of this study, conducted on a cohort of 201 hospitalized children who had an enteral tube inserted, show that in approximately 14% of them the feeding tube was misplaced (e.g. the tip of the tube was in the esophagus and in the intestine when it was meant to be in the stomach, or in the esophagus and stomach when it was meant to be in the intestine).
SURGICAL COMPLICATIONS
73. The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice Study II. Leape LL, et al. N Engl J Med 1991 Feb 7;324(6):377-84. This study analyzed the medical records of 30,195 randomly selected in-hospital patients and found that the incidence of patient injuries due to medical treatment was 3.7%. Fortyeight percent of events were due to surgical procedures, 19% to drug-related complications, 14% to wound infections, and 13% due to technical complications.
74. Proportion of hospital deaths associated with adverse events. Garcia-Martin M, et al. J Clin Epidemiol 1997 Dec;50(12):1319-26. This study shows that 56% of hospital deaths secondary to adverse events are due to surgical complications and 22% are due to hospital-related infections.
75. The incidence and nature of surgical adverse events in Colorado and Utah in 1992. Gawande AA, Thomas EJ, Zinner MJ, Brennan TA. Surgery 1999 Jul;126(1):66-75. This study evaluated the medical records of 15,000 patients hospitalized in Utah and Colorado, and found that the incidence of surgical adverse events in this cohort was 3.0%. Fifty-four percent of surgical adverse events were preventable and this type of complication accounted for 12.2% of all hospital deaths occurring in Utah and Colorado.
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76. Are in-hospital deaths and long stay markers for errors in surgery? Troeng T; Janzon L. Qual Assur Health Care, 2(2):149-59 1990. In this study, surgical errors were found in the care of 23% of patients who died in the hospital during a 1-year study period, in 10% of those who had a long hospital stay, and in 3% of those referred to other departments.
NURSING HOME PROTOCOL

THE SOLUTION The problems of malnutrition and dehydration are due in particular to the institutional food provided by vendors who have used RDAs which have been shown to be: a) insufficient and b) grossly inadequate for people who have compromised immune systems and multiple nutritional deficiencies. We offer a detailed examination of the scientific literature citing actual therapeutic dosages in relation to the category of illnesses that affect a nursing home population. We conclude, after reviewing thousands of scientific articles and using data from test groups of 300 individuals, most of whom are in senior citizen age groups, that nutrition and exercise, as presented in this proposed protocol, play a key role in the health and well-being of senior citizens. 7 In January, 1997, 300 seniors were enrolled in a "Reverse the Aging Process Study" that ran for 18 months. Sixty-five people completed the study; 235 became controls. This was a lifestyle modification study that measured changes in blood chemistry, weight, physical dimensions, physical appearance, memory, energy levels, sleep patterns, bowel movements, night time urination, muscle strength, digestion, olfactory senses, visual senses, tactile senses, skin texture, hair texture, and stress levels. The results of the study showed that of the 65 participants that completed the study: 1. 52% had lower cholesterol and triglyceride levels 2. 68% had increased DHEA levels 3. 78% had a significant improvement in their fat to muscle ratio 4. 90% had an increase in bowel movements 5. 92% had a decreased need for sleep 6. 95% had increased energy levels 7. 97% had lowered stress levels Additional data from numerical diaries kept by participants reflected subjective data, citing improvements in overall quality of life. We propose that this protocol would benefit the vast majority of people in Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 112
nursing homes and hospices. We offer the anecdotal case history of Harry Biele as an example of our protocol. Harry is a 90 year-old man who just 10 years ago had chronic sinusitis, asthma, arthritis, enlarged prostate, a precancerous lower bowel and main coronary artery blockage. He is now a marathoner living life to its fullest. His cardiologist has taken him off his heart medication, including beta blockers, and his general practitioner has taken him off his asthma inhalers. He is not an exception. Harry is an example of someone who has taken positive action toward his own health. He improved his nutrition by applying a protocol similar to this one. Exercise became part of Harrys daily ritual. He now appears to be closer to 70 than 90. NURSING HOME INTERVENTION PROTOCOL
The nursing home intervention protocol consists of a) diet, b) supplementation, c) exercise. DIET 1. Intake of animal protein should be reduced (1 x week) and consumption of cold-water fish should be increased (3 x week). 2. Additional protein should be derived from whole grains, legumes and seeds. If needed a protein powder supplement may be used. 3. The diet should provide 40-50 grams of fiber a day. 4. At least one (preferably 3) serving of a cruciferous vegetable should be provided daily: Brussell sprouts, broccoli, cabbage, or cauliflower. 5. 1-2 glasses of dark green leafy vegetable juices/day. The juice should also include 1inch length of ginger, aloe concentrate and protein powder (optional). 6. 1/2-1 gallon of water ingested/day. 7. Caffeine, soda, white sugar, and refined white flour products should be reduced to a minimum. For optimal results, they should be eliminated completely. 8. Olive oil should be used for cooking purposes. 9. Supplements should be taken with meals in divided doses where noted. Following the description of the supplement protocol there are detailed peer review journal articles of human studies and trials demonstrating the efficacy and suggested dosages of vitamins, nutrients, and herbs.
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Vitamins, Nutrients & Herbal Supplements 9 SEE TABLES Physical Exercise It is no secret anymore: exercise is a very important element in the overall health of people of all ages. However, as we age our tendons shrink and our muscle mass decreases. So in order to keep the body as youthful as possible, muscle mass needs to be retained, and if possible, increased. Tendons need to be stretched. So as we get older we actually need more exercise and longer stretching. All forms of exercise should be preceded with a thorough stretching routine. Stretching will elongate and strengthen the tendons and get the muscles warmed up and ready for movement. Senior citizens in general will take a longer time to warm up. Some exercises that are recommended for senior citizens are: fast walking, low impact aerobics, weight lifting, Yoga (for stretching), treadmill and the stair climbing machine. All exercises that are not too impacting on the joints are beneficial. We learned in our Reversing the Aging Process Study that most of the participants and 100% of the controls were not exercising properly. They were not doing enough exercise and not exercising with enough intensity. Our exercise protocol is modified specifically for senior citizens: a) Build up gradually to 45 minutes/day of aerobic activity. b) Take the pulse during a workout to maintain the target heart rate. A heart rate monitor is very useful and can be purchased at any local sports store. Generally, the target heart rate is determined by taking 220, subtracting your age (this is the maximal heart rate), and then multiplying the result by 50%-60%. Therefore, an 81 year-old person would have a rate of 220 minus 81 times 50%-60%, or 70 to 83 beats per minute. After a few months of training, increase to 70% of the maximal heart rate. c) As well as aerobic exercise, do weight training 3 times per week. Vitamins, Nutrients & Herbal Supplements Suggested Dosages Dosages Based on PeerReview Journal Articles** B Complex 50 mg 10-200 mg B6 25-75 mg 50-200 mg Folic Acid 400 mcg 2.5-35 mg B12 100 mcg 1,000 mcg-3 mg Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 114
Choline 500 mg 500 mg-16,000 mg Vitamin E 400-800 IU 30-4,800 mg L-Methionine 500 mg 2,000-10,000 mg Vitamin C 2,000-15,000 mg 30-17,000 mg Silybum Marianum 50 mg 140-600 mg Garlic 500 mg 4xday 3,000-10,000 mg Evening Primrose Oil 500 mg 2xday 3,000-6,000 mg Fish oil lipids 1,000 mg 2,600-24,000 mg Ginkgo Biloba 60-120 mg 50-600 mg Lecithin/Choline 5 gm 0.500 gm-16 gm N-Acetyl Cysteine 500-1,000 mg 300 mg-42,000 mg DHEA 25 mg 30-500 mg DMAE 200 mg Phosphatidyl serine 200 mg 3xday 50-800 mg Acetyl L-Carnitine 500 mg 2xday 1,000-3,000 mg Co-enzyme Q-10 100-300 mg 30-390 mg Calcium/Magnesium 800-1,400 mg 1,000-1,400 mg (Ca++) Niacin 100-500 mg 500-3,000 mg Glutathione 500-1,000 mg 2,500-5,000 mg Curcumine 250 mg 500 mg Alpha Lipoic Acid 200 mg 100-600 mg Melatonin 5 mg 0.3-75 mg Pregnenolone 10 mg 70 mg (based on 70 kg male) Precursors to growth Hormone Arginine 1,000 mg 4,000-35,000 mg Ornithine 1,000 mg 10,000-18,000 mg Glutamine 1,000 mg 1,500-4,000 mg TMG-Betaine 500 mg 6,000-20,000 mg Linoleic acid (Conjugated FA) 500 mg Herbs for Cleansing Apple pectin 25-50 mg 8,500-20,000 mg Bee Pollen 25-50 mg Burdock root 25-50 mg Chrysanthemum 25-50 mg Dandelion root 25-50 mg Hibiscus 25-50 mg Kelp 25-50 mg Oregano 25-50 mg Peppermint 25-50 mg Enteric-coated capsules Psyllium 25-50 mg 3,400-15,000 mg Red clover 25-50 mg 100 mg (Coumarin) Vitamin and Mineral Indexes Nutrients Recommended Adult Intake Source of Recommended Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 115
Intake Therapeutic Intake Range based on Peer-Review Journals** Vitamin A 5,000 IU USRDA* Vitamin D 400 IU USRDA Vitamin E 30 IU USRDA 30-2,800mg 12 Vitamin C 60 mg RDA* 30-17,000mg Thiamin (B1) 1.5 mg USRDA 10-200mg Riboflavin (B2) 1.7 mg USRDA 10-400mg Niacin (B3) (nicotinamide) 20 mg USRDA 500-3,000mg Pyridoxine (B6) 2.0 mg RDA 50-200mg Folacin 0.4 mg USRDA .02mg-35mg Folic acid Biotin 0.3 mg USRDA Pantothenic acid (B5) 10 mg USRDA Calcium 1,200 mg RDA 1,000-1,400mg Phosphorus 1,200 mg RDA Magnesium 400 mg USRDA Iron 18 mg USRDA Zinc 15 mg USRDA Copper 3 mg ESAADDI* Fluoride 4 mg ESAADDI Iodine 0.15 mg USRDA Selenium 0.2 mg ESAADDI *RDA-Recommended Dietary Allowances; USRDA-United States Recommended Daily Allowances; ESAADDI-Estimated Safe and Adequate Daily Dietary Intakes. Shils, et al. 1994. Modern Nutrition in Health and Disease, Eighth Edition Volume 2. Lea & Febiger, p. 1582. **The therapeutic doses are based on Peer-Review Journals with a focus on human trials and studies. These articles are cited within the proposal. Please refer to the Reference Section for details. All senior citizens and baby boomers can improve their health. This is the scientific literature that justifies the use of recommended supplements in this protocol. Applying this protocol can play an important role in anyones life. Peer-Review Journal References for Vitamins, Nutrients and Herbs B-Complex B1 Alzheimer's disease Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 116
Gold M, Hauser RA, Chen MF. Plasma thiamine deficiency associated with Alzheimer's disease but not Parkinson's disease. Metab Brain Dis. 1998 Mar;13(1):43-53. Mimori, Y. et al. 1966. Thiamine therapy in Alzheimer's disease. Metab Brain Disease, 11(1), Mar., 89-94. Dose: 100mg/day, 12 weeks Cardiovascular/Coronary Heart Disease Ito M, Tanabe Y, Suzuki K, Kumakura M, Aizawa Y. Shoshin beriberi with vasospastic angina pectoris possible mechanism of mid-ventricular obstruction: possible mechanism of mid-ventricular obstruction. Circ J. 2002Nov;66(11):1070-2. Shimon, I. et al. 1995. Improved left ventricular function after thiamine supplementation in patients with congestive heart failure receiving longterm Furosemide therapy. Am J Med, 98(5), 485-490. Dose: 200mg day Freye and Hartung, E. 1982. The Potential use of thiamine in patients with cardiac insufficiency. Acta Vitamino Enzymol, 4(4), 285-290. Dose: 50mg/kg Epilepsy Naito E, Ito M, Yokota I, Saijo T, Chen S, Maehara M, Kuroda Y. Concomitant administration of sodium dichloroacetate and thiamine in west syndrome caused by thiamine-responsive pyruvate dehydrogenase complex deficiency. J Neurol Sci. 1999 Dec 1;171(1):56-9. Botez, M. I. et al. 1993. Thiamine and folate treatment of chronic epileptic patients: A controlled study with the Wechsler IQ scale. Epilepsy Res, 16(2), Oct., 157-163. Fatigue Heap LC, Peters TJ, Wessely S. Vitamin B status in patients with chronic fatigue syndrome. J R Soc Med. 1999 Apr;92(4):183-5. Suzuki, M. and Itokawa, Y. 1996. Effects of thiamine supplementation on exercise-induced fatigue, Metabolic Pr Brain Dis., 11(1), Mar., 95-106. Febrile Lymphadenopathy Lonsdale D. Recurrent febrile lymphadenopathy treated with large doses of vitamin B1: report of two cases. Dev Pharmacol Ther. 1980;1(4):254-64. Lonsdale, D. 1980. Recurrent febrile lymphadenopathy treated with large doses of vitamin B1: Report of two cases. Dev Pharmacol Ther., 1(4), 254264.
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General Hinze-Selch D, Weber MM, Zimmermann U, Pollmacher T. Thiamine treatment in psychiatry and neurology. Fortschr Neurol Psychiatr. 2000 Mar;68(3):113-20. Meador, K. J. et al. 1993. Evidence for a clinical cholinergic effect of highdose thiamine. Ann Neurol, 34(5), Nov., 724-726. Smidt, L. J. et al. 1991. Influence of thiamin supplementation on the health and general well-being of an elderly Irish population with marginal thiamin deficiency. J Gereontology, 46(1), Jan., M16-22. Dose: 10mg/day Lactic Acidosis McComsey GA, Lederman MM. High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia. AIDS Read. 2002 May;12(5):222-4. Klein, G. et al. 1990. [Life-threatening lactic acidosis during total parenteral nutrition. Successful therapy with thiamine]. Dtsch Med Wochenschr, 115(7), Feb., 254-256. Dose: 400mg Liver Disease Levy S, Herve C, Delacoux E, Erlinger S. Thiamine deficiency in hepatitis C virus and alcohol-related liver diseases. Dig Dis Sci. 2002 Mar;47(3):543-8. 15 Hassan, R. et al. 1991. Effect of thiamine on glucose utilization in hepatic cirrhosis. J Gastroenterology Hepatology, 6(1), Jan.-Feb., 59-60. Dose: 50 mg/day for 30 days Rossouw, J. E. et al. 1978. Red blood cell transketolase activity and the effect of thiamine supplementation in patients with chronic liver disease. Scandinavian J Gastroenterology, 13(2), 133-138. Dose: 200 mg/day Seasonal Ataxia Nishimune T, Watanabe Y, Okazaki H, Akai H. Thiamin is decomposed due to Anaphe spp. entomophagy in seasonal ataxia patients in Nigeria. J Nutr. 2000 Jun;130(6):1625-8. Adamolekun, B. et al. 1994. A double-blind, placebo-controlled study of the efficacy of thiamine hydrochloride in a seasonal ataxia in Nigerians. Neurology, 44(3 Pt 1), Mar., 549-551.
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Surgical Stress Vinogradov, V. V. et al. 1981. [Thiamine prevention of the corticosteroid reaction after surgery]. Probl Endokrinol, 27(3), May-June, 11-16. Dose: IV administration of 0.12 g one day and 1.5-2 hours prior to surgery B2 Congenital Methaemoglobinaemia Svecova D, Bohmer D. Congenital and acquired methemoglobinemia and its therapy. Cas Lek Cesk. 1998 Mar 23;137(6):168-70. Hirano, M. et al. 1981. Congenital methaemoglobinaemia due to NADH methaemoglobin reductase deficiency: Successful treatment with oral riboflavin. British J Haematology, 47(3), Mar., 353-359. Dose: 120 mg/day Depression Tolmunen T, Voutilainen S, Hintikka J, Rissanen T, Tanskanen A, Viinamaki H, Kaplan GA, Salonen JT. Dietary folate and depressive symptoms are associated in middle-aged Finnish men. J Nutr. 2003 Oct;133(10):3233-6. Bell, I. R. et al. 1992. Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction. J Am Coll Nutr., 11(2), Apr., 159-163. Dose: 10mg B1, B2 and B6 each with antidepressants Migraine Mauskop A. Alternative therapies in headache. Is there a role? Med Clin North Am. 2001 Jul;85(4):1077-84. Schoenen, J. et al. 1994. High-dose riboflavin as a prophylactic treatment of migraine: Results of an open pilot study. Cephalalgia, 14(5), Oct., 328-329. Dose: 400mg for at least 3 months Sickle Cell Disease Ajayi OA, George BO, Ipadeola T. Clinical trial of riboflavin in sickle cell disease. East Afr Med J. 1993 Jul;70(7):418-21. Ajayi, O. A. et al. 1993. Clinical trial of riboflavin in sickle cell disease. East African Med J, 70(7), 418-421. Dose: 5mg 2x/day for 8 weeks B6 Anemia Shoolingin-Jordan PM, Al-Daihan S, Alexeev D, Baxter RL, Bottomley SS, Kahari ID, Roy I, Sarwar M, Sawyer L, Wang SF. 5-Aminolevulinic acid synthase: mechanism, mutations and medicine. Biochim Biophys Acta. 2003 Apr 11;1647(1-2):361-6. Toriyama, T. et al. 1993. Effects of high-dose vitamin B6 therapy on Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 119
microcytic and hypochromic anemia in hemodialysis patients. Nippon Jinzo Gakkai Shi 35(8), Aug., 975-980. Dose: 180mg for 20 weeks Asthma Gaby AR. Intravenous nutrient therapy: the "Myers' cocktail". Altern Med Rev. 2002 Oct;7(5):389-403. Ubbink JB, van der Merwe A, Delport R, Allen RH, Stabler SP, Riezler R, Vermaak WJ. The effect of a subnormal vitamin B-6 status on homocysteine metabolism. J Clin Invest. 1996 Jul 1;98(1):177-84. Collipp, P. J. et al. 1975. Pyridoxine treatment of childhood bronchial asthma. Ann Allergy 35(2), Aug., 93-97.Dose: 200mg/day Cardiovascular/Coronary Heart Disease Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteinelowering therapy with folic acid, vitamin B12, and vitamin B6 on clinical outcome after percutaneous coronary intervention: the Swiss Heart study: a randomized controlled trial. JAMA. 2002 Aug 28;288(8):973-9. Van den Berg, M. et al. 1994. Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J Vascular Surg. 20(6), Dec., 933-940. Dose: 250mg for 6 weeks Ellis, J. M. and McCully, K. S. 1995. Prevention of myocardial infarction by vitamin B6. Res Commun Mol Pathol Pharmac 89(2) Aug., 208-220. Carpal Tunnel Syndrome Holm G, Moody LE. Carpal tunnel syndrome: current theory, treatment, and the use of B6. J Am Acad Nurse Pract. 2003 Jan;15(1):18-22. Ellis, J. et al. 1979. Clinical results of a cross-over treatment with pyridoxine and placebo of the Carpal Tunnel Syndrome. Am J Clin Nutr 32(10), Oct., 2040-2046. Dose: 100mg/day Kasdan, M. L. and Janes, C. 1987. Carpal Tunnel Syndrome and vitamin B6. Plastic Reconstructive Surgery 79(3), Mar., 456-462. Dose: 100mg/day Stransky, M. et al. 1989. Treatment of Carpal Tunnel Syndrome with vitamin Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 120
B6: A double-blind study. Southern Med J 82(7), July, 841-842. Ellis, J. M. 1987. Treatment of Carpal Tunnel Syndrome with vitamin B6. Southern Med J 80(7), July, 882-884. Dose: 100mg to 200mg/day for 12 weeks Guzman, F. J. L. et al. 1989. Carpal Tunnel Syndrome and vitamin B6. Klin Wochenschr, 67(1), Jan. 4, 38-41. Dose: 150mg/day for 3 months Ellis, J. et al. 1981. Therapy with vitamin B6 with and without surgery for treatment of patients having the Idiopathic Carpal Tunnel Syndrome. Res Commun Pathol Pharmacol 33(2) Aug., 331-344. Diabetes Okada M, Shibuya M, Yamamoto E, Murakami Y. Effect of diabetes on vitamin B6 requirement in experimental animals. Diabetes Obes Metab. 1999 Jul;1(4):221-5. Bennink, H. J. and Schreurs, W. H. 1975. Improvement of oral glucose tolerance in gestational diabetes by pyridoxine. Br Med J 3(5974), 13-15. Immune Function Grimble RF. Effect of antioxidative vitamins on immune function with clinical applications. Int J Vitam Nutr Res. 1997;67(5):312-20. Casciato, D. A. et al. 1984. Immunologic abnormalities in hemodialysis patients: Improvement after pyridoxine therapy. Nephron 38(1), 9-16. Dose: 50mg/day for 3-5 weeks Primary Hyperoxaluria van Woerden CS, Groothoff JW, Wanders RJ, Davin JC, Wijburg FA. Primary hyperoxaluria type 1 in The Netherlands: prevalence and outcome. Nephrol Dial Transplant. 2003 Feb;18(2):273-9. Milliner, D. S. et al. 1994. Results of long-term treatment with orthophosphate and pyridoxine in patients with primary hyperoxaluria. NEJM. 331(23), Dec. 8, 1553-1558. B12 Anemia de Lonlay P, Fenneteau O, Touati G, Mignot C, Billette de Villemeur T, Rabier D, Blanche S, Ogier de Baulny H, Saudubray JM. Hematologic manifestations of inborn errors of metabolism. Arch Pediatr. 2002 Aug;9(8):822-35. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 121
Samson, D. et al. 1977. Reversal of ineffective erythropoiesis in pernicious anaemia following vitamin B12 therapy. Br J Haematology 35(2), Feb., 217224. Kafetz, K. 1985. Immunoglobulin deficiency responding to vitamin B12 in two elderly patients with megaloblastic anaemia. Postgrad Med J 61(722), Dec., 1065-1056. Kubota, K. et al. 1987. Restoration of decreased suppressor cells by vitamin B12 therapy in a patient with pernicious anemia. Am J Hematol 24(2), Feb., 221-223. Kubota, K. et al. 1992. Restoration of abnormally high CD4/CD8 ratio and low natural killer cell activity by vitamin B12 therapy in a patient with postgastrectomy megaloblastic anemia. Internal Med 31(1), Jan., 125-126. Apthae Wray, D. et al. 1975. Recurrent aphthae: Treatment with vitamin B12, folic acid, and iron. British Med J 2(5969), May 31, 490-493. Bronchial Squamous Metaplasia Heimburger, D. C> et al. 1988. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. JAMA 259(10), Mar. 11, 1525-1530. Dose: 500mcg for 4 months Dementia Serot JM, Christmann D, Dubost T, Bene MC, Faure GC. CSF-folate levels are decreased in late-onset AD patients. J Neural Transm. 2001;108(1):93-9. Regland, B. et al. 1991. Vitamin B12-induced reduction of platelet monoamine oxidase activity in patients with dementia and pernicious anaemia. Eur Arch Psychiatry Clin Neurosci 240(4-5), 288-291. General Tschop M, Folwaczny C, Schindlbeck N, Loeschke K. Megaloblastic anemia due to inadequate nutrition. Dtsch Med Wochenschr. 1997 Jun 20;122(25-26):820-4. Newbold, H. L. 1989. Vitamin B-12: Placebo or neglected therapeutic tool? Med Hypothesis, 28(3), May, 155-164. Hepatitis Mathe G, Morette C, Hallard M, Pontiggia P, Blanquet D, Hage F. Viral and 20 immunologic follow up of 4 to 9 years of AIDS treatments by quadruple Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 122
combinations of virostatics including integrase inhibitors applied in short sequences differing by drug rotation. Acta Pharmacol Sin. 2002 Jan;23(1):1-15. Iwarson, S. and Lindberg, J. 1977. Coenzyme-B12 therapy in acute viral hepatitis. Scandinavian J Infectious Dis 9(2), 157-158. Komar, I. V. 1982. [Use of vitamin B12 in the combined therapy of viral hepatitis]. Vopr Pitan (1), Feb., 26-29. Dose: 100mcg every other day Imerslund-Grasbeck Syndrome Salameh, M. M. et al. 1991. Reversal of severe neurological abnormalities after vitamin B12 replacement in the Imerslund-Grasbeck Syndrome. J Neurology 238(6), Sept., 349-350. Methylmalonic Acidemia Gordon, B. A. and Carson, R. A. 1976. Methylmalonic acidemia controlled with oral administration of vitamin B12. Canadian Med Assoc J 115(3), Aug. 7, 233-236. Dose: Continuous intramuscular supplements in doses of 1 mg on alternate days followed by 15 mg/day taken orally Multiple Sclerosis Kira, J. et al. 1994. Vitamin B12 metabolism and massive-dose methyl vitamin B12 therapy in Japanese patients with multiple sclerosis. Internal Med 33(2), Feb., 82-86. Dose: 60mg/day for 6 months Sleep Honma, K. et al. 1992. Effects of vitamin B12 on plasma melatonin rhythm in humans: Increased light sensitivity phase-advances the Circadian Clock? Experentia 48(4), Aug. 15, 716-720. Dose: 3mg/day Ohta, T. et al. 1991. Treatment of persistent sleep-wake schedule disorders in adolescents with methylcobalamin (vitamin B12). Sleep 14(5), Oct., 414418. Dose: 3,000mcg/day Okawa, M. et al. 1990. Vitamin B12 treatment for sleep-wake rhythm disorders. Sleep 13(1), Feb., 15-23. Dose: 1.5 mg /day tid Vitiligo Montes, L. F. et al. 1992. Folic acid and vitamin B12 in vitiligo: A nutritional approach. Cutis 50(1), July, 39-42. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 123
Choline/Lecithin Head Injury Dempsey RJ, Raghavendra Rao VL. Cytidinediphosphocholine treatment to decrease traumatic brain injury-induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. J Neurosurg. 2003 Apr;98(4):867-73. Levin, H. S. 1991. Treatment of postconcussional symptoms with CDPcholine. J Neurol Sci 103 Suppl, July, S39-S42. Dose: 1 gm of CDP-choline Maldonado, V. C. et al. 1991. Effects of CDP-choline on the recovery of patients with head injury. J. Neurol Sci 103 Suppl, July, S15-S18. Hemiplegia Hazama T, Hasegawa T, Ueda S, Sakuma A. Evaluation of the effect of CDPcholine on poststroke hemiplegia employing a double-blind controlled trial. Assessed by a new rating scale for recovery in hemiplegia. Int J Neurosci. 1980;11(3):211-25. Hazama, T. et al. 1980. Evaluation of the effect of CDP-choline on poststroke hemiplegia employing a double-blind controlled trial. Assessed by a rating scale for recovery in hemiplegia. Int J Neurosci 11(3), 211-215. Dose: ranging from 250-1000 mg over an 8 week period Hepatic Steatosis Oliveira CP, da Costa Gayotto LC, Tatai C, Della Bina BI, Janiszewski M, Lima ES, Abdalla DS, Lopasso FP, Laurindo FR, Laudanna AA. Oxidative stress in the pathogenesis of nonalcoholic fatty liver disease, in rats fed with a cholinedeficient diet. J Cell Mol Med. 2002 Jul-Sep;6(3):399-406. Buchman, A. L. et al. 1995. Choline deficiency: A cause of hepatic steatosis during parenteral nutrition that can be reversed with intravenous choline supplementation. Hepatology 22(5), Nov., 1399-1403. Dose: 1-4 g choline chloride over a period of 4 weeks Neurological Function Uteshev VV, Meyer EM, Papke RL. Regulation of neuronal function by choline and 4OH-GTS-21 through alpha 7 nicotinic receptors. J Neurophysiol. 2003 Apr;89(4):1797-806. Epub 2002 Dec 04 Fernandez, R. L. 1983. Efficacy and safety of oral CDP-choline. Drug surveillance study in 2817 cases. Arzeimittelforschung 33(7A), 1073-1080. Dose: 6 ml/day mean dose of CDP-choline
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Seizures Yang Y, Liu Z, Cermak JM, Tandon P, Sarkisian MR, Stafstrom CE, Neill JC, Blusztajn JK, Holmes GL. Protective effects of prenatal choline supplementation on seizure-induced memory impairment. J Neurosci. 2000 Nov 15;20(22):RC109. McNamara, J. O. et al. 1980. Effects of oral choline on human complex partial seizures. Neurology 30(12), 1334-1336. Dose: 12-16 g/day Stroke Rao AM, Hatcher JF, Dempsey RJ. CDP-choline: neuroprotection in transient forebrain ischemia of gerbils. J Neurosci Res. 1999 Dec 1;58(5):697-705. Tazaki, Y. et al. 1988. Treatment of acute cerebral infarction with a choline precursor in a multicenter double-blind placebo-controlled study. Stroke 19(2), Feb., 211-216. Dose: 1000 mg iv CDP-choline/day for 14 days Tardive Dyskinesia Tammenmaa IA, McGrath JJ, Sailas E, Soares-Weiser K. Cholinergic medication for neuroleptic-induced tardive dyskinesia. Cochrane Database Syst Rev. 2002;(3):CD000207. Gelenberg, A. J. et al. 1979. Choline and lecithin in the treatment of tardive dyskinesia: Preliminary results from a pilot study. Am J Psychiatry 136(6), June, 772-776. Growdon, . H. et al. 1977. Oral choline administration to patients with tardive dyskinesia. NEJM 297(10), Sept. 8, 524-527. Arranz, J. and Ganoza, G. 1983. Treatment of chronic dyskinesia with CDPcholine. Arzneimittelforschung 33(&a), 1071-1073. Dose: 500-1200 mg CDP-choline/day Nasrallah, H. A. et al. 1984. Variable clinical response to choline in tardive dyskinesia. Psychol Med 14(3), Aug., 697-700. Folic acid Anemia Agarwal KN, Gomber S, Bisht H, Som M. Anemia prophylaxis in adolescent school girls by weekly or daily iron-folate supplementation. Indian Pediatr. 2003 Apr;40(4):296-301.
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Rahpael, J. C. et al. 1975. [Myelopathy and macrocytic anemia associated with a folate deficiency. Cure by folic acid]. Ann Med Interne 126(5), May, 339-348. Arthritis Endresen GK, Husby G. Folate supplementation during methotrexate treatment of patients with rheumatoid arthritis. An update and proposals for guidelines. Scand J Rheumatol. 2001;30(3):129-34. Morgan, S. L. et al. 1994. Supplementation with folic acid during methotrexate therapy for rheumatoid arthritis. A double-blind, placebocontrolled trial. Annals Intern Med 121(11), Dec. 1, 833-841. Dose: 5mg or 27.5 mg at weekly doses Morgan, S. L. et al. 1990. The effect of folic acid supplementation on the toxicity of lowdose methotrexate in patients with rheumatoid arthritis. Arthritis Rheum 33(1), Jan., 9-18. Dose: 1mg folic acid/day Flynn, M. A. et al. 1994. The effect of folate and cobalamin on osteoarthritic hands. J American Colle Nutr 13(4), Aug., 351-356. Dose: 6400mcg folate/day Cancer Bajetta E, Celio L, Buzzoni R, Ferrari L, Marchiano A, Martinetti A, Longarini R, Becerra C, Ilardi C, John W. Phase II study of pemetrexed disodium (Alimta) administered with oral folic acid in patients with advanced gastric cancer. Ann Oncol. 2003 Oct;14(10):1543-8. Saito, M. et al. 1994. Chemoprevention effects on bronchial squamous metaplasia by folate and vitamin B12 in heavy smokers. Chest 106(2), Aug., 496-499. Jennings, E. 1995. Folic acid as a cancer-preventing agent. Med Hypotheses 45(3), Sept., 297-303. Cardiovascular/Coronary Heart Disease Das UN. Folic acid says NO to vascular diseases. Nutrition. 2003 Jul-Aug;19(78):686-92. Landgren, F. et al. 1995. Plasma homocysteine in acute myocardial infarction: Homocysteine-lowering effect of folic acid. J Intern Med 237(4), Apr., 381-388. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 126
Dose: 2.5mg or 10mg over a 6 week period van den Berg, M. et al. 1994. Combined vitamin B6 plus folic acid therapy in young patients with arteriosclerosis and hyperhomocysteinemia. J Vascular Surgery 20(6), Dec., 933-940. Dose: 5mg folic acid/day Morrison, H. I. et al. 1996. Serum folate and risk of fatal coronary heart disease. JAMA 275(24), June 26, 1893-1896. Wilcken, D. E. et al. 1988. Folic acid lowers elevated plasma homocysteine in chronic renal insufficiency: Possible implications for prevention of vascular disease. Metabolism 37(7), July, 697-701. Dose: 5mg folic acid/day for average of 15 days Arnadottir, M. et al. 1993. The effect of high-dose pyridoxine and folic acid supplementation on serum lipid and plasma homocysteine concentrations in dialysis patients. Clinical J Nephrol 40(4), Oct., 236-240. Dose: 5mg/day Cervical Dysplasia Thomson SW, Heimburger DC, Cornwell PE, Turner ME, Sauberlich HE, Fox LM, 25 Butterworth CE. Correlates of total plasma homocysteine: folic acid, copper, and cervical dysplasia. Nutrition. 2000 Jun;16(6):411-6. Butterworth, Jr. C. E. 1982. Improvement of cervical dysplasia associated with folic acid therapy in users of oral contraceptives. Am J Clin Nutr, 35(1) Jan., 73-82. Dose: 10mg folic acid/day for 3 months Fragile X Syndrome Strom CM, Brusca RM, Pizzi WJ. Double-blind, placebo-controlled crossover study of folinic acid (Leucovorin for the treatment of fragile X syndrome. Am J Med Genet. 1992 Nov 15;44(5):676-82. Brown, W. T. et al. Folic acid therapy in the Fragile X Syndrome. Am. J Med Genetics 17(1), Jan., 289-297. Hagerman, R. J. et al. 1986. Oral folic acid versus placebo in the treatment of males with the Fragile X Syndrome. Am. J Med Genetics 23(1-2), Jan.Feb., 241-262. Dose: 10mg/day Lejeune, J. et al. 1984. [Trial of folic acid treatment in Fragile X Syndrome] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 127
Ann Genet 27(4), 230-232. Dose: 0.5 mg/kg per day of folic acid Gingival Health Munoz CA, Kiger RD, Stephens JA, Kim J, Wilson AC. Effects of a nutritional supplement on periodontal status. Compend Contin Educ Dent. 2001 May;22(5):425-8, 430, 432 passim; quiz 440. Vogel, R. I. et al. 1976. The effect of folic acid on gingival health. J Periodontology 47(11), Nov., 667-668. Dose: 4mg/day for 30 days Homocystinuria Ashfield-Watt PA, Moat SJ, Doshi SN, McDowell IF. Folate, homocysteine, endothelial function and cardiovascular disease. What is the link? Biomed Pharmacother. 2001 Oct;55(8):425-33. Takenaka, T. et al. 1993. [Effect of folic acid for treatment of homocystinuria due to 5,10-methylenetetrahydrofolate reductase deficiency]. Rinsho Shinkeigaku 33(11), Nov., 1140-1145. Dose: 400mcg/day of folic acid over approx 70 days Kidney Damage Manns B, Hyndman E, Burgess E, Parsons H, Schaefer J, Snyder F, Scott-Douglas N. Oral vitamin B(12) and high-dose folic acid in hemodialysis patients with hyper-homocyst(e)inemia. Kidney Int. 2001 Mar;59(3):1103-9. Chauveau, P. et al. 1996. Long-term folic acid (but not pyridoxine) supplementation lowers elevated plasma homocysteine level in chronic renal failure. Miner Electrolyte Metab 22(1-3), 106-109. Dose: 10mg/day folate for 3 months Lithium Prophylaxis McKeon P, Shelley R, O'Regan S, O'Broin J. Serum and red cell folate and affective morbidity in lithium prophylaxis. Acta Psychiatr Scand. 1991 Mar;83(3):199-201. Coppen, A. et al. 1986. Folic acid enhances lithium prophylaxis. J Affective Disorders 10(1), Jan.-Feb., 9-13. Dose: 200mcg/day folic acid Multiple Sclerosis Bottiglieri T. Folate, vitamin B12, and neuropsychiatric disorders. Nutr Rev. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 128
1996 Dec;54(12):382-90. Kanevskaia, S. A. et al. 1990. [Folic acid in the combined treatment of patients with disseminated sclerosis and chronic gastritis] Vrach Delo (4), Apr. 96-97. Dose: 200-300mcg/day Zinc Absorption Tavares E, Carreras O, Gomez-Tubio A, Murillo D, Murillo ML. Effects of folic acid and amino acids supplementation on zinc intestinal absorption in the progeny of ethanol-treated rats. J Physiol Biochem. 2000 Sep;56(3):247-56. Milne, D. B. et al. 1984. Effect of oral folic acid supplements on zinc, copper, and iron absorption and excretion. Am J Clin Nutr 39(4), Apr., 535539. Dose: 400mcg folic acid every other day for 16 weeks Niacin General Talpur N, Echard BW, Yasmin T, Bagchi D, Preuss HG. Effects of niacin-bound chromium, Maitake mushroom fraction SX and (-)-hydroxycitric acid on the metabolic syndrome in aged diabetic Zucker fatty rats. Mol Cell Biochem. 2003 Oct;252(1-2):369-77. Chojnowska-Jezierska, J,. and Adamska-Dyniewska, H. 1998. Efficacy and safety of one-year treatment with slow-release nicotinic acid. Monitoring of drug concentration in serum. Int J Clin Pharmacol Ther, 36(6), Jun., 326332. Dose: 1.5 g/d (2 months), and subsequently 2-3 g/d (10 months), on average 2.13 g/d. During the treatment with 2.0 g/d dose. Hoogerbrugge, N. et al. 1998. The additional effects of acipimox to simvastatin in the treatment of combined hyperlipidaemia. J Intern Med, 243(5) May, 151-156. Dose: Acipimox in a daily dose of 3 X 250 mg for 12 weeks. Brown, B. G. et al. 1998. Lipid altering or antioxidant vitamins for patients with coronary disease and very low HDL cholesterol? The HDLAtherosclerosis Treatment Study Design. Can J Cardiol, Suppl A, Apr. 14, 6A-13A. Chojnowska-Jezierska, J. and Adamska-Dyniewska, H. 1997. [Prolonged treatment with slow release nicotinic acid in patients with type II Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 129
hyperlipidemia]. Pol Arch Med Wewn, 98(11) Nov., 391-399 Dose: one-year therapy with slow-release nicotinic acid McKenney, J.M. et al. 1998. A randomized trial of the effects of atorvastatin and niacin in patients with combined hyperlipidemia or isolated hypertriglyceridemia. Collaborative Atorvastatin Study Group. Am J Med, 104(2) Feb., 137-143 Dose: immediate-release niacin 1 g 3x/day for 12 weeks Brown, B. G. et al. 1998. Use of niacin, statins, and resins in patients with combined hyperlipidemia. Am J Cardiol, 81(4A) Feb. 26, 52B-59B Fagerberg, B. et al. 1998. Mortality rates in treated hypertensive men with additional risk factors are high but can be reduced: a randomized intervention study. Am J Hypertens, 11(1 Pt 1) Jan., 14-22. Kukharchuk, V. V. et al. 1997. [The effect of long-term Enduracin monotherapy on the clinical and biochemical status of patients with ischemic heart disease]. Ter Arkh, 69(9), 41-45 Dose: enduracin in a dose 1500 mg/day. Brown, B. G. et al. 1997. Moderate dose, three-drug therapy with niacin, lovastatin, and colestipol to reduce low-density lipoprotein cholesterol <100 mg/dl in patients with hyperlipidemia and coronary artery disease. Am J Cardiol, 80(2) Jul. 15, 111-115. Dose: initial 12-month phase, regular niacin 500 mg qid alternated with a polygel controlled-release formula. Gardner, S. F. et al. 1997. Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycemic control. Ann Pharmacother, 31(6) Jun., 677-682 Dose: low-dose niacin (1.5 g/d) over a 14 week period. Vitamin C Aging Parle M, Dhingra D. Ascorbic Acid: a promising memory-enhancer in mice. J Pharmacol Sci. 2003 Oct;93(2):129-35. Phillips, C. L. et al. 1994. Effects of ascorbic acid on proliferation and collagen synthesis in relation to the donor age of human dermal fibroblasts. J Invest Dermatol 103(2) Aug., 228-232. Postaire, E. et al. 1995. Increase of singlet oxygen protection of erythrocytes by Vitamin E, Vitamin C and Beta Carotene intakes. Biochem Mol Biol Int, 35(2), Feb., 371-375. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 130
Dose: 30mg/day Vitamin C Okamoto, K et al. 1992. [The relationship between dietary ascorbic acid intake and serum lipid concentration in the aged.] Nippon Ronen Igakkai Zasshi 29(12), Dec., 908-911. Cheraskin, E. 1994. Chronologic versus biologic age. J Advancement Med 7(1), Spring, 31-41. Dose: 100mg-200mg/day Vitamin C Cheraskin, E. 1993. Vitamin C, cancer and aging. Age 16, 55-58. Delafuente, J. C. et al. 1986. Immunologic modulation by vitamin C in elderly. Int J Immunopharmacol 8(2), 205-211. Alcohol Toxicity Sivaram AG, Suresh MV, Indira M. Combined effect of ascorbic acid and selenium supplementation on alcohol-induced oxidative stress in guinea pigs. Comp Biochem Physiol C Toxicol Pharmacol. 2003 Mar;134(3):397-401 Susick, R. L. and Zannoni, V. G. 1987. Effect of ascorbic acid on the consequences of acute alcohol consumption in humans. Clin Pharmacol Ther, 41(5), May, 502-509. Dose: 0.95gm/kg body weight over 2.5 hours for 2 weeks Wickramasinghe, S. N. and Hasan, R. 1994. In vivo effects of Vitamin C on the cytotoxicity of post-ethanol serum. Biochem Pharmacol, 48(3), Aug. 3, 621-624. Dose: 1gm/day for 3 days Chen, M. F. et al. 1990. Effect of ascorbic acid on plasma alcohol clearance. J Am Coll Nutr, 9(3), June, 185-189. Arthritis Jensen NH. Reduced pain from osteoarthritis in hip joint or knee joint during treatment with calcium ascorbate. A randomized, placebocontrolled cross-over trial in general practice. Ugeskr Laeger. 2003 Jun 16;165(25):2563-6.s Oldroyd, K. G. and Dawes, P. T. 1985. Clinically significant vitamin C deficiency in rheumatoid arthritis. British J Rheumatology 24(4) Nov, 362363. Davis, R. H. et al. 1990. Vitamin C influence of localized adjuvant arthritis. J American Podiatry Med Assoc 80(8) Aug, 414-418. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 131
Dose: 150mg/kg of subcutaneous Vitamin C for 20 days Asthma Kongerud J, Crissman K, Hatch G, Alexis N. Ascorbic acid is decreased in induced sputum of mild asthmatics. Inhal Toxicol. 2003 Feb;15(2):101-9. Hatch, G. E. 1995. Asthma, inhaled oxidants, and dietary antioxidants. American J Clin Nutr 61(3 Suppl), Mar, 625S-630S. Anderson, R. et al. 1980. The effect of ascorbate on cellular humoral immunity in asthmatic children. South African Med J 58(24) Dec 13, 974977. Dose: 1g ascorbic single daily dose for a 6-month period Anah, C. O. et al. 1980. High dose ascorbic acid in Nigerian asthmatics. Trop Geogr Med 32(2) June, 132-137. Dose: 1g of ascorbic acid daily Rozanov, E. M. et al. 1987. [Vitamin PP and C allowances and their correction in the treatment of bronchial asthma patients.] Vopr Pitan (6):214, Nov-Dec, 21-24. Dose: 275-300 mg of Vitamin C Cancer Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003 Apr;22(2):118-23. Block, G. et al. 1991. Epidemiologic evidence regarding vitamin C and cancer. Am J Clin Nutr 54(6 Suppl) Dec., 1310S-1314S. Herrero, R. et al. A case-control study of nutrient status and invasive cervical cancer: I. Dietary indicators. Am J Epi 134(11), Dec. 1, 1335-1346. Stahelin, H. B. et al. Plasma antioxidant vitamins and subsequent cancer mortality in the 12-year follow-up of the prospective based study. Am J Epi 133(8), Apr. 15, 766-775. Knekt, P et al. 1991. Dietary antioxidants and the risk of lung cancer. Am J Epi 134(5), Sept. 1, 471-479. Trizna, Z. et al. 1991. Effects of N-acetyl-L-cysteine and ascorbic acid on mutagen-induced chromosomal sensitivity in patients with head and neck cancers. Am J Surgery 162(4), Oct., 294-298. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 132
Ferraroni, M et al. 1994. Selected micronutrient intake and the risk of colorectal cancer. British J Cancer 70(6), Dec., 1150-1155. Shibata, A. et al. 1992. Intake of vegetables, fruits, beta-carotene, vitamin C and vitamin supplements and cancer incidence among the elderly: A prospective study. British J Cancer 66(4) Oct., 673-679. Bussey, H. J. et al. A randomized trial of ascorbic acid in polyposis coli. Cancer 50(7) Oct. 1, 1434-1439. Dose: 3g/day of ascorbic acid for 9 months Fontham, E. T. et al. 1988. Dietary vitamins A and C and lung cancer risk in Louisiana. Cancer 62(10), Nov. 15, 2267-2273. Park, C. H. et al. 1980. Growth suppression of human leukemic cells in vitro by L-ascorbic acid. Cancer Res 40(4), 1062-1065. Kaugars, G. et al. 1993. Serum and tissue antioxidant levels in supplemented patients with premalignant oral lesions (meeting abstract). FASEB J 7(4), A519. Dose: 1000mg Vitamin C for 9 months Sobala, G. M. et al. 1989. Ascorbic acid in the human stomach. Gastroenterology 97(2) Aug., 357-363. Paganelli, G. M. et al. 1992. Effect of vitamin A, C, and E supplementation on rectal cell proliferation in patients with colorectal adenomas. J National Cancer Inst. 84(1) Jan. 1, 47-51. Brock, K. E. et al. Nutrients in diet and plasma and risk of in situ cervical cancer. J National Cancer Inst. 80(8) June 15, 580-585. Potter, J. D. and McMichael, A. J. 1986. Diet and cancer of the colon and rectum: A case-control study. J National Cancer Inst. 76(4) Apr., 557-569. Moffat, L. et al. 1983. High dose ascorbate therapy and cancer. NFCR Cancer Res Assoc Symp. (2), 243-256. Dose: 2.5 g Vitamin C 4x/day Kaugars, G. et al. 1993. The role of antioxidants in the treatment of oral leukoplakia. CCPC-93: Second Int Cancer Chemo Prevention Conf. Berlin, Germany, Apr. 28-30, 65. Dose: 1000mg/day of ascorbic acid for 9 months Greco, A. M. et al. 1982. Study of blood vitamin C in lung and bladder cancer patients before and after treatment with ascorbic acid: A preliminary report. Acta Vitaminol Enzymol 4(1-2), 155-162. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 133
Dose: 5g/day Glatthaar, B. E. et al. The role of ascorbic acid in carcinogenesis. Adv Exp Med Biol 206, 357-377. Chen, L H. et al. 1988. Vitamin C, vitamin E and cancer. Anticancer Res 8(4), July-Aug., 739-748. Garcia-Alejo Hernandez, R. et al. 1989. [Radioprotective effect of ascorbic acid on oral structures in patients with cancer of the head and neck]. Av odontoestomatol 5(7), Sept., 469-472. La Vecchia, C. et al. Selected micronutrient intake and the risk of gastric cancer. Cancer Epidemiol Biomarkers Prev. 3(5) July-Aug., 393-398. Dyke, G. W. et al. Effect of vitamin C supplementation on gastric mucosal DNA damage. Carcinogenesis 15(2), 291-295. Slattery, M. L. et al. 1990. Dietary vitamins A, C, and E and selenium as risk factors for cervical cancer. Epidemiology 1(1), Jan., 8-15. Reed, P. I. et al. 1991. Effect of ascorbic acid on the intragastric environment in patients at increased risk of developing gastric cancer. IARC Sci Publ. (105), 139-142. Nomura, A. M. et al. 1991. Dietary factors in cancer of the lower urinary tract. Int. J Cancer 48(2), May 10, 199-205. Verreault, R. et al. 1989. A case-control study of diet and invasive cervical cancer. Int J Cancer 43(6), June 15, 1050-1054. Cameron, E. 1982. Vitamin C and cancer: An overview. Int J Vitamin Nutr Res Suppl 23, 115-127. Murata,, A. et al. 1982. Prolongation of survival times of terminal cancer patients by administration of large doses of ascorbate. Int J Vitamin Nutr Res Suppl 23, 103-113. Waddell, . R. and Germer, R. E. 1980. Indomethacin and ascorbate inhibit desmoid tumors. J Surg Oncol 15(1), 85-90. Ghosh, J and Das, S. 1995. Evaluation of vitamin A and C status in normal and malignant conditions and their possible role in cancer prevention. Japanese J Cancer Res 76(12) Dec., 1174-1178. Cameron, E. and Campbell, A. 1991. Innovation vs. quality control: An 'Unpublishable' clinical trial on supplemental ascorbate in incurable Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 134
cancer. Med Hyp 36(3), Nov., 185-189. Jaffey, M. Vitamin C and cancer: Examination of the value of eleven trial results using broad inductive reasoning. Med Hyp 8(1), 49-84. Dose: 10g/day Vitamin C Campbell, A. et al. 1991. Reticulum cell sarcoma: Two complete spontaneous' regressions in response to high-dose ascorbic acid therapy. A report on subsequent progress. Oncology 48(6), 495-497. Kaminski, M. and Boal, R. 1992. An effect of ascorbate acid on delayedonset muscle soreness. Pain 50(3), Sept., 317-321. Raushenbakh, M. O. et al. [Effect of ascorbic acid on formation and leukemogenic activity of p-hydroxyphenyllactic acid]. Probl Gematol Pereliv Krovi 27(7), 3-6. Dose: 8g/day over 8-10 days before chemotherapy Stahelin, H. B. 1989. [Vitamins and cancer: Results of a Basel study]. Soz Praventivmed 34(2), 75-77. Gorozhanskaia. E. G. et al. [The role of ascorbic acid in the combined preoperative preparation of cancer patients]. Vopr Onkol 35(4), 436-441. Dose: 1.5g/day of ascorbic acid for 7 days. Baikova, V. N. et al. 1982. [The effect of large doses of ascorbic acid on tyrosine metabolism and hemoblastosis course in children]. Vopr Onkol 28(9), 28-34. Dose: 100mg/kg/day. Yuan, J. M. et al. 1995. Diet and breast cancer in Shanghai and Tianjin, China. British J Cancer 71, 1353-1358. Howe, G. R. et al. 1990. Dietary factors and the risk of breast cancer: Combined analysis of 12 case-controlled studies. J National Cancer Inst. 82, 561-569. VanEenwyk, J. 1993. The role of vitamins in the development of cervical cancer. The Nutrition Report. 11(1), Jan., 1-8. Amburgey, C. F. et al. 1993. Undernutrition as a risk factor for cervical intraepithelial neoplasia: A case control analysis. Nutrition and Cancer 20(1), 51-60. Cardiovascular/Coronary Heart Disease Mak S, Newton GE. Vitamin C augments the inotropic response to Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 135
dobutamine in humans with normal left ventricular function. Circulation. 2001 Feb 13;103(6):826-30. Salonen, J. T. et al. 1991. Effects of antioxidant supplementation on platelet function: A randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status. Am J Clin Nutr. 53(5), May, 1222-1229. Dose: 600mg of ascorbic acid/day. Trout, D. L. 1991. Vitamin C and cardiovascular risk factors. Am J Clin Nutr 53(1 Suppl), Jan., 322S-325S. 34 Sisto, T. et al. 1995. Pretreatment with antioxidants and allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg 59(6) June, 1519-1523. Khaw, K. T. and Woodhouse, P. 1988. Interrelation of vitamin C, infection, haemostatic factors and cardiovascular disease. British Med J 310(6994), June 17, 1559-1563. Dose: 60mg. Brox, A. G. et al. 1988. Treatment of idiopathic thrombocytopenic purpura with ascorbate. British J Haematology 70(3) Nov., 341-344. Singh, R. B. et al. 1995. Effect of antioxidant-rich foods on plasma ascorbic acid, cardiac enzyme, and lipid peroxide levels in patients hospitalized with acute myocardial infarction. J Am Dietetic Assoc. 95(7), July, 775-780. Singh, R. B. et al. 1994. Plasma levels of antioxidant vitamins and oxidative stress in patients with acute myocardial infarction. Acta Cardiol 49(5), 441452. Riemersma. R. A. et al. 1989. Low plasma vitamins E and C. Increased risk of angina in Scottish men. Annals NY Academy Sci. 570, 291-295. Gey, K. F. et al. 1987. Relationship of plasma level of vitamin C to mortality from ischemic heart disease. Annals NY Academy Sci. 498, 110-123. Cordova, C, et al. 1982. Influence of ascorbic acid on platelet aggregation in vitro and in vivo. Atherosclerosis 41(1), Jan., 15-19. Dose: 2g of ascorbic acid. Bordia, A. K. 1980. The effect of vitamin C on blood lipids, fibrinolytic activity and platelet adhesiveness in patients with coronary artery disease. Atherosclerosis 35(2), Feb., 181-187. Dose: 2g/day Vitamin C. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 136
Li, C. C. 1990. [Changes on creatine phosphokinase and malondialdehyde in the serum and clinical use of large doses of vitamin C following open heart surgery]. Chung Hua Wai Ko Tsa Chih 28(1) Jan., 16-17, 60-61. Dose: 250mg/kg Vitamin C prior to heart surgery. Bordia, A. and Verma, S. K. 1985. Effect of vitamin C on platelet adhesiveness and platelet aggregation in coronary artery disease patients. Clinical Cardiology 8(10) Oct.., 552-554. Dose: 1g and 1 g every 8 hours over 10 days. Yoshioka, M. et al. 1984. Inverse association of serum ascorbic acid level and blood pressure or rate of hypertension in male adults aged 30-39 years. Int J Vitamin Nutr Res. 54(4), 343-347. Simon, J. A. 1992. Vitamin C and cardiovascular disease: A review. J Am Coll Nutr. 11(2) Apr., 107-125. Mostafa, S. et al. 1989. Beneficial effects of vitamin C on risk factors of cardiovascular diseases. J Egyptian Public health Assoc. 64(1-2), 123-133. Dose: 500mg/day of Vitamin C. Fujimura, I. et al. [Correlation between hypercholesterolemia and vitamin C deficient diet]. Rev Hosp Clin Fac Med Sao Paulo 46(1), Jan.-Feb., 14-18. Dobson, H. M. et al. 1984. The effect of ascorbic acid on the seasonal variations in serum cholesterol levels. Scottish Med J 29(3) July, 176-182. Dose: 1g of ascorbic acid for 2 months. Gey, K. F. et al. [Essential antioxidants in cardiovascular diseases-Lessons for Europe]. Ther Umsch 51(7) July, 475-482. Dingchao, H. et al. 1994. The protective effects of high-dose ascorbic acid on myocardium against reperfusion injury after cardiopulmonary bypass. Thorac Cardiovasc Surg 42(5) Oct., 276-278. Dose: 250 mg/kg. Cataracts Serum ascorbic acid and other correlates of self-reported cataract among older Americans. Simon JA, Hudes ES. Serum ascorbic acid and other correlates of selfreported cataract among older Americans. J Clin Epidemiol. 1999 Dec;52(12):1207-11. Jacques, P. F. and Chylack Jr., L. T. Epidemiologic evidence of a role for the antioxidant vitamins and carotenoids in cataract prevention. Am J Clin Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 137
Nutr 53(1 Suppl) Jan., 352S-355S. Robertson, J. M. et al. 1991. A possible role for vitamins C and E in cataract prevention. Am J Clin Nutr. 53(1 Suppl), Jan., 346S-351S. Jacques, P. F. et al. 1988. Antioxidant status in persons with and without senile cataract. Arch Ophthalmol 106(3)m Mar., 337-340. Gerster, H. 1989. Antioxidant vitamins in cataract prevention. Z Ernahrungswiss. 28(1), Mar., 56-75. Cervical Dysplasia Ho GY, Palan PR, Basu J, Romney SL, Kadish AS, Mikhail M, Wassertheil-Smoller S, Runowicz C, Burk RD. Viral characteristics of human papillomavirus infection and antioxidant levels as risk factors for cervical dysplasia. Int J Cancer. 1998 Nov 23;78(5):594-9. Wassertheil-Smoller, S. et al. 1981. Dietary Vitamin C and uterine cervical Dysplasia. Am J Epi, 114(5), No., 714-724. Romney, S. L. et al. 1985. Plasma Vitamin C and uterine cervical dysplasia. Am J Obstetrics Gynecology, 151(7), Apr. 1, 976-980. Common Cold Van Straten M, Josling P. Preventing the common cold with a vitamin C supplement: a double-blind, placebo-controlled survey. Adv Ther. 2002 MayJun;19(3):151-9. Hemila, H. 1994. Does Vitamin C alleviate the symptoms of the common cold?-A review of current evidence. Scandanavian J Infect Dis, 26(1), 1-6. Dose: 1g Vitamin C. Diabetes Krawczuk-Rybak M, Peczynska J, Urban M. Usefulness of antioxidant vitamin supplementation in children and adolescents with newly diagnosed diabetes mellitus type. Endokrynol Diabetol Chor Przemiany Materii Wieku Rozw. 1999;5(1):11-20. Johnson, C. S. and Yen, M. F. 1994. Megadose of vitamin C delays insulin response to a glucose challenge in normoglycemic adults. Am J Clin Nutr 60(5), Nov., 735-738. Dose: 2g/day for 2 weeks. Paolisso, G. et al. 1994. Plasma vitamin C affects glucose homeostasis in healthy subjects and in non-insulin-dependent diabetics. Am J Physiol Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 138
266(2 Pt 1), Feb., E261-268. Davie, S. J. et al. Effect of vitamin C on glycosylation of proteins. Diabetes 41(2), Feb., 167-173. Dose: 1g/day of Vitamin C for 3 months. Vinson, J. A. et al. 1989. In vitro and in vivo reduction of erythrocyte sorbitol by ascorbic acid. Diabetes 38(8), Aug., 1036-1041. Dose: 500mg/day for 2 weeks. Yue, D. K. et al. 1990. Abnormalities of ascorbic acid metabolism and diabetic control: Differences between diabetic patients and diabetic rats. Diabetes Res Clin Pract. 9(3) July, 239-244. Kodama, M. et al. 1993. Diabetes mellitus is controlled by vitamin C treatment. In vivo 7(6A), Nov.-Dec., 535-350. Cunningham, J. J. et al. 1994. Vitamin C: An aldose reductase inhibitor that normalizes erythrocyte sorbitol in insulin-dependent diabetes mellitus. J Am Coll Nutr. 13(4), Aug., 344-350. Dose: 100-600mg/day of Vitamin C for 58 days. Cunningham, J. J. et al. Reduced mononuclear leukocyte ascorbic acid content in adults with insulin-dependent diabetes mellitus consuming adequate dietary vitamin C. Metabolism 40, 146-149. Fatigue Thompson D, Williams C, McGregor SJ, Nicholas CW, McArdle F, Jackson MJ, Powell JR. Prolonged vitamin C supplementation and recovery from demanding exercise. Int J Sport Nutr Exerc Metab. 2001 Dec;11(4):466-81. Cheraskin, E. et al. 1976. Daily Vitamin C consumption and fatigability. J Am Geriatric Soc., 24(3), 136-137. Glaucoma Filina AA, Sporova NA. Effect of lipoic acid on tyrosine metabolism in patients with open-angle glaucoma. Vestn Oftalmol. 1991 May-Jun;107(3):19-21. Jampel, H. D. 1990. Ascorbic acid is cytotoxic to dividing human Tenon's capsule fibroblasts: A possible contributing factor in glaucoma filtration surgery success. Arch Ophthalmol. 108(9) Sept., 1323-1325. Glutathione Deficiency Lenton KJ, Sane AT, Therriault H, Cantin AM, Payette H, Wagner JR. Vitamin C augments lymphocyte glutathione in subjects with ascorbate deficiency. Am J Clin Nutr. 2003 Jan;77(1):189-95.
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Jain, A. et al. 1994. Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency. J Pediatrics, 124(2), Feb., 229-233. Dose: 0.7 mmol/kg/day for 1-2 weeks. Herpes Hovi T, Hirvimies A, Stenvik M, Vuola E, Pippuri R. Topical treatment of recurrent mucocutaneous herpes with ascorbic acid-containing solution. Antiviral Res. 1995 Jun;27(3):263-70. Fitzherbert, J. 1979. Genital herpes and zinc. Med J Aust, 1, 399. Dose: 250mg Vitamin C 2x/day Terezhalmy, G. T. et al. 1978. The use of water-soluble bioflavonoidascorbic acid complex in the treatment of recurrent herpes labialis. Oral Surgery, 45, 56-62. Dose: 200mg Vitamin C for 3-5 times/day for 3 days beginning after onset of symptoms. Immune enhancement Heuser G, Vojdani A. Enhancement of natural killer cell activity and T and B cell function by buffered vitamin C in patients exposed to toxic chemicals: the role of protein kinase-C. Immunopharmacol Immunotoxicol. 1997 Aug;19(3):291-312. Anderson, R. et al. 1980. The effects of increasing weekly doses of ascorbate on certain cellular and humoral immune functions in normal volunteers. Am J Clin Nutr. 33(1) Jan., 71-76. Dose: 2-3g/day. Penn, N. D. et al. 1991. The effect of dietary supplementation with vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: A randomized controlled trial. Age Ageing 20(3) May, 169-174. Kodama, M. et al. 1994. Autoimmune disease and allergy are controlled by vitamin C treatment. In vivo 8(2), Nar.-Apr., 251-257. Delafuente, J. C. et al. 1986. Immunologic modulation by vitamin C in the elderly. Int J Immunopharmacol 8(2), 205-211. Dose: 2g/day for 3 weeks. Menopause Vihtamaki T, Parantainen J, Koivisto AM, Metsa-Ketela T, Tuimala R. Oral Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 140
ascorbic acid increases plasma oestradiol during postmenopausal hormone replacement therapy. Maturitas. 2002 Jun 25;42(2):129-35. Horoschak, A. 1959. Nocturnal leg cramps, easy bruisability and epistaxis in menopausal patients: Treated with Hesperidin and ascorbic acid. Delaware State Med J. 19-22. Dose: 200mg of Vitamin C following each meal and at bedtime for 2 weeks plus another 100mg of both 4x/day for 4 weeks. Neutrophil Dysfunction Demertzis S, Scherer M, Langer F, Dwenger A, Hausen B, Schafers HJ. Ascorbic acid for amelioration of reperfusion injury in a lung autotransplantation model in sheep. Ann Thorac Surg. 2000 Nov;70(5):1684-9. Rebora, A. et al. 1980. Neutrophil dysfunction and repeated infections: Influence of levamisole and ascorbic avid. British J Dermatology, 102(1), Jan., 49-56. Levy, R. and Schlaeffer, F. 1993. Successful treatment of a patient with recurrent furunculosis by Vitamin C: Improvement of clinical course and of impaired neutrophil functions. Int J Dermatology, 32(11), Nov., 832-834. Dose: 500mg/day of Vitamin C for 30 days. Obesity Harnroongroj T, Jintaridhi P, Vudhivai N, Pongpaew P, Tungtrongchitr R, Phonrat B, Changbumrung S, Schelp FP. B vitamins, vitamin C and hematological measurements in overweight and obese Thais in Bangkok. J Med Assoc Thai. 2002 Jan;85(1):17-25. Naylor, G. J. et al. 1985. A double blind placebo controlled trial of ascorbic acid in obesity. Nutr Health, 4(1), 25-28. Dose: 3g/day for 6 weeks. Paget's Disease Basu TK, Smethurst M, Gillett MB, Donaldson D, Jordan SJ, Williams DC, Hicklin JA. Acta Vitaminol Enzymol. 1978;32(1-4):45-9. Ascorbic acid therapy for the relief of bone pain in Paget's disease. Smethurst, M. et al. 1981. Combined therapy with ascorbic acid and calcitonin for the relief of bone pain in Paget's disease. Acta Vitaminol Enzymol, 3(1), 8-11.
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Pancreatitis Shishlov VI. The status of ascorbate oxidation-reduction system of blood in patients with chronic pancreatitis throughout parenteral nutrition. Klin Khir. 1999;(10):7-9. Bonham MJ, Abu-Zidan FM, Simovic MO, Sluis KB, Wilkinson A, Winterbourn CC, Windsor JA. Early ascorbic acid depletion is related to the severity of acute pancreatitis. Br J Surg. 1999 Oct;86(10):1296-301. Scott, P. et al. 1993. Vitamin C status in patients with acute pancreatitis. British J Surgery, 80(6), June, 750-754. Parkinson's disease Martin A, Youdim K, Szprengiel A, Shukitt-Hale B, Joseph J. Roles of vitamins E and C on neurodegenerative diseases and cognitive performance. Nutr Rev. 2002 Oct;60(10 Pt 1):308-26. Fahn, S. 1992. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease. Annals Neurology 32 Suppl., S128-S132. Reilly, D. K. et al. 1983. On-off effects in Parkinson's disease: A controlled investigation of ascorbic acid therapy. Advanc Neurol 37, 51-60. Linazasoro, G. and Gorospe, A. [Treatment of complicated Parkinson disease with a solution of levodopa-carbidopa and ascorbic acid]. Neurologia 10(6) June-July, 220-223. Yapa, S. C. 1992. Detection of subclinical ascorbate deficiency in early Parkinson's Disease. Public Health 106(5) Sept., 393-395. Periodontal Disease Lowe G, Woodward M, Rumley A, Morrison C, Tunstall-Pedoe H, Stephen K. Total tooth loss and prevalent cardiovascular disease in men and women: possible roles of citrus fruit consumption, vitamin C, and inflammatory and thrombotic variables. J Clin Epidemiol. 2003 Jul;56(7):694-700. Leggott, P. J. et al. 1991. Effects of ascorbic acid depletion and supplementation of periodontal health and subgingival microflora in humans. J Dental Res, 70(12), Dec., 1531-1536. Leggott, P. J. et al. 1986. The effect of controlled ascorbic acid depletion and supplementation on periodontal health. J Periodonotal, 57(8), Aug., 480-485. Respiration Kelly Y, Sacker A, Marmot M. Nutrition and respiratory health in adults: 41 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 142
findings from the health survey for Scotland. Eur Respir J. 2003 Apr;21(4):66471. Lee MH, Shiau SY. Increase of dietary vitamin C improves haemocyte respiratory burst response and growth of juvenile grass shrimp, Penaeus monodon, fed with high dietary copper. Fish Shellfish Immunol. 2003 Apr;14(4):305-15. Peters, E. M. et al. 1993. Vitamin C supplementation reduces the incidence of postrace symptoms of upper-respiratory-tract infection in ultramarathon runners. Am J Clin Nutr. (2) Feb., 170-174. Dose: 600mg/day Vitamin C. Mohsenin, V. 1987. Effect of vitamin C on NO2-induced airway hyperresponsiveness in normal subjects: A randomized double-blind experiment. Am Rev Resp Dis 136(6), Dec., 1408-1411. Dose: 500mg 4x/day of ascorbic acid for 3 days. Bucca, C. et al. 1990. Effect of vitamin C on histamine bronchial responsiveness of patients with allergic rhinitis. Ann Allergy 65(4), Oct., 311-314. Dose: 2g of Vitamin C. Bucca, C. et al. 1989. Effects of vitamin C on airway responsiveness to inhaled histamine in heavy smokers. European Respir J 2(3), Mar., 229-233. Dose: 2g of Vitamin C. Schizophrenia Rachkauskas GS. The efficacy of enterosorption and a combination of antioxidants in schizophrenics. Lik Sprava. 1998 Jun;(4):122-4. Sandyk, R. and Kanofsky, J. D. 1993. Vitamin C in the treatment of schizophrenia. Int J Neuroscience, 68(1-2), Jan., 67-71. Sickle Cell Anemia Jaja SI, Ikotun AR, Gbenebitse S, Temiye EO. Blood pressure, hematologic and erythrocyte fragility changes in children suffering from sickle cell anemia following ascorbic acid supplementation. J Trop Pediatr. 2002 Dec;48(6):366-70. 42 Jain, S. K. et al. 1985. Reduced levels of plasma ascorbic acid (Vitamin C) in sickle cell disease patients: Its possible role in the oxidant damage to sickle cells in vivo. Clin Chim Acta, 149(2-3), July 15, 257-161. Smoking Cessation Dietrich M, Block G, Hudes M, Morrow JD, Norkus EP, Traber MG, Cross CE, Packer L. Antioxidant supplementation decreases lipid peroxidation biomarker F(2)-isoprostanes in plasma of smokers. Cancer Epidemiol Biomarkers Prev. 2002 Jan;11(1):7-13. Levin, E. D. et al. 1993. Clinical trials using ascorbic acid aerosal to aid smoking cessation. Drug Alcohol Depend, 33(3), Oct., 211-223. Stroke Kurl S, Tuomainen TP, Laukkanen JA, Nyyssonen K, Lakka T, Sivenius J, Salonen JT. Plasma vitamin C modifies the association between hypertension and risk of stroke. Stroke. 2002 Jun;33(6):1568-73. Gale, C. R. et al. 1995. Vitamin C and risk of death from stroke and coronary Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 143
heart disease in cohort of elderly people. British Med J 310(6994) June 17, 1563-1566. Tetanus Jahan, J. K. et al. 1985. Effect of ascorbic acid in the treatment of tetanus. Bangladesh Med Res Council Bull, 10(1), June, 24-28. Dose: 1000 mg/day iv Wound healing Jagetia GC, Rajanikant GK, Rao SK. Evaluation of the effect of ascorbic acid treatment on wound healing in mice exposed to different doses of fractionated gamma radiation. Radiat Res. 2003 Mar;159(3):371-80. Ringsdorf Jr., W. M. and Cheraskin, E. 1982. Vitamin C and human wound healing. Oral Surg Med Oral Pathol 53(3) Mar., 231-236. Dose: 500-3000mg/day. Goode, H. F. et al. 1992. Vitamin C depletion and pressure sores in elderly patients with femoral neck fractures. British Med J 305(6859) Oct. 17, 925927. Vitamin E 43 Abetalipoproteinemia Chowers I, Banin E, Merin S, Cooper M, Granot E. Long-term assessment of combined vitamin A and E treatment for the prevention of retinal degeneration in abetalipoproteinaemia and hypobetalipoproteinaemia patients. Eye. 2001 Aug;15(Pt 4):525-30. Illingworth, D. R. et al. 1980. Abetalipoprotein. Report of two cases and review of therapy. Arch Neurol 37(10), Oct., 659-662. Bishara, S. et al. 1982. Combined Vitamin A and therapy prevents retinal electrophysiological deterioration in abetalipoprotein. British J Ophthalmology 66(12), Dec., 767-770. Muller, D. P. et al. 1983. Vitamin E and neurological function: Abetalipoproteinaemia and other disorders of fat absorption. Ciba Found Symp 101, 106-121. Hegele, R. A. and Angel, A. 1985. Arrest of neuropathy and myopathy in abetalipoproteinemia with high-dose Vitamin E therapy. Canadian Med Assoc J 132(1), Jan., 1, 41-44. Dose: 3200mg/day over 7 years. Aging Polidori MC. Antioxidant micronutrients in the prevention of age-related diseases. J Postgrad Med. 2003 Jul-Sep;49(3):229-35. Courtiere, A. et al. 1989. [Lipid peroxidation in aged patients. Influence of an antioxidant combination (vitamin C-vitamin E-rutin)]. Therapie 44(1) Jan.-Feb., 13-17. Alzheimer's disease Sano M. Noncholinergic treatment options for Alzheimer's disease. J Clin Psychiatry. 2003;64 Suppl 9:23-8. Klatte ET, Scharre DW, Nagaraja HN, Davis RA, Beversdorf DQ. Combination therapy of donepezil and vitamin E in Alzheimer disease. Alzheimer Dis Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 144
Assoc Disord. 2003 Apr-Jun;17(2):113-6. Adams, Jr., J. D. et al. 1991. Alzheimer's and Parkinson's Disease. Brain levels of glutathione, glutathione disulfide, and Vitamin E. Mol Chem Neuropathol. 14(3), June, 213-226. Anemia 44 Juan-Salles C, Prats N, Resendes A, Domingo M, Hilton D, Ruiz JM, Garner MM, Valls X, Marco AJ. Anemia, myopathy, and pansteatitis in vitamin Edeficient captive marmosets (Callithrix spp.). Vet Pathol. 2003 Sep;40(5):540-7. Ono, K. 1985. Effects of large dose of Vitamin E supplementation on anemia in hemodialysis patients. Nephron, 40(4), 440-445. Dose: 600mg/day for 30 days. Arthritis Can C, Cinar MG, Kosay S, Evinc A. Vascular endothelial dysfunction associated with elevated serum homocysteine levels in rat adjuvant arthritis: effect of vitamin E administration. Life Sci. 2002 Jun 14;71(4):401-10. Honkanen, V. E. et al. 1990. Serum cholesterol and Vitamins A and E in juvenile chronic arthritis. Clin Exp Pheumatol 8(2), Mar.-Apr., 187-191. Honkanen, V. E. et al. 1989. Vitamins A and E, retinol binding protein and zinc in Rheumatoid Arthritis. Clin Exp Pheumatol 7(5), Sept.-Oct., 465-469. Ataxia Roubertie A, Biolsi B, Rivier F, Humbertclaude V, Cheminal R, Echenne B. Ataxia with vitamin E deficiency and severe dystonia: report of a case. Brain Dev. 2003 Sep;25(6):442-5. Rayner, R. J. et al. 1993. Isolated Vitamin E deficiency and progressive ataxia. Arch Dis Child 69(5), Nov., 602-603. Brain injury Ikeda Y, Mochizuki Y, Nakamura Y, Dohi K, Matsumoto H, Jimbo H, Hayashi M, Matsumoto K, Yoshikawa T, Murase H, Sato K. Protective effect of a novel vitamin E derivative on experimental traumatic brain edema in rats-preliminary study. Acta Neurochir Suppl. 2000;76:343-5. Dzandzhgava, T. G. and Shakarishvili, R. R. 1991. [Effect of alphatocopherol and selenium on the activity of antioxidant enzymes and level of lipid peroxidation products in erythrocytes of patients with cerebral ischemia]. Vopr Med Khim 37(5), Sept.-Oct. 79-82. Cancer Neuzil J. Vitamin E succinate and cancer treatment: a vitamin E prototype for selective antitumour activity. Br J Cancer. 2003 Nov 17;89(10):1822-6. 45 Zu K, Ip C. Synergy between selenium and vitamin E in apoptosis induction is associated with activation of distinctive initiator caspases in human prostate cancer cells. Cancer Res. 2003 Oct 15;63(20):6988-95. Kneky, P. et al. 1991. Vitamin E and cancer prevention. Am J Clin Nutr 53(1 Suppl), Jan., 283S-286S. Kneky, R. et al. 1988. Serum Vitamin E and risk of cancer among Finnish men during a 10-year follow-up. Am J Epidemiology 127(1), Jan., 28-41. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 145
Knekt, P. et al. 1991. Dietary antioxidants and the risk of lung cancer. Am J Epidemiology 134(5), Sept. 1, 471-479. Garewal, H. S. and Schantz, S. 1995. Emerging role of beta-carotene and antioxidant nutrients in prevention of oral cancer. Arch Otalaryngol Head Neck Surg 121(2), Feb., 141-144. Wald, N. J. et al. 1984. Plasma retinol, beta-carotene and Vitamin E levels in relation to the future risk of breast cancer. British J Cancer 49(3), Mar., 321324. Wald, N. J. et al. 1987. Serum Vitamin E and subsequent risk of cancer. British J Cancer 56(1), July, 69-72. Salonen, J. T. et al. 1985. Risk of cancer in relation to serum concentrations of selenium and Vitamins A and E: Matched case-control analysis of prospective data. British Med J 290(6466), Feb. 9, 417-420. London, R. S. et al. 1981. Endocrine parameters and alpha-tocopherol therapy of patients with mammary dysplasia. Cancer Res 41(9 Pt 2), Sept., 3811-3813. Dose: 600 units/day. Taylor, P. R. et al. 1994. Prevention of esophageal cancer: The nutrition intervention trials in Linxian, China: Linxian nutrition intervention trials study group. Cancer Res. 54(7 Suppl), April 1, 2029s-2031s. Dose: 30-60IU/day for 5.25 years. Bostick, R. M. et al. 1993. Reduced risk of colon cancer with high intake of Vitamin E: The Iowa Women's Health Study. Cancer Res 53(18), Sept. 15, 4230-4237. Zheng, W. et al. 1993. Serum micronutrients and the subsequent risk of oral and pharyngeal cancer. Cancer Res 53(4) Feb. 15, 795-798. Menkes, M. J. 1986. Vitamin A, E, Selenium and risk of lung cancer. Dissertation Abstracts Int. 46(11), 3807. 46 Longnecker, M. P. et al. 1992. Serum alpha-tocopherol concentration in relation to subsequent colorectal cancer: Pooled data from five cohorts. J National Cancer Inst. 84(6), Mar. 18, 430-435. Menkes, M. S. et al. 1986. Serum beta-carotene, Vitamins A and E, selenium, and the risk of lung cancer. NEJM 315(20), Nov. 13, 1250-1254. Wei, Q. et al. 1993. Vitamin supplementation has a protective effect on basal cell carcinoma. Am Soc Preventive Oncology, 17th Annual Meeting, Mar. 20-23, Tuscon, AR. Does: greater than 100 IU/day. Knekt, P. 1993. Vitamin E and smoking and the risk of lung cancer. Annals NY Acad Sci. 686, May 28, 280-287. London, S. J. et al. 1992. Carotenoids, retinol, and Vitamin E and risk of proliferative benign breast disease and breast cancer. Cancer Causes Control 3(6), Nov., 503-512. Benner, S. F. et al. 1994. Reduction in oral mucosa micronuclei frequency following alpha-tocopherol treatment of oral leukoplakia. Cancer Epidemiol Biomarkers Prev. 3(1), Jan.-Feb., 73-76. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 146
Dose: 400 IU. de Vries, N. and Snow, G. B. 1990. Relationships of Vitamins A and E and beta-carotene serum levels to head and neck cancer patients with and without second primary tumors. Eur Arch Otorhinolaryngol 247(6), 368-370. Garewal, H. 1982. Chemoprevention of oral cancer: Beta-carotene and Vitamin E in leukoplakia. European J Cell Biology 28(1), Aug., 92-97. Knekt, P. et al. 1988. Serum Vitamin E, serum selenium and the risk of gastrointestinal cancer. Int J Cancer 42(6), Dec. 15, 846-850. Knekt, P. 1988. Serum Vitamin E level and risk of female cancers. Int J Epidemiology 17(2), June, 281-286. Prasad, K. N. and Edwards-Prasad, J. 1992. Vitamin E and cancer prevention: Recent advances and future potentials. J Am College Nutr. 11(5), Oct. 487-500. Torun, M. et al. 1995. Serum Vitamin E level in patients with breast cancer. J Clin Pharm Ther., 20(3), June, 173-178. Lockwood, K. et al. ?. Apparent partial remission of breast cancer in 'high risk' patients supplemented with nutritional antioxidants, essential fatty acids and coenzyme Q10. Mol Aspects Med., 15(Suppl), 231-240. Dose: 2500 IU. Palan, R. R. et al. 1991. Plasma levels of antioxidant beta-carotene and alpha-tocopherol in uterine cervix dysplasias and cancer. Nutr Cancer 15(1), 13-20. LeGardeur, B. Y. et al. 1990. A case-control study of serum Vitamins A, E, and C in lung cancer patients. Nutr Cancer 14(2), 133-140. Wadleigh, R. et al. 1990. Vitamin E in the treatment of chemotherapyinduced mucosisitis. Proceedings Annual Meeting Am Soc Clin Oncologists 9, A1237. Dose: 400 mg/ml applied to lesions for 1 week. Dimery, I. et al. 1992. Reduction in toxicity of high dose 13-CIS-Retinoic acid (13-CRA) with alpha-tocopherol. Proc Annual Meeting Am Soc Clin Oncologists 11, A399. Dose: 800, 1200, 1600, 2000 IU/day 4 week cycle. Sukolinskii, V. N. and Morozkina, T. S. 1989. [Prevention of postoperative complications in patients with stomach cancer using an antioxidant complex]. Vopr Onkol 35 (10), 1242-1245. Gorozhanskaia, E. G. et al. 1995. [The role of alpha-tocopherol and retinol in correcting disorders of lipid peroxidation in patients with malignant liver neoplasms]. Vopr Onkol 41(1), 47-51. Dose: 600 mg for 7 days prior to surgery. Cardiovascular/Coronary heart disease Salonen, J. T. et al. 1991. Effects of antioxidant supplementation on platelet function: A randomized pair-matched, placebo-controlled, double-blind trial in men with low antioxidant status. Am J Clin Nutr 53(5) May, 1222-1229. Dose: 300 mg/day for 5 months. Bellizz, M. C. et al. 1994. Vitamin E and coronary heart disease: The Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 147
European paradox. Eur J Clin Nutr. 48(11), Nov., 822-831. Dose: 1 capsule of palmvitee/day for 30 days. Tan, D. T. et al. 1991. Effect of a palm-oil-vitamin E concentrate on the serum and lipoprotein lipids in humans. Am J Clin Nutr. 53(4 Suppl), Apr. 1027S-1030S. Qureshi, A. A. et al. 1991. Lowering of serum cholesterol in hypercholesterolemic humans by tocopherols (Palmvitee). Am J Clin Nutr. 53(4 Suppl), Apr. 1021S-1026S. Dose: 200 mg palmvitee capsules/day or 200mg gamma-tocotrienol/day for 4 weeks. 48 Paolisso, G. et al. 1995. Chronic intake of pharmacological doses of Vitamin E might be useful in the therapy of elderly patients with coronary heart disease. Am J Clin Nutr. 61(4), Apr., 848-852. Dose: 900 mg/day for 4 months. Brown, K. M. et al. 1994. Vitamin E supplementation suppresses indexes of lipid peroxidation and platelet counts in blood of smokers and nonsmokers but plasma lipoprotein concentrations remain unchanged. Am J Clin Nutr. 60(3), Sept., 383-387. Dose: 280 mg/day for 10 weeks. Steiner, M. et al. 1995. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks. Am J Clin Nutr 62(6 Suppl), Dec., 1381S-1384S. Dose: 400 IU/day for up to 2 years. Chan, A. C. et al. 1986. Transitory stimulation of human platelet 12lipoxygenase by Vitamin E supplementation . Am J Clin Nutr. 44(2), Aug., 278-282. 400 IU/day of either D- or DL- alpha-tocopherol for 4 weeks. Guetta, V. et al. 1995. Effect of combined 17 beta-estradiol and Vitamin E on low-density lipoprotein oxidation in postmenopausal women. Am J Clin Cardiology 75(17), June 15, 1274-1276. Knekt, P. et al. 1994. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiology. 139(12), June 15, 11801189. Sisto, T. et al. 1995. Pretreatment with antioxidants and Allopurinol diminishes cardiac onset events in coronary artery bypass grafting. Ann Thorac Surg, 59(6), June, 1519-1523. Princen, H. M. et al. 1992. Supplementation with Vitamin E but not betacarotene in vivo protects low density lipoprotein from lipid peroxidation in vitro: Effect of cigarette smoking. Arteriosclerosis Thrombosis 12(5), May, 554-562. Dose: 100 IU/day of DL-alpha-tocopherol. Reaven, P. D. and Witzum, J. L. 1993. Comparisons of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans. Effects on lipid levels and lipoprotein susceptibility to oxidation. Arterioscler Thromb 13 (4), Apr., 601-608. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 148
Reaven, P. D. et al. 1993. Effect of dietary antioxidant combinations in humans: Protection of LDL by vitamin E but not by beta-carotene. Arterioscler Thromb 13(4), Apr., 590-600. 49 Kritchevsky, S. B. et al. Dietary antioxidants and carotid artery wall thickness: The ARIC study. Atherosclerosis risk in communities study. Circulation 92(8), Oct. 15, 2142-2150. Jialal, I. and Grundy, S. M. 1993. Effect of combined supplementation with alpha-tocopherol, ascorbate, and beta-carotene on low-density lipoprotein oxidation. Circulation 88(6), Dec., 2780-2786. Dose: 800 IU/day. Luoma, P. V. et al. 1995. High serum alpha-tocopherol, albumin, selenium and cholesterol, and low mortality from coronary heart disease in Northern Finland. J Internal Med 237(1), Jan., 49-54. Haglund, O. et al. 1991. The effects of fish oil on triglycerides, cholesterol, fibrinogen and malondialehyde in humans supplemented with Vitamin E. J Nutr. 121(2), Feb., 165-169. Hodis, H. N. et al. 1995. Serial coronary angiographic evidence that antioxidant Vitamin intake reduces progression of coronary artery atherosclerosis. JAMA 273(23), June 21, 1849-1854. Dose: 100 IU/day or more. Fuenmayor, A. J. et al. Vitamin E and ventricular fibrillation threshold in myocardial ischemia. Japanese Circulation J 53(10), Oct., 1229-1232. Riemersma, R. A. et al. 1991. Risk of angina pectoris and plasma concentrations of Vitamins A, C, and E and Carotene. Lancet 337(8732), Jan. 5, 1-5. Kardinaal, A. F. et al. Antioxidants in adipose tissue and risk of myocardial infarction: The EURAMIC study. Lancet 342(8884), Dec. 4, 1379-1384. Rimm, E. B. et al. 1993. Vitamin E consumption and the risk of coronary heart disease in men. NEJM 328(20), May 20, 1450-1456. Dose: 60 IU/day or more. Stampfer, M. J. et al. 1993. Vitamin E consumption and the risk of coronary disease in women. NEJM 328(20), May 20, 1444-1449. Singh, R. B. et al. 1994. Diet, antioxidant vitamins, oxidative stress and risk of coronary artery disease: The Peerzada prospective study. Acta Cardiol 49(5), 453-467. Knight, J. A. et al. 1993. The effect of Vitamins C and E on lipid peroxidation in stored erythrocytes. Ann Clin Lab Sci 23(1), Jan.-Feb., 51-56. Postaire, E. et al. 1995. Increase of singlet oxygen protection of erythrocytes by Vitamin E, Vitamin C, and beta-carotene intakes. Biochem Mol Biol Int 35(2) Feb., 371-374. 50 Dose: 15 mg/day for 15 days. Kleijnen, J. et al. 1989. Vitamin E and cardiovascular disease. European J Clin Pharmacol 37(6), 541-544. Gey, K. F. 1989. Inverse correlation of Vitamin E and ischemic heart Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 149
disease. Int J Vitamin Nutr Res Suppl 30, 224-231. Dmoszynska-Giannopoulou, A. et al. 1987. Alpha-tocopherol: Effect of sulphinpyrazone and alpha-tocopherol on platelet activation and function in haemodialysed patients. Int Urol Nephrol 22(6), 561-566. Cloarec, M. J. et al. Alpha-tocopherol: Effect on plasma lipoproteins in hypercholesterolemic patients. Israeli J Med Sci 23(8), Aug., 869-872. Dose: 500 IU/day for 3 months. Rifici, V. A. and Khachadurian, A. K. 1993. Dietary supplementation with Vitamins C and E inhibits in vitro oxidation of lipoproteins. J Am Coll Nutr 12(6), Dec., 631-637. Dose: 800 IU/day. Lenzhofer, R. et al. 1983. Acute cardian toxicity in patients after Doxorubucin treatment and the effect of combined tocopherol and Nifedipine pretreatment. J Cancer Res Clin Oncol 106(2), 143-147. Yukawa, S. et al. 1992. Prevention of aortic calcification in patients on hemodialysis by long-term administration of Vitamin E. J Nutr Sci Vitaminol. Spec No:187-90. Dose: 600 mg/day for 2 weeks. Gey, K. F. et al. 1994. [Essential antioxidants on cardiovascular diseasesLessons for Europe]. Ther Unsch 51(7), July, 475-482. Dose: 100 mg/day. Steiner, M. 1993. Effect of alpha-tocopherol administration on platelet function in man. Thromb Haemost 49(2), Apr. 28, 73-77. Dose: 400-1200 IU/day over 6 weeks. Cataracts Mathew JP, Thomas VC, Thomas I. Selenite cataract and its attenuation by vitamin E in Wistar rats. Indian J Ophthalmol. 2003 Jun;51(2):161-70. Jacques, P. F. et al. 1988. Antioxidants status in persons with and without senile cataract. Arch Ophthalmol 106(3), Mar., 337-340. 51 Knekt, P. et al. 1992. Serum antioxidant Vitamins and risk of cataract. British Med J 305(6866), Dec. 5, 1392-1394. Robertson, J. M. et al. 1989. Vitamin E intake and risk of cataracts in humans. Ann NY Acad Sci 570, 372-382. Cystic Fibrosis Winklhofer-Roob BM, Rock E, Ribalta J, Shmerling DH, Roob JM. Effects of vitamin E and carotenoid status on oxidative stress in health and disease. Evidence obtained from human intervention studies. Mol Aspects Med. 2003 Dec;24(6):391-402. Sitrin, M. D. et al. 1987. Vitamin E deficiency and neurologic disease in adults with cystic fibrosis. Annals Int Med, 107(1), July, 51-54. Sung, J. H. et al. 1980. Axonal dystrophy in the gracile nucleus in congenital biliary atresia and cystic fibrosis (mucoviscidosis): Beneficial effect of Vitamin E therapy. J Neuropathol Exp Neurol, 39(5), Sept., 584-597. Cynamon, H. A. et al. 1988. Effect of Vitamin E deficiency on neurologic function in patients with cystic fibrosis. J Pediatrics, 113(4), Oct., 637-640. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 150
Elias, E. et al. 1981. Association of spinocerebellar disorders with cystic fibrosis or chronic childhood cholestasis and very low serum Vitamin E. Lancet, 2(8259), Dec. 12, 1319-1321. James. D. R. et al. 1991. Increased susceptibility to peroxide-induced haemolysis with normal Vitamin E concentrations in cystic fibrosis. Clin Chim Acta, 204(1-3), Dec. 31, 279-290. Diabetes Hirnerova E, Krahulec B, Strbova L, Stecova A, Dekret J, Hajovska A. Effect of vitamin E therapy on progression of diabetic nephropathy. Vnitr Lek. 2003 Jul;49(7):529-34. Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, Griffin M, Ippolito E, Bavera P. Evaluation of the local effects of vitamin E (EMousse) on free radicals in diabetic microangiopathy: a randomized, controlled trial. Angiology. 2003 Jul-Aug;54(4):415-21. Colette, C. et al. 1988. Platelet function in Type I diabetes: Effects of supplementation with large doses of Vitamin E. Am J Clin Nutr 47(2), Feb., 256-261. Dose: 1 gm/day for 35 days. Paolisso, G. et al. Pharmacologic doses of Vitamin E improve insulin action in healthy subjects and non-insulin-dependent diabetic patients. Am J Clin Nutr 57(5), May, 650-656. Dose: 900 mg/day for 4 months. Salonen, J. T. et al. 1995. Increased risk of non-insulin dependent Diabetes Mellitus at low plasma Vitamin E concentrations: A four year follow-up study in men. British Med J 311(7013), Oct. 28, 1124-1127. Karpen, C. W. et al. 1984. Interrelation of platelet Vitamin E and thromboxane synthesis in type I Diabetes Mellitus. Diabetes, 33(3), Mar., 239-243. Watanabe, J. et al. 1984. Effect of Vitamin E on platelet aggregation in Diabetes Mellitus. Thromb Haemost, 51(3), July 29, 3130316. Karpen, C. W. et al. 1985. Production of 12-hydroyeicosatetraenoic acid and Vitamin E status in platelets from type I human diabetic subjects. Diabetes 34(6), June, 526-531. Caballero, B. 1993. Vitamin E improves the action of insulin. Nutr Rev, 51(11), Nov., 339-340. Kunisaki, M. et al. 1990. Effects of Vitamin E administration on platelet function in Diabetes Mellitus. Diabetes Res, 14(1), May, 37-42. Dose: 600 mg/day. Dmoszynska-Giannopoulou, A. et al. 1989. [Effect of Vitamin E on the function of blood platelets in patients with Diabetes Mellitus], Pol Tyg Lek, 44(21-22), May 22-29, 496-498. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 151
Dose: 1000 mg/day. Dzhavad-zade, M. D. et al. 1992. [Disorders of pulmonary hemodynamics in patients with Diabetic Nephroangiopathy and its correction with antioxidants], Probl Endokrinol, 38(2), Mar.-Apr., 20-22. Dose: 8 mcg/kg/day for 2 weeks. Mamedgasanov, R. M. and Rakhmani, S. A. [Dynamics of lipid peroxidation in patients with noninsulin-dependent Diabetes Mellitus], Probl Endokrinol, 35(1), Jan.-Feb., 19-21. Balabolkin, M. I. et al. 1994. [Effect of high doses of tocopherol on the process of lipid peroxidation and insulin secretion in patients with noninsulindependent Diabetes Mellitus], Probl Endokrinol, 40(3), May-June, 10-12. Dose: 600-1200 mg/day. Kuznetsov, N. S. et al. 1993. [The use of antioxidants (alpha-tocopherol acetate) in the treatment of Diabetes Mellitus], Probl Endokrinol, 39(2), Mar.-Apr., 9-11. Dose: 300 mg/day. Watanabe, J. et al. 1984. Effect of Vitamin E in platelet aggregation in Diabetes Mellitus. Tohoku J Exp Med, 143(2), June, 161-169. Splavskii, O. I. 1982. [Effectiveness of Vitamin E in the combined therapy of the hepatobiliary system lesions in Diabetes Mellitus]. Vopr Pitan, (6), Nov.Dec., 36-39. Gerster, H. et al. 1993. Prevention of platelet dysfunction by Vitamin E in diabetic athersclerosis. Z Ernahrungswiss 32(4), Dec., 243-261. Disseminated Granuloma Anulare Burg G. Disseminated granuloma anulare: therapy with vitamin E topically. Dermatology. 1992;184(4):308-9. Goldstein RK, Zillikens D, Miller K, Elsner P, Burg G. Local treatment of disseminated granuloma anulare with a vitamin E emulsion. Hautarzt. 1991 Mar;42(3):176-8. Epilepsy Oztas B, Kilic S, Dural E, Ispir T. Influence of antioxidants on the blood-brain barrier permeability during epileptic seizures. J Neurosci Res. 2001 Nov 15;66(4):674-8. Ogunmekan, A. O. and Hwang, P. A. 1989. A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopherol acetate (Vitamin E), as Add-on therapy, for epilepsy in children. Epilepsia, 30(1), Jan.-Feb., 8489. Kovalenko, V. M. et al. 1984. [Alpha-tocopherol in the complex treatment of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 152
several forms of epilepsy]. Zh Nevropatol Psikhiatr, 84(6), 892-897. Dose: 600 mg/day Megrabian, A. A. et al. 1986. [Use of lithium carbonate and Vitamin E in the complex treatment of epileptics]. Zh Nevropatol Psikhiatr, 86(9), 1407-1410. Gastrointestinal Disease Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot WJ, Dong ZW, Mark SD. Prospective study of serum vitamin E levels and esophageal and gastric cancers. J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6. Beno, I. et al. 1994. The activity of Cu/Zn-superoxide dismutase and catalase of gastric mucosa in chronic gastritis, and the effect of alphatocopherol. Bratisl Lek Listy, 95(1), Jan., 9-14. Feher, J. and Pronai, L. 1993. [Role of free radical scavengers in gastrointestinal diseases], Orv Hetil, 34(13), Mar. 28, 693-696. General Bidoli E, Bosetti C, La Vecchia C, Levi F, Parpinel M, Talamini R, Negri E, Maso LD, Franceschi S. Micronutrients and laryngeal cancer risk in Italy and Switzerland: a case-control study. Cancer Causes Control. 2003 Jun;14(5):477-84 Johnson KA, Bernard MA, Funderburg K. Vitamin nutrition in older adults. Clin Geriatr Med. 2002 Nov;18(4):773-99. Wartanowicz, W. et al. 1984. The effect of alpha-tocopherol and ascorbic acid on the serum lipid peroxide level in elderly people. Anna Nutr Metab, 28(3), 186-191. Dose: 200 mg/day for 4 months. Regnault, C. et al. 1993. Influence of beta carotene,, Vitamin E, and Vitamin C on endogenous antioxidant defenses in erythrocytes. Ann Pharmacother, 27(11), Nov., 1349-1350. Denzlinger, C. et al. 1995. Modulation of the endogenous leukotriene production by fish oil and Vitamin E. J Lipid Mediat Cell Signal, 11(2), Mar., 119-132. Dose: 800 IU/day. Hearing loss Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. Antioxidants in treatment of idiopathic sudden hearing loss. Otol Neurotol. 2003 Jul;24(4):5725. Romeo, G. 1985. The therapeutic effect of Vitamins a and E in neurosensory hearing loss. Acta Vitaminol Enzymol, 7 Suppl, 85-92. Romeo, G. and Giorgetti, M. 1985. [Therapeutic effects of Vitamin A associated with Vitamin E in perceptual hearing loss], Acta Vitaminol Enzymol, 7(1-2), 139-143. Hemodialysis Badiou S, Cristol JP, Morena M, Bosc JY, Carbonneau MA, Dupuy AM, Descomps B, Canaud B. Vitamin E supplementation increases LDL resistance to ex Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 153
vivo oxidation in hemodialysis patients. Int J Vitam Nutr Res. 2003 Jul;73(4):2906. Giardini, O. et al. 1984. Effects of alpha-tocopherol administration on red blood cell membrane lipid peroxidation in hemodialysis patients. Clin Nephrol, 21(3), Mar., 174-177. Hemolysis Usberti M, Gerardi G, Micheli A, Tira P, Bufano G, Gaggia P, Movilli E, Cancarini GC, De Marinis S, D'Avolio G, Broccoli R, Manganoni A, Albertin A, Di Lorenzo D. Effects of a vitamin E-bonded membrane and of glutathione on anemia and erythropoietin requirements in hemodialysis patients. J Nephrol. 2002 Sep-Oct;15(5):558-64. Prussick, R. et al. 1992. The protective effect of Vitamin E on the hemolysis associated with dapsone treatment in patients with dermatitis herpetiformis. Arch Dermatol, 128(2)Feb., 210-213. Dose: 800 IU/day for 4 weeks. Hafez, M, et al. 1986. Improved erythrocyte survival with combined vitamin E and selenium therapy in children with glucose-6-phosphate dehydrogenase deficiency and mild chronic hemolysis. J Pediatrics, 108(4), Apr., 558-561. Dose: 800 IU/day for 2 months. Corash, L. et al. 1980. Reduced chronic hemolysis during high-dose Vitamin E administration in Mediterranean-type glucose-6-phosphate dehydrogenase deficiency. New England J Med, 303(8), Aug. 12, 416-420. Yalcin, A. S. et al. 1989. The effect of Vitamin E therapy on plasma and erythrocyte lipid peroxidation in chronic hemodialysis patients. Clin Chim Acta, 185(1), Oct. 31, 109-112. Dose: 300 mg/day for 1 month. Hepatitis Xu M, Hou J, Wu Y, Ling Y. Study on the modulation of the inflammatory response in mouse hepatic vasculitis with sodium selenite and vitamin E antioxidants. Zhonghua Bing Li Xue Za Zhi. 2000 Aug;29(4):279-83. Han, Y. C. 1993. [Study of anti-lipid peroxidation of Vitamin E in human body]. Chung Hua Yu Fang I Hsueh Tsa Chih, 27(3), May, 132-134. Dose: 200 mg/day after 10 days. Immune enhancement Ortuno J, Esteban MA, Meseguer J. High dietary intake of alpha-tocopherol acetate enhances the non-specific immune response of gilthead seabream (Sparus aurata L.). Fish Shellfish Immunol. 2000 May;10(4):293-307. Meydani, S. N. et al. 1990. Vitamin E supplementation enhances cellmediated immunity in healthy elderly subjects. Am J Clin Nutr, 52(3), Sept., 557-563. Dose: 800 mg/day for 30 days. Kowdley, K. V. et al. 1992. Vitamin E deficiency and impaired cellular Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 154
immunity related to intestinal fat malabsorption. Gastroenterology 102(6), June, 2139-2142. Penn, N. D. et al. 1991. The effect of dietary supplementation with Vitamins A, C and E on cell-mediated immune function in elderly long-stay patients: A randomized controlled trial. Age Ageing, 20(3), May, 169-174. Taccone-Gallucci, M. et al. 1986. Vitamin E supplementation in hemodialysis patients: Effects on peripheral blood mononuclear cells lipid peroxidation and immune response. Clin Nephrol, 25(2), Feb., 81-86. Gaidova, O. S. et al. 1990. [The immunomodulating properties of Vitamin E in surgery involving artificial circulation], Grud serdechnososudistaia Khir, (12), Dec., 30-33. Dose: 40 mg/kg 3.5 hours prior to open heart surgery. Kidney disease/Damage Saran R, Novak JE, Desai A, Abdulhayoglu E, Warren JS, Bustami R, Handelman GJ, Barbato D, Weitzel W, D'Alecy LG, Rajagopalan S. Impact of vitamin E on plasma asymmetric dimethylarginine (ADMA) in chronic kidney disease (CKD): a pilot study. Nephrol Dial Transplant. 2003 Nov;18(11):2415-20. Bilenko, M. V. et al. 1983. [Use of antioxidants to prevent damage during acute ischemia and reperfusion of the kidneys], Biull Eksp Biol Med, 96(9), Sept., 8-11. Leg cramps Roca AO, Jarjoura D, Blend D, Cugino A, Rutecki GW, Nuchikat PS, Whittier FC. Dialysis leg cramps. Efficacy of quinine versus vitamin E. ASAIO J. 1992 JulSep;38(3):M481-5. Roca, A. O. et al. 1992. Dialysis leg cramps: Efficacy of quinine versus Vitamin E. ASAIO J, 38(3), July-Sept., M481-485. Dose: 400 IU/day. Mucositis Lopez I, Goudou C, Ribrag V, Sauvage C, Hazebroucq G, Dreyfus F. Treatment of mucositis with vitamin E during administration of neutropenic antineoplastic agents. Ann Med Interne (Paris). 1994;145(6):405-8. Wadleigh, R. G. et al. 1992. Vitamin E in the treatment of chemotherapyinduced Mucositis. Am J Med. 92(5) May, 481-484. Myotonic dystrophy Backman E, Henriksson KG. Effect of sodium selenite and vitamin E treatment in myotonic dystrophy. J Intern Med. 1990 Dec;228(6):577-81. Orndahl, G. et al. 1986. Myotonic dystrophy treated with selenium and Vitamin E. Acta Med Scand, 219(4), 407-414. Dose: 600 mg Vitamin E. Neurological function Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 155
Yargicoglu P, Yaras N, Agar A, Gumuslu S, Bilmen S, Ozkaya G. The effect of vitamin E on stress-induced changes in visual evoked potentials (VEPs) in rats exposed to different experimental stress models. Acta Ophthalmol Scand. 2003 Apr;81(2):181-7. Muller, D. P. et al. 1983. Vitamin E and neurological function. Lancet 1(8318), Jan. 29, 225-228. Muller, D. P. 1986. Vitamin E-Its role in neurological function. Postgraduate Med J, 62(724), Feb., 107-112. Lloyd, B. W. and Dubowitz, V. 1992. Progressive neurological disorders associated with obstructive jaundice and Vitamin E deficiency. Neuropediactrics, 13(3), Aug., 155-157. Davidai, G. et al. 1986. Hypovitaminosis E induced neuropathy in exocrine pancreatic failure. Arch Dis Child, 61(9), Sept., 901-903. Palmucci, L. et al. 1988. Neuropathy secondary to Vitamin E deficiency in acquired in acquired intestinal malabsorption. Italian J Neurol Sci, 9(6), Dec., 599-602. Neutrophil Hou J, Wu Y, Ling Y. Modulation of the inflammatory response through complement-neutrophil activation feedback mechanism with selenium and vitamin E. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2000 Dec;22(6):580-4. Chai, J. et al. 1995. [Protective effects of Vitamin E on impaired neutrophil phagocytic function in patients with severe burn]. Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 11(1), Jan., 32-35. Osteoarthritis Kaiki G, Tsuji H, Yonezawa T, Sekido H, Takano T, Yamashita S, Hirano N, Sano A. Osteoarthrosis induced by intra-articular hydrogen peroxide injection and running load. J Orthop Res. 1990 Sep;8(5):731-40. Blankenhorn, G. 1986. [Clinical effectiveness of Spondyvit (vitamin E) in activated arthroses: A multicenter placebo-controlled double-blind study], Z Orthop, 124(3), May-June, 340-343. Dose: 400 IU/day for 6 weeks. Scherak, O. et al. 1990. [High dose Vitamin E therapy in patients with activated arthrosis], Z Rheumatol, 49(6), Nov.-Dec., 369-373. Dose: 400 IU/day for 3 weeks. Machtey, I. and Ouaknine, L. 1978. Tocopherol in osteoarthritis: A Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 156
controlled pilot study. J Am Geriatric Soc, 26(7), July, 328-330. Dose: 600 mg/day for 10 days. Parkinson's disease Fariss MW, Zhang JG. Vitamin E therapy in Parkinson's disease. Toxicology. 2003 Jul 15;189(1-2):129-46. Fahn, S. 1992. A pilot trial of high-dose alpha-tocopherol and ascorbate in early Parkinson's disease. Ann Neurol, 32(Suppl), S128-S132. Dexter, D. T. et al. 1994. Nigrostriatal function in Vitamin E deficiency: Clinical, experimental, and positron emission tomographic studies. Ann Neurol, 35(3), Mar., 298-303. Peripheral neuropathy Lagueny A. Metabolic and nutritional neuropathies. Rev Prat. 2000 Apr 1;50(7):731-5. Traber, M. G. et al. 1987. Lack of tocopherol in peripheral nerves of vitamin E-deficient patients with peripheral neuropathy. NEJM, 317(5), July 30, 262265. Physical Performance Asha Devi S, Prathima S, Subramanyam MV. Dietary vitamin E and physical exercise: I. Altered endurance capacity and plasma lipid profile in ageing rats. Exp Gerontol. 2003 Mar;38(3):285-90. Simon-Schnass, I. and Pabst, H. 1988. Influence of Vitamin E on physical performance. Int J Vitam Nutr Res, 58(1), 49-54. Dose: 2x200 mg dl-alpha-tocopherol acetate for 10 weeks. Pulmonary health Wang S, Sun NN, Zhang J, Watson RR, Witten ML. Immunomodulatory effects of high-dose alpha-tocopherol acetate on mice subjected to sidestream cigarette smoke. Toxicology. 2002 Jun 14;175(1-3):235-45. Mohsenin, V. 1991. 1991. Lipid peroxidation and antielastase activity in the lung under oxidant stress: Role of antioxidant defenses. J Appl Physiology, 70(4), Apr., 1456-1462. Respiration Rocksen D, Ekstrand-Hammarstrom B, Johansson L, Bucht A. Vitamin E reduces transendothelial migration of neutrophils and prevents lung injury in endotoxin-induced airway inflammation. Am J Respir Cell Mol Biol. 2003 Feb;28(2):199-207. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 157
Richards, G. et al. 1990. Investigations of the effects of oral administration of Vitamin E and beta-carotene on the chemiluminescence responses and the frequency of sister chromatid exchanges in circulating leukocytes from cigarette smokers. Am Rev Respiratory Dis, 142(3), Sept., 648-654. Dose: 900 IU for 6 weeks. Skopinska-Rozewska, E. et al. 1987. The effect of Vitamin E treatment on the incidence of OKT+4 lymphocytes in the peripheral blood of children with chronic respiratory tract infections. Archives Immunol Ther Exp, 35(2), 207-210. Short Bowel Syndrome Tanyel MC, Mancano LD. Neurologic findings in vitamin E deficiency. Am Fam Physician. 1997 Jan;55(1):197-201. Howard, L. et al. 1982. Reversible neurological symptoms caused by Vitamin E deficiency in a patient with short bowel syndrome. Am J Clin Nutr, 36(6), Dec., 1243-1249. Traber, M. G. et al. 1994. Efficacy of water-soluble Vitamin E in the treatment of Vitamin E malabsorption in short-bowel syndrome. Am J Clin Nutr, 59(6), June, 1270-1274. Smoking Dyer AR, Elliott P, Stamler J, Chan Q, Ueshima H, Zhou BF; INTERMAP Research Group. Dietary intake in male and female smokers, ex-smokers, and never smokers: the INTERMAP study. J Hum Hypertens. 2003 Sep;17(9):641-54. Pacht, E. R. et al. 1986. Deficiency of Vitamin E in the alveolar fluid of cigarette smokers: Influence on alveolar macrophage cytotoxicity. J Clin Invest 77(3), Mar., 789-796. Hoshino, E. et al. 1990. Vitamin E suppresses increased lipid peroxidation in cigarette smokers. J Parenteral Enteral Nutr, 14(3), May-June, 300-305. Dose: 800 mg/day for 2 weeks. Spinocerebeller dysfunction Brin, M. F. et al. 1985. Blind loop syndrome, Vitamin E malabsorption, and spinocerebellar degeneration. Neurology, 35(3), Mar., 338-342. Spondylosis Mahmud, Z. and Ali, S. M. 1992. Role of Vitamin A and E in spondylosis. Bangladesh Med Res Counc Bull, 18(1), Apr., 47-59. Dose: 100 mg/day for 3 weeks. Steatorrhoea Rovner AJ, Schall JI, Jawad AF, Piccoli DA, Stallings VA, Mulberg AE, Zemel BS. Rethinking growth failure in Alagille syndrome: the role of dietary intake Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 158
and steatorrhea. J Pediatr Gastroenterol Nutr. 2002 Oct;35(4):495-502. Evans, D. J. et al. 1995. Symptomatic Vitamin E deficiency diagnosed after histological recognition of myometrial lipofuscinosis. Lancet 346(8974), Aug. 26, 545-546. Stress Banerjee AK, Mandal A, Chanda D, Chakraborti S. Oxidant, antioxidant and physical exercise. Mol Cell Biochem. 2003 Nov;253(1-2):307-12. Micheletta F, Natoli S, Misuraca M, Sbarigia E, Diczfalusy U, Iuliano L. Vitamin E Supplementation in Patients With Carotid Atherosclerosis. Reversal of Altered Oxidative Stress Status in Plasma But Not in Plaque. Arterioscler Thromb Vasc Biol. 2003 Oct 30. Meydani, M. et al. 1992. Vitamin E requirement in relation to dietary fish oil and oxidative stress in elderly. EXS, 62, 411-418. Rokitzki, L. et al. 1994. Alpha-tocopherol supplementation in racing cyclists during extreme endurance training. Int J Sport Nutr, 4(3), Sept., 253-264. Hartmann, A. et al. 1995. Vitamin E prevents exercise-induced DNA damage. Mutation Res, 346(4), Apr., 195-202. Dose: 1200 mg/day for 14 days. Tardive Dyskinesia Michael N, Sourgens H, Arolt V, Erfurth A. Severe tardive dyskinesia in affective disorders: treatment with vitamin E and C. Neuropsychobiology. 2002;46 Suppl 1:28-30. Egan, M. F. et al. 1992. Treatment of Tardive Dyskinesia with Vitamin E. Am J Psychiatry, 149(6), June, 773-777. Dose: 1600 IU/day for 6 weeks. Elkashef, A. M. et al. 1990. Vitamin E in the treatment of Tardive Dyskinesia. Am J Psychiatry 147(4), Apr., 505-506. Dabiri, L. M. et al. 1994. Effectiveness of Vitamin E for treatment of longterm Tardive Dyskinesia. Am J Psychiatry, 151(6), June, 925-926. Adler, L. A. et al. 1993. Vitamin E treatment of Tardive Dyskinesia. Am J Psychiatry, 150(9), Sept., 1405-1407. Dose: 1600 IU/day for 8-12 weeks. Bischot, L. et al. 1993. Vitamin E in extrapyramidal disorders. Pharm World Sci 15(4), Aug. 20, 1993, 146-150. Dose: 1600 IU/day. Adler, L. A. et al. 1993. Vitamin E in Tardive Dyskinesia: Time course of effect after placebo substitution. Psychopharmacol Bull, 29(3), 371-374. Lohr, J. B. et al. 1988. Vitamin E in the treatment of Tardive Dyskinesia: The possible involvement of free radical mechanisms. Schizophrenia Bull, 14(2), 291-296.
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Thyroid Dysfunction Mano T, Iwase K, Hayashi R, Hayakawa N, Uchimura K, Makino M, Nagata M, Sawai Y, Oda N, Hamada M, Aono T, Nakai A, Nagasaka A, Itoh M. Vitamin E and coenzyme Q concentrations in the thyroid tissues of patients with various thyroid disorders. Am J Med Sci. 1998 Apr;315(4):230-2. Venditti P, De Leo T, Di Meo S. Vitamin E administration attenuates the triiodothyronine-induced modification of heart electrical activity in the rat. J Exp Biol. 1997 Mar;200 ( Pt 5):909-14. Krishnamurthy, S. and Prasanna, D. 1984. Serum Vitamin E and lipid peroxides in malnutrition, hyper and hypothyroidism. Acta Vitaminol Exzymol, 6(1), 17-21. Danis, I. et al. 1990. [Vitamin E and malondialdehyde in the blood serum of thyrotoxicosis patients]. Probl Endokrinol, 36(5), Sept.-Oct. 21-24. Tuberculosis Plit ML, Theron AJ, Fickl H, van Rensburg CE, Pendel S, Anderson R. Influence of antimicrobial chemotherapy and smoking status on the plasma concentrations of vitamin C, vitamin E, beta-carotene, acute phase reactants, iron and lipid peroxides in patients with pulmonary tuberculosis. Int J Tuberc Lung Dis. 1998 Jul;2(7):590-6. Gur'eva, I. G. et al. [Antioxidants-Effective pathogenic agents in the combined therapy of Pulmonary Tuberculosis]. Ter Arkh 59(7), 72-74. Ulcerative colitis Sato K, Kanazawa A, Ota N, Nakamura T, Fujimoto K. Dietary supplementation of catechins and alpha-tocopherol accelerates the healing of trinitrobenzene sulfonic acid-induced ulcerative colitis in rats. J Nutr Sci Vitaminol (Tokyo). 1998 Dec;44(6):769-78. Bennet, J. D. 1986. Use of alpha-tocopherylquinone in the treatment of ulcerative colitis. Gut, 27(6), June, 695-697. Dose: 3 gm/day. Vitiligo Potapenko AY, Kyagova AA. The application of antioxidants in investigations and optimization of photochemotherapy. Membr Cell Biol. 1998;12(2):269-78. Koshevenko, I. 1989. [Alpha-tocopherol in the combined treatment of Vitiligo]. Vestn Dermatol Venerol, (10), 70-72. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 160
Wound healing Susaman N, Yalcin S, Ilhan N, Ozercan IH, Kaygusuz I, Karlidag T, Gok U. The effect of vitamin E on histopathologic healing and lipid peroxidation levels in experimentally induced traumatic tympanic membrane perforations. Kulak Burun Bogaz Ihtis Derg. 2003 Mar;10(3):87-92. Haberal, M. et al. 1988. The effects of Vitamin E on immune regulations after thermal injury. Burns Incl Therm Injuries, 14(5) Oct., 388-393. Yellow Nail Syndrome Tosti A, Piraccini BM, Iorizzo M. Systemic itraconazole in the yellow nail syndrome. Br J Dermatol. 2002 Jun;146(6):1064-7. Williams, H. C. et al. 1991. Successful use of topical Vitamin E solution in the treatment of nail changes in Yellow Nail Syndrome. Arch Dermatol, 127(7), July, 1023-1028. Omega fatty acids Arthritis Rennie KL, Hughes J, Lang R, Jebb SA. Nutritional management of rheumatoid arthritis: a review of the evidence. J Hum Nutr Diet. 2003 Apr;16(2):97-109. 64 Kremer, J. M. 1991. Clinical studies of Omega-3 fatty acid supplementation in patients who have Rheumatoid arthritis. Rheum Dis Clin North Am, 17(2) May, 391-402. Geusens, P. et al. 1994. Long-term effect of Omega-3 fatty acid supplementation in active Rheumatoid Arthritis. A 12-month, double-blind, controlled study. Arthritis Rheum 37(6), June, 824-829. Dose: 2.6 gm/day for 12 months. Cancer Dewailly E, Mulvad G, Sloth Pedersen H, Hansen JC, Behrendt N, Hart Hansen JP. Inuit are protected against prostate cancer. Cancer Epidemiol Biomarkers Prev. 2003 Sep;12(9):926-7. Kemen, M. et al. 1995 Early postoperative enteral nutrition with arginineomega3 fatty acids and ribonucleic acid-supplemented diet versus placebo in cancer patients: An immunologic evaluation of impact. Crit Care med 23(4), Apr., 652-659. Anti, M. et al. 1992. Effect of omega-3 fatty acids on rectal mucosal cell proliferation in subjects at risk for colon cancer. Gastroenterology, 103(3) Sept., 883-891. Dose: 4 g EPA, 3.6 g DHA for 12 weeks. Cardiovascular/Coronary heart disease Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 161
Lee KW, Lip GY. The role of omega-3 fatty acids in the secondary prevention of cardiovascular disease. QJM. 2003 Jul;96(7):465-80. Levine, P. H. et al. 1989. Dietary supplementation with Omega-3 fatty acids prolongs platelet survival in hyperlipidemic patients with atherosclerosis. Arch Intern Med 149(5) May, 1113-1116. Illingworth, D. R. et al. 1984. Inhibition of low density lipoprotein synthesis by dietary omega-3 fatty acids in humans. Arteriosclerosis. Arch Intern Med, 4(3), May-June, 270-275. Dose: 24 gm/day for 4 weeks. Harris, W. S. et al. 1984. Dietary omega-3 fatty acids prevent carbohydrateinduced hypertriglyceridemia. Metabolism, 33(11), Nov., 1016-1019. d'Ivernois, C. et al. [Potential value of omega-3 polyunsaturated fatty acids in the prevention of atherosclerosis and cardiovascular diseases], Arch Mal Coeur Vaiss, 85(6), June, 899-904. 65 Lox, C. D. 1990. The effects of dietary marine fish oils (Omega-3 fatty acids) on coagulation profiles in men. Gen Pharmacol, 21(2), 241-246. Dose: 900 mg over a period of 30 days. Engler, M. B. 1994. Vascular effects of omega-3 fatty acids: Possible therapeutic mechanisms in cardiovascular disease. J Cardiovascular Nurs, 8(3) Apr., 53-67. Lungershausen, Y. K. et al. 1994. Reduction of blood pressure and plasma triglycerides by omega-3 fatty acids in treated hypertensives. J Hypertension, 12(9), Sept., 1041-1045. Diabetes Christopher CL, Mathuram LN, Genitta G, Cyrus I, Jaya Sundar S. Omega-3 polyunsaturated fatty acids inhibit the accumulation of PAS-positive material in the myocardium of STZ-diabetic wistar rats. Int J Cardiol. 2003 Apr;88(2-3):183-90. Landgraf-Leurs, M. M. et al. 1990. Pilot study on omega-3 fatty acids in type I Diabetes Mellitus. Diabetes, 39(3), Mar., 369-375. Dose: 5.4 gm EPA, 2.3 gm DHA. Popp-Snijders, C. et al. 1987. Dietary supplementation of omega-3 polyunsaturated fatty acids improves insulin sensitivity in non-insulindependent diabetes. Diabetes Res, 4(3), Mar., 141-147. Dose: EPA and DHA 3 gm for 8 weeks. Evening Primrose Oil Arthritis Belch JJ, Hill A. Evening primrose oil and borage oil in rheumatologic conditions. Am J Clin Nutr. 2000 Jan;71(1 Suppl):352S-6S. Jantti, J. et al. 1989. Evening primrose oil in rheumatoid arthritis: Changes in serum lipids and fatty acids. Ann Rheum Disease, 48(2), Feb., 1240127. Dose: 20 ml evening primrose oil (EPO) containing 9% of gamma-linolenic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 162
acid for 12 weeks. Brzeski, M. et al. 1991. Evening primrose oil in patients with rheumatoid arthritis and side-effects of non-steroidal anti-inflammatory drugs. British J Rhheumatology, 30(5), Oct., 370-372. Dose: 6 gm/day 66 Eczema Ashcroft DM, Po AL. Herbal remedies: issues in licensing and economic evaluation. Pharmacoeconomics. 1999 Oct;16(4):321-8. Schlin-Karrila, M. et al. Evening primrose oil in the treatment of atopic eczema: Effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. British J Dermatology, 117(1), July, 11-19. Biagi, P. L. et al. 1988. A long-term study on the use of evening primrose oil (Efamol) in atopic children. Drugs Exp Clin Res, 14(4), 285-290. Diabetes Uccella, R. et al. [Action of evening primrose oil on cardiovascular risk factors in insulin-dependent diabetics]. Clin Ter, 129(5), June 15, 381-388. Dose: 3 gm/day. Schlin-Karrila, M. et al. Evening primrose oil in the treatment of atopic eczema: Effect on clinical status, plasma phospholipid fatty acids and circulating blood prostaglandins. British J Dermatology, 117(1), July, 11-19. Biagi, P. L. et al. 1988. A long-term study on the use of evening primrose oil (Efamol) in atopic children. Drugs Exp Clin Res, 14(4), 285-290. Diabetes Uccella, R. et al. [Action of evening primrose oil on cardiovascular risk factors in insulin-dependent diabetics]. Clin Ter, 129(5), June 15, 381-388. Dose: 3 gm/day. Takahashi, R. et al. 1993. Evening primrose oil and fish oil in non-insulindependentdiabetes. Prostaglandins Leukot Essent Fatt Acids, 49(2), Aug., 569-571. Dose: 4gm/day for 4 weeks. DMAE Hemiballismus-hemichorea Jameson, H. D. et al. 1977. Hemiballismus-hemichorea treated with dimethylaminoethanol. Dis Nerv Syst 38(11) Nov., 931-932 Phosphatidyl serine Alzheimer's disease Shea TB. Phospholipids alter tau conformation, phosphorylation, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 163
proteolysis, and association with microtubules: implication for tau function under normal and degenerative conditions. J Neurosci Res. 1997 Oct 1;50(1):114-22. Heiss, W. D. et al. 1994. Long-term effects of phosphatidylserine, pyritinol, and cognitive training in Alzheimer's Disease. A neuropsychological, EEG, and PET investigation. Dementia, 5(2), Mar.-Apr., 88-98. Dose: 400 mg/day. Engel, R. R. et al. 1992. Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol 2(2), June, 1992, 149-155. Dose: 300 mg/day for 8 weeks. Crook, T. et al. 1992. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull, 28(1), 61-66. Dose: 100 mg/day for 12 weeks. Brain Function Mitoma J, Kasama T, Furuya S, Hirabayashi Y. Occurrence of an unusual phospholipid, phosphatidyl-L-threonine, in cultured hippocampal neurons. Exogenous L-serine is required for the synthesis of neuronal phosphatidyl-L-serine and sphingolipids. J Biol Chem. 1998 Jul 31;273(31):19363-6. Lombardi, G. F. 1989. [Pharmacological treatment with phosphatidyl serine of 40 ambulatory patients with senile dementia syndrome]. Minerva Med 80(6), June, 599-602. Crook, T. H. et al. 1991. Effects of phosphatidylserine in the age-associated memory impairment. Neurology 41(5), May, 644-649. Dose: 100 mg for 12 weeks. Delwaide, P. J. et al. 1986. Double-blind randomized controlled study of phosphatidylserine in senile demented patients. Acta Neurol Scand, 73(2) Feb., 136-140. Dose: 3x100 mg. Maggioni, M. et al. (1990). Effects of phosphatidylserine therapy in geriatric patients with depressive disorders. Acta Psychiatr Scand, 81(3), Mar., 265270. Dose: 300 mg/day for 30 days. Cenacchi, T. t al. 1993. Cognitive decline in elderly: A double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging 5(2), Apr., 123-133. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 164
Dose: 300 mg/day Sakai, M. et al. 1996. Pharmacological effect of phosphatidylserine enzymatically synthesized from soybean lecithin on brain functions in rodents. J Nutr Sci Vitaminol 42(1), Feb., 47-54. Dose: 300 mg/day. Epilepsy Loeb, C. et al. 1987. Preliminary evaluation of the effect of GABA and phosphatidylserine in epileptic patients. Epilepsy Res, 1(3), May, 209-212. Parkinson's disease Finfgeld, E. W. et al. 1989. Double-blind study with phosphatidylserine (PS) in Parkinsonian patients with senile dementia of Alzheimer's type. Prog Clin Biol Res, 1235-1246. Schizophrenia Tachik, K. H. et al. 1986. Phosphatidyleserine inhibition of monoamine oxidase in platelets of schizophrenics. Biol Psychiatry 21(1), Jan., 59-68. Stress Sohi KK, Mittal N, Hundal MK, Khanduja KL. Gallic acid, an antioxidant, exhibits antiapoptotic potential in normal human lymphocytes: A Bcl-2 independent mechanism. J Nutr Sci Vitaminol (Tokyo). 2003 Aug;49(4):221-7. Monteleone, P. et al. 1992. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamopituitaryadrenal axis in healthy men. European J Clin Pharmacol 42(4), 385-388. Dose: 800 mg/day for 10 days. Monteleone, P. et al. 1990. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology, 52(3), 243-248. Dose: 50 and 75 mg/day. Calcium Calcium Pancreatitis Kaur, N. et al. 1996. Chronic calcific pancreatitis associated with osteomalacia and secondary hyperparathyroidism. Indian J Gastroenterology 15(4) Oct., 147-148. Calcium absorption
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Harvey, J. A. et al. 1990. Superior calcium absorption from calcium citrate than calcium carbonate using external forearm counting. J Am Coll Nutr, 9(6), Dec., 583-587. Cancer Kim JA, Kang YS, Lee YS. Role of Ca2+-activated Cl- channels in the mechanism of apoptosis induced by cyclosporin A in a human hepatoma cell line. Biochem Biophys Res Commun. 2003 Sep 19;309(2):291-7. Duris, I. et al. Calcium chemoprevention in colorectal cancer. Hepatogastroenterology, 43(7), Jan.-Feb., 152-154. Dental health Krall EA, Wehler C, Garcia RI, Harris SS, Dawson-Hughes B. Calcium and vitamin D supplements reduce tooth loss in the elderly. Am J Med. 2001 Oct 15;111(6):452-6. Gupta, S. K. et al. 1994. Reversal of clinical and dental fluorosis. Indian Pediatr, Apr., 439-443. Dose: 250 mg/day for 44 days. Hip fracture Dawson-Hughes B. Calcium and protein in bone health. Proc Nutr Soc. 2003 May;62(2):505-9. Meunier, P. 1996. Prevention of hip fractures by correcting calcium and Vitamin D insufficiencies in elderly people. Scand J Rheumatology, 103(Suppl), 75-78. Dose: 1.2 gm/day for a 3 year study. Hypertension Liao XD, Tang AH, Chen Q, Jin HJ, Wu CH, Chen LY, Wang SQ. Role of Ca2+ signaling in initiation of stretch-induced apoptosis in neonatal heart cells. Biochem Biophys Res Commun. 2003 Oct 17;310(2):405-11. Wimalawansa, S. J. 1993. Antihypertensive effects of oral calcium supplementation may be mediated through the potent vasodilator CGRP. Am J Hypertension, 6(12), Dec., 996-1002. Dose: 1.4 gm/day. Osteoporosis Koo WW, Warren L. Calcium and bone health in infants. Neonatal Netw. 2003 Sep-Oct;22(5):23-37. Adachi, J. D. et al. 1996. Vitamin D and calcium in the prevention of corticosteroid induced osteoporosis: A 3 year follow-up. J Rheumatology 23(6), June, 995-1000. Dose:1000 mg/day. Leyes-Vence, M. et al. 1996. Transient osteoporosis of the hip. Presentation of a case and literature review. Acta Orthop Belg, 62(1), Mar., 56-59. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 166
Prince, R. et al. 1995. The effects of calcium supplementation (milk powder of tablets) and exercise on bone density in postmodern women. J Bone Mineral Res 10(7), July, 1068-1075. Dose: 1 gm/night over a period of 2 years. Haines, C. J. et al. 1995. Calcium supplementation and bone mineral density in postmenopausal women using estrogen replacement therapy. Bone 16(5), may, 529-531. Warady, B. D. 1994. Effects of nutritional supplementation and bone mineral status of children with Rheumatic diseases receiving corticosteroid therapy. J Rheumatology, 21(3), mar., 530-535. Vestibulitis Metts JF. Vulvodynia and vulvar vestibulitis: challenges in diagnosis and management. Am Fam Physician. 1999 Mar 15;59(6):1547-56, 1561-2. Solomons, C. C. et al. 1991. Calcium citrate of vulvar vestibulitis. A case report. J Reproductive Med, 36(12), Dec., 879-882. Magnesium Gastrointestinal Problems Witham CL, Stull CL. Metabolic responses of chronically starved horses to refeeding with three isoenergetic diets. J Am Vet Med Assoc. 1998 Mar 1;212(5):691-6. Zartarian M, Perez JP, Gelas B, Thomas JL. Comparative study of the shortterm acceptability and tolerance of a new oral formulation of magnesium (TX 1341) and a reference magnesium. J Gynecol Obstet Biol Reprod (Paris). 1997;26(2):182-6. Sue, Y. J. et al. 1994. Efficacy of magnesium citrate cathartic in pediatric toxic ingestions. Ann Emerg Med, 24(4), Oct., 709-712. Acetyl L-Carnitine Aging Scapagnini G, Ravagna A, Bella R, Colombrita C, Pennisi G, Calvani M, Alkon D, Calabrese V. Long-term ethanol administration enhances age-dependent modulation of redox state in brain and peripheral organs of rat: protection by acetyl carnitine. Int J Tissue React. 2002;24(3):89-96. Cipolli, C. and Chiari, G. 1990. [Effects of L-acetylcarnitine on mental deterioration in the aged: Initial results]. Clin Ter, 132(6Suppl), Mar. 31, 479510. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 167
Dose: 1500 mg/day. Salvioli, G. and Neri, M. 1994. L-acetylcarnitine treatment of mental decline in the elderly. Drugs Exp Clin Res, 20(4), 169-176. Dose: 1500 mg/day for 90 days. Bella, R. et al. 1990. Effect of acetyle-L-carnitine on geriatric patients suffering from dysthymic disorders. Int J Clin Pharmacol Res, 10(6), 355360. Dose: 3 gm/day for 30-60 days. Passeri, M. et al. 1990. Acetyl-L-carnitine in the treatment of mildly demented elderly patients. Int J Clin Pharmacol Res, 101(1-2), 75-79. Dose: 2 gm/day for 3 months. Franceschi, C. et al. 1990. Immunological parameters in aging: Studies on natural immunomodulatory substances. Int J Clin Pharmacology Res 10(12), 53-57. Alcoholism Calabrese V, Scapagnini G, Latteri S, Colombrita C, Ravagna A, Catalano C, Pennisi G, Calvani M, Butterfield DA. Long-term ethanol administration enhances age-dependent modulation of redox state in different brain regions in the rat: protection by acetyl carnitine. Int J Tissue React. 2002;24(3):97-104. Tempesta, E. et al. 1990. Role of acetyl-L-carnitine in the treatment of cognitive deficit in chronic alcoholism. Int J Clin Pharmacology Res, 10(12), 101-107. Alzheimer's disease Bianchetti A, Rozzini R, Trabucchi M. Effects of acetyl-L-carnitine in Alzheimer's disease patients unresponsive to acetylcholinesterase inhibitors. Curr Med Res Opin. 2003;19(4):350-3. Sano, M. et al. 1992. Double-blind parallel design pilot study of acetyl levocarnitine in patients with Alzheimer's disease. Arch Neurol, 49(11), Nov., 1137-1141. Dose: 2.5 gm/day for 3 months. Spagnoli, A. et al. 1991. Long-term acetyl-L-carnitine treatment in Alzheimer's disease. Neurology, 41(11), Nov., 1726-1732. Rai, G. et al. 1990. Double-blind, placebo controlled study of acetyl-Lcarnitine in patients with Alzheimer's dementia. Curr Med Res Opin, 11(10), 638-647. Dose: 2 gm/day for 24 weeks. Parnetti, L. et al. 1992. Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 168
European J Clin Pharmacology, 42(1), 89-93. Pettegrew, J. W. et al. 1995. Clinical and neurochemical effects of acetyl-Lcarnitine in Alzheimer's disease. Neurobiol Aging, 16(1), Jan.-Feb., 1-4. Amenorrhea Genazzani, A. D. et al. 1991. Acetyl-L-carnitine as possible drug in the treatment of hypothalamic amenorrhea. Acta Obstet Gynecol Scand, 70(6), 487-492. Dose: 2 gm/day for 6 months. Cardiovascular/Coronary heart disease Adembri, C. et al. 1994. Ischemia-reperfusion of human skeletal muscle during aortoiliac surgery: Effects of acetylcarnitine. Histol Histopathol, 9(4), Oct., 683-690. Dose:3 mg/day iv prior to surgery. Dementia Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Altern Med Rev. 1999 Jun;4(3):144-61. Sinforiani, E. et al. 1990. Neuropsychological changes in demented patients treated with acetyl-L-carnitine. Int J Clin Pharmacology Res 10(1-2), 69-74. Bonavita, E. 1986. Study of the efficacy and tolerability of L-acetylcarnitine therapy in the senile brain. Int J Clin Pharmacol Ther Toxicol, 24(9), Sept., 511-516. Dose: 1,000 mg/day. Depression Pettegrew JW, Levine J, Gershon S, Stanley JA, Servan-Schreiber D, Panchalingam K, McClure RJ. 31P-MRS study of acetyl-L-carnitine treatment in geriatric depression: preliminary results. Bipolar Disord. 2002 Feb;4(1):61-6. Garzya, G. et al. 1990. Evaluation of the effects of L-acetylcarnitine on senile patients suffering from depression. Drugs Exp Clin Res, 16(2), 101-16. Dose: 1,500 mg/day. Neurological function Tafti M, Petit B, Chollet D, Neidhart E, de Bilbao F, Kiss JZ, Wood PA, Franken P. Deficiency in short-chain fatty acid beta-oxidation affects theta oscillations during sleep. Nat Genet. 2003 Jul;34(3):320-5. De Grandis D, Minardi C. Acetyl-L-carnitine (levacecarnine) in the treatment of diabetic neuropathy. A long-term, randomised, double-blind, placebocontrolled study. Drugs R D. 2002;3(4):223-31.
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Mezzina, C. et al. 1992. Idiopathic facial paralysis: New therapeutic prospects with acetyl-L-carnitine. Int J Clin Pharmacology Res, 12(5-6), 299-304. Dose: 3 gm/day for 14 days. Mazzocchio, R. et al. 1990. Enhancement of recurrent inhibition by intravenous administration of L-acetylcarnitine in spastic patients. J Neurol Neurosurg Psychiatry, 53(4), Apr., 321-326. Parkinson's disease Beal MF. Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-8. Kidd PM. Parkinson's disease as multifactorial oxidative neurodegeneration: implications for integrative management. Altern Med Rev. 2000 Dec;5(6):502-29. Puca, F. M. et al. 1990. Clinical pharmodynamics of acetyl-L-carnitine in patients with Parkinson's disease. Int J Clin Pharmacol Res, 10(1-2), 139143. Dose: 1 or 2 gm/day for 7 days. Stroke Lolic MM, Fiskum G, Rosenthal RE. Neuroprotective effects of acetyl-Lcarnitine after stroke in rats. Ann Emerg Med. 1997 Jun;29(6):758-65. Arrigo, A. et al. 1990. Effects of acetyl-L-carnitine on reaction times in patients with cerebrovascular insufficiency. Int J Clin Pharmacol Res, 10(12), 133-137. Postiglione, A. et al. 1990. Cerebral blood flow in patients with chronic cerebrovascular disease: Effect of acetyl-L-carnitine. Int J Clin Pharmacology Res, 10(1-2), 129-132. Dose: 1.5 gm iv. Rosadini, G. et al. 1990. Acute effects of acetyl-L-carnitine on regional cerebral blood flow in patients with brain ischaemia. Int J Clin Pharmacol Res, 10(1-2), 123-128. Dose: 1,500 mg iv. Postiglione, A. et al. 1991. Effect of acute administration of L-acetyl carnitine on cerebral blood flow in patients with chronic cerebral infarct. Pharmacology Res.23(3), Apr., 241-246. Dose: 1.5 gm iv. Co-enzyme Q-10 Cancer Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 170
Palan PR, Mikhail MS, Shaban DW, Romney SL. Plasma concentrations of coenzyme Q10 and tocopherols in cervical intraepithelial neoplasia and cervical cancer. Eur J Cancer Prev. 2003 Aug;12(4):321-6. Drisko JA, Chapman J, Hunter VJ. The use of antioxidants with first-line chemotherapy in two cases of ovarian cancer. J Am Coll Nutr. 2003 Apr;22(2):118-23. Lockwood, K. et al. 1995. Progress therapy on breast cancer with Vitamin Q10 and the regression of metastases. Biochem Biophys Res Commun, 212(1), July 6, 172-177. Dose: 390 mg/day for 3-5 years. Lockwood, K. et al. 1994. Partial and complete regression of breast cancer in patients in relation to dosage of coenzyme Q10, Biochem Biophys Res Commun, 199(3), Mar. 30, 1504-1508. Dose: 390 mg/day after 1 month tumor no longer palpable, after 2 months mammagrophy indicated no tumor. Tsubaki, K. et al. 1984. [Investigation of the preventive effect of CoQ10 against the side-effects of anthracycline antineoplastic agents], Gan To Kagaku Ryoho, 11(7) July, 1420-1427. Dose: 1 mg/kg/day iv. Okuma, K. et al. 1983. [Protective effect of coenzyme Q10 in cardiotoxicity induced by adriamycin], Gan To Kagaku Ryoho, 11(3), Mar., 502-508. Cardiovascular/Coronary heart disease Kamikawa, T. et al. 1985. Effects of coenzyme Q10 on exercise tolerance in chronic stable angina pectoris. Am J Cardiology, 56(4), Aug. 1, 1985, 247251. Dose: 150 mg/day for 4 weeks. Tanaka, J. et al. 1983. Coenzyme Q10: The prophylactic effect on low cardiac output following cardiac valve replacement. Annals Thoraci Surg. 33(2), Feb., 145-151. Dose: 30-60 mg/day orally for 6 days. 76 Chello, M. et al. 1994. Protection by Coenzyme Q10 from myocardial reperfusion injury during coronary artery bypass grafting. Annals Thoracic Surg. 58(5), Nov., 1427-1432. Dose:150 mg/day for 7 days before surgery. Chen, Y. F. et al. 1994. Effectiveness of coenzyme Q10 in myocardial preservation during hypothermic cardioplegic arrest. J Thoracic Cardiovascular Surg. 107(1), Jan., 242-247.
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Greenberg, S. M. and Frishman, W. H. 1988. Coenzyme Q10: A new drug for myocardial ischemia? Med Clin North America, 72(1), Jan., 243-258. Nishikawa, Y. et al. 1989. Long-term coenzyme Q10 therapy for a mitochondrial encephalomyopathy with cytochrome C oxidase deficiency: A 31P NMR study. Neurology, 39(3), Mar., 399-403. Ogasahara, S. et al. 1985. Improvement of abnormal pyruvate metabolism and cardia conduction defect with coenzyme Q10 in Kearns-Sayre syndrome, Neurology, 35(3), Mar., 372-373. Dose: 60-120 mg/day for 3 months. Folkers, K. et al. 1992. Therapy with coenzyme Q10 of patients in heart failure who are eligible of ineligible for a transplant. Biochem Biophys Res Commun, 182(1) Jan. 15, 247-253. Sunamori, M. et al. 1991. Clinical experience of coenzyme Q10 to enhance intraoperative myocardial protection in coronary artery revascularization, Cardiovasc Drugs Ther, 5 Suppl 2, Mar., 297-300. Dose: pretreatment with 5mg/kg iv. Baggio, E. et al. 1993. Italian multicenter study of the safety and efficacy of coenzyme Q10 as adjunctive therapy in heart failure (interim analysis). The CoQ10 drug surveillance investigators. Clin Investigations, 71(8 Suppl), S145-149. Dose: 50-100 mg/day for 3 months. Langsjoen, P. H. et al. 1993. Isolated diastolic dysfunction of the myocardium and its response to CoQ10 treatment. Clin Investigations, 71(8 Suppl), S140-144. Morisco, C. et al. 1993. Effect of coenzyme Q10 therapy in patients with congestive heart failure: A long-term multicenter randomized study. Clin Investigations, 71(8 Suppl), S134-146. Dose: 2 mg/kg/day for 1 year. Lampertico, M. and Conis, S. 1993. Italian multicenter study on the efficacy and safety of coenzyme Q10 as adjuvant therapy in heart failure. Clin Investigations, 71(8 Suppl), S129-S133. Dose: 50 mg/day for 4 weeks. Mortensen, S. A. 1993. Perspectives on therapy of cardiovascular diseases with coenzyme Q10 (Ubiquinonq). Clin Investigations, 71(8 Suppl), S116S123. Mortensen, S. A. et al. 1985. Long-term coenzyme Q10 therapy: A major advance in the management of resistant myocardial failure. Drugs Exp Clin Res, 11(8), 581-593. Dose: 100 mg/day. Langsjoen. P. H. et al. 1985. Effective treatment with coenzyme Q10 of patients with chronic myocardial disease. Drugs Exp Clin Res, 11(8), 577Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 172
579. Oda, T. 1985. Effect of coenzyme Q10 on stress-induced cardiac dysfunction in paediatric patients with mitral valve prolapse: A study by stress echocardiography. Drugs Exp Clin Res, 11(8), 557-576. Dose: 3-3.4 mg/day. Suzuki, H. et al. 1984. Cardiac performance and coenzyme Q10 levels in thyroid disorders. Endocrinol Japan, 31(6), Dec., 755-761. Kato, T. et al. 1990. Reduction in blood viscosity by treatment with coenzyme Q10 in patients with ischemic heart disease. Int J Clin Pharmacol Ther Toxicol, 28(3), Mar., 123-126. Dose: 60 mg/day for 2 months. Manzoli, U. et al. 1990. Coenzyme Q10 in dilated cardiomyopathy. Int J Tissue React 12(3), 173-178. Dose: 100 mg/day orally. Langsjoen, P. H. et al. 1990. A six-year clinical study of therapy of cardiomyopathy with coenzyme Q10. Int J Tissue React, 12(3), 168-171. Langsjoen, P. H. et al. 1990. Pronounced increase of survival of patients with cardiomyopathy when treated with coenzyme Q10 and conventional therapy. Int J Tissue React, 12(3), 163-168. Diabetes Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus. Diabetologia. 2002 Mar;45(3):420-6. Suzuki, Y. et al. 1995. A case of Diabetic amyotrophy associated with 3243 mitochondrial tRNA(leu: UUR) Mutation and successful therapy with coenzyme Q10, Endocr J, 42(2), Apr., 141-145. Immune enhancement Folkers, K. et al. 1993. The activities of coenzyme Q10 and vitamin B6 for immune responses. Biochem Biophys Res Commun, 193(1), May 28, 88-92. Lung disease Gazdik F, Gvozdjakova A, Nadvornikova R, Repicka L, Jahnova E, Kucharska J, Pijak MR, Gazdikova K. Decreased levels of coenzyme Q(10) in patients with bronchial asthma. Allergy. 2002 Sep;57(9):811-4. Fujimoto, S. et al. 1993. Effects of coenzyme Q10 administration on pulmonary function and exercise performance in patients with chronic lung diseases. Clin Investigations, 71(8 Suppl), S126-S166. Dose: 90 mg/day for 8 weeks. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 173
Muscular Injury Folkers, K. and Simonsen, R. 1995. Two successful double-blind trials with coenzyme Q10 (vitamin Q10) on muscular dystrophies and neurogenic atrophies. Biochim Biophys Acta, 127(1), May 24, 281-286. Glutathione Aging Cruz R, Almaguer Melian W, Bergado Rosado JA. Glutathione in cognitive function and neurodegeneration. Rev Neurol. 2003 May 1-15;36(9):877-86. Julius, M. et al. 1994. Glutathione and morbidity in a community-based sample of elderly. J Clin Epi, 47(9), Sept., 1021-1026. Cancer Kaufmann Y, Kornbluth J, Feng Z, Fahr M, Schaefer RF, Klimberg VS. Effect of glutamine on the initiation and promotion phases of DMBA-induced mammary tumor development. JPEN J Parenter Enteral Nutr. 2003 NovDec;27(6):411-8. Flagg, E. W. et al. 1994. Dietary glutathione intake and the risk of oral and pharyngeal cancer. Am J Epi, 139(5), Mar. 1, 453-465. Cascinu, S. et al. 1995. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: A randomized double-blind placebo-controlled trial. J Clin Oncology, 13(1), Jan., 26-32. Bowman, A. et al. 1994. Effect of adding glutathione (GSH) to cisplatin (CDDP) in the treatment of stage I-IV ovarian cancer. British J Cancer, 71(Suppl 24), 14. Dose: 3 gm/m2 for 21 days. Spatti, G. B. et al. 1990. Cisplatin with minimal hydration and glutathione protection in the treatment of ovarian carcinoma. Anticancer Res, 10(5B), 1425-1456. Dose: 2.5-5 gm in 100-200 ml of normal saline over 15 minutes iv. Dalhoff, K. et al. 1992. Glutathione treatment of hepatocellular carcinoma. Liver, 12(5), Oct., 341-343. Dose: 5 gm/day. Trickler, D. et al. 1993. Inhibition of oral carcinogenesis by glutathione. Nutr Cancer, 20(2), 139-144. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 174
Smyth, J. et al. 1995. Glutathione improves the therapeutic index of cisplatin and quality of life for patients with ovarian cancer. Proceedings Annual Meeting Am Soc Clin Oncologists, 14, A761. Cataracts Reddy VN, Giblin FJ, Lin LR, Dang L, Unakar NJ, Musch DC, Boyle DL, Takemoto LJ, Ho YS, Knoernschild T, Juenemann A, Lutjen-Drecoll E. Glutathione peroxidase-1 deficiency leads to increased nuclear light scattering, membrane damage, and cataract formation in gene-knockout mice. Invest Ophthalmol Vis Sci. 2001 Dec;42(13):3247-55. Sternberg Jr., P. 1993. Protection of retinal pigment epithelium from oxidative injury by glutathione and precursors. Invest Ophthalmol Vis Sci, 34(13), Dec., 3661-3668. Gastric injury Yajima N, Hiraishi H, Yamaguchi N, Ishida M, Shimada T, Terano A. Monochloramine-induced cytolysis to cultured rat gastric mucosal cells: role of glutathione and iron in protection and injury. J Lab Clin Med. 1999 Oct;134(4):372-7. Loguericio, C. et al. 1953. Glutathione prevents ethanol induced gastric mucosal damage and depletion of sulfydryl compounds in humans. Gut, 34(2), Feb., 161-165. Liver damage Grattagliano I, Lauterburg BH, Portincasa P, Caruso ML, Vendemiale G, Valentini AM, Palmieri VO, Palasciano G. Mitochondrial glutathione content determines the rate of liver regeneration after partial hepatectomy in euand hypothyroid rats. J Hepatol. 2003 Oct;39(4):571-9. Nardi, E. A. et al. 1991. [High-dose reduced glutathione in the therapy of alcoholic hepatopathy]. Clin Ter, 136(1), Jan. 15, 47-51. Dentico, P. et al. 1995. [Glutathione in the treatment of chronic fatty liver diseases], Recenti Prog Med, 86(7-8), July-Aug., 290-293. N-Acetyl-Cysteine Adult respiratory distress syndrome Davreux CJ, Soric I, Nathens AB, Watson RW, McGilvray ID, Suntres ZE, Shek PN, Rotstein OD. N-acetyl cysteine attenuates acute lung injury in the rat. Shock. 1997 Dec;8(6):432-8. Laurent, T. et al. 1996. Oxidant-antioxidant balance in granulocytes during ARDS. Effect of N-acetylcysteine. Chest, 109(1), Jan., 163-166. Bernard, G. R. 1990. Potential of N-acetylcysteine as treatment for the Adult Respiratory Distress Syndrome. European Resp J Suppl, 11 Oct., 496sCopyright Gary Null & Associates, Inc., 2005 All Rights Reserved 175
498s. Cardiovascuar/Coronary heart disease Reinhart, K. et al. 1995. N-acetylcysteine preserves oxygen consumption and gastric mucosal pH during hyperoxic ventilation. Am J Resp Critical Care Med, 151(3 Pt 1), Mar., 773-779. Dose: 150 mg/kg-1. Boesgaard, S. et al. 1992. Preventive administration of intravenous Nacetylcysteine and development of tolerance to isosorbide dinitrate in patients with angina pectoris. Circulatio, 85(1), Jan., 143-149. Dose: 2 gm NAC over 15 minutes iv. Horowitz, J. D. et al. 1993. Potentiation of the cardiovascular effects of nitroglycerin by N-acetylcysteine. Circulation, 68(6), Dec., 1247-1253. Dose: 100 mg/kg of NAC iv. Arstall, M. A. et al. 1995. N-acetylcysteine in combination with nitroglycerin and streptokinase for the treatment of evolving acute myocardial infarction. Safety and biochemical effects. Circulation, 92(10), Nov. 15, 2855-2862. Dose: 15 gm iv NAC. Boesgaard, S. et al. 1994. Altered peripheral vasodilator profile of nitroglycerin during long-term infusion of N-acetylcysteine. J Am Coll Cardiology, 23(1), Jan., 163-169. Dose: 2 gm iv NAC followed by 5 mg/kg per hour on human veins. Spies, C. et al. 1996. [Effect of prophylactically administered Nacetylcysteine on clinical indicators for tissue oxygenation during hyperoxic ventilation in cardiac risk patients], Anaesthesist, 45(4), Apr., 343-350. Dose: 150 mg/kg NAC. Horowitz, J. D. et al. 1990. Nitroglycerine/N-acetylecysteine in the management of unstable angina pectoris. European Heart J, 9(Suppl A) Jan., 95-100. Dose: 5 gm 6 hourly iv. Svendsen, J. H. et al. 1989. N-acetylcysteine modifies the acute effects of isosorbide-5-mononitrate in angina pectoris patients. Pharmacol, 13(2), Feb., 320-323. Andersen, L. W. et al. 1995. The role of N-acetylcysteine administration on the oxidative response of neutrophils during cardiopulmonary bypass. Perfusion, 10(1), 21-26. Dose: bolus of 100 mg/kg of NAC followed by a continuous infusion of 20 mg/kg. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 176
Chronic Bronchitis Jaber R. Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Prim Care. 2002 Jun;29(2):231-61. Rasmussen, J. B. and Glennow, C. 1988. Reduction in days of illness after long-term treatment with N-acetylcysteine controlled-release tablets in patients with chronic bronchitis. European Respir J, 1(4), Apr., 351-355. Dose: 300 mg bid. 82 Gerards, H. H. and Vits, U. 1991. [Therapy of bronchitis. Successful singledosage treatment with N-acetylcysteine, results of an administration surveillance study in 3,076 patients]. Fortschr Med, 109(34), Nov. 30, 707710. Dose: 600 mg/kg. Boner, A. L. et al. 1984. A combination of cefuroxine and N-acetyl-cysteine for the treatment of maxillary sinusitis in children with respiratory allergy. Int J Clin Pharmacol Ther Toxicol, 22(9), Sept, 511-514. Dose: 15-25 mg/kg/day over a 10 day period. Santagelo, G. et al. 1985. A combination of Cefuroxime and N-acetylcysteine for the treatment of lower respiratory tract infections in children. Int J Clin Pharmacol Ther Toxicol, 23(5), May, 279-281. General Simkeviciene V, Straukas J, Uleckiene S. N-acetil-l-cysteine and 2-amino-2thiiazoline N-acetyl-l-cysteinate as a possible cancer chemopreventive agents in murine models. Acta Biol Hung. 2002;53(3):293-8. Smilkstein, M. J. et al. 1991. Acetaminophen overdose: A 48-hour intravenous N-acetylcysteine treatment protocol. Annals Emergency Med., 20(10), Oct., 1058-1063. Dose: (12) 70 mg/kg dose every 4 hours and a loading dose of 140mg/kg. Lund, M. E. et al. 1984. Treatment of acute methylmercury ingestion by hemodialysis with N-acetylcysteine (Mucomyst) infusion and 2,3dimercaptopropane sulfonate. J Toxicol Clin Yoxicol, 22(1), July, 31-49. Jensen, T. et al. 1988. Effect of oral N-acetylcyteine administration on human blood neutrophil and monocyte function. APMIS, 96(1), Jan., 62-67. Dose: 400 mg oral dose. De Groote, J. and Van Steenbergen, W. 1995. Paracetamol intoxication and N-acetyl-cysteine treatment. Acta Gastroenterol Belg, 58(3-4), May-Aug., 326-334. Todisco, T. et al. 1985. Effect of N-acetylcysteine in subjects with slow pulmonary mucociliary clearance. European J Respir Diseases Suppl, 139, 136-141. Dose: 0.6 gm/day. 83 Beckett, G. J. et al. 1990. Intravenous N-acetylcysteine, hepatoxicity and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 177
plasma glutathione S-transferase in patients with Paracetamol overdosage. Hum Exp Toxicol, 9(3) May, 183-186. Brahm, J. et al. 1992. [Paracetamol overdose: A new form of suicide in Chile and the value of N-acetylcysteine administration]. Rev Med Chil, 120(4), Apr., 427-499. Glutathione deficiency Boulares AH, Contreras FJ, Espinoza LA, Smulson ME. Roles of oxidative stress and glutathione depletion in JP-8 jet fuel-induced apoptosis in rat lung epithelial cells. Toxicol Appl Pharmacol. 2002 Apr 15;180(2):92-9. Jan, A. et al. 1994. Effect of ascorbate or N-acetylcysteine treatment in a patient with hereditary glutathione synthetase deficiency. J Pediatrics, 124(2), Feb., 229-233. Martensson, J. et al. 1989. A therapeutic trial with N-acetylcysteine in subjects with hereditary glutathione synthetase deficiency (5oxoprolinuria), J Inherist Metab Dis, 12(2), 120-130. Dose: 15 mg/kg/day. Hepatitis Neri S, Ierna D, Antoci S, Campanile E, D'Amico RA, Noto R. Association of alpha-interferon and acetyl cysteine in patients with chronic C hepatitis. Panminerva Med. 2000 Sep;42(3):187-92. Hepatitis viral load correlates to glutathione levels. Posit Health News. 1998 Fall;(No 17):14-5. Hansen, R. M. et al. 1991. Gold induced hepatitis and pure red cell aplasia. Complete recovery after corticosteroid and N-acetylcysteine therapy. J Pheumatology, 18(8), Aug., 1251-1253. Liver damage Neal R, Matthews RH, Lutz P, Ercal N. Antioxidant role of N-acetyl cysteine isomers following high dose irradiation. Free Radic Biol Med. 2003 Mar 15;34(6):689-95. Bromley, P. N. et al. 1995. Effects of intraoperative N-acetylcysteine on orthotopic liver transplantation. British J Anaesth, 75(3), Sept., 352-354. Oh, T. E. and Shenfield, G. M. 1980. Intravenous N-acetylcysteine for Paracetamol poisoning. Med J Australia, 1(13), June 28, 664-665. Lung damage Rahman Q, Abidi P, Afaq F, Schiffmann D, Mossman BT, Kamp DW, Athar M. Glutathione redox system in oxidative lung injury. Crit Rev Toxicol. 1999 Nov;29(6):543-68. Meyer, A. et al. 1995. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respiratory Crit Care Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 178
Med, 152(3), Sept., 1055-1060. Dose: 1.8 gm. Suter, P. M. et al. 1994. N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Chest, 105(1), Jan., 190-194. Dose: 40 mg/kg/day iv over a period of 72 hours. Eklund, A. et al. 1988. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: Correlation to effects on cellular variables. European Respir J, 1(9), Oct., 832-838. Dose: 200 mg tid over an 8 week period. Linden, M. et al. 1988. Effects of oral N-acetylecysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers. European Respiratory J, 1(7), July, 645-650. Dose: 200 mg tid over an 8 week period. Muscle fatigue Khawli FA, Reid MB. N-acetylcysteine depresses contractile function and inhibits fatigue of diaphragm in vitro. J Appl Physiol. 1994 Jul;77(1):317-24. Reid, M. B. et al. 1994. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Investigations, 94(6), Dec., 2468-2474. Dose: pretreatment with 150 mg/kg. Sjogren's Syndrome Walters, M. T. et al. 1986. A double-blind, cross-over, study of oral Nacetylcysteine in Sjogren's syndrome. Scandanavian J Pheumatol Suppl, 61, 253-258. Alpha Lipoic acid Diabetes Gouty S, Regalia J, Cai F, Helke CJ. Alpha-Lipoic acid treatment prevents the diabetes-induced attenuation of the afferent limb of the baroreceptor reflex in rats. Auton Neurosci. 2003 Oct 31;108(1-2):32-44. Kahler, W. et al. 1993. Diabetes Mellitus-A free radical-associated disease. Results of adjuvant supplementation. Z. Gesante Inn Med, 48(5), May, 223232. Dose: 600 mg/day for 3 months. Jacob, S. et al. 1995. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Arzneimittelforschung, 45(8), Aug., 872-874. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 179
Dose: 1000 mg. Ziegler, D. et al. 1995. Treatment of symptomatic diabetic peripheral neuropathy with anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial. Diabetologia, 38(12), Dec., 1425-1433. Dose: 600 mg/day over a 3 week period. Klein, W. 1975. [Treatment of diabetic neuropathy with oral alpha-lipoic acid]. MMW Munch Med Wochenschr, 117(22), May 30, 957-958. Dose: 2x50 mg or 2x100 mg/day. General Andreassen OA, Ferrante RJ, Dedeoglu A, Beal MF. Lipoic acid improves survival in transgenic mouse models of Huntington's disease. Neuroreport. 2001 Oct 29;12(15):3371-3. Mottley C, Mason RP. Sulfur-centered radical formation from the antioxidant dihydrolipoic acid. J Biol Chem. 2001 Nov 16;276(46):42677-83. Epub 2001 Sep 06 Barbirolli, B. et al. 1995. Lipoic (thiotic) acid increases brain energy availability and skeletal muscle performance as shown by an in vivo 31PMRS in a patient with mitochondrial cytopathy. J Neurology, 242(7), July, 472-477. Dose: 600 mg/day for 1 month. Glaucoma Head KA. Natural therapies for ocular disorders, part two: cataracts and glaucoma. Altern Med Rev. 2001 Apr;6(2):141-66. Filina, A. A. et al. 1995. Lipoic acid as a means of metabolic therapy of open-angle glaucoma. Vestn Oftalmol, 111(4), Oct.-Dec., 6-8. Dose: 0.15 gm/day for 1 month. DHEA Aging Kamel HK. Sarcopenia and aging. Nutr Rev. 2003 May;61(5 Pt 1):157-67. Ponholzer A, Plas E, Schatzl G, Jungwirth A, Madersbacher S; Austrian Society of Urology. Association of DHEA-S and estradiol serum levels to symptoms of aging men. Aging Male. 2002 Dec;5(4):233-8. Yen, S. S. et al. 1995. Replacement of DHEA in aging men and women. Potential remedial effects. Ann NY Acad Sci, 774, Dec. 29, 128-142. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 180
Alzheimer's disease Leowattana W. DHEA(S): the fountain of youth. J Med Assoc Thai. 2001 Oct;84 Suppl 2:S605-12. Hillen T, Lun A, Reischies FM, Borchelt M, Steinhagen-Thiessen E, Schaub RT. DHEA-S plasma levels and incidence of Alzheimer's disease. Biol Psychiatry. 2000 Jan 15;47(2):161-3. Yanase, T. et al. 1996. Serum dehyfroepiandrosterone (DHEA) and DHEAsulfate (DHEA-S) in Alzheimer's Disease and in cerebrovascular dementia. Endocr J, 43(1), Feb., 119-123. Cognitive function Harris DS, Wolkowitz OM, Reus VI. Movement disorder, memory, psychiatric symptoms and serum DHEA levels in schizophrenic and schizoaffective patients. World J Biol Psychiatry. 2001 Apr;2(2):99-102. Friess, E. et al. 1995. DHEA administration increases rapid eye movement sleep and EEG power in the Sigma frequency range. Am J Physiol, 268(1 Pt 1), Jan., E107-13. Dose: 500 mg oral dose. 87 Depression Goodyer IM, Herbert J, Tamplin A. Psychoendocrine antecedents of persistent first-episode major depression in adolescents: a community-based longitudinal enquiry. Psychol Med. 2003 May;33(4):601-10. Wolkowitz, O. M. et al. 1997. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry, 41(3), Feb. 1, 311-318. Dose: 30-90 mg/day for 4 weeks. General Netherton C, Goodyer I, Tamplin A, Herbert J. Salivary cortisol and dehydroepiandrosterone in relation to puberty and gender. Psychoneuroendocrinology. 2004 Feb;29(2):125-40. Khorram, O. 1996. DHEA: A hormone with multiple effects. Curr Opin Obstet Gynecol, 8(5), Oct., 351-354. Lupus Chang DM, Lan JL, Lin HY, Luo SF. Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 2002 Nov;46(11):2924-7. Van Vollenhoven, R. F. and McGuire, J. L. 1996. Studies of dehydroepiandrosterone (DHEA) as a therapeutic agent in systemic lupus erythematosus. Ann Med Interne, 147(4), 290-296.
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Melatonin Cancer Sainz RM, Mayo JC, Rodriguez C, Tan DX, Lopez-Burillo S, Reiter RJ. Melatonin and cell death: differential actions on apoptosis in normal and cancer cells. Cell Mol Life Sci. 2003 Jul;60(7):1407-26. Lissoni, P. et al. 1992. Biological and clinical results of a neuroimmunotherapy with interleukin-2 and the pineal hormone melatonin as a first line treatment in advanced non-small cell lung cancer. British J Cancer, 66(1), July, 155-158. Dose: 10 mg/day. Lissoni, P. et al. 1995. Modulation of cancer endocrine therapy by melatonin: A phase II study of Taxoifen plus melatonin in metastatic breast cancer patients progressing under Tamoxifen alone. British J Cancer, 71(4), Apr., 854-856. Dose: 20 mg/day. Neri, B. et al. 1994. Modulation of human lymphoblastoid interferon activity by melatonin in metastatic renal cell carcinoma: A phase II study. Cancer, 73(12), June 15, 3015-3019. Dose: 10 mg/day. Lissoni, P. et al 1994. A randomized study with the pineal hormone melatonin versus supportive care alone in patients with brain metastases due to solid neoplasms. Cancer, 73(3), Feb 1, 699-701. Lissoni, P. et al. 1989. Endocrine and immune effects of melatonin therapy in metastic cancer patients. European J Cancer Clin Oncol, 25(5), May, 789795. Dose: 20 mg/day intramuscular, followed with 10mg/day in patients experiencing remission. Viviani, S. et al. 1990. Preliminary studies on melatonin in the treatment of Myelodysplastic Syndromes following cancer chemotherapy. J Pineal Res, 8(4), 347-354. Dose: 20 mg/day. Gonzalez, R. et al. 1991. Melatonin therapy of advanced human malignant melanoma. Melanoma Res, 1(4), Nov.-Dec., 237-243. Dose: daily oral dose of 5 mg/m2 to 700mg/m2 after 5 weeks. Lissoni, P. et al. 1991. Clinical results with pineal hormone melatonin in advanced cancer resistant to standard antitumor therapies. Oncology, 48(6), 448-450. Dose: 20 mg/day followed with 10mg/day orally. Jet Lag Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 182
Beaumont M, Batejat D, Pierard C, Van Beers P, Denis JB, Coste O, Doireau P, Chauffard F, French J, Lagarde D. CAFFEINE OR MELATONIN EFFECTS ON SLEEP AND SLEEPINESS AFTER RAPID EASTWARD TRANSMERIDIAN TRAVEL. J Appl Physiol. 2003 Sep 5. Petri, K. et al. 1989. Effect of melatonin of jet lag after long haul flights. BMJ, 298(6675), Mar. 18, 705-707. Dose: 5 mg 3 days prior to flight. Petrie, K. et al. A double-blind trial of melatonin as a treatment for jet lag in internatinal cabin crew. Biological Psychiatry, 33(7), Apr. 1, 526-530. Dose: 5 mg 3 days prior to flight. Sleep Turk J. Melatonin supplementation for severe and intractable sleep disturbance in young people with genetically determined developmental disabilities: short review and commentary. J Med Genet. 2003 Nov;40(11):7936. Palm, L. et al. 1991. Correction of non-24-hour sleep/wake cycle by melatonin in a blind retarded boy. Ann Neurol, 29(3), Mar., 336-339. Zhdanova, I. V. et al. 1995. Sleep-inducing effects of low doses of melatonin ingested in the evening. Clin Pharmacol Therapy, 57(5), 552-558. Dose: 0.3 or 1.0 mg at 6, 8 or 9PM. Dahlitz, M. et al. 1991. Delayed sleep phase syndrome response to melatonin. Lancet, 337(8750), May 11, 1121-1124. Dose: 5 mg for 4 weeks. Garfinkel, D. et al. 1995. Improvement of sleep quality in elderly people by controlled-release melatonin. Lancet, 346(8974), Aug. 26, 541-544. Dose: 2 mg/night for 3 weeks. Etzioni, A. et al. 1996. Melatonin replacement corrects sleep disturbances in a child with pineal tumor. Neurology, 46(1), Jan, 261-263. Dose: 3 mg/night for 2 weeks. MacFarlane, J. G. et al. 1991. The effects of exogenous melatonin on the total sleep time and daytime alertness of chronic insomniacs: A preliminary study. Biological Psychiatry, 30(4), Aug. 15, 371-376. Dose: 75 mg per os/night. Folkard, S. et al. 1993. Can melatonin improve shift workers' tolerance of the night shift? Some preliminary findings. Chronobiol Int, 10(5), Oct., 315320. Dose: 5 mg/night. Jan, J. E. et al. 1994. The treatment of sleep disorders with melatonin. Dev Med Child Neurol, 36(2), Feb., 970107. Dose: 2-10 mg.
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Waldhauser, F. et al. 1990. Sleep laboratory investigations on hypnotic properties of melatonin. Psychopharmacology, 100(2), 222-226. Tzischinsky, O. and Lavie, P. 1994. Melatonin possesses time-dependent hypnotic effects. Sleep, 17(7), Oct., 638-645. Dose: 5 mg. Haimov, I. et al. 1995. Melatonin replacement therapy of elderly insomniacs. Sleep, 18(7), Sept., 598-603. Dose: 2 mg/night for 7 consecutive days. 1 mg of sustained-release. Vision Scher J, Wankiewicz E, Brown GM, Fujieda H. MT(1) melatonin receptor in the human retina: expression and localization. Invest Ophthalmol Vis Sci. 2002 Mar;43(3):889-97. Samples, J. R. et al. 1988. Effect of melatonin on intraocular pressure. Current Eye Res 7(7), July, 649-653. Pregnenolone Kamei H, Noda Y, Nabeshima T, Yamada K. Effects of sigma receptor ligands on psychiatric disorders. Nihon Shinkei Seishin Yakurigaku Zasshi. 2003 Oct;23(5):187-96. Araneo, B. A. et al. 1995. Dehydroepiandrosterone reduces progressive dermal ischemia caused by thermal&127;&127;&127;&127;&127;&127;&127;&127;&127; injury. J Surg Res, 59(2) Aug., 250-262 Dose: Subcutaneous administration of DHEA at approximately 1 mg/kg/day achieved optimal protection against the&127; development of progressive dermal ischemia. Arginine Cancer Bonafe M, Ceccarelli C, Farabegoli F, Santini D, Taffurelli M, Barbi C, Marzi E, Trapassi C, Storci G, Olivieri F, Franceschi C. Retention of the p53 codon 72 arginine allele is associated with a reduction of disease-free and overall survival in arginine/proline heterozygous breast cancer patients. Clin Cancer Res. 2003 Oct 15;9(13):4860-4. Brittenden, J. et al. 1994. L-arginine stimulates host defenses in patients with breast cancer. Surgery, 115(2), Feb., 205-212. Dose: 30 gm/day for 3 days. Cardiovascuar/Coronary heart disease Tousoulis D, Davies GJ, Tentolouris C, Crake T, Goumas G, Stefanadis C, Toutouzas P. Effects of L-arginine on flow mediated dilatation induced by Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 184
atrial pacing in diseased epicardial coronary arteries. Heart. 2003 May;89(5):531-4. Rector, T. S. et al. 1996. Randomized, double-blind, placebo controlled study of supplemental oral L-arginine in patients with heart failure. Circulation, 93(12), June 15, 2135-2141. Dose: 5.6 to 12.6 gm/day over 6 weeks. Koifman, B. et al. 1995. Improvement of cardiac performance by intravenous infusion of L-arginine in patients with moderate congestive heart failure. J Am Coll Cardiol, 26(5), Nov. 1, 1251-1256. Dose: 20 gm iv. Clarkson, P. et al. 1996. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Investigation, 97(8), Apr. 15, 1989-1994. Dose: 7 gm 3x/day over 4 weeks. McCaffrey, M. J. et al. 1995. Effect of L-arginine infusion on infants with persistent pulmonary hypertension on the newborn. Biol Neonate, 6794), 240-243. Dose: 500 mg/kg infused over 30 minutes. Hishikawa, K. et al. 1992. L-arginine as a antihypertensive agent. J Cardiovascular Pharmacol, 20(suppl 12), S196-S197. Kilbourn, R. G. et al. 1995. NG-methyl-L-arginine, an inhibitor of nitric oxide synthase, reverses interleukin-2-induced hypotension. Crit Care Med, 23(6), June, 1018-1024. Dose: 12 mg/kg followed by 4mg/kg every 4 hours. General Huang ZH, Lin HW, Li Z, Feng HM, Sun YG, Zhang QG. L-arginine decreases P-selectin expression in traumatic shock. Di Yi Jun Yi Da Xue Xue Bao. 2003 Aug;23(8):777-80. Pittari, A. M. et al. 1993. Therapy with arginine chlorohydrate in children with short constitutional stature. Minerva Pediatr, 45(1-2), Jan.-Feb., 61-65. Dose: 4 gm/day. Hepatitis Rizzo, S. 1986. Clinical trial with arginine tidiacicate in symptomatic chronic persistent hepatitis. Int J Clin Pharmacol Res, 6(3), 225-230. Dose: 80 ml of 10% L-arginine HCL daily per os over 6 months. Pain Harima, A. et al. 1991. Analgesic effect of L-arginine in patients with persistent pain. European Neuropsychopharmacol, 1(4), Dec., 529-533. Dose: iv 10% solution, 300ml (30g)/patient over a 60-70 minute period. Wound healimg Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 185
Lu, S. L. 1993. Effect of arginine supplementation on T-lymphocyte function in burn patients. Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 9(5), Sept., 368-371. Ornithine Aging Virgili M, Necchi D, Scherini E, Contestabile A. Increase of the ornithine decarboxylase/polyamine system and transglutaminase upregulation in the spinal cord of aged rats. Neurosci Lett. 2001 Aug 17;309(1):62-6. Brocker, P. et al. 1994. A two-centre, randomized, double-blind trial or ornithine oxoglutarate in 194 elderly, ambulatory, convalescent subjects, Age Ageing, 23(4), July, 303-306. Dose: 10 gm/day for 2 months. Cancer Sandgren S, Belting M. Suramin selectively inhibits carcinoma cell growth that is dependent on extracellular polyamines. Anticancer Res. 2003 MarApr;23(2B):1223-8. Dunzendorfer, U. 1981. Alpha-difluoromethyornithine (alpha DFMO) and phenoxybenzamine hydrochloride in the treatment of chronic nonsuppurative prostatitis. Arzneimittelforschung, 31(2), 382-385. Dose: 18 gm/day over 1 month. Alberts, D. S. et al. 1996. Positive randomized, double blinded, placebo controlled study of topical difluoromethyl ornithine (DFMO) in the chemoprevention of skin cancer. Proc Annual Meeting Am Soc Clin Oncology, 15, A342. Dose: 10% w/w topical solution of DFMO applied for 6 months. Encephalopathy Nicolaides P, Liebsch D, Dale N, Leonard J, Surtees R. Neurological outcome of patients with ornithine carbamoyltransferase deficiency. Arch Dis Child. 2002 Jan;86(1):54-6. Herlong, H. F. et al. 1980. The use of ornithine salts of branched-chain ketoacids in portal-systemic encephalopathy. Ann Intern Med, 93(4), Oct., 545-550. Dose: 34 mmol/day over 7-10 days. Surgical Trauma Yin L. Effects on the normalization of amino acids in metabolic support for trauma surgical patients Zhonghua Wai Ke Za Zhi. 1992 Nov;30(11):659-62, 699. Wernerman, J. et al. 1989. Glutamine and ornithine-alpha-ketoglutarate but not branched-chain amino acids reduce the loss of muscle glutamine after surgical trauma. Metabolism, 38(8 Suppl 1), Aug., 63-66. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 186
Glutamine Cancer Todorova VK, Harms SA, Luo S, Kaufmann Y, Babb KB, Klimberg VS. Oral glutamine (AES-14) supplementation inhibits PI-3k/Akt signaling in experimental breast cancer. JPEN J Parenter Enteral Nutr. 2003 NovDec;27(6):404-10. 94 Skubitz, K. M. and Anderson, P. M. 1996. Oral glutamine to prevent chemotherapy induced stomatitis: A pilot study. J Lab Clin Med, 127(2), Feb., 223-228. Dose: 4 gm swish and swallow. Cardiovascuar/Coronary heart disease Khogali SE, Pringle SD, Weryk BV, Rennie MJ. Is glutamine beneficial in ischemic heart disease? Nutrition. 2002 Feb;18(2):123-6. Svedjeholm, R. et al. 1995. Glutamate and high-dose glucose-insulinpotassium (GIK) in the treatment of severe cardiac failure after cardiac operations. Ann Thirac Surg, 59(2 Suppl), Feb., S23-S30. General Zhu M, Tang D, Zhao X, Cao J, Wei J, Chen Y, Xiao L, Sun Q. Impact of glutamine of gut permeability and clinical prognosis on the aging patients undergoing gastric-intestinal operation. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2000 Oct;22(5):425-7. Castell, L. M. et al. 1996. Does glutamine have a role in reducing infections in athletes? Eur J Appl Physiol, 73(5), 488-490. Liver damage Dhar A, Kujath S, Van Way CW 3rd. Glutamine administration during total parenteral nutrition protects liver adenosine nucleotides during and after subsequent hemorrhagic shock. JPEN J Parenter Enteral Nutr. 2003 JulAug;27(4):246-51. Santagati, G. et al. 1978. [Glutamic acid gamma-ethyl ester in high doses in the treatment of high blood ammonia levels in severe hepatic failure]. Minerva Med, 69(20), Apr. 28, 1367-1374. Neurotoxicity Hasegawa K, Mizutani Y, Kuramoto H, Nagao S, Masuyama H, Hongo A, Kodama J, Yoshinouchi M, Hiramatsu Y, Kudo T, Okuda H. The effect of L-Glutamine and Shakuyaku-Kanzo-to for paclitaxel-induced myalgia/arthralgia. Gan To Kagaku Ryoho. 2002 Apr;29(4):569-74. Cooper AJ. Role of glutamine in cerebral nitrogen metabolism and ammonia neurotoxicity. Ment Retard Dev Disabil Res Rev. 2001;7(4):280-6. 95 Jackson, D. V. et al. 1988. Amelioration of vincristine neurotoxicity by glutamic acid. Am J Med. 84(6), June, 1016-1022. Dose: 1,500 mg/day. Short Bowel Syndrome Wilmore DW. Indications for specific therapy in the rehabilitation of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 187
patients with the short-bowel syndrome. Best Pract Res Clin Gastroenterol. 2003 Dec;17(6):895-906. Byrne, T. A. et al. 1995. A new treatment for patients with short-bowel syndrome. Growth hormone, glutamine, and a modified diet. Annals Surg, 222(3), Sept., 243-254. Tinnitus Ehrenberger, K. and Brix, R. 1983. Glutamic acid and glutamic acid diethylester in tinnitus treatment. Acta Otolaryngol, 95(5-6), May-June, 599605. Wound injury MacKay D, Miller AL. Nutritional support for wound healing. Altern Med Rev. 2003 Nov;8(4):359-377. Yan, R. et al. 1995. Early enteral feeding and supplement of glutamine prevent occurence of stress ulcer following severe thermal injury. Chung Hua Cheng Hsing Shao Shang Wai Ko Tsa Chih, 11(3), May, 189-192. L-Methionine Hepatitis Gazarian KG, Gening LV, Gazarian TG. L-Homoserine: a novel excreted metabolic marker of hepatitis B abnormally produced in liver from methionine. Med Hypotheses. 2002 Apr;58(4):279-83. Cho MK, Kim SG. Enhanced expression of rat hepatic microsomal epoxide hydrolase by methylthiazole in conjunction with liver injury. Toxicology. 2000 May 5;146(2-3):111-22. Windsor, J. A. and Wynne-Jones, G. 1988. Halothane hepatitis and prompt resolution with methionine therapy: Case report. New Zealand Med J 101(851), Aug. 10, 502-503. 96 Neuropathy Tan SV, Guiloff RJ. Hypothesis on the pathogenesis of vacuolar myelopathy, dementia, and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry. 1998 Jul;65(1):23-8. Stacy, C. B. et al. 1992. Methionine in the treatment of nitrous-oxideinduced neuropathy and myeloneuropathy. J Neurol, 239(7), Aug., 401-403. Paracetamol Poisoning Wallace KP, Center SA, Hickford FH, Warner KL, Smith S. S-adenosyl-Lmethionine (SAMe) for the treatment of acetaminophen toxicity in a dog. J Am Anim Hosp Assoc. 2002 May-Jun;38(3):246-54. Vale, J. A. et al. 1981. Treatment of acetaminophen poisoning. The use of oral methionine. Arch Intern Med, 141(3 Spec No), Feb. 23, 394-396. Crome, P. et al. 1976. Oral methionine in the treatment of severe Paracetamol (Acetaminophen) overdose. Lancet, 2(7990), Oct. 6, 829-830. Dose: 2-5 gm every 4 hours up to a total of 10g beginning within 10 hours of overdose. Breen, K. J. et al. 1982. Paracetamol self-poisoning: Diagnosis, management, and outcome. Med J Australia, 1(2), Jan. 23, 77-79. Trimethyl glycine Betaine Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 188
Dry Mouth Soderling, E. et al. 1998. Betaine-containing toothpaste relieves subjective symptoms of dry mouth. Acta Odontol Scand, 56(2) Apr., 65-69 Dose: Betaine-containing toothpaste. Homocystinuria Montero Brens C, Dalmau Serra J, Cabello Tomas ML, Garcia Gomez AM, Rodes Monegal M, Vilaseca Busca A. Homocystinuria: effectiveness of the treatment with pyridoxine, folic acid, and betaine. An Esp Pediatr. 1993 Jul;39(1):37-41. Wilcken, D. E. et al. 1985. Homocystinuria due to cystathionine betasynthase deficiency--the effects of betaine treatment in pyridoxineresponsive patients. Metabolism, 34(12) Dec., 1115-1121 Dose: Betaine (trimethylglycine) 6 g/d. 97 Wendel, U. and Bremer, H. J. 1984. Betaine in the treatment of homocystinuria die to 5,10-methylenetetrahydrofolate reductase deficiency. Europ J Pediatrics 142(2), June, 147-150. Dose: 15-20 gm/day. Aloe Cardiovascular/Coronary Heart Disease Agarwal, O. P. 1985. Prevention of atheromaous heart disease. Angiology, 36(8), Aug., 485-492. Constipation Odes, H. A. and Madar, Z. 1991. A double-blind trial of a celandin, Aloe vera and psyllium laxative preparation in adult patients with constipation. Digestion, 49(2), 65-71. Diabetes Abdullah KM, Abdullah A, Johnson ML, Bilski JJ, Petry K, Redmer DA, Reynolds LP, Grazul-Bilska AT. Effects of Aloe vera on gap junctional intercellular communication and proliferation of human diabetic and nondiabetic skin fibroblasts. J Altern Complement Med. 2003 Oct;9(5):711-8. Ghannam, N. et al. 1986. The antidiabetic activity of aloes: Preliminary clinical and experimental observations. Hormone Res, 24(4), 288-294. Dose: 1/2 tsp/day for 4-14 weeks. Ghannam, N. et al. 1986. The antidiabetic activity of aloes. Hormone Res, 24, 288-294. Dose: 1/2 tsp 4x/day for 14 weeks. Skin Damage Strickland FM, Pelley RP, Kripke ML. Prevention of ultraviolet radiationinduced suppression of contact and delayed hypersensitivity by Aloe barbadensis gel extract. J Invest Dermatol. 1994 Feb;102(2):197-204. Syed, T. A. et al. 1996. Management of psoriasis with aloe vera extract in a hydrophilic cream: A placebo-controlled, double-blind study. Trop Med Int Health, 1(4), Aug., 505-509. Dose: 0.5% Aloe vera extract in a hydrophilic cream. 98 Wound Healing Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 189
Muller MJ, Hollyoak MA, Moaveni Z, Brown TL, Herndon DN, Heggers JP. Retardation of wound healing by silver sulfadiazine is reversed by Aloe vera and nystatin. Burns. 2003 Dec;29(8):834-6. Fulton Jr., J. E. The stimulation of postdermabrasion wound healing with stabilized aloe vera gel-polyethylene oxide dressing. J Dermatol Surg Oncology, 16(5), may, 460-467. Dose: stabilized Aloe vera. Visuthiokosol, V. et al. 1995. Effect of aloe vera gel to healing of burn wound a clinical and histologic study. J Med Assoc Thailand, 78(8), Aug., 403-409. Dose: Aloe vera gel. Apple Pectin Acute Intestinal Infections Potievskii, E. G. et al. 1994. [Experimental and clinical studies of the effect of pectin on the causative agents of acute intestinal infections]. Zh Mikrobiol Epidemiol Immunobiol, Suppl 1 Aug., 106-109 Dose: 5% pectin solution. Diarrhea Potievskii EG, Shavakhabov ShSh, Bondarenko VM, Ashubaeva ZD. Experimental and clinical studies of the effect of pectin on the causative agents of acute intestinal infections. Zh Mikrobiol Epidemiol Immunobiol. 1994 Aug-Sep;Suppl 1:106-9. de la Motte, S. et al. 1997. [Double-blind comparison of an apple pectinchamomile extract preparation with placebo in children with diarrhea]. Arzneimittelforschung, 47(11) Nov., 1247-1249 Dose: Apple pectin and chamomille. Hypercholesterolemia Biesenbach, G. et al. 1993. [The lipid lowering effect of a new guar-pectin fiber mixture in type II diabetic patients with hypercholesterolemia]. Leber Magen Darm, 23(5) Sept., 204. Dose: 1 package of 17 gm with about 5.9 gm water-soluble fiber) dissolved in 250 ml water for the next 9 weeks: during the first 3 weeks 2 portions per 99 day, the next 3 weeks twice 1/2 portion and the last 3 weeks one 1/2 portion daily. The fiber mixture had to been consumed 30 minutes before taking a main meal. Pirich, C. et al. 1992. [Lowering cholesterol with Anticholest--a high fiber guar-apple pectin drink]. Wien Klin Wochenschr, 104(11):314-316. Dose: (group 1) at dosages of 1 cup (17 gm) every second day, or (group 2) of 1 cup a day or (group 3) of 2 cups a day. Hyperlipidemia Biesenbach G, Grafinger P, Janko P, Kaiser W, Stuby U, Moser E. The lipid lowering effect of a new guar-pectin fiber mixture in type II diabetic patients with hypercholesterolemia. Leber Magen Darm. 1993 Sep;23(5):204, 207-9. Grudeva-Popova, J. and Sirakova, I. 1998. Effect of pectin on some Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 190
electrolytes and trace elements in patients with hyperlipoproteinemia. Folia Med (Plovdiv), 40(1):41-45 Dose: 15 gm/day high-esterified pectin for 3 months. Grudeva-Popova, J. et al. 1997. Application of soluble dietary fibres in treatment of hyperlipoproteinemias. Folia Med (Plovdiv), 39(1), 39-43. Satiety Tiwary, C. M. et al. 1997. Effect of pectin on satiety in healthy US Army adults. J Am Coll Nutr, 16(5) Oct., 423-428 Dose: 5, 10, 15, 20g Bee Pollen Climacteric Symptoms Szanto, E. et al. 1994. [Placebo-controlled study of melbrosia in treatment of climacteric symptoms]. Wien Med Wochenschr, 144(7):130-133. Memory Function Iversen, T. et al. 1997. The effect of Nao Li Su on memory functions and blood chemistry in elderly people. J Ethnopharmacol, 56(2) Apr., 109-116. Memory Function 100 Iarosh, A. A. 1990. [Changes in the immunological reactivity of patients with disseminated sclerosis treated by prednisolone and the preparation Proper-Myl]. Syringomyelia Ludianskii, E. A. 1991. [The use of apiotherapy and radon baths in treating syringomyelia]. Zh Nevropatol Psikhiatr Im S Korsakova, 91(3), 102-103. Chrysanthemum Lee JS, Kim HJ, Lee YS. A new anti-HIV flavonoid glucuronide from Chrysanthemum morifolium. Planta Med. 2003 Sep;69(9):859-61. Urzua A, Mendoza L. Antibacterial activity of fresh flower heads of Chrysantemum coronarium. Fitoterapia. 2003 Sep;74(6):606-8. Yu, X. Y. 1993. [A prospective clinical study on reversion of 200 precancerous patients with hua-sheng-ping]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih 13(3) Mar., 147-149 Zhou , Y. L. 1987. [Chrysanthemum morifolium in the treatment of hypertension]. Chung Hsi I Chieh Ho Tsa Chih, 7(1) Jan., 18-20. Cruciferous vegetables Cancer Jackson SJ, Singletary KW. Sulforaphane: a naturally occurring mammary carcinoma mitotic inhibitor which disrupts tubulin polymerization. Carcinogenesis. 2003 Oct 24. Yuan, &127; J. M. et al. 1998. Cruciferous vegetables in relation to renal cell carcinoma. Int J Cancer, 77(2) Jul. 17, 211-216. Rosen, C. A. 1998. &127;Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngol Head Neck Surg, 118(6) Jun., 810-815. &127;&127;&127;Dose: oral indole-3-carbinol and had a minimum follow-up of 8 months and a mean follow-up of 14.6 months. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 191
DeMarini, D. M. et al. 1997. Pilot study of free and conjugated urinary mutagenicity during consumption of pan-fried meats: possible modulation by cruciferous vegetables, glutathione S-transferase-M1, and Nacetyltransferase2. Mutat Res, 381(1) Nov. 19, 83-96. 101 Dose: Ingestion of cruciferous vegetables. Witte, J. S. et al. 1996. Relation of vegetable, fruit, and grain consumption to colorectal adenomatous&127; polyps. Am J Epidemiol, 144(11) Dec. 1, 1015-1025. Steinmetz, K. A. and&127; Potter, J. D. 1996. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc, 96(10) Oct, &127;1027-1039. General Nagle CM, Purdie DM, Webb PM, Green A, Harvey PW, Bain CJ. Dietary influences on survival after ovarian cancer. Int J Cancer. 2003 Aug 20;106(2):264-9. Michnovicz, J. J. et al. 1997. Changes in levels of urinary estrogen metabolites after oral indole-3-carbinol&127; treatment in humans. J Natl Cancer Inst, 89(10) May 21, 718-723. Dose: Oral ingestion of 13C (6-7 mg/kg/day. Men received for &127;1 week, women received for 2 months. Chen, L. et al. 1996. Decrease of plasma and urinary oxidative metabolites of acetaminophen after consumption of watercress by human volunteers. Clin Pharmacol Ther, 60(6) Dec., 651-660. Dose: Watercress homogenates (50 gm). Smokers Caicoya M. Lung cancer and vegetable consumption in Asturias, Spain. A case control study. Med Clin (Barc). 2002 Jul 13;119(6):206-10. Seow A, Poh WT, Teh M, Eng P, Wang YT, Tan WC, Chia KS, Yu MC, Lee HP. Diet, reproductive factors and lung cancer risk among Chinese women in Singapore: evidence for a protective effect of soy in nonsmokers. Int J Cancer. 2002 Jan 20;97(3):365-71. Hecht SS, Chung FL, Richie JP Jr, Akerkar SA, Borukhova A, Skowronski L, Carmella SG. Effects of watercress consumption on metabolism of a tobacco-specific lung carcinogen in smokers. Cancer Epidemiol Biomarkers Prev. 1995 Dec;4(8):877-84. Taioli, E. et al. 1997. Effects of indole-3-carbinol on the metabolism of 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone in smokers. Cancer Epidemiol Biomarkers Prev, 6(7) Jul., 517-522. Dose: 400 mg of I3C on 5 consecutive days and maintained constant smoking habits during this period. 102 Curcumine (Turmeric) Anti-inflammatory Effects Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J Ethnopharmacol. 1993 Mar;38(23):113-9. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 192
Satoskar, R. R. et al. 1986. Evaluation of anti-inflammatory property of curcumin (Diferuloyl Methane) in patients with postoperative inflammation. Int J Clin Pharmacol Ther Toxicol, 24(12), Dec., 651-654. Cancer Zhang H, Yang L, Liu S, Ren L. Study on active constituents of traditional Chinese medicine reversing multidrug resistance of tumor cells in vitro. Zhong Yao Cai. 2001 Sep;24(9):655-7. Polasa, K. et al. 1992. Effect of turmeric on urinary mutagens in smokers. Mutagenesis, 7(2), Mar., 107-109. Kuttan, R. et al. 1987. Turmeric and curcumin as topical agents in cancer therapy. Tumori, 73(1), Feb. 28, 29-31. Cardiovascular/Coronary Heart Disease Ammon HP, Safayhi H, Mack T, Sabieraj J. Mechanism of antiinflammatory actions of curcumine and boswellic acids. J Ethnopharmacol. 1993 Mar;38(23):113-9. Soni, K. B. and Kuttan, R. 1992. Effect of oral curcumin administration on serum peroxides and cholesterol levels in human volunteers. Indian J Physiol Pharmacol, 36(4), Oct., 273-275. Dose: 500 mg/day for 7 days. Dandelion Root Chronic Colitis Chakurski, I. et al.&127; 1981. [Treatment of chronic colitis with an herbal combination of Taraxacum officinale, Hipericum perforatum, Melissa officinaliss, Calendula officinalis and Foeniculum vulgare]. Vutr Boles, 20(6), 51-54. Garlic 103 Cancer Das S. Garlic - A Natural Source of Cancer Preventive Compounds. Asian Pac J Cancer Prev. 2002;3(4):305-311. You, W. C. et al. 1989. Allium vegetables and reduced risk of stomach cancer. J National Cancer Inst, 81(2), Jan. 18, 162-164. Cardiovascular/Coronary Heart Disease Li G, Shi Z, Jia H, Ju J, Wang X, Xia Z, Qin L, Ge C, Xu Y, Cheng L, Chen P, Yuan G. A clinical investigation on garlicin injectio for treatment of unstable angina pectoris and its actions on plasma endothelin and blood sugar levels. J Tradit Chin Med. 2000 Dec;20(4):243-6. Bordia A, Verma SK, Srivastava KC. Effect of garlic on platelet aggregation in humans: a study in healthy subjects and patients with coronary artery disease. Prostaglandins Leukot Essent Fatty Acids. 1996 Sep;55(3):201-5. Gadkari, J. V. and Joshi, V. D. 1991. Effect of ingestion of raw garlic on serum cholesterol level, clotting time and fibrinolytic activity in normal subjects. J Postgrad Med, 37(3), July, 128-131. Dose: 10 gm/day for 2 months. Bordia, A. 1981. Effect of garlic on blood lipids in patients with coronary heart disease. Am J Clin Nutr, 34(10), Oct., 2100-2103. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 193
Jain, A. K. et al. 1993. Can garlic reduce levels of serum lipids? A controlled clinical study. Am J Med, 94(6), June, 632-635. Dose: 300 mg 3x/day. Warhafsky, S. et al. 1993. Effect of garlic on total serum cholesterol. A meta-analysis. Annals Int Med, 119(7 Pt 1), Oct. 1, 599-605. Vorberg, G. and Schneider, B. 1990. Therapy with garlic: Results of a placebo-controlled, double-blind study. British J Clin Pract Symp Suppl, 69, Aug., 7-11. Dose: 900 mg garlic powder for 4 months. Auer, W. et al. 1990. Hypertension and hyperlipidaemia: Garlic helps in mild cases. British J Clin Pract Symp Suppl, 69, Aug., 3-6. McMahon, F. G. and Vargas, R. 1993. Can garlic lower blood pressure? A pilot study. Pharmacotherapy, 13(4), July-Aug., 406-407. 104 Dose: 1.3% allicin at 2400mg. Ali, M. and Thomson, M. 1995. Consumption of a garlic clove a day could be beneficial in preventing thrombosis. Prostaglandins Leukot Essent Fatty Acids, 53(3), Sept., 211-212. Dose: 1 fresh clove of garlic/day for 16 weeks. Kieswetter, H. et al. 1993. Effect of garlic on platelet aggregation in patients with increased risk of juvenile ischaemic attack. European J Pharmacology, 45(333-336. Dose: 800 mg powdered garlic over 4 weeks. Silagy, C. A. and Neil, A. W. 1994. A meta-analysis of this effect of garlic on blood pressure. J Hypertension, 12, 463-468. Dose: 600-900 mg/day of dried garlic powder for 12 weeks. Hepatopulmonary Syndrome Abrams GA, Fallon MB. Treatment of hepatopulmonary syndrome with Allium sativum L. (garlic): a pilot trial. J Clin Gastroenterol. 1998 Oct;27(3):2325. Caldwell, S. H. et al. 1992. Ancient remedies revisited: Does Allium Sativum palliate the hepatopulmonary syndrome? J Clin Gastroenterology, 15(3), Oct., 248-250. Meningitis Shen J, Davis LE, Wallace JM, Cai Y, Lawson LD. Enhanced diallyl trisulfide has in vitro synergy with amphotericin B against Cryptococcus neoformans. Planta Med. 1996 Oct;62(5):415-8. Davis LE, Shen J, Royer RE. In vitro synergism of concentrated Allium sativum extract and amphotericin B against Cryptococcus neoformans. Planta Med. 1994 Dec;60(6):546-9. Davis, L. E. et al. 1990. Anitfungal activity in human cerebrospinal fluid and plasma after intravenous administration of Allium Sativum. Antimicrob Agents Chemother, 34(4), Apr., 651-653. Gingko Biloba Aging Topic B, Tani E, Tsiakitzis K, Kourounakis PN, Dere E, Hasenohrl RU, Hacker R, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 194
105 Mattern CM, Huston JP. Enhanced maze performance and reduced oxidative stress by combined extracts of zingiber officinale and ginkgo biloba in the aged rat. Neurobiol Aging. 2002 Jan-Feb;23(1):135-43. Taillandier, J. et al. 1986. [Treatment of cerebral aging disorders with Ginko Biloba extract. A longitudinal multicenter double-blind drug vs. placebo study]. Presse Med, 15(31), Sept. 25, 1583-1587. Allard, M. 1986. [Treatment of the disorders of aging with Ginko Biloba extract. From pharmacology to clinical medicine]. Presse Med, 15(31), Sept. 25, 1540, 1545. Anti-Clastogenic Effects Emerit, I. et al. 1995. Clastogenic factors in the plasma of Chernobyl accident recovery workers: Anticlastogenic effect of Gingko Biloba extract. Radiat Res, 144(2), Nov., 198-205. Dose: 120 mg/day for 2 months. Brain Function/ Injury Siddique MS, Eddeb F, Mantle D, Mendelow AD. Extracts of Ginkgo biloba and Panax ginseng protect brain proteins from free radical induced oxidative damage in vitro. Acta Neurochir Suppl. 2000;76:87-90. Hofferberth, B. 1989. [The effect of Ginko Biloba extract on neurophysiological and psychometric measurement results in patients with psychotic organic brain syndrome. A double-blind study against placebo]. Arzneimittelforschung, 39(8), Aug., 918-922. Dose: 120 mg/day for 8 weeks. Hopfenmuller, W. 1994. [Evidence for a therapeutic effect of Ginko Biloba special extract. Meta-analysis of 11 clinical studies in patients with cerebrovascular insufficiency in old age]. Arzneimittelforschung, 44(9), Sept., 1005-1013. Dose: 150 mg/day. Gessner, B. et al. 1985. Study of the long-term action of a Ginkgo Biloba extract on vigilance and mental performance as determined by means of quantitative pharmaco-EEg and psychometric measurements. Arzneimittelforschung, 35(9), 1459-1465. Dose: 120 mg/day Kleijnen, J. and Knipschild, P. 1992. Ginkgo Biloba for cerebral insufficiency. British J Clin Pharmacology, 34(4), Oct., 352-358. 106 Dose: 120 mg/day for 4-6 weeks. Allain, H. et al 1993. Effect of two doses of Ginkgo Biloba extract (EGb 761) on the dual coding test in elderly subjects. Clin Ther, 15(3), may-June, 549558. Dose: 320 or 600 mg. Rai, G. S. et al. 1991. A double-blind, placebo controlled study of Gingko Biloba extract ('tanakan') in elderly outpatients with mild to moderate memory impairment. Curr Med Res Opin, 12(6), 350-355. Dose: 120 mg/day at 12 and 24 weeks. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 195
Grassel, E. 1992. [Effect of Ginkgo-biloba extract on mental performance: Double-blind study using computerized measurement conditions in patients with cerebral insufficiency]. Fortschr Med, 110(5), Feb. 20, 73-76. Eckmann, F. 1990. [Cerebral insufficiency-Treatment with Gingko-biloba extract. Time of onset of effect in a double-blind study with 60 inpatients]. Fortschr Med, 108(29), Oct. 10, 557-560. Dose: 160 mg/day. Gerhardt, G. et al. 1990. [Drug therapy of disorders of cerebral performance: Randomized comparative study of dihydroergotoxine and Ginkgo Biloba extract]. Fortschr Med, 108(19), June 30, 384-388. Subhan, Z. and Hindmarch, I. 1984. The psychopharmacological effects of Ginkgo Biloba extract in normal healthy volunteers. Int J Clin Pharmacology Res, 4(2), 89-93. Dose: 120, 240, or 600 mg/day. Raabe, A. et al. 1991. [Therapeutic follow-up using automatic perimetry in chronic cerebroretinal ischemia in elderly patients. prospective doubleblind study with graduated dose Ginkgo Biloba treatment (EGb 761), Klin Monatsbl Augenheilkd, 199(6), Dec., 432-438. Dose: 160 mg/day for 4 weeks. Lebuisson, D. A. et al. 1986. [Treatment of senile macular degeneration with Ginkgo Biloba extract. A preliminary double-blind drug vs. placebo study]. Presse Med, 15(31), Sept. 25, 1556-1558. Funfgeld, E. W. 1989. A natural and broad spectrum nootropic substance for treatment of SDAT-the Ginkgo Biloba extract. Prog Clin Biol Res, 317, 1247-1260. Cardiovascular/Coronary Heart Disease Mahady GB. Ginkgo biloba for the prevention and treatment of 107 cardiovascular disease: a review of the literature. J Cardiovasc Nurs. 2002 Jul;16(4):21-32. Schneider, B. 1992. [Ginkgo biloba extract in peripheral arterial diseases. Meat-analysis of controlled clinical studies]. Arzneimittelforschung, 42(4), Apr., 428-436. Jung, F. et al. 1990. Effect of Ginkgo Biloba on fluidity of blood and peripheral microcirculation in volunteers. Arzneimittelforschung, 40(5), May, 589-593. Bauer, U. 1984. 6-month double-blind randomised clinical trial of Ginkgo Biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency. Arzneimittelforschung, 34(6), 716-720. Schaffler, K. and Reeh, P. W. 1985. [Double blind study of the hypoxia protective effect of a standardized Ginkgo Biloba preparation after repeated administration in healthy subjects]. Arzneimittelforschung, 35(8), 12831286. Witte, S. et al. 1992. [Improvement of hemorheology with Ginkgo Biloba extract. Decreasing a cardiovascular risk factor]. Fortschr Med, 110(13), May 10m 247-250. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 196
Dose: 240 mg/day for 12 weeks. Koltringer, P. et al. 1993. [Hemorheologic effects of Ginkgo Biloba extract EFb 671. Dose-dependent effect of EGb 761 on microcirculation and visoelasticity of blood]. Fortschr Med, 111(10), Apr. 10, 170-172. Dose: single injection of 50, 100, 150, 200 mg. Bauer, U. 1986. [Ginkgo Biloba extract in the treatment of arteriopathy of the lower extremities. A 65-week trial]. Presse Med, 15(31), Sept. 25, 15461549. Koltringer, P. et al. 1989. [Microcirculation in parenteral Ginkgo Biloba extract therapy]. Wien Klin Wochenschr, 101(6), Mar. 17, 198-200. Claudication Pittler MH, Ernst E. Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials. Am J Med. 2000 Mar;108(4):276-81. Erns, E. 1996. [Ginkgo Biloba in treatment of intermittent claudication. A systematic research based on controlled studies in the literature]. Fortschr Med, 114(8), Mar. 20, 85-87. Drabaek, H. et al. 1986. [The effect of Ginkgo Biloba extract in patients with intermittent claudication]. Ugeskr Laeger, 158(27), July 1, 3928-3931. 108 Dose: 120 mg/day for 3 months. Diabetes Fitzl G, Welt K, Wassilew G, Clemens N, Penka K, Mukke N. The influence of hypoxia on the myocardium of experimentally diabetic rats with and without protection by Ginkgo biloba extract. III: Ultrastructural investigations on mitochondria. Exp Toxicol Pathol. 2001 Feb;52(6):557-68. Lanthony, P. and Cosson, J. P. 1988. [The course of color vision in early diabetic retinopathy treated with Ginkgo Biloba extract. A preliminary double-blind versus placebo study]. J Fr Ophtalmol, 11(10), 671-674. Edema Westman J, Drieu K, Sharma HS. Antioxidant compounds EGB-761 and BN520 21 attenuate heat shock protein (HSP 72 kD) response, edema and cell changes following hyperthermic brain injury. An experimental study using immunohistochemistry in the rat. Amino Acids. 2000;19(1):339-50. Lagrue, G. et al. [Idiopathic cyclic edema. The role of capillary hyperpermeability and its correction by Ginkgo Biloba extract]. Presse Med, 15(31), Sept. 25, 1550-1553. General Schulz V. Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trials and guidelines fail to consider. Phytomedicine. 2003;10 Suppl 4:74-9. Lagrue, G. et al. 1986. [Recurrent shock with monoclonal gammopathy. Treatment in the acute and chronic phases with oral and parenteral Ginkgo Biloba extract]. Presse Med, 15(31), Sept. 25, 1554-1555. Hearing Loss Hoffman, F. et al. 1994. [Ginkgo extract EGb 761 )tenobin)/HAES versus Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 197
Naftidrofuryl (Dusodril)/HAES. A randomized study of therapy of sudden deafness]. Laryngorhinootologie, 73(3), Mar., 149-152. Dubreuil, C. 1986. [Therapeutic trial in acute cochlear deafness. A comparative study of Ginkgo Biloba extract and Nicergoline]. Presse Med, 15(31), Sept. 25, 1559-1561. Hepatitis 109 Li, W. et al. [Preliminary study of early fibrosis of chronic hepatitis B treated with Ginkgo Biloba composita]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih, 15(10) Oct., 593-595. Neuropathy Yoshikawa T, Naito Y, Kondo M. Ginkgo biloba leaf extract: review of biological actions and clinical applications. Antioxid Redox Signal. 1999 Winter;1(4):469-80. Koltringer, P. et al. 1989. [Ginkgo Biloba extract and folic acid in the therapy of changes caused by autonomic neuropathy]. Acta Med Austriaca, 16(2), 35-37. Dose; 87.5 mg for 4 days. Tinnitus Morgenstern C, Biermann E. The efficacy of Ginkgo special extract EGb 761 in patients with tinnitus. Int J Clin Pharmacol Ther. 2002 May;40(5):188-97. Meyer, B. 1986. [Multicenter randomized double-blind drug vs. placebo study of the treatment of Tinnitus with Ginkgo Biloba extract]. Presse med, 15(31), Sept. 25, 1562-1564. Vertigo Cesarani A, Meloni F, Alpini D, Barozzi S, Verderio L, Boscani PF. Ginkgo biloba (EGb 761) in the treatment of equilibrium disorders. Adv Ther. 1998 SepOct;15(5):291-304. Haguenaauer, J. P. et al. 1986. [Treatment of equilibrium disorders with Ginkgo Biloba extract. A multicenter double-blind drug vs. placebo study]. Presse Med, 15(310, Sept. 25, 1569-1572. Hibiscus Renal Stone Disease Kirdpon, S. et al. 1994. Changes in urinary chemical composition in healthy volunteers after consuming roselle (Hibiscus sabdariffa Linn.) juice. J Med Assoc Thai, 77(6) Jun., 314-321. Dose: Roselle juice consumption, 16 gm/day. Peppermint 110 General Hiki N, Kurosaka H, Tatsutomi Y, Shimoyama S, Tsuji E, Kojima J, Shimizu N, Ono H, Hirooka T, Noguchi C, Mafune K, Kaminishi M. Peppermint oil reduces gastric spasm during upper endoscopy: a randomized, double-blind, double-dummy controlled trial. Gastrointest Endosc. 2003 Apr;57(4):475-82. Spirling LI, Daniels IR. Botanical perspectives on health peppermint: more than just an after-dinner mint. J R Soc Health. 2001 Mar;121(1):62-3. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 198
Gobel, H. et al. 1994. Effect of peppermint and eucalyptus oil preparations on neurophysiological and experimental algesimetric headache parameters. Cephalalgia, 14(3), June, 228-234. Irritable Bowel Syndrome Gaby AR. Treatment with enteric-coated peppermint oil reduced smallintestinal bacterial overgrowth in a patient with irritable bowel syndrome. Altern Med Rev. 2003 Feb;8(1):3. Logan AC, Beaulne TM. The treatment of small intestinal bacterial overgrowth with enteric-coated peppermint oil: a case report. Altern Med Rev. 2002 Oct;7(5):410-7. Treating irritable bowel syndrome with peppermint oil. British Med J, Oct. 6, 835-836. Dose: Peppermint oil in enteric-coated capsules. Ulcers Meyer, J. et al. 1945. Action of oil of peppermint on the secretion and motility of the stomach in man. Arch Int Med, 56,88-97. Psyllium Jenkins DJ, Kendall CW, Marchie A, Jenkins AL, Connelly PW, Jones PJ, Vuksan V. The Garden of Eden--plant based diets, the genetic drive to conserve cholesterol and its implications for heart disease in the 21st century. Comp Biochem Physiol A Mol Integr Physiol. 2003 Sep;136(1):141-51 Sierra M, Garcia JJ, Fernandez N, Diez MJ, Calle AP. Therapeutic effects of psyllium in type 2 diabetic patients. Eur J Clin Nutr. 2002 Sep;56(9):830-42. 111 Zumarraga, L. et al. 1997. Absence of gaseous symptoms during ingestion of commercial fibre preparations. Aliment Pharmacol Ther, 11(6) Dec., 1067-1072. Dose: Psyllium 3.4 gm. McRorie, J. W. et al. 1998. Psyllium is superior to docusate sodium for treatment of chronic constipation. Aliment Pharmacol Ther, 12(5) May, 491497. Dose: Psyllium (5.1 gm b.d.). Moran, S. et al. 1997. [Effects of fiber administration in the prevention of gallstones in obese patients on a reducing diet. A clinical trial]. Rev Gastroenterol Mex, 62(4) Oct., 266-272. Dose: Psyllium 15 gm. Rigaud, D. et al. 1998. Effect of psyllium on gastric emptying, hunger feeling and food intake in normal volunteers: a double blind study. Eur J Clin Nutr, 52(4) Apr., 239-245. Dose: Psyllium 7.4 gm. Segawa, K. et al. 1998. Cholesterol-lowering effects of psyllium seed associated with urea metabolism. Biol Pharm Bull, 21(2) Feb., &127;184187. Davidson, M. H. et al. 1998. Long-term effects of consuming foods containing psyllium seed husk on serum lipids in subjects with hypercholesterolemia. Am J Clin Nutr, 67(3) Mar., 367-376. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 199
Dose: Psyllium seed 0, 3.4, 6.8, or 10.2 gm for 24 weeks. Washington, N. et al. 1998. Moderation of lactulose-induced diarrhea by psyllium: Effects on motility and fermentation. Am J Clin Nutr, 67(2) Feb., 317-321. Dose: Psyllium 3.5 gm 3x/day. Olson, B. H. et al. 1997. Psyllium-enriched cereals lower blood total cholesterol and LDL cholesterol, but not HDL cholesterol, in hypercholesterolemic adults: results of a meta-analysis. J Nutr, 127(10) Oct., 1973-1980. Dose: 3 gm soluble fiber/day. Red Clover Cancer 112 Rock E, DeMichele A. Nutritional approaches to late toxicities of adjuvant chemotherapy in breast cancer survivors. J Nutr. 2003 Nov;133(11 Suppl 1):3785S-3793S. Katz AE. Flavonoid and botanical approaches to prostate health. J Altern Complement Med. 2002 Dec;8(6):813-21. Jarred RA, Keikha M, Dowling C, McPherson SJ, Clare AM, Husband AJ, Pedersen JS, Frydenberg M, Risbridger GP. Induction of apoptosis in low to moderate-grade human prostate carcinoma by red clover-derived dietary isoflavones. Cancer Epidemiol Biomarkers Prev. 2002 Dec;11(12):1689-96. Marshal, M. E. et al. 1987. Treatment of metastatic renal cell carcinoma with coumarin (1,2-benzopyrone) and cimetide: A pilot study. J Clin Oncology, 5f(6), June, 862-866. Dose:100 mg/day coumarin. Silybum Marianum (Milk Thistle) Alcohol Abuse Jacobs BP, Dennehy C, Ramirez G, Sapp J, Lawrence VA. Milk thistle for the treatment of liver disease: a systematic review and meta-analysis. Am J Med. 2002 Oct 15;113(6):506-15. Fintelmann, V. 1970. [Zur therapie der fettleber mit silymarin]. Therapiewoche, 20, 1055. Cirrhosis Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61(14):2035-63. Ferenci, P. et al. 1989. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol,&127; 9(1) Jul., 105-113. Dose:140 mg silymarin 3x/day. Diabetes Savickiene N, Dagilyte A, Lukosius A, Zitkevicius V. Importance of biologically active components and plants in the prevention of complications of diabetes mellitus. Medicina (Kaunas). 2002;38(10):970-5. 113 Velussi, M. 1997 et al. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 200
and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol, 26(4) Apr., 871-879. Dose: 600 mg silymarin/day. Zhang. J. Q. et al. 1993. [Effects of silybin on red blood cell sorbitol and nerve conduction velocity in diabetic patients]. Chung Kuo Chung Hsi I Chieh Ho Tsa Chih, 13(12) Dec., 725-726. Dose: Silybin 231 mg/day for 4 weeks. Geller, L. I. et al. 1993. [Treatment of fatty hepatosis in diabetics]. Probl Endokrinol (Mosk), 39(5) Sept., 20-22. Drug Abuse Carrescia, O. et al. 1980. Silymarin in the prevention of hepatic damage by psychopharmacologic drugs. Experimental premises and clinical evaluation. Clin Ter, 95, 157. Hepatitis Giese LA. Milk thistle and the treatment of hepatitis. Gastroenterol Nurs. 2001 Mar-Apr;24(2):95-7. Buzzelli, G. et al. 1993. A pilot study on the liver protective effect of silybinphosphatidylcholine complex (IdB1016) in chronic active hepatitis. Int J Clin Pharmacol Ther Toxicol, 31(9), Sept., 456-460. Dose: 240 mg silybin bid. Liver damage Schumann J, Prockl J, Kiemer AK, Vollmar AM, Bang R, Tiegs G. Silibinin protects mice from T cell-dependent liver injury. J Hepatol. 2003 Sep;39(3):333-40. Bromley, P. N. et al. 1995. Effects of intraoperative N-acetylcysteine on orthotopic liver transplantation. British J Anaesth, 75(3), Sept., 352-354. Oh, T. E. and Shenfield, G. M. 1980. Intravenous N-acetylcysteine for Paracetamol poisoning. Med J Australia, 1(13), June 28, 664-665. Lung damage Meyer, A. et al. 1995. Intravenous N-acetylcysteine and lung glutathione of patients with pulmonary fibrosis and normals. Am J Respiratory Crit Care Med, 152(3), Sept., 10551060. 114 Dose: 1.8 gm. Suter, P. M. et al. 1994. N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Chest, 105(1), Jan., 190194. Dose: 40 mg/kg/day iv over a period of 72 hours. Eklund, A. et al. 1988. Oral N-acetylcysteine reduces selected humoral markers of inflammatory cell activity in BAL fluid from healthy smokers: Correlation to effects on cellular variables. European Respir J, 1(9), Oct., 832-838. Dose: 200 mg tid over an 8 week period. Linden, M. et al. 1988. Effects of oral N-acetylecysteine on cell content and macrophage function in bronchoalveolar lavage from healthy smokers. European Respiratory J, 1(7), Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 201
July, 645-650. Dose: 200 mg tid over an 8 week period. Muscle fatigue Reid, M. B. et al. 1994. N-acetylcysteine inhibits muscle fatigue in humans. J Clin Investigations, 94(6), Dec., 2468-2474. Dose: pretreatment with 150 mg/kg. Sjogren's Syndrome Walters, M. T. et al. 1986. A double-blind, cross-over, study of oral N-acetylcysteine in Sjogren's syndrome. Scandanavian J Pheumatol Suppl, 61, 253-258. 115
Vitamin B1 120 Studies

1. J Neurol Neurosurg Psychiatry. 2003 May;74(5):674-6. Reversible acute axonal polyneuropathy associated with Wernicke-Korsakoff syndrome: impaired physiological nerve conduction due to thiamine deficiency? Ishibashi S, Yokota T, Shiojiri T, Matunaga T, Tanaka H, Nishina K, Hirota H, Inaba A, Yamada M, Kanda T, Mizusawa H. Japan 2. J Clin Pharm Ther. 2003 Feb;28(1):47-51. Effect of intravenous infusions of thiamine on the disposition kinetics of thiamine and its pyrophosphate. Drewe J, Delco F, Kissel T, Beglinger C. Switzerland
3. Ke ZJ, DeGiorgio LA, Volpe BT et al. Reversal of thiamine deficiency-induced neurodegeneration. J Neuropathol Exp Neurol 2003 Feb;62(2):195-207. 4. Anti-obesity effects of a mixture of thiamin, arginine, caffeine, and citric acid in noninsulin dependent diabetic KK mice. Muroyama K, Murosaki S, Yamamoto Y, Odaka H, Chung HC, Miyoshi M. J Nutr Sci Vitaminol (Tokyo). 2003 Feb;49(1):56-63. PMID: 12882397
5. Anaesthesiol Reanim. 2003;28(1):13-20. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 202
Can alcoholic withdrawal delirium be prevented? Hensel M, Kox WJ. 6. Cardiology. 2003;99(4):177-81. Dietary intake of various nutrients in older patients with congestive heart failure. Gorelik O, Almoznino-Sarafian D, Feder I, Wachsman O, Alon I, Litvinjuk V, Roshovsky M, Modai D, Cohen N.
7. Eur J Clin Nutr. 2002 Dec;56(12):1162-8. Changes in the intake of vitamins and minerals by men and women with hyperlipidemia and overweight during dietetic treatment. Grzybek A, Klosiewicz-Latoszek L, Targosz U. 8. Psychiatr Genet. 2002 Dec;12(4):217-24. Individual susceptibility to Wernicke-Korsakoff syndrome and alcoholism-induced cognitive deficit: impaired thiamine utilization found in alcoholics and alcohol abusers. Heap LC, Pratt OE, Ward RJ, Waller S, Thomson AD, Shaw GK, Peters TJ. 9. Alcohol Alcohol. 2002 Nov-Dec;37(6):513-21. The Royal College of Physicians report on alcohol: guidelines for managing Wernicke's encephalopathy in the accident and Emergency Department Thomson AD, Cook CC, Touquet R, Henry JA; Royal College of Physicians, London. 10. Bras Cardiol. 2002 Nov;79(5):454. Thiamin, selenium, and copper levels in patients with idiopathic dilated cardiomyopathy taking diuretics. da Cunha S, Albanesi Filho FM, da Cunha Bastos VL, Antelo DS, Souza MM. 11. Circ J. 2002 Nov;66(11):1070-2. Shoshin beriberi with vasospastic angina pectoris possible mechanism of mid-ventricular obstruction: possible mechanism of mid-ventricular obstruction. Ito M, Tanabe Y, Suzuki K, Kumakura M, Aizawa Y. Japan 12. Mol Genet. 2002 Nov 1;11(23):2951-60. Targeted disruption of Slc19a2, the gene encoding the high-affinity thiamin transporter Thtr-1, causes diabetes mellitus, sensorineural deafness and megaloblastosis in mice. Oishi K, Hofmann S, Diaz GA, Brown T, Manwani D, Ng L, Young R, Vlassara H, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 203
Ioannou YA, Forrest D, Gelb BD. 13. Biochim Biophys Acta. 2002 Oct 9;1588(1):79-84. Thiamine-responsive pyruvate dehydrogenase deficiency in two patients caused by a point mutation (F205L and L216F) within the thiamine pyrophosphate binding region. Naito E, Ito M, Yokota I, Saijo T, Matsuda J, Ogawa Y, Kitamura S, Takada E, Horii Y, Kuroda Y. 14. Nutr Rev. 2002 Sep;60(9):277-80. Acute versus marginal deficiencies of nutrients. Carpenter KJ.. 15. Ann Neurol. 2002 Aug;52(2):195-204. Cofactors of mitochondrial enzymes attenuate copper-induced death in vitro and in vivo. Sheline CT, Choi EH, Kim-Han JS, Dugan LL, Choi DW. 16. AIDS Read. 2002 May;12(5):222-4. High doses of riboflavin and thiamine may help in secondary prevention of hyperlactatemia. McComsey GA, Lederman MM. 17. Med Sci Monit. 2002 May;8(5):CR357-63. Alcohol consumption and the risk of colorectal cancer at low levels of micronutrient intake. Jedrychowski W, Steindorf K, Popiela T, Wahrendorf J, Tobiasz-Adamczyk B, Kulig J, Penar A.
18. Neurochem Int. 2002 May;40(6):493-504 Interactions of oxidative stress with thiamine homeostasis promote neurodegeneration. Gibson GE, Zhang H. 19. Obstet Gynecol. 2002 May;99(5 Pt 2):875-7. Hyperemesis gravidarum complicated by Wernicke's encephalopathy. Spruill SC, Kuller JA. 20. Proc Nutr Soc. 2002 May;61(2):251-7. Meeting the challenges of micronutrient deficiencies in emergency-affected populations. Weise Prinzo Z, de Benoist B. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 204
21. Dig Dis Sci. 2002 Mar;47(3):543-8. Thiamine deficiency in hepatitis C virus and alcohol-related liver diseases. Levy S, Herve C, Delacoux E, Erlinger S. 22. Int J Geriatr Psychiatry. 2002 Feb;17(2):189-92. Using thiamine to reduce post-ECT confusion. Linton CR, Reynolds MT, Warner NJ. 23. J Am Coll Nutr. 2002 Feb;21(1):33-7. Vitamin profile of 563 gravidas during trimesters of pregnancy. Baker H, DeAngelis B, Holland B, Gittens-Williams L, Barrett T Jr.. 24. Gastric Cancer. 2002;5(2):77-82. Reduced thiamine (vitamin B1) levels following gastrectomy for gastric cancer. Iwase K, Higaki J, Yoon HE, Mikata S, Miyazaki M, Kamiike W. 25. J Nutr Health Aging. 2002;6(4):237-42. Dietary intake analysis in institutionalized elderly: a focus on nutrient density. Dror Y, Berner YN, Stern F, Polyak Z. 26. J Nutr Health Aging. 2002;6(1):75-7. Reduced serum concentrations of riboflavine and ascorbic acid, and blood thiamine pyrophosphate and pyridoxal-5-phosphate in geriatric patients with and without pressure sores. Selvaag E, Bohmer T, Benkestock K. 27. Medicina (B Aires). 2002;62(4):331-4. Acute cardiovascular beriberi (shoshin-beriberi). Lopez Gaston OD, Malvino ER, McLoughlin D, Osatnik J, Chavez Zambrano MA, Pino C. 28. Rocz Panstw Zakl Hig. 2002;53(3):243-52. Changes in vitamins intake in overweight and obese adults after low-energy diets Pachocka L, Klosiewicz-Latoszek L. 29. Sci Total Environ. 2001 Dec 17;281(1-3):177-82. Lead poisoning in Indian silver refiners. Tandon SK, Chatterjee M, Bhargava A, Shukla V, Bihari V.
205
30. Am J Clin Nutr. 2001 Dec;74(6):808-13. Postpartum thiamine deficiency in a Karen displaced population. McGready R, Simpson JA, Cho T, Dubowitz L, Changbumrung S, Bohm V, Munger RG, Sauberlich HE, White NJ, Nosten F. 31. J Nutr Sci Vitaminol (Tokyo). 2001 Dec;47(6):385-6. Cooperation of divalent ions and thiamin diphosphate in regulation of the function of pig heart pyruvate dehydrogenase complex. Czerniecki J, Czygier M. 32. Mech Ageing Dev. 2001 Dec;123(1):21-7. Co-culture with astrocytes or microglia protects metabolically impaired neurons. Park LC, Zhang H, Gibson GE. 33. Psychiatry Res. 2001 Nov 5;108(1):49-55. Serial MRI and (1)H-MRS of Wernicke's encephalopathy: report of a case with remarkable cerebellar lesions on MRI. Murata T, Fujito T, Kimura H, Omori M, Itoh H, Wada Y. 34. Am J Kidney Dis. 2001 Nov;38(5):941-7. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP. 35. Aust N Z J Obstet Gynaecol. 2001 Nov;41(4):453-6. Wernicke's encephalopathy due to hyperemesis gravidarum: an under-recognised condition. Togay-Isikay C, Yigit A, Mutluer N. 36. Harefuah. 2001 Nov;140(11):1062-7, 1117. Micronutrient (vitamins and minerals) supplementation for the elderly, suggested by a special committee nominated by Ministry of Health Dror Y, Stern F, Berner YN, Kaufmann NA, Berry E, Maaravi Y, Altman H, Cohen A, Leventhal A, Kaluski DN. 37. Surgery. 2001 Nov;130(5):851-8. Thiamine reverses hyperglycemia-induced dysfunction in cultured endothelial cells. Ascher E, Gade PV, Hingorani A, Puthukkeril S, Kallakuri S, Scheinman M, Jacob T.
206
38. J Hum Nutr Diet. 2001 Oct;14(5):365-70. Riboflavin deficiency in cystic fibrosis: three case reports. McCabe H. 39. Am J Physiol Cell Physiol. 2001 Sep;281(3):C786-92. Mechanism of thiamine uptake by human jejunal brush-border membrane vesicles. Dudeja PK, Tyagi S, Kavilaveettil RJ, Gill R, Said HM.
40. J Neurol Neurosurg Psychiatry. 2001 Sep;71(3):357-62. Postgastrectomy polyneuropathy with thiamine deficiency. Koike H, Misu K, Hattori N, Ito S, Ichimura M, Ito H, Hirayama M, Nagamatsu M, Sasaki I, Sobue G. 41. Wei Sheng Yan Jiu. 2001 Sep;30(5):273-5. Effect of multi-micronutrient on heat adaptation and its probable mechanism. Guo J, Zhao F, Qiu L, Li X.
42. Eur J Biochem. 2001 Aug;268(15):4177-82. The effect of thiamine supplementation on tumour proliferation. A metabolic control analysis study. Comin-Anduix B, Boren J, Martinez S, Moro C, Centelles JJ, Trebukhina R, Petushok N, Lee WN, Boros LG, Cascante M.
43. Life Sci. 2001 Jul 27;69(10):1181-91. Characteristics of depressive behavior induced by feeding thiamine-deficient diet in mice. Nakagawasai O, Tadano T, Hozumi S, Taniguchi R, Tan-No K, Esashi A, Niijima F, Kisara K.
44. Am J Ophthalmol. 2001 Jul;132(1):19-26. Use of vitamin supplements and cataract: the Blue Mountains Eye Study. Kuzniarz M, Mitchell P, Cumming RG, Flood VM. 45. Am J Physiol Gastrointest Liver Physiol. 2001 Jul;281(1):G144-50. Mechanism of thiamine uptake by human colonocytes: studies with cultured colonic
207
epithelial cell line NCM460. Said HM, Ortiz A, Subramanian VS, Neufeld EJ, Moyer MP, Dudeja PK. 46. Eur J Pharmacol. 2001 Jun 15;421(3):157-64. B vitamins induce an antinociceptive effect in the acetic acid and formaldehyde models of nociception in mice. Franca DS, Souza AL, Almeida KR, Dolabella SS, Martinelli C, Coelho MM.
47. Br J Nutr. 2001 Jun;85(6):741-8. Vitamin B intake and status in healthy Havanan men, 2 years after the Cuban neuropathy epidemic. Arnaud J, Fleites-Mestre P, Chassagne M, Verdura T, Garcia Garcia I, HernandezFernandez T, Gautier H, Favier A, Perez-Cristia R, Barnouin J. France/Cuba
48. Int J STD AIDS. 2001 Jun;12(6):407-9. Severe lactic acidosis and thiamine administration in an HIV-infected patient on HAART. Arici C, Tebaldi A, Quinzan GP, Maggiolo F, Ripamonti D, Suter F.
49. Aquat Toxicol. 2001 May;52(3-4):229-39. The use of thiamine and thiamine antagonists to investigate the etiology of early mortality syndrome in lake trout (Salvelinus namaycush). Fitzsimons JD, Vandenbyllaardt L, Brown SB.
50. Mt Sinai J Med. 2001 May;68(3):216-8. Wernicke's encephalopathy in a non-alcoholic man: case report and brief review. Munir A, Hussain SA, Sondhi D, Ameh J, Rosner F.
51. J Biochem (Tokyo). 2001 Apr;129(4):543-9. Suppression of the accumulation of triosephosphates and increased formation of methylglyoxal in human red blood cells during hyperglycaemia by thiamine in vitro. Thornalley PJ, Jahan I, Ng R.
208
52. Nutrition. 2001 Apr;17(4):351-2. Severe metabolic acidosis and heart failure due to thiamine deficiency. Ozawa H, Homma Y, Arisawa H, Fukuuchi F, Handa S.
53. Am J Gastroenterol. 2001 Mar;96(3):864-8. Thiamine treatment of chronic hepatitis B infection. Wallace AE, Weeks WB. 54. Public Health. 2001 Mar;115(2):133-8. Relationships between dietary intake and cognitive function level in Korean elderly people. Lee L, Kang SA, Lee HO, Lee BH, Park JS, Kim JH, Jung IK, Park YJ, Lee JE. 55. Rev Med Liege. 2001 Mar;56(3):155-8. Shoshin beriberi: myth or reality? Masset C, Lancellotti P, Nkoghe D. 56. Ukr Biokhim Zh. 2001 Mar-Apr;73(2):51-6. Interaction of rat brain thiamine kinase with thiamine and its derivatives Pylypchuk Siu, Parkhomenko IuM, Protasova ZS, Vovk AI, Donchenko HV. 57. Brain Research. 2001 Feb 16;892(1):218-27. Glucose induced IEG expression in the thiamin-deficient rat brain. Zimitat C, Nixon PF. Australia 58. Can J Neurol Sci. 2001 Feb;28(1):89-92. Wernickes encephalopathy following gastroplasty for morbid obesity. Toth C, Voll C.
59. Alcohol Clin Exp Res. 2001 Jan;25(1):112-6. Thiamin treatment and working memory function of alcohol-dependent people: preliminary findings. Ambrose ML, Bowden SC, Whelan G. 60. Ann Nutr Metab. 2001;45(4):175-80. Nutritional disorders among workers in North China during national turmoil. Lee BY, Thurmon TF.
209
61. Behav Neurol. 2001-2002;13(3-4):89-94. Wernicke-Korsakoff syndrome following small bowel obstruction. Deb S, Law-Min R, Fearnley D. 62. Blood Cells Mol Dis. 2001 Jan-Feb;27(1):135-8. Thiamine-responsive megaloblastic anemia syndrome: a disorder of high-affinity thiamine transport. Neufeld EJ, Fleming JC, Tartaglini E, Steinkamp MP. 63. Br J Nutr. 2001 Jan;85(1):49-58. Longitudinal vitamin and homocysteine levels in normal pregnancy. Cikot RJ, Steegers-Theunissen RP, Thomas CM, de Boo TM, Merkus HM, Steegers EA. 64. J Int Med Res. 2001 Jan-Feb;29(1):37-40. Cardiac beriberi among illegal mainland Chinese immigrants. Chen KT, Chiou ST, Chang YC, Pan WH, Twu SJ. China
65. Rev Environ Health. 2001 Jul-Sep;16(3):213-22. Risk of colorectal cancer from alcohol consumption at lower vitamin intakes. A hospitalbased case-control study in Poland. Jedrychowski W, Steindorf K, Popiela T, Wahrendorf J, Tobiasz-Adamczyk B, Kulig J, Penar A. Poland
66. J Am Coll Cardiol. 2001 Jun 1;37(7):1765-74. Chronic heart failure and micronutrients. Witte KK, Clark AL, Cleland JG. UK
67. Molecular mechanisms of thiamine utilization. Singleton CK, Martin PR. USA
68. J Clin Anesth. 2001 May;13(3):230-8. Early recognition of acute cardiovascular beriberi by interpretation of hemodynamics Gabrielli A, Caruso L, Stacpoole PW. USA.. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 210
69. Behav Brain Res. 2001 Mar 15;119(2):167-77. Aging potentiates the acute and chronic neurological symptoms of pyrithiamine-induced thiamine deficiency in the rodent. Pitkin SR, Savage LM. USA
70. Clin Nephrol. 2001 Mar;55(3):248-53. Central and extrapontine myelinolysis in a patient in spite of a careful correction of hyponatremia. Leens C, Mukendi R, Foret F, Hacourt A, Devuyst O, Colin IM. Belgium
71. J Am Med Dir Assoc. 2001 Mar-Apr;2(2):71-5. Wernicke's Encephalopathy: The Subacute Setting as Safety Net. Buxbaum RC, Yurkofsky M. USA
72. Pediatr Radiol. 2001 Mar;31(3):167-8. Wernicke's encephalopathy in a child: case report and MR findings. Coe M, Carfagnini F, Tani G, Ambrosetto P. Italy
73. Am J Kidney Dis. 2001 Feb;37(2):427-30. Chorea induced by thiamine deficiency in hemodialysis patients. Hung SC, Hung SH, Tarng DC, Yang WC, Huang TP. China
74. J Magn Reson Imaging. 2001 Feb;13(2):163-6. In vivo and in vitro proton NMR spectroscopic studies of thiamine-deficient rat brains. Lee H, Holburn GE, Price RR. USA
75. Ann Fr Anesth Reanim. 2001 Jan;20(1):40-3. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 211
Postoperative encephalopathies: thiamine deficiency, an unrecognized etiology S, Andrianjatovo JJ, Dubau B, Winnock S, Maurette P. France
76. Ann Hematol. 1999 Feb;78(2):105-7. Downbeat nystagmus caused by thiamine deficiency: an unusual presentation of CNS localization of large cell anaplastic CD 30-positive non-Hodgkin's lymphoma. Mulder AH, Raemaekers JM, Boerman RH, Mattijssen V. Netherlands
77. Fortschr Neurol Psychiatr. 2000 Mar;68(3):113-20. Thiamine treatment in psychiatry and neurology Hinze-Selch D, Weber MM, Zimmermann U, Pollmacher T. Garmany
78. Eur J Paediatr Neurol. 2000;4(3):115-7. Outcome of thiamine treatment in a child with Leigh disease due to thiamine-responsive pyruvate dehydrogenase deficiency. Di Rocco M, Lamba LD, Minniti G, Caruso U, Naito E. Italy ANIMAL RESEARCH 79. Brain Res Bull. 2000 Jan 1;51(1):47-55. Immunohistochemical estimation of rat brain somatostatin on avoidance learning impairment induced by thiamine deficiency. Nakagawasai O, Tadano T, Niijima F, Tan-No K, Kisara K. Japan. 80. Ann Vasc Surg. 2000 Jan;14(1):37-43. Thiamine (Vitamin B1) protects against glucose- and insulin-mediated proliferation of human infragenicular arterial smooth muscle cells. Avena R, Arora S, Carmody BJ, Cosby K, Sidawy AN. USA
81. Acta Haematol. 2000;102(3):157-9. Graft failure of autologous peripheral blood stem cell transplantation due to acute Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 212
metabolic acidosis associated with total parenteral nutrition in a patient with relapsed breast cancer. Sawada M, Tsurumi H, Hara T, Goto H, Yamada T, Oyama M, Moriwaki H. Japan. 82. Nihon Arukoru Yakubutsu Igakkai Zasshi. 2000 Feb;35(1):19-27. Alcohol intake and nutrition. Itokawa Y. Japan
83. Presse Med. 2000 Feb 12;29(5):240-1. Right heart failure caused by thiamine deficiency (cardiac beriberi)] Akpan T, Peschard S, Brinkane AH, Bergheul S, Leroy-Terquem E, Levy R. France
84. J Neurochem. 2000 Jan;74(1):114-24. Metabolic impairment elicits brain cell type-selective changes in oxidative stress and cell death in culture. Park LC, Calingasan NY, Uchida K, Zhang H, Gibson GE. USA
85. J Nutr Health Aging. 2000;4(2):69-71. Diuretic use: a risk for subclinical thiamine deficiency in elderly patients. Suter PM, Haller J, Hany A, Vetter W. Switzerland
86. Neurol Neurochir Pol. 2000;34 Suppl 8:59-66. Disturbances of glucose metabolism in epilepsy and other neurodegenerative diseases Szutowicz A, Jankowska A, Tomaszewicz M. Poland
87. No To Shinkei. 2000 Jan;52(1):59-63. A case of Wernicke-Korsakoff syndrome with dramatic improvement in consciousness immediately after intravenous infusion of thiamine Kikuchi A, Chida K, Misu T, Okita N, Nomura H, Konno H, Takase S, Takeda A, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 213
Itoyama Y. Japan
88. Acta Neuropathol (Berl). 1999 Dec;98(6):614-21. Changes in serotonergic neurons in the brain of pyrithiamine-induced acute thiaminedeficient mice. Matsushita H, Takeuchi Y, Kosaka K, Fushiki S, Kawata M, Sawada T. Japan
89. Clin Nutr. 1999 Dec;18(6):375-8. Thiamin deficiency in HIV-positive patients: evaluation by erythrocyte transketolase activity and thiamin pyrophosphate effect. Muri RM, Von Overbeck J, Furrer J, Ballmer PE. Switzerland.
90. Endocr J. 1999 Dec;46(6):787-93. Gestational thyrotoxicosis with acute Wernicke encephalopathy: a case report. Ohmori N, Tushima T, Sekine Y, Sato K, Shibagaki Y, Ijuchi S, Akano K. Japan. 91. Am Fam Physician. 1999 Oct 1;60(5):1468-76. Management of the hyperosmolar hyperglycemic syndrome. Matz R. USA.. 92. Eur J Anaesthesiol. 1999 Oct;16(10):733-5. Thiamine for the treatment of nucleoside analogue-induced severe lactic acidosis. Schramm C, Wanitschke R, Galle PR. Germany
93. Nippon Rinsho. 1999 Oct;57(10):2362-5. Diabetes and vitamin levels Tamai H. Japan
214
94. Acta Neurol Belg. 1999 Sep;99(3):198-201. Acute axonal polyneuropathy in chronic alcoholism and malnutrition. Vandenbulcke M, Janssens J. Belgium
95. J Lab Clin Med. 1999 Sep;134(3):238-43. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. Rieck J, Halkin H, Almog S, Seligman H, Lubetsky A, Olchovsky D, Ezra D. Isreal
96. J Neuropathol Exp Neurol. 1999 Sep;58(9):946-58. Oxidative stress is associated with region-specific neuronal death during thiamine deficiency. Calingasan NY, Chun WJ, Park LC, Uchida K, Gibson GE. USA.
97. Metab Brain Dis. 1999 Sep;14(3):137-48. The relationship between thiamine deficiency and performance of a learning task in rats. Terasawa M, Nakahara T, Tsukada N, Sugawara A, Itokawa Y. Japan
98. Public Health Nutr. 1999 Sep;2(3A):403-9. The effects of nutrients on mood. Benton D, Donohoe RT. UK
99. Neurosci Lett. 1999 Aug 13;271(1):33-6. Cerebrospinal fluid levels of thiamine in patients with Parkinson's disease. Jimenez-Jimenez FJ, Molina JA, Hernanz A, Fernandez-Vivancos E, de Bustos F,Barcenilla B, Gomez-Escalonilla C, Zurdo M, Berbel A, Villanueva C. Spain
100. Pediatr Radiol. 1999 Aug;29(8):581-4. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 215
Reversible MRI abnormalities in an unusual paediatric presentation of Wernicke's encephalopathy. Sparacia G, Banco A, Lagalla R. Italy 101. Ambrose, ML, Bowden SC, Whelan G. Thiamin treatment and working memory function of alcohol-dependent people: preliminary findings. Alcohol Clin Exp Res. 2001;25(1):112-116. 102. Antoon AY, Donovan DK. Burn Injuries. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia, Pa: W.B. Saunders Company; 2000:287-294. 103. Bell I, Edman J, Morrow F, et al. Brief communication. Vitamin B1, B2, and B6 augmentation of tricyclic antidepressant treatment in geriatric depression with cognitive dysfunction. J Am Coll Nutr. 1992;11:159-163. 104. Boros LG, Brandes JL, Lee W-N P, et al. Thiamine supplementation to cancer patients: a double-edged sword. Anticancer Res. 1998;18:595602. 105. Cumming RG, Mitchell P, Smith W. Diet and cataract: the Blue Mountains Eye Study. Ophthalmology. 2000;107(3):450-456. 106. De-Souza DA, Greene LJ. Pharmacological nutrition after burn injury. J Nutr. 1998;128:797-803. 107. Jacques PF, Chylack LT Jr, Hankinson SE, et al. Long-term nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol. 2001;119(7):1009-1019. 108. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Alt Med Rev. 1999;4(4):249-265. 109. Kirschmann GJ, Kirschmann JD. Nutrition Almanac. 4th ed. New York: McGrawHill;1996:80-83. 110. Kuzniarz M, Mitchell P, Cumming RG, Flood VM. Use of vitamin supplements and cataract: the Blue Mountains Eye Study. Am J Ophthalmol. 2001;132(1):19-26. 111. Leslie D, Gheorghiade M. Is there a role for thiamine supplementation in the management of heart failure? Am Heart J. 1996;131:12481250. 112. Lindberg MC, Oyler RA. Wernick's encephalopathy. Am Fam Physician. 1990;41:12051209.
216
113. Lubetsky A, Winaver J, Seligmann H, et al. Urinary thiamine excretion in the rat: effects of furosemide, other diuretics, and volume load [see comments]. J Lab Clin Med. 1999;134(3):232-237. 114. Meador KJ, Nichols ME, Franke P, et al. Evidence for a central cholinergic effect of high-dose thiamine. Ann Neurol. 1993;34:724-726. 115. Meyer NA, Muller MJ, Herndon DN. Nutrient support of the healing wound. New Horizons. 1994;2(2):202-214. 116. Ott BR, Owens NJ. Complementary and alternative medicines for Alzheimer's disease. J Geriatr Psychiatry Neurol. 1998;11:163-173. 117. Rieck J, Halkin H, Almog S, et al. Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab Clin Med. 1999;134(3):238-243. 118. Rodriquez-Martin JL, Qizilbash N, Lopez-Arrieta JM. Thiamine for Alzheimer's disease (Cochrane Review). Cochrane Database Syst Rev. 2001;2:CD001498. 119. Witte KK, Clark AL, Cleland JG. Chronic heart failure and micronutrients. J Am Coll Cardiol. 2001;37(7):1765-1774. 120. Zangen A, Botzer D, Zanger R, Shainberg A. Furosemide and digoxin inhibit thiamine uptake in cardiac cells. Eur J Pharmacol. 1998;361(1):151-155.
Vitamin B12 64 Studies

1. Araki A, et al. 1993. Plasma homocysteine concentrations in Japanese patients with non-insulin-dependent diabetes mellitus: effect of parenteral methylcobalamin treatment. Atherosclerosis 103(2):149-57. 2. Berlin R, et al. 1978. Vitamin B12 body stores during oral and parenteral treatment of pernicious anaemia. Acta Med Scand 204(1-2):81-4. 3. Bernard MA, et al. 1998. The effect of vitamin B12 deficiency on older veterans and its relationship to health [see comments]. J Am Geriatr Soc 46(10):1199-206. 4. Freeman AG. 1992. Cyanocobalamin-a case for withdrawal: discussion paper. J R Soc Med 85:686-7. 5. Honma K, et al. 1992. Effects of vitamin B12 on plasma melatonin rhythm in humans: increased light sensitivity phase-advances the circadian clock? Experientia 48:716-20. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 217
6. Houston DK, et al. Age-related hearing loss, vitamin B-12, and folate in elderly women. Am J Clin Nutr 69:564-71. 7. Kaji R, et al. 1998. Effect of ultra high-dose methylcobalamin on compound muscle action potentials in amyotrophic lateral sclerosis: a double-blind controlled study. Muscle Nerve 21:1775-8. 8. Kamgar-Parsi B, et al. 1983. Successful treatment of human non-24-hour sleep-wake syndrome. Sleep 6:257-64. 9. Kuzminski AM, et al. 1998. Effective treatment of cobalamin deficiency with oral cobalamin. Blood 92:1191-98. 10. Mayer G, et al. 1996. Effects of vitamin B12 on performance and circadian rhythm in normal subjects. Neuropsychopharm 15:456-464. 11. Parnetti L, et al. 1992. Platelet MAO-B activity and vitamin B12 in old age dementias. Mol Chem Neuropathol 16(1-2):23-32. 12. Salom IL, et al. Effect of cimetidine on the absorption of vitamin B12. 1982. Scand J Gastroenterol 17(1):129-31. 13. Shane B, et al. 1985. Vitamin B12--folate interrelationships. Ann Rev Nutr 5:115-41. 14. van Asselt DZ, et al. 1998. Role of cobalamin intake and atrophic gastritis in mild cobalamin deficiency in older Dutch subjects [see comments]. Am J Clin Nutr 68(2):32834. 15. Watanabe T, et al. 1994. Ultra-high dose methylcobalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci 122:140-3 16. Yamazaki K, et al. 1994. Methylcobalamin (methyl-B12) promotes regeneration of motor nerve terminals degenerating in anterior gracile muscle of gracile axonal dystrophy (GAD) mutant mouse. Neurosci Lett 170:195-7. 17. Shane B. Folic acid, vitamin B-12, and vitamin B-6. In: Stipanuk M, ed. Biochemical and Physiological Aspects of Human Nutrition. Philadelphia: W.B. Saunders Co.; 2000:483-518. 18. Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377. (PubMed) 19. Herbert V. Vitamin B-12. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:191-205.
218
20. Food and Nutrition Board, Institute of Medicine. Vitamin B12. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington D.C.: National Academy Press; 1998:306-356. (National Academy Press) 21. Ho C, Kauwell GP, Bailey LB. Practitioners' guide to meeting the vitamin B-12 recommended dietary allowance for people aged 51 years and older. J Am Diet Assoc. 1999;99(6):725-727. (PubMed) 22. Weir DG, Scott JM. Vitamin B-12 "Cobalamin". In: Shils M, ed. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:447-458. 23. Homocysteine Lowering Trialists' Collaboration. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials. Homocysteine Lowering Trialists' Collaboration. BMJ. 1998;316(7135):894-898. (PubMed) 24. Quinlivan EP, McPartlin J, McNulty H, et al. Importance of both folic acid and vitamin B12 in reduction of risk of vascular disease. Lancet. 2002;359(9302):227-228. (PubMed) 25. Stabler SP, Lindenbaum J, Allen RH. Vitamin B-12 deficiency in the elderly: current dilemmas. Am J Clin Nutr. 1997;66(4):741-749. (PubMed) 26. Fenech M. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Mutat Res. 1999;428(1-2):299-304. (PubMed) 27. Wu K, Helzlsouer KJ, Comstock GW, Hoffman SC, Nadeau MR, Selhub J. A prospective study on folate, B12, and pyridoxal 5'-phosphate (B6) and breast cancer. Cancer Epidemiol Biomarkers Prev. 1999;8(3):209-217. (PubMed) 28. Eskes TK. Open or closed? A world of difference: a history of homocysteine research. Nutr Rev. 1998;56(8):236-244. (PubMed) 29. Mills JL, Scott JM, Kirke PN, et al. Homocysteine and neural tube defects. J Nutr. 1996;126(3):756S-760S. (PubMed) 30. Nourhashemi F, Gillette-Guyonnet S, Andrieu S, et al. Alzheimer disease: protective factors. Am J Clin Nutr. 2000;71(2):643S-649S. (PubMed) 31. Clarke R, Smith AD, Jobst KA, Refsum H, Sutton L, Ueland PM. Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol. 1998;55(11):1449-1455. (PubMed) 32. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology. 2001;56(9):1188-1194. (PubMed) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 219
33. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346(7):476-483. (PubMed) 34. Hutto BR. Folate and cobalamin in psychiatric illness. Compr Psychiatry. 1997;38(6):305-314. (PubMed) 35. Penninx BW, Guralnik JM, Ferrucci L, Fried LP, Allen RH, Stabler SP. Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study. Am J Psychiatry. 2000;157(5):715721. (PubMed) 36. Hadded EH, et al. 1999. Dietary intake and biochemical, hematologic, and immune status of vegans compared with nonvegetarians. Am J Clin Nutr 70(3 Suppl):586S-93S. 37. Hall CA, et al. 1986. Methionine synthetase activity of human lymphocytes both replete in and depleted of vitamin B12. J Lab Clin Med 108:325-31. 38. Tamura J, et al. 1999. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activityin vitamin B12-deficient patients by methyl-B12 tratment. Clin Exp Immunol 116:28-32. 39. Tang AM, et al. 1997. Low serum vitamin B-12 concentrations are associated with faster human immunodeficiency virus type 1 (HIV-1) disease progression. J Nutr 127:345-51. 41. Adachi S, et al. 2000. Enteral vitamin B12 supplements reverse postgastrectomy B12 deficiency. Ann Surg 232:199-201. 42. Akaike A, et al. 1993. Protective effects of a vitamin B12 analog, methylcobalamin, against glutamate cytotoxicity in cultured cortical neurons. Eur J Pharm 241:1-6. 43. Aytemir K, et al. 2000. Assessment of autonomic nervous system functions in patients with vitamin B12 deficiency by power spectral analysis of heart rate variability. Pacing Clin Electrophysiol 23:975-78. 44. Baik HW, et al. 1999. Vitamin B12 deficiency in the elderly. Annu Rev Nutr 19:35777. 45. Eastley R, et al. 2000. Vitamin B12 deficiency in dementia and cognitive impairment: the effects of treatment on neuropshychological function. Int J Geriatr Psychiatry 15:22633. 46. Fenech M. 1999. Micronucleus frequency in human lymphocytes is related to plasma vitamin B12 and homocysteine. Muta Res 428:299-304. 47. Freeman AG. 1992. Cyanocobalamina case for withdrawal: discussion paper. J Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 220
Royal Soc Med 85:686-7. 48. Haddad EH, et al. 1999. Dietary intake and biochemical, hematologic and immune status of vegans compared with nonvegetarians. Am J Clin Nutr 70(3 suppl):586S-93S. 49. Kaptan K, et al. 2000. Helicobacter pyloriis it a novel causative agent in vitamin B12 deficiency? Arch Intern Med 160(9):1349-53. 50. Kikuchi M, et al. 1997. Protective effects of methylcobalamin, a vitamin B12 analog, against glutamate-induced neurotoxicity in retinal cell culture. Invest Ophthal Vis Sci 38:848-54. 51. Kuwabara S, et al. 1999. Intravenous methylcobalamin treatment for uremic and diabetic neuropathy in chronic hemodialysis patients. Intern Med 38:472-5. 52. Laine L, et al. 2000. Review article: potential gastrointestinal effects of long-term acid suppression with proton pump inhibitors. Aliment Pharmacol Ther 14:651-68. 53. Lederle FA. Oral cobalamin for pernicious anemia: back from the verge of extinction. J Am Geratr Soc 46:1125-27. 54. Lindeman RD, et al. 2000. Serum vitamin B12, C and folate concentrations in the New Mexico elder health surve: correlations with cognitive and affective functions. J Am Coll Nutr 19:68-76. 55. Mayer G, et al. 1996. Effects of vitamin B12 on performance and circadian rhythm in normal subjects. Neuropsychopharm 15:456-64. 56. Meins W, et al. 2000. Subnormal serum vitamin B12 and behavioural and psychological symptoms in Alzheimers disease. Int J Geriatr Psychiatry 15:415-18. 57. Moelby L, et al. 2000. Relationahip between methylmalonic acid and cobalamin in uremia. Kindey Int 57:265-73. 58. Pongstaporn W, et al. 1999. Hematological parameters, ferritin and vitamin B12 in vegetarians. J Med Assoc Thai 82:304-11. 59. Silver H. 2000. Vitamin B12 levels are low in hospitalized psychiatric patients. Isr J Psychiatry Relat Sci 37:41-45. 60. Sponne IE, et al. 2000. Inhibition of vitamin B12 metabolism by OH-cobalamin clactam in rat oligodendrocytes in culture: a model for studying neuropathy due to vitamin B12 deficiency. Neurosci Lett 288:191-4. 61. Tamura J, et al. 1999. Immunomodulation by vitamin B12: augmentation of CD8+ T lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 221
methyl-B12 treatment. Clin Exp Immunol 116:28-32. 62. Temple ME, et al. 2000. Homocysteine as a risk factor for atherosclerosis. Ann Pharmacother 34:57-65. 63. Watanabe T, et al. 1994. Ultra-high dose methylcogalamin promotes nerve regeneration in experimental acrylamide neuropathy. J Neurol Sci 122:140-43. 64. Yagihashi S, et al. 1982. In vivo effect of methylcobalamin on the periopheral nerve structure in streptozotocin diabetic rats. Horm Metab Res 14:10-13.
Pantothenic Acid (B5) 47 Studies

1. Effects of ethanol and pantothenic acid on brain acetylcholine synthesis. Rivera-Calimlim L, Hartley D, Osterhout D. Department of Pharmacology, University of Rochester, School of Medicine and Dentistry, NY 14642. Br J Pharmacol. 1988 Sep;95(1):77-82. 2. Pantothenic acid transport and metabolism in the central nervous system. Spector R. Am J Physiol. 1986 Feb;250(2 Pt 2):R292-7. Vitamins and lipid metabolism. 3. Fidanza A, Audisio M. Acta Vitaminol Enzymol. 1982;4(1-2):105-14. 4. Pantothenic acid protects jurkat cells against ultraviolet light-induced apoptosis. Slyshenkov VS, Piwocka K, Sikora E, Wojtczak L. Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland. Free Radic Biol Med. 2001 Jun 1;30(11):1303-10. 5. Mitochondrial, but not peroxisomal, beta-oxidation of fatty acids is conserved in coenzyme A-deficient rat liver.
222
Youssef JA, Song WO, Badr MZ. Division of Pharmacology, University of MissouriKansas City 64108, USA. Mol Cell Biochem. 1997 Oct;175(1-2):37-42. 6. Amelioration of adverse effects of valproic acid on ketogenesis and liver coenzyme A metabolism by cotreatment with pantothenate and carnitine in developing mice: possible clinical significance. Thurston JH, Hauhart RE. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110. Pediatr Res. 1992 Apr;31(4 Pt 1):419-23. 7. Pantothenic acid and its derivatives protect Ehrlich ascites tumor cells against lipid peroxidation. Slyshenkov VS, Rakowska M, Moiseenok AG, Wojtczak L. Nencki Institute of Experimental Biology, Warsaw, Poland. Free Radic Biol Med. 1995 Dec;19(6):767-72. Erratum in:Free Radic Biol Med 1996;20(3):493. 8. Topical use of dexpanthenol in skin disorders. Ebner F, Heller A, Rippke F, Tausch I. Technical University of Munich, Allershausen, Germany. fritz.ebner@t-online.de Am J Clin Dermatol. 2002;3(6):427-33. 9. Topical corticosteroid therapy for acute radiation dermatitis: a prospective, randomized, double-blind study. 10. Tahiliani AG, Beinlich CJ. Pantothenic acid in health and disease. Vitam Horm. 1991;46:165-228. 11. Bender DA. Optimum nutrition: thiamin, biotin and pantothenate. Proc Nutr Soc. 1999;58(2):427-433. 12. Hodges RE, Ohlson MA, Bean WB. Pantothenic acid deficiency in man. J Clin Invest. 1958;37:1642-1657. 13. Fry PC, Fox HM, Tao HG. Metabolic response to a pantothenic acid deficient diet in humans. J Nutr Sci Vitaminol (Tokyo). 1976;22(4):339-346.
223
14. Plesofsky-Vig N. Pantothenic acid. In: Filer LJ, ed. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996. 15. Food and Nutrition Board, Institute of Medicine. Pantothenic acid. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, D.C.: National Academy Press; 1998:357-373. 16. Weimann BI, Hermann D. Studies on wound healing: effects of calcium Dpantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts in culture. Int J Vitam Nutr Res. 1999;69(2):113-119. 17. Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound, in patients with different forms of hyperlipoproteinemia. Atherosclerosis. 1984;50(1):73-83. 18. Coronel F, Tornero F, Torrente J, et al. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol. 1991;11(1):32-36. 19. Said HM, Ortiz A, McCloud E, Dyer D, Moyer MP, Rubin S. Biotin uptake by human colonic epithelial NCM460 cells: a carrier-mediated process shared with pantothenic acid. Am J Physiol. 1998;275(5 Pt 1):C1365-1371. 21. Effect of pantothenic acid and ascorbic acid supplementation on human skin wound healing process. A double-blind, prospective and randomized trial. Vaxman F, Olender S, Lambert A, Nisand G, Aprahamian M, Bruch JF, Didier E, Volkmar P, Grenier JF. INSERM U 61, Hospices Civils, Strasbourg, France. Eur Surg Res. 1995;27(3):158-66. 23. Role of pantothenic and ascorbic acid in wound healing processes: in vitro study on fibroblasts. Lacroix B, Didier E, Grenier JF. INSERM Unite 61-Service de Chirurgie B, Hopital Civil, Strasbourg. Int J Vitam Nutr Res. 1988;58(4):407-13. 24. Effects of supplemental pantothenic acid on wound healing: experimental study in rabbit. Aprahamian M, Dentinger A, Stock-Damge C, Kouassi JC, Grenier JF. Am J Clin Nutr. 1985 Mar;41(3):578-89.
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25. A new drug combination for treating polyneuropathy 26. Munchener Medizinische Wochenschrift (Germany), 1997, 139/12 (34-37) 27. [Therapeutic efficacy of pantothenic acid preparations in ischemic heart disease patients] Vopr Pitan (USSR) Mar-Apr 1987, (2) p15-7 28. Vitamins and immunity: II. Influence of L-carnitine on the immune system. Acta Vitaminol Enzymol (ITALY) 1982, 4 (1-2) p135-40 29. Adding vitamins to the mix: skin care products that can benefit the skin [press release]. American Academy of Dermatology; March 11, 2000. 30. Antoon AY, Donovan DK. Burn Injuries. In: Behrman RE, Kliegman RM, Jenson HB, eds. Nelson Textbook of Pediatrics. Philadelphia, Pa: W.B. Saunders Company; 2000:287-294. 31. Aprahamian M, Dentinger A, Stock-Damge C, Kouassi JC, Grenier JF. Effects of supplemental pantothenic acid on wound healing: experimental study in rabbit. Am J Clin Nutr. 1985;41(3):578-89. 32. Arsenio L, Bodria P, Magnati G, Strata A, Trovato R.. Effectiveness of long-term treatment with pantethine in patients with dyslipidemia. Clin Ther. 1986;8:537545. 33. Bertolini S, Donati C, Elicio N, et al. Lipoprotein changes induced by pantethine in hyperlipoproteinemic patients: adults and children. Int J Clin Pharmacol Ther Toxicol. 1986;24:630637. 34. Coronel F, Tornero F, Torrente J, et al. Treatment of hyperlipemia in diabetic patients on dialysis with a physiological substance. Am J Nephrol. 1991;11:3236. 35. De-Souza DA, Greene LJ. Pharmacological nutrition after burn injury. J Nutr. 1998;128:797-803. 36. Gaddi A, Descovich GC, Noseda G, et al. Controlled evaluation of pantethine, a natural hypolipidemic compound in patients with different forms of hyperlipoproteinemia. Atherosclerosis. 1984;50:7383. 37. General Practitioner Research Group. Calcium pantothenate in arthritic conditions. A report from the General Practitioner Research Group. Practitioner. 1980;224(1340):208211. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 225
38. Hoeg JM. Pharmacologic and surgical treatment of dyslipidemic children and adolescents. Ann NY Acad Sci. 1991;623:275-284. 39. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. [Review]. Altern Med Rev. 1999 Aug;4(4):249-265. 40. Kirschmann GJ, Kirschmann JD. Nutrition Almanac. 4th ed. New York: McGrawHill;1996:115-118. 41. Lacroix B, Didier E, Grenier JF. Role of pantothenic and ascorbic acid in wound healing processes: in vitro study on fibroblasts. Int J Vitam Nutr Res. 1988;58(4):407413. 42. McCarty MF. Inhibition of acetyl-CoA carboxylase by cystamine may mediate the hypotriglyceridemic activity of pantethine. Med Hypotheses. 2001;56(3):314-317. 43. Meyer NA, Muller MJ, Herndon DN. Nutrient support of the healing wound. New Horizons. 1994;2(2):202-214. 44. Naruta E, Buko V. Hypolipidemic effect of pantothenic acid derivatives in mice with hypothalamic obesity induced by aurothioglucose. Exp Toxicol Pathol. 2001;53(5):393398. 45. Weimann BI, Hermann D. Studies on wound healing: effects of calcium Dpantothenate on the migration, proliferation and protein synthesis of human dermal fibroblasts in culture. Int J Vitam Nutr Res. 1999;69(2):113-119. 46. Brenner A. The effects of megadoses of selected B complex vitamins on children with hyperkinesis: controlled studies with long-term follow-up. J Learn Disabil. 1982 May;15(5):258-64. No abstract available. PMID: 7086283 47. American Diet Inadequate in Vitamin B5. Availability of vitamin B6 and pantothenate in an average American diet in man. Tarr JB. Tamura T. Stokstad EL. American Journal of Clinical Nutrition. 34(7):1328-37, 1981 Jul.
Calcium Carbonate - 86 Studies

1. Effect of dietary calcium on urinary oxalate excretion afteroxalate loads. American Journal of Clinical Nutrition (USA), 1997, 65/5 (1453-1459). 2. Heated oyster shell-seaweed calcium (AAA Ca) on osteoporosis. Calcified Tissue International (USA), 1996, 58/4 (226-230). Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 226
3. Holt, P.R. et al Modulation of Abnormal Colonic Epithelial Cell Proliferation and Differentiation by Low-fat Dairy Foods. AM. J. CLIN. NUTR. 1998, 68 (3) 648-655. 4. Calcium for Hypertension. J.A.M.A. 1998, 280 (12) 1074-9. 5. Clark, S. More Effort Needed to Halt Osteoporotic Bone Loss. LANCET 1998, 351 (9112) 1335. 6. Macready, N. Vitamins Associated With Lower Colon-Cancer Risk. The Lancet 1997, 350 (9089) 1452. 7. Dawson-Hughes, B et al. Effect of Calcium and Vitamin D Supplementation on Bone Density in Men and Women 65 Years of Age or Older. N. ENGL. J. MED. 1997, 337 (10) 670-6. 8. Allender PS, Cutler JA, Follmann D, Cappuccio FP, Pryer J, Elliott P. Dietary calcium and blood pressure: a meta-analysis of randomized clinical trials. Ann Intern Med. 1996;124(9):825-831. 9. O'sullivan AJ, Lawson JA, Chan M, Kelly JJ. Body composition and energy metabolism in chronic renal insufficiency. Am J Kidney Dis. 2002 Feb;39(2):369-375. 10. Appel L, Moore T, Obarzonek E, et al. A clinical trial of the effects of dietary patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med. 1997;336:1117-1124. 11. Baeksgaard L, Andersen KP, and Hyldstrup L. Calcium and vitamin D supplementation increases spinal BMD in healthy, postmenopausal women. Osteoporos Int. 1998;8:255-260. 12. Balfour JA, Wiseman LR. Moxifloxacin. Drugs. 1999;57(3):363-374. 13. Baron JA, Beach M, Mandel JS, et al. Calcium supplements for the prevention of colorectal adenomas. N Eng J Med. 1999;340:101-107. 14. Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin. Diabetes Care. 2000;23(9):1227-1231. 15. Bendich A. The potential for dietary supplements to reduce premenstrual syndrome (PMS) symptoms [review]. J Am Coll Nutr. 2000;19(1);3-12. 16. Blanch J, Pros A. Calcium as a treatment of osteoporosis. Drugs Today. 1999;35:631639.
227
17. Bonithon-Kopp C, Kronborg O, Giacosa A, Rath U, Faivre J. Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomised intervention trial. European Cancer Prevention Organisation Study Group. Lancet. 2000;356:1300-1306. 18. Borghi L, Schianchi T, Meschi T, et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med. 2002;346(2):77-84. 19. Bostick RM, Fosdick L, Grandits GA, Grambsch P, Gross M, Louis TA. Effect of calcium supplementation on serum cholesterol and blood pressure. Arch Fam Med. 2000;9:31-39. 20. Brouwers JR. Drug interactions with quinolone antibacterials. Drug Safety. 1992;7(4):268-281. 21. Bryant RJ, Cadogan J, Weaver CM. The new dietary reference intakes for calcium: implications for osteoporosis. J Am Coll Nutr. 1999;18:406S-412S. 22. Burgess E, Lewanczuk R, Bolli P, et al. Recommendations on potassium, magnesium and calcium. CMAJ. 1999;160:S35-S45. 23. Campbell NR, Hasinoff BB. Iron supplements: a common cause of drug interactions. Br J Clin Pharmacol. 1991;31(3):251-255. 24. Cardona PD. Drug-food interactions [in Spanish]. Nutr Hosp. 1999;14(suppl 2):129S140S. 25. Chan JM, Stampfer MJ, Ma J, Gann PH, Gaziano JM, Giovannucci EL. Dairy products, calcium, and prostate cancer risk in the Physicians' Health Study. Am J Clin Nutr. 2001;74(4):549-554. 26. Coburn JW, Mischel MG, Goodman WG, Salusky IB. Calcium citrate markedly enhances aluminum absorption from aluminum hydroxide. Am J Kidney Dis. 1991;17(6):708-711. 27. Consensus Opinion. The role of calcium in peri- and postmenopausal women: consensus opinion of the North American Menopause Society. Menopause. 2001;8:8495. 28. Davies KM, Heaney RP, Recker RR, et al. Calcium intake and body weight. J Clin Endocrinol Metab. 2000;85(12):4635-4638. 29. Garland CF, Garland FC, Gorham ED. Calcium and vitamin D: their potential roles in colon and breast cancer prevention. Ann NY Acad Sci. 1999;889:107-119.
228
30. Gugler R, Allgayer H. Effects on antacids on the clinical pharmacokinetics of drugs. An update. Clin Pharmacokinet. 1990;18(3): 210-219. 31. Gulson BL, Mizon KJ, Palmer Jm, Korsch MJ, Taylor AJ. Contribution of lead from calcium supplements to blood lead. Environ Health Perspect. 2001;109(3):283-288. 32. Haft JJ, Habbab MA. Treatment of atrial arrhythmias. Effectiveness of verapamil when preceeded by calcium infusion. Arch Intern Med. 1986; 146(6):1085-1089. 33. Hardman JG, Gilman AG, Limbird LE, eds. Goodman and Gilman's Pharmacological Basis of Therapeutics. 9th ed. New York, NY: McGraw-Hill; 1996:839874. 34. Hathcock JN. Metabolic mechanisms of drug-nutrient interactions. Fed Proc. 1985;44(1):124-129. 35. Heaney RP. Lead in calcium supplements: cause for alarm or celebration [editorial]? JAMA. 2000;284(11):1432-1433. 36. Heaney RP, Dowell SD, Bierman J, Hale CA, Bendich A. Absorbability and cost effectiveness in calcium supplementation. J Am Coll Nutr. 2001;20(3):239-246. 37. Heller HJ, Stewart A, Haynes S, Pak CYC. Pharmacokinetics of calcium absorption from two commercial calcium supplements. J Clin Pharmacol. 1999;39:1151-1154. 38. Hermensen K. Diet, blood pressure and hypertension. Br J Nutr. 2000;83(Suppl 1):S113-S119. 39. Hines Burnham T, et al, eds. Drug Facts and Comparisons. St. Louis, MO:Facts and Comparisons; 2000. 40. Holt PR. Dairy foods and prevention of colon cancer: human studies. J Am Coll Nutr. 1999;18(suppl 5):379S-391S. 41. Institute of Medicine. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes. Dietary Reference Intakes: Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: National Academy Press; 1997. 42. Iso H, Stampfer MJ, Manson JE, et al. Prospective study of calcium, potassium, and magnesium intake and risk of stroke in women. Stroke. 1999;30(9):1772-1779. 43. Jnne PA, Mayer RJ. Chemoprevention of colorectal cancer. N Engl J Med. 2000;342(26):1960-1968.
229
44. Joint National Committee. Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure. Arch Int Med. 1997;157:2413-2446. 45. Kampman E, Slattery ML, Caan B, Potter JD. Calcium, vitamin D, sunshine exposure, dairy products and colon cancer risk (United States). Cancer Causes Control. 2000:11:459-466. 46. Kara M, Hasinoff BB, McKay DW, et al. Clinical and chemical interactions between iron preparations and ciprofloxacin. Br J Clin Pharmacol. 1991;31(3):257-261. 47. Kirch W, Schfer-Korting M, Axthelm T, et al. Interaction of atenolol with furosemide and calcium and aluminum salts. Clin Pharm Ther. 1981;30(4):429-435. 48. Kirschmann GJ, Kirschmann JD, eds. Nutrition Almanac. 4th ed. New York: McGraw-Hill; 1996. 49. Krall EA, Wehler C, Garcia RI, et al. Calcium and vitamin D supplements reduce tooth loss in the elderly. Am J Med. 2001 Oct 15;111(6):452-456. 50. Krauss RM, Eckel RH, Howard B, et al. AHA dietary guidelines. Revision 2000: A statement for healthcare professionals from the Nutrition Committee of the American Heart Association. Circulation. 2000;102:2284-2299. 51. Leppla D, Browne R, Hill K, Pak C. Effect of amiloride with or without hydrochlorothiazide on urinary calcium and saturation of calcium salts. J Clin Endocrinol Metab. 1983;57(5):920-924. 52. Li RC, Lo KN, Lam JS, et al. Effects of order of magnesium exposure on the postantibiotic effect and bactericidal activity of ciprofloxacin. J Chemother. 1999;11(4):243-247. 53. Lin Y-C, Lyle RM, McCabe LD, et al. Dairy calcium is related to changes in body composition during a two-year exercise intervention in young women. J Am Coll Nutr. 2000;19(6):754-760. 54. Lobo RA, Roy S, Shoupe D, et al. Estrogen and progestin effects on urinary calcium and calciotropic hormones in surgically-induced postmenopausal women. Horm Metab Res. 1985;17(7):370-373. 55. Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Intern Med. 1990;112(5):352-364. 56. Mazariegos-Ramos E, Guerrero-Romero F, Rodriquez-Moran M, Lazcano-Burciago G,
230
57. Paniagua R, Amato D. Consumption of soft drinks with phosphoric acid as a risk factor for the development of hypocalcemia in children: a case-control study. J Pediatr. 1995;126(6):940-942. 58. McCarron D, Reusser M. Finding Consensus in the Dietary Calcium-Blood Pressure Debate. J Am Coll Nutr. 1999;18:398S-405S. 59. NAMS Consensus. Consensus Opinion: the role of calcium in peri-and postmenopausal women: consensus opinion of The North American Menopause Society. Menopause. 2001;8(20):84-95. 60. Nieves JW, Komar L, Cosman F, Lindsay R. Caclium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis. Am J Clin Nutr. 1998;67(1):18-24. 61. NIH Consensus Development Panel. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285(6):785-795. 62. Nolan CR, DeGoes JJ, Alfrey AC. Aluminum and lead absorption from dietary sources in women ingesting calcium citrate. South Med J. 1994;8(9):894-898. 63. Nutrients and Nutritional Agents. In: Kastrup EK, Hines Burnham T, Short RM, et al, eds. Drug Facts and Comparisons. St. Louis, Mo: Facts and Comparisons; 2000:4-5. 64. Peacock M, Liu G, Carey M, et al. Effect of calcium or 25OH vitamin D3 supplementation on bone loss at the hip in men and women over the age of 60. J Clin Endocrinol Metabol. 2000;85(9):3011-3019. 65. Petti S, Cairella G, Tarsitani G. Nutritional variables related to gingival health in adolescent girls. Community Dent Oral Epidemiol. 2000 Dec;28(6):407-413. 66. Physicians' Desk Reference. 55th ed. Montvale, NJ: Medical Economics Co., Inc; 2000:1418-1422. 67. Pietinen P, Malila N, Virtanen M, et al. Diet and risk of colorectal cancer in a cohort of Finnish men. Cancer Causes Control. 1999;10:387-396. 68. Potter JD. Nutrition and colorectal cancer. Cancer Causes Control. 1996;7:127-146. 69. Reid IR, Veale AG, France JT. Glucocorticoid osteoporosis. J Asthma. 1994;31(1):718. 69. Ross EA, Szabo NJ, Tebbett IR. Lead content of calcium supplements. JAMA. 2000;284(11):1425-1429.
231
70. Ruml LA, Sakhaee K, Peterson R, et al. The effect of calcium citrate on bone density in the early and mid-postmenopausal period: a randomized placebo-controlled study. Am J Ther. 1999;6:303-311. 71. Sacks FM, Svetkey LP, Volmer WM, et al. Effects on blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet. N Engl J Med. 2001;344:3-10. 72. Sakhaee K, Bhuket T, Adams-Huet B, Rao DS. Meta-analysis of calcium bioavailability: a comparison of calcium citrate with calcium carbonate. Am J Ther. 1999;6:313-321. 73. Sakhaee K, Nicar M, Glass K, Zerwekh J, Pak C. Reduction in intestinal calcium absorption by hydrochlorothiazide in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1984;59(6):1037-1043. 74. Schneider M, Valentine S, Clarke GM, Newman MA, Peacock J. Acute renal failure in cardiac surgical patients, potentiated by gentamicin and calcium. Anaesth Intens Care. 1996;24(6):647-650. 75. Shils ME, Olson JA, Shike M, Ross AC. Modern Nutrition in Health and Disease. 9th ed. Baltimore, Md: Williams & Wilkins; 1999:169192, A127A128. 76. Sonnenblick M, Abraham AS, Meshulam Z, Eylath U. Correlation between manifestations of digoxin toxicity and serum digoxin, calcium, potassium, and magnesium concentrations and arterial pH. BMJ. 1983;286(6371):1089-1091. 77. Stier CT Jr, Itskovitz HD. Renal calcium metabolism and diuretics. Ann Rev Pharmacol Toxicol. 1986;26:101-116. 78. Thatcher TD, Fischer PR, Pettifor JM, et al. A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children. N Engl J Med. 1999;341:563-568. 79. Thys-Jacobs S. Micronutrients and the premenstrual syndrome: the case for calcium. J Am Coll Nutr. 2000;19(2):220-227. 80. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premenstrual Syndrome Study Group. Am J Obstet Gynecol. 1998;179:444452. 81. Torkos S. Drug-nutrient interactions: a focus on cholesterol-lowering agents. Int J Integrative Med. 2000;2(3):9-13. 82. van den Elzen HJ, Wladimiroff JW, Overbeek TE, Morris CD, Grobbee DE. Calcium metabolism, calcium supplementation and hypertensive disorders of pregnancy. Eur J Obstet Gynecol Reprod Biol. 1995;59(1):5-16. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 232
83. Weiss AT, Lewis BS, Halon DA, Hasin Y, Gotsman MS. The use of calcium with verapamil in the management of supraventricular tachyarrhythmias. Int J Cardiol. 1983;4(3):275-284. 84. Wyshak G, Frisch RE. Carbonated beverages, dietary calcium, the dietary calcium/phosphorus ratio, and bone fractures in girls and boys. J Adolesc Health. 1994;15(3):210-215. 85. Zemel MB, Shi H, Greer B, Dirienzo D, Zemel PC. Regulation of adiposity by dietary calcium. FASEB. 2000;14:1132-1138. 86.Thys-Jacobs,S.et al. Calcium for Hypertension. AMER. J .OBSTET. GYNECOL. 1998, 179 (2) 444-52.
Magnesium 68 Studies
1. Rude RK. Magnesium deficiency: a cause of heterogeneous disease in humans. J Bone Miner Res. 1998 Apr;13(4):749-58. 2. Cohen JS. High-dose oral magnesium in the treatment of chronic, intractable erythromelalgia. Ann Pharmacother. 2002 Feb;36(2):255-60. 3. Iseri LT, French JH. Magnesium: natures physiologic calcium blocker. Am Heart J. 1984 Jul;108(1):18893. 4. Leppert J, Myrdal U, Hedner T, Edvinsson L, Tracz Z, Ringqvist I. Effect of magnesium sulfate infusion on circulating levels of noradrenaline and neuropeptide-Ylike immunoreactivity in patients with primary Raynauds phenomenon. Angiology. 1994 Jul;45(7):637-45. 5. Rogers SA. Tired or Toxic? A Blueprint for Health. Syracuse, NY: Prestige Publishing; 1990. 6. Altura BM, Altura BT. Magnesium in cardiovascular biology. Scientific American Science & Medicine. May/June 1995:28-37. 7. Altura BM, Altura BT. Role of magnesium in the pathogenesis of hypertension updated: relationship to its actions on cardiac, vascular smooth muscle, and endothelial cells. In: Laragh JH, Brenner BM, eds. Hypertension: Pathophysiology, Diagnosis, and Management. 2nd ed. New York, NY: Raven Press; 1995. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 233
8. Motoyama T, Sano H, Fukuzaki H. Oral magnesium supplementation in patients with essential hypertension. Hypertension. 1989 Mar;13(3):22732. 9. Widman L, Wester PO, Stegmayr BK, Wirell M. The dosedependent reduction in blood pressure through administration of magnesium. A double-blind placebo-controlled crossover study. Am J Hypertens. 1993 Jan;6(1):41-5. 10. Sanjuliani AF, de Abreu Fagundes VG, Francischetti EA. Effects of magnesium on blood pressure and intracellular ion levels of Brazilian hypertensive patients. Int J Cardiol. 1996 Oct 11;56(2):177-83. 11. Itoh K, Kawasaka T, Nakamura M. The effects of high oral magnesium supplementation on blood pressure, serum lipids and related variables in apparently healthy Japanese subjects. Br J Nutr. 1997 Nov;78(5):737-50. 12. Kawano Y, Matsuoka H, Takishita S, Omae T. Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension. 1998 Aug;32(2):2605. 13. Dyckner T, Wester PO. Effect of magnesium on blood pressure. Br Med J (Clin Res Ed). 1983 Jun 11;286(6381):1847-9. 14. Witteman JC, Grobbee DE, Derkx FH, Bouillon R, de Bruijn AM, Hofman A. Reduction of blood pressure with oral magnesium supplementation in women with mild to moderate hypertension. Am J Clin Nutr. 1994 Jul;60(1):129-35. 15. Seelig MS, Rosanoff A. The Magnesium Factor. New York, NY: Avery Publishers; 2003. 16. Johnson S. The multifaceted and widespread pathology of magnesium deficiency. Med Hypotheses. 2001 Feb;56(2):16370. 17. Galan P, Preziosi P, Durlach V, et al. Dietary magnesium intake in a French adult population. In: Theophanides T, Anastassopoulou J. Magnesium: Current Status and New Developments: Theoretical, Biological, and Medical Aspects. 1st ed. Dordrecht, Netherlands: Kluwer Academic Publishers; 1997. 18. Healy DP, Dansereau RJ, Dunn AB, Clendening CE, Mounts AW, Deepe GS Jr. Reduced tetracycline bioavailability caused by magnesium aluminum silicate in liquid formulations of bismuth subsalicylate. Ann Pharmacother. 1997;31:1460-1464. 19. June CH, Thompson CB, Kennedy MS, Loughran TP Jr, Deeg HJ. Correlation of hypomagnesemia with the onset of cyclosporine-associated hypertension in marrow transplant patients. Transplantation. 1986;41:47-51.
234
20. Lajer H, Daugaard G. Cisplatin and hypomagnesemia. Cancer Treat Rev. 1999;25:4758. 21. Nanji AA, Denegri JF. Hypomagnesemia associated with gentamicin therapy. Drug Intell Clin Pharm. 1984;18:596-598. 22. Quamme GA. Renal magnesium handling: new insights in understanding old problems. Kidney Int. 1997;52:1180-1195. 23. Rivlin RS. Magnesium deficiency and alcohol intake: mechanisms, clinical significance and possible relation to cancer development (a review). J Am Coll Nutr. 1994;13:416-423. 24. Rob PM, Lebeau A, Nobiling R, et al. Magnesium metabolism: basic aspects and implications of ciclosporine [sic] toxicity in rats. Nephron. 1996;72:59-66. 25. Sadowski DC. Drug interactions with antacids. Mechanisms and clinical significance. Drug Saf. 1994;11:395-407. 26.Schaafsma G. Bioavailability of calcium and magnesium. Eur J Clin Nutr. 1997;51(Suppl 1):S13-S16. 27. Spencer H, Norris C, Williams D. Inhibitory effects of zinc on magnesium balance and magnesium absorption in man. J Am Coll Nutr. 1994;13:479-484.
28. Food Nutrition Board, Natl Acad Sci., Chapter3.1997.
29. Pao E.M, Mickle S.J. (1981) Food Technology35:58 30. Lakshmanan F.L., Rao R.B., Kim W.W., Kelsay J.L. (1984). Am J Clin Nutr.40:1380 31. Morgan K.J., Stampley G.L. (1988). Magnesium, 7:225 32. Morgan K.J., Stampley G.L., Zabik M.E., Fischer D.R. (I 985), J Am Coll Nutr.4: 195 33. Abdulla M., Behbehani A., Dashti H. (I 989) ed Itokawa Y., and Durlach J., Magnesium in Health and Disease, Publ. J. Libbey, London: III. 34. Pennington J.A., Young B.E. (1991). J Am Diet Assoc 91:179183. 35. Schmidt C.L.A., Greenberg D.M., Physiol Rev, 15: 297. 36. Hathaway F.W., Home Economics Research Report #19, Agricultural Research Service, Washington D.C., 1962.
235
37. Seelig M. S. (1964). Am 3 Clin Nutr 14:342. 38. Irwin M.I., Feeley R.M. (1967) Am J Clin Nutr,20:816. 39. Spiller G.A., Jensen C.D., Whittam J.H. (1988). FASEBJ.,2:A1099. 40. Seelig M.S. (1980). Magnesium Deficiency in the pathogenesis of disease. Early Roots of Cardiovascular, Skeletal, and Renal Abnormalities. Pub] Plenum Press, NY, pp 41. Karppannen H. (1990). Magnesium Bulletin 12:80-86. 42. Simonen H. (1991). Calcif Tiss Res (Suppl) 49:S8. 43. Seelig M.S. (1990). Magnesium Res 3:197. 44. Weaver K. (1986).Magnesium 5:191200. 45. Hwang DL, Yen CF, Nadler JL (1992). Am J Hypertens 5:700. 46. Seelig M.S. (1993). J Am Coll Nutr 12:442- 458. 47. Seelig M.S. (1994). J Am Coll Nutr 12:429. 48. Farago, M., Szabo, C., Dora, E., et al (1991). J Cerebr Blood Flow Metab 11:161. 49. Gormican A, Catli, E [1971] Nutr Metab 13:364-377. 50. Whyte K.F., Addis G.J., Whitesmith R., Reid J.L. (1987). Clin Sci 72:135. 51. Resnick L.M. (1992). Am J Med 93(2A): 11S20S. 52. Barbagallo M., Novo S., Licata G., Resnick L.M. (1993). Intl Angiol 12:365370. 53. Rueddel H., Baehr M., Schaechinger H., Schmieder R., Ising G. (1989). Magnesium Bulletin 11:9398. 54. Parlier R., Hioco D., LeBlanc R. (I 963). Rev Franc Endocr Clin, 4:93.31 55. Leichsenring J.M., Norris L.M., Lamison S.A. (1951) J Nutr 45:477. 56. Briscoe A.M., Ragan C. (1966). Am J Clin Nutr, 19:296. 57. Lichton, J (1989). Magnesium 8:117. 58. Fatemi S, Ryzen E, Flores J, Endres DB, Rude RK (1991). J Clin Endocrinol Metab 73:1067. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 236
59. Kimura M., Nagai, K, Itokawa, Y. (1989). In Magnesium in Health and Disease. eds Itokawa Y, Durlach J, Publ J. Libbey, London: 63. 60. Wang, R., Flink, E.B., Dyckner, T. et al. (1985): Magnesium depletion as a cause of refractory potassium repletion Arch. Intern. Med. 145, 1686. 61. Hasselbach, W., Makinose, M. (1961): Die Calciumpumpe des Muskels und ihre Abhngigkeit von der ATP-Spaltung Biochem. Z. 333, 518. 62. Achenbach, C., Daying, H., Schweikart, P. et al. (1991): Unterschiedliche Effekte von Mg, Ca, Mn und Nifedipin auf den Na/Ca-Austausch whrend des Aktionspotentials der Herzmuskelzelle. Int. Symposium Edinburgh New approaches in the Pathophysiology and Treatment of Cardiovascular Disease. 63. Dyckner T., Wester, P.O. (1979): Ventricular extrasystoles and intracellular electrolytes before and after potassium and magnesium infusions in patients on diuretic treatment Am. Heart J. 97, 12. 64. Schroll, A. (1981): Optimierte Magnesium-Substitution bei extrakorporaler Zirkulation Mg. Bull. 3, 163. 65. Schroll, A. (1986): Magnesium in open heart surgery: its role in ischemia and arrhythmia Internat. Symposium on Anaesthesia for Cardiac Patients, Mnchen. 66. Wischnik, A., Schroll A., Kollmer, W.E. et al. (1982): Magnesium-aspartat als Kardioprotektivum und Adjuvans bei Tokolyse mit Betamimetika Z. Geburtsh. und Perinat. 186, 326. 67. Borman, B. von, Scheld, H.H., Kling, D. et al. (1983): Concentrations of cations in the tissue of papillary muscle under different modes of supplementation 5th Annual Meeting of the Society of Cardiovascular Anesthesiologists, San Diego. 68. Kahles, H., Riegger, A.J.G., Kromer, E.P. et al. (1991): Wirkungen von hochdosiertem Magnesium-aspartat wahrend Koronarangioplastie Deutscher Ansthesiekongre Mannheim.
Ginkgo Biloba 33 Studies

1. Antagonistic effects of extract from leaves of Ginkgo biloba on glutamate neurotoxicity. Zhu L Wu J Liao H Gao J Zhao XN Zhang ZX Acta Pharmacol Sin 1997 JUL;18(4):344 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 237
Zhu L, Nanjing Univ, Sch Med, Nanjing 210093, PEOPLES R CHINA 2. Attenuation of salicylate-induced tinnitus by Ginkgo biloba extract in rats. Jastreboff PJ Zhou ST Jastreboff MM Kwapisz U Gryczynska U Audiol Neuro Otol 1997 JUL-AUG;2(4):197-212 Jastreboff PJ, Univ Maryland, Sch Med, Dept Surg, Tinnitus & Hyperacusis Ctr, 10 S Pine St, Mstf Bldg, RM 436, Baltimore,MD 21201 USA 3. Phospholipid breakdown and choline release under hypoxic conditions: Inhibition by bilobalide, a constituent of Ginkgo biloba. Klein J Chatterjee SS Loffelholz K Brain Res 1997 MAY 2;755(2):347-350 Klein J, Univ Mainz, Dept Pharmacol, Obere Zahlbacher Str 67, D 55101 Mainz, GERMANY 4. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multiinfarct dementia (Reprinted f rom Pharmacopsychiat, vol 29, pg 47-56, 1996). Kanowski S Herrmann WM Stephan K Wierich W Horr R Phytomedicine 1997 MAR;4(1):3-13 Kanowski S, Free Univ Berlin, Klinikum Benjamin Franklin, ABT Gerontopsychiat, Dept Gerontopsychiat, D 14050 Berlin, GERMANY 5. Effect of Ginkgo biloba extract (EGb 761) on the vasospastic response of mouse cutaneous arterioles to platelet activation. Stucker O Pons C Duverger JP Drieu K DArbigny P Int J Microcirc Clin Exp 1997 MAR-APR;17(2):61-66 Stucker O, Cerom, 155 Rue Faubourg St Denis, F 75010 Paris, FRANCE 6. Agnoli, A., J. R. Rapin, V. Scapagnini, and W. V. Weitbrecht (eds.). 1985. Effects of Ginkgo Biloba Extract on Organic Cerebral Impairment. London: John Libbey Eurotext, Ltd. 7. Bauer, U. 1984. Six-month Double-blind Randomized Clinical Trial of Ginkgo Biloba Extracts Versus Placebo in Two Parallel Groups in Patients Suffering from Peripheral Arterial Insufficiency. Arzneim-Forsch. 34: 716-721. 8. Boralle, N., P. Braquet and O. R. Gottlieb. 1988. Chemical Composition of Ginkgo. In P. Braquet (ed.) 1988. Op. cit. Pp. 9-25. 9. Braquet, P. 1985. BN 52021 and related compounds: A new series of highly specific PAF-Acether receptor antagonists isolated from Ginkgo biloba. Blood Vessels. 16: 559572. 10. Braquet, P. (ed.) 1988. Ginkgolides-Chemistry, Biology, Pharmacology and Clinical Perspectives. Vol. I. Barcelona, Spain: J. R. Prous. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 238
11. Chatterjee, S. S. 1985. Effects of Ginkgo Biloba Extract on Cerebral Metabolic Processes. In A. Agnoli, J. R. Rapin, V. Scapagnini, and W. V. Weitbrecht (eds.) 1985. Op. cit. Pp. 5-15. 12. Chung, K. F. and P. J. Barnes. 1988. Clinical Perspectives of PAF-Acether Antagonists. In P. Braquet (ed.) 1988. Op. cit. Pp. 333-344. 13. Claussen, C. F. 1988. Diagnostic and Practical Value of Craniocopography in Vertiginous Syndromes. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 251-259. 14. Cory, E. J., M. C. Kang, M. C. Desai, A. K. Ghosh, and I. N. Houpis. 1988. Total Synthesis of Ginkgolide B. J. Am. Chem. Soc. 110: 649-651. 15. DeFeudis, F. V. 1991. Ginkgo biloba Extract (EGb 761): Pharmacological Activities and Clinical Applications. Amsterdam: Elsevier. 16. Drieu, K. 1985. Multiplicity of effects of Ginkgo Biloba Extract: Current status and new trends. In A. Agnoli, J.R. Rapin, V. Scapagini, and W. V. Weitbrecht (eds.). Op. cit. Pp. 63-68. 17. Drieu, K. 1988. Preparation and Definition of Ginkgo Biloba. Extract. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 32-36. 18. Funfgeld, E. W. (ed.) 1988. Rokan (Ginkgo biloba), Recent Results in Pharmacology, and Clinic. Berlin: Springer-Verlag. 19. Hindmarch, I. 1988. Activity of Ginkgo Biloba Extract on Short-term Memory. In E. W. Funfgeld (ed.) 1988. Op. cit. Pp. 321-326. 20. Huh, H. and E. J. Staba. 1992. The Botany and Chemistry of Ginkgo biloba L. Journal of Herbs, Spices & Medicinal Plants. 1(1/2):91-124. 21. Kleijnen, J. and P. Knipschild. 1992. Ginkgo biloba for cerebral insufficiency. Br. J. Clin. Pharmac. 34:352-358. 22. Leung, A. 1990. Personal communication, Feb. 13. 23. Li, H. L. 1956. A Horticultural and Botanical History of Ginkgo. Morris Arb. Bull. 7:3-12. 24. Liberti, L. (ed.) 1988. Ginkgo. The Lawrence Review of Natural Products. Feb. 1988. 25. Meyer, B. 1988. A Multicenter Randomized Double-Blind Study of Ginkgo Biloba Extract Versus Placebo in the Treatment of Tinnitus. In E. W. Funfgeld (ed.) 1988. Op. cit. Pp. 245-250.
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26. Michel, P. F. and D. Hosford. 1988. Ginkgo Biloba: From "Living Fossil" to Modern Therapeutic Agent. In P. Braquet (ed.) 1988. Op. cit. pp.1-8. 27. Nakanishi, K. 1988. Ginkgolides - Isolation and Structural Studies Carried out in the Mid-1960s. In P. Braquet (ed.) 1988. Op. cit. pp. 27-36. 28. Pincemail, J. and C. Deby. 1988. The Antiradical Properties of Ginkgo Biloba Extract. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 71-182. 29. Schaffler, V. K. and P. W. Reeh. 1985. Double-blind Study of the Hypoxia-protective Effect of a Standardized Ginkgo Biloba Preparation after Repeated Administration in Healthy Volunteers. Arzneim-Forsch. 35: 1283-1286. 30. Stalleicken, D. and P. Ihm. 1989. Observation of the Course of Cognitive Deficits. Results of a Multicenter Study Involving Psychological Test Operations. Neurologie Psychiatrie. Special Issue 1: 64-69. 31. Vorberg, G. 1985. Ginkgo Biloba Extract (GBE): A Long-term Study of Chronic Cerebral Insufficiency in Geriatric Patients. Clinical Trials Journal 22:149-157. 32. Warburton, D. M. 1988. Clinical Psychopharmacology of Ginkgo Biloba Extract. In E. W. Funfgeld (ed.) 1988. Op. cit. pp. 327-345. 33. Weiss, R. F. 1989. Herbal Medicine. Beaconsfeld, England: Beaconsfield Publishers Ltd.
L-Phenylalanine 33 Studies
1. Plasma tryptophan and five other amino acids in depressed and normal subjects. Archives of General Psychiatry 38(6):642-646, 1981 2. Trace amine deficit in depressive illness: the phenylalanine connexion. Acta Psychiatrica Scandinavica 61(Suppl. 280):29-39, 1980 3. Phenylalanine levels in endogenous psychoses. Psychiatrie, Neurologie und Medizinische Psychologie 32(10):631-633, 1980 4. Evaluation of the relative potency of individual competing amino acids to tryptophan transport in endogenously depressed patients. Psychiatry Research 3(2):141-150, 1980 5. Amino acids in mental illness. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 240
Biological psychiatry today. Vol. B Amsterdam, Elsevier/North Holland, 1979, p1581-4 6. Depression, pregnancy and phenylalanine. Neuropisiquiatria (Buenos Aires) 8(1):60-64, 1977 7. Theoretical and therapeutic potential of indoleamine precursors in affective disorders. Neuropsychobiology (Basel) 3(4):199-233, 1977 8. Phenylethylamine and glucose in true depression. Journal of Orthomolecular Psychiatry (Regina) 5(3):199-202, 1976 9. Therapeutic action of D-phenylalanine in Parkinson's disease. Arzneimittel-Forschung (Aulendorf) 26(4):577-579, 1976 10. Effects of D-phenylalanine on clinical picture and phenethylaminuria in depression. Biological Psychiatry 10(2):235-239, 1975 11. Phenylalanine for endogenous depression. Joof Orthomolecular Psychiatry (Regina) 3(2):80-81, 1974 12. Antoniou C, Katsambas A. Guidelines for the treatment of vitiligo. Drugs. 1992;43(4):490-498. 13. Bugard P, Bremer HJ, Buhrdel P, et al. Rationale for the German recommendations for phenylalanine level control in phenylketonuria 1997. Eur J Pediatr. 1999;158:4654. 14. Burkhart CG, Burkhart CN. Phenylalanine with UVA for the treatment of vitiligo needs more testing for possible side effects. J Am Acad Dermatol. 1999;40(6 Pt 1):1015. 15. Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Arch Dermatol. 1999;135(2):216-217. 16. Cejudo-Ferragud E, Nacher A, Polache A, Ceros-Fortea T, Merino M, Casabo VG. Evidence of competitive inhibition for the intestinal absorption of baclofen by phenylalanine. Int J Pharmaceutics. 1996;132:63-69. 17. Cormane RH, Siddiqui AH, Westerhof W, Schutgens RB. Phenylalanine and UVA light for the treatment of vitiligo. Arch Dermatol Res. 1985;277(2):126-130. 18. Fugh-Berman A, Cott JM. Dietary supplements and natural products as psychotherapeutic agents. Psychomatic Med. 1999;61:712-728. 19. Kovacs SO. Vitiligo. J Am Acad Dermatol. 1998 May;38(5 Pt 1):647-666.
241
20. Meyers S. Use of neurotransmitter precursors for treatment of depression. Alt Med Rev. 2000;5(1):64-71. 21. Pietz J. Neurological aspects of adult phenylketonuria. Curr Opin Neurol. 1998;11:679688. 22. Pietz J, Dunckelmann R, Rupp A, et al. Neurological outcome in adult patients with early-treated phenylketonuria. Eur J Pediatr. 1998;157:824830. 23. Rezvani I. Defects in metabolism of amino acids; Phenylalanine. In: Behrman RE, Kliefman RM, and Jenson HB, eds. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, PA: W.B. Saunders Company; 2000: 344-346. 24. Russell AL, McCarty MF. DL-phenylalanine markedly potentiates opiate analgesia an example of nutrient pharmaceutical up-regulation of the endogenous analgesia system. Med Hypotheses. 2000;55(4):283-288. 25. Sabelli HC, Fawcett J, Gusovsky F, et al. Clinical studies on the phenylethylamine hypothesis of affective disorder: urine and blood phenylacetic acid and phenylalanine dietary supplements. J Clin Psychiatry. 1986;47:66-70. 26. Schallreuter KU, Zschiesche M, Moore J, et al. In vivo evidence for compromised phenylalalanine metabolism in vitiligo. Biochem Biophys Res Commun. 1998;243(2):395399. 27. Schulpis CH, Antoniou C, Michas T, Strarigos J. Phenylalanine plus ultraviolet light: preliminary report of a promising treatment for childhood vitiligo. Pediat Dermatol. 1989;6(4):332-335. 28. Shils ME, Olson JA, Shike M, Ross AC. Modern Nutrition in Health and Disease. 9th ed. Baltimore, Md: Williams & Wilkins; 1999(41):1010. 29. Siddiqui AH, Stolk LM, Bhaggoe R, et al. L-phenylalanine and UVA irradiation in the treatment of vitiligo. Dermatology. 1994;188(3):215-218. 30. Start K. Treating phenylketonuria by a phenylalanine-free diet. Prof Care Mother Child. 1998;8:109110. 31. Walsh NE, Ramamurthy S, Schoenfeld L, Hoffman J. Analgesic effectiveness of Dphenylalanine in chronic pain patients. Arch Phys Med Rehabil. 1986;67(7):436-439. 32. Werbach MR. Nutritional Influences on Illness. 2nd ed. Tarzana, Calif: Third Line Press; 1993:159160, 384, 434, 494495, 506, 580, 613614, 636.
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33. Woodward WR, Olanow CW, Beckner RM, et al. The effect of L-dopa infusions with and without phenylalanine challenges in parkinsonian patients: Plasma and ventricular CSF L-dopa levels and clinical responses. Neurol. 1993;43:1704-1708.
L-Glutathione 67 Studies
1. Medical Hypotheses (1999) 53(4): 347-349 - 1999 Harcourt Publishers Ltd. - Article No. mehy. 1998.0780 Competition For Glutathione Precursors Between The Immune System And The Skeletal Muscle: Pathogenesis Of Chronic Fatigue Syndrome G. Bounous1, J Molson2 2. Anticancer Research 15: 2643-2650, 1995 The Use of a Whey Protein Concentrate in the Treatment of Patients with metastatic Carcinoma: A Phase I-II Clinical Study RENEE S. KENNEDY1, GEORGE P. KONOK1, GUSTAVO BOUNOUS2, SYLVAIN BARUCHEL3 and TIMOTHY D.G. LEE4 3. Clin Invest Med, 16: 204-209, 1993 Whey Proteins As A Food Supplement In HIV-Seropositive Individuals G. Bounous, S. Baruchel, J. Falutz, P. Gold 4. Clin Invest Med, 14: 296-309, 1991 The Biological Activity Of Undenatured Dietary Whey Proteins: Role Of Glutathione. G. Bounous, P. Gold 5. Cancer Letters, 57: 91-94, 1991 Whey Proteins In Cancer Prevention G. Bounous*, G. Batist** and P. Gold*** 6. Tumor Biol 11: 129-136, 1990 Dietary Milk Proteins Inhibit the Development of Dimethylhydrazine-Induced Malignancy R. Papenburga, G. Bounousa, D. Fleiszera, P. Goldb 7. Clin Invest Med, 12: 343-349, 1989 The Influence Of Dietary Whey Protein On Tissue Glutathione And The Diseases Of Aging Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 243
Gustavo Bounous, Francine Gervais,Victor Amer, Gerald Batist, and Phil Gold. 8. Clin Invest Med, 12: 154-61, 1989 Immunoenhancing Property Of Dietary Whey Protein In Mice: Role Of Glutathione G. Bounous, G. Batist, P. Gold 9. Clinical and Investigative Medicine, Vol. 11,.No. 4,.pp 271-278,. 1988. The Immunoenhancing Property Of Dietary Whey Protein Concentrate Gustavo Bounous, Patricia A.L. Kongshavn, and Phil Gold. 10. Clin Inv Med, 11: 213-217, 1988 Dietary Whey Protein Inhibits the Development of Dimethylhydrazine-Induced Malignancy G. Bounous, R. Papenburg, P.A.L Kongshavn, P. Gold, and D. Fleiszer. 11. J. Nutr. 115: 1409-1417, 1985 Mechanism Of Altered B-Cell Response Induced By Changes In Dietary Protein Type In Mice G. Bounous, N. Shenouda,* P.A.L. Kongshavn and D.G. Osmond* 12. J. Nutr. 115: 1403-1408, 1985. Differential Effect of Dietary Protein Type on the B-Cell and T-Cell Immune Responses in Mice Gustavo Bounous and Patricia A.L. Kongshavn. 13. J. Nutr. 113: 1415-1421, 1983 Influence Of Dietary Protein Type On The Immune System Of Mice G. Bounous, L. Ltourneau and P.A.L. Kongshavn. 14. Minerva Dietol Gastroenterol 35(4): 241-5, 1989 Changes in Biliary Secretory Immunoglobulins A in Mice Fed Whey Proteins Costantino AM, Balzola F, Bounous G. 15. Oxidative Stress, Cell Activation and Viral infection C. Pasquier et al. (eds) 1994 Birkhuser Verlag Basel/Switzerland Place For An Antioxidant Therapy In Human Immunodeficiency Virus (HIV) Infection 16, J. Nutr. 112:1747-1755, 1982. - Reprinted from The Journal of Nutrition Vol. 112, no. 9, September 1982 The American Institute of Nutrition 1982 Influence Of Dietary Proteins On The Immune System Of Mice. 17. The Journal of Infectious Diseases, 144: 281, 1981 Influence Of Dietary Lactalbumin Hydrolysate On The Immune System Of Mice And Resistance To Salmonellosis Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 244
G. Bounous, M.M. Stevenson*, P.A.L. Kongshavn. 18. Journal of Applied Physiology, 87: 1381-1385, 1999 The Effect Of Supplementation With A Cysteine Donor On Muscular Performance LC Lands, MD, PhD*, VL Grey, PhD, AA Smountas, BSc. 19. Accepted for publication in Chest Treatment Of Obstructive Airway Disease With A Cysteine Donor Protein Supplement: A Case Report Bryce Lothian, MD, Vijaylaxmi Grey, PhD, R. John Kimoff, MD, Larry Lands, MD, PhD. 20. PR514 Treatment Of Chronic Hepatitis Using Whey Protein (Non-Heated) A. Watanabe, K. Higuchi, K. Okada, Y. Shimizu, Y. Kondo* and H. Kohri. 21. Anticancer Research 20: 4785-4792, 2000. Whey Protein Concentrate (WPC) and Glutathione Modulation in Cancer Treatment Gustavo Bounous, M.D. 22. Accepted for publication in Nutrition and Cancer, Vol 38, Issue #2 Enhancing Effect of Patented Whey Protein Isolate (IMMUNOCAL) on the Cytotoxicity of Anti-cancer Drug Wayne Y. Tsai, Wen-Huei Chang, Ching-Hsein Chen, and Fung-Jou Lu Department of Biochemistry, College of Medicine National Taiwan University, Taipei, Taiwan, R.O.C. 23. Oxidative Stress in Cancer, AIDS, and Neurodegenerative Diseases Luc Montagnier et al., (Ed.) Marcel Dekker Inc., New York: 447-461, 1998 Nutriceutical Modulation Of Glutathione With A Humanized Native Milk Serum Protein Isolate, Immunocal: Application In AIDS And Cancer. S. Baruchel, G. Viau, R. Olivier, G. Bounous, M.A. Wainberg. 24. Anderson ME, Luo JL. Glutathione therapy: from prodrugs to genes. Semin Liver Dis. 1998; 18:415-424. 25. Aw TW, Wierzbicka G, Jones DP. Oral glutathione increases tissue glutathione in vivo. Chem Biol Interact. 1991; 80:89-97. 26. Bains JS, Shaw CA. Neurodegenerative disorders in humans: the role of glutathione in oxidative stress-mediated neuronal death. Brain Res Brain Res Rev. 1997; 25:335-358.
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27. Borok Z, Buhl R, Grimes GJ, et al. Effect of glutathione aerosol on oxidantantioxidant imbalance in ideopathic pulmonary fibrosis. Lancet. 1991; 338:215-216. 28. Broquist HP. Buthionine sulfoximine, an experimental tool to induce glutathionine deficiency: elucidation of glutathionine and ascorbate in their role as antioxidants. Nutr Rev. 1992; 50:110-111. 29. Brown LA, Bai C, Jones DP. Glutathione protection in aveolar type II cells from fetal and neonatal rabbits. Am J Physiol. 1992; 262:L305-L312. 30. Cascinu S, Cordella L, Del Ferro E, et al. Neuroprotective effect of reduced glutathione on cisplatin-based chemotherapy in advanced gastric cancer: a randomized double-blind placebo-controlled study. J Clin Oncol. 1995; 13:26-32. 31. Cheung P-Y, Wang W, Schulz R. Glutathione protects against ischemia-perfusion injury by detoxifying peroxynitrite. J Mol Cell Cardiol. 2000; 32:1669-1678. 32. De Mattia G, Bravi MC, Laurenti O, et al. Influence of reduced glutathione infusion on glucose metabolism in patients with non-insulin-dependent diabetes mellitus. Metabolism. 1998; 47:993-997. 33. Exner R, Wessner B, Manhart N, Roth E. Therapeutic potential of glutathione. Wien Klin Wochenschr. 2000; 112:610-616. 34. Favilli F, Marraccini P, Iantomasi T, Vincenzini MT. Effect of orally administered glutathione levels in osme organs of rats: role of specific transporters. Br J Nutr. 1997; 78:293-300. 35. Flagg EW, Coates RJ, Eley JW, et al. Dietary glutathione intake in humans and the relationship between intake and plasma total glutathionine level. Nutr Canc. 1994; 21:3346. 36. Furukawa T, Meydani SN, Blumberg JB. Reversal of age-associated decline in immune responsiveness by dietary glutathione supplementation in mice. Mech Ageing Dev. 1987; 38:107-117. 37. Griffith OW. Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Rad Biol Med. 1999; 27:922-935. 38. Hagen TM, Jones DP. Transepithelial transport of glutathione in vascularly perfused small intestine of rat. Am J Physiol. 1987; 252(5 Pt 1):G607-G613. 39. Hagen TM, Wierzbicka GT, Sillau AH, et al. Bioavailability of dietary glutathione: effect on plasma concentration. Am J Physiol. 1990; 259(4 Pt 1):G524-G529.
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40. Hayes JD, McLellan LI. Glutathione and glutathione-dependent enzymes represent a co-ordinately regulated defence against oxidative stress. Free Rad Res. 1999; 31:273300. 41. Hayes JD, Strange RC. Glutathione S-transferase polymorphisms and their biological consequences. Pharmacology. 2000; 61:154-166. 42. Hercbergs A, Brok-Simoni F, Holtzman F, et al. Erythrocyte glutathione and tumor response to chemotherapy. Lancet. 1992; 339:1074-1076. 43. Holroyd KJ, Buhl R, Borok Z, et al. Correction of glutathione deficiency in the lower respiratory tract of HIV seropositive individuals by glutathione aerosol treatment. Thorax. 1993; 48:985-989. 44. Hwang C, Sinskey AJ, Lodish HF. Oxidized redox state of glutathione in the endoplasmic reticulum. Science. 1992; 257:1496-1502. 45. Janaky R, Ogita K, Pasqualotta BA, et al. Glutathione and signal transduction in the mammalian CNS. J Neurochem. 1999; 73:889-902. 46. Lash LH, Hagen TM, Jones DP. Exogenous glutathione protects intestinal epithelial cells from oxidative injury. Proc Natl Acad Sci USA. 1986; 83:4641-4645. 47.Lenzi A, Culasso F, Gandini L, et al. Placebo-controlled, double-blind, cross-over trial of glutathione therapy in male infertility. Hum Reprod. 1993; 8:1657-1662. 48. Lenzi A, Picardo M, Gandini L, et al. Glutathione treatment of dyspermia: effect on the lipoperoxidation process. Hum Reprod. 1994; 9:2044-2050. 49. Loguercio C, Di Pierro M. The role of glutathione in the gastrointestinal tract: a review. Ital J Gastroenterol Hepatol. 1999; 31:401-407. 50. Lyons J, Rauh-Pfeiffer A, Yu YM, et al. Blood glutathione synthesis rates in healthy adults receiving a sulfur amino acid-free diet. Proc Natl Acad Sci USA. 2000; 97:50715076. 51. Martensson J, Jain A, Meister A. Glutathione is required for intestinal function. Proc Natl Acad Sci USA. 1990; 87:1715-1719. 52. Meister A. On the antioxidant effects of ascorbic acid and glutathionine. Biochem Pharmacol. 1992; 44:1905-1915. 53. Murphy ME, Scholich H, Sies H. Protection by glutathione and other thiol compounds against the loss of protein thiols and tocopherol homologs during microsomal lipid peroxidation. Eur J Biochem. 1992; 210:139-146.
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54. Rahman I, MacNee W: Regulation of redox glutathione levels and gene transcription in lung inflammation: therapeutic approaches. Free Radic Biol Med 2000, 28:1405-1420. 55. Nagasawa HT, Cohen JF, Holleschau AM, Rathbun WB. Augmentation of human and rat lenticular glutathione in vitro by prodrugs of gamma-L-glutamyl-L-cysteine. J Med Chem. 1996; 39:1676-1681. 56. Novi AM. Regression of aflatoxin B1-induced hepatocellular carcinomas by reduced glutathione. Science. 1981; 212:541-542. 57. Ohinataab Y, Yamasobac T, Schachta J, Millera JM. Glutathione limits noise-induced hearing loss. Hear Res. 2000; 146:28-34. 58. Palamara AT, Perno C-F, Ciriolo MR, et al. Evidence for antiviral activity of glutathione: in vitro inhibition of herpes simplex virus type 1 replication. Antiviral Res. 1995; 27:237-253. 59. Paolisso G, Giugliano D, Pizza G, et al. Glutathione infusion potentiates glucoseinduced insulin secretion in aged patients with impaired glucose tolerance. Diabetes Care. 1992; 15:1-7. 60. Roum JH, Borok Z, McElvaney NG, et al. Glutathione aerosol suppresses lung epithelial surface inflammatory cell-derived oxidants in cystic fibrosis. J Appl Physiol. 1999; 87:438-443. 61. Samiec PS, Drews-Botsch C, Flagg EW, et al. Glutathione in human plasma: decline in association with aging, age-related macular degeneration, and diabetes. Free Radic Biol Med. 1998; 24:699-704. 62. Schmidinger M, Budinsky AC, Wenzel C, et al. Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancer and non small cell lung cancer. Wien Klin Wochenschr. 2000; 112:617623. 63. Shaw CA, ed. Glutathione in the Nervous System. London: Taylor and Francis; 1998. 64. Sies H. Glutathione and its role in cellular functions. Free Rad Biol Med. 1999; 27:916-921. 65. Smyth JF, Bowman A, Perren T, et al. Glutathione reduces the toxicity and improves quality of life of women diagnosed with ovarian cancer treated with cisplatin: results of a double-blind, randomized trial. Ann Oncol. 1997; 8:569-573.
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66.Sternberg P Jr, Davidson PC, Jones DP, et al. Protection of retinal pigment epithelium from oxidative injury by glutathione and precursors. Invest Opthalmol Vis Sci. 1993; 34:3661-3668. 67. Witschi A, Reddy S, Stofer B, Lauterburg BH. The systemic availability of oral glutathione. Eur J Clin Pharmacol. 1992; 43:667-669.
L-Taurine 94 Studies
1. Arzneimittelforschung. 1993 Mar;43(3):308-12. Effects on heart membranes after taurine treatment in rabbits with congestive heart failure. Elizarova EP, Orlova TR, Medvedeva NV. 2. Jpn Circ J. 1992 Jan;56(1):95-9. Usefulness of taurine in chronic congestive heart failure and its prospective application. Azuma J, Sawamura A, Awata N. Third Department of Internal Medicine, Osaka University Medical School, Japan. 3. Kardiologiia. 1991 Jun;31(6):77-80. (Animal Study) [Use of taurine in the treatment of experimental congestive heart failure] [Article in Russian] Orlova TsR, Elizarova EP, Ryff IM, Fetisova NI, Mit'kina LI. 4. Am Heart J. 1986 Dec;112(6):1278-84. (Animal Study) Beneficial effect of taurine in rabbits with chronic congestive heart failure. Takihara K, Azuma J, Awata N, Ohta H, Hamaguchi T, Sawamura A, Tanaka Y, Kishimoto S, Sperelakis N. 5. Clin Cardiol. 1985 May;8(5):276-82. Therapeutic effect of taurine in congestive heart failure: a double-blind crossover trial. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 249
Azuma J, Sawamura A, Awata N, Ohta H, Hamaguchi T, Harada H, Takihara K, Hasegawa H, Yamagami T, Ishiyama T, et al. 6. Res Commun Chem Pathol Pharmacol. 1984 Aug;45(2):261-70. (Animal Study) Beneficial effect of taurine on congestive heart failure induced by chronic aortic regurgitation in rabbits. Azuma J, Takihara K, Awata N, Ohta H, Sawamura A, Harada H, Kishimoto S. 7. Clin Ther. 1983;5(4):398-408. Therapy of congestive heart failure with orally administered taurine. Azuma J, Hasegawa H, Sawamura A, Awata N, Ogura K, Harada H, Yamamura Y, Kishimoto S. 8. Physiol Chem Phys. 1977;9(3):259-63. (Animal Study) A relation between myocardial taurine contest and pulmonary wedge pressure in dogs with heart failure. Newman WH, Frangakis CJ, Grosso DS, Bressler R. 9. Amino Acids. 2002;23(4):381-93. Treatment of hypertension with oral taurine: experimental and clinical studies. Militante JD, Lombardini JB. Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA. 10. Poult Sci. 2001 Nov;80(11):1607-18. (Animal Study) Taurine, cardiopulmonary hemodynamics, and pulmonary hypertension syndrome in broilers. Ruiz-Feria CA, Wideman RF Jr. Department of Poultry Science, University of Arkansas, Fayetteville 72701, USA. cruizfe@hotmail.com 11. Amino Acids. 2000;19(3-4):643-65. (Animal Study)
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Effects of high salt diets and taurine on the development of hypertension in the strokeprone spontaneously hypertensive rat. Dawson R Jr, Liu S, Jung B, Messina S, Eppler B. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA. dawson@cop.health.ufl.edu 12. Amino Acids. 2000;19(3-4):643-65. (Animal Study) Effects of high salt diets and taurine on the development of hypertension in the strokeprone spontaneously hypertensive rat. Dawson R Jr, Liu S, Jung B, Messina S, Eppler B. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA. dawson@cop.health.ufl.edu 13. Hypertens Res. 2000 May;23(3):277-84. Oral taurine supplementation prevents the development of ethanol-induced hypertension in rats. Harada H, Kitazaki K, Tsujino T, Watari Y, Iwata S, Nonaka H, Hayashi T, Takeshita T, Morimoto K, Yokoyama M. First Department of Internal Medicine, Kobe University School of Medicine, Japan. 14. Can J Physiol Pharmacol. 1999 Oct;77(10):749-54. (Animal Study) Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, an animal model of insulin resistance. Anuradha CV, Balakrishnan SD. Department of Biochemistry, Annamalai University, Annamalai Nagar, Tamil Nadu, India. 15. Poult Sci. 1999 Nov;78(11):1627-33. (Animal Study) Plasma taurine levels in broilers with pulmonary hypertension syndrome induced by unilateral pulmonary artery occlusion. Ruiz-Feria CA, Beers KW, Kidd MT, Wideman RF Jr.
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Department of Poultry Science, University of Arkansas, Fayetteville 72701, USA. cruizfe@comp.uark.edu 16. J Hypertens. 1994 Jun;12(6):653-61. (Animal Study) Taurine amplifies renal kallikrein and prevents salt-induced hypertension in Dahl rats. Ideishi M, Miura S, Sakai T, Sasaguri M, Misumi Y, Arakawa K. Department of Internal Medicine, Fukuoka University School of Medicine, Japan. 17. Cardiovasc Res. 1988 May;22(5):351-8. (Animal Study) Retardation of the development of hypertension in DOCA salt rats by taurine supplement. Inoue A, Takahashi H, Lee LC, Sasaki S, Kohno Y, Takeda K, Yoshimura M, Nakagawa M. 2nd Department of Medicine, Kyoto Prefectural University of Medicine, Japan. 18. Hypertension. 1987 Oct;10(4):383-9. Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats. Abe M, Shibata K, Matsuda T, Furukawa T. Department of Pharmacology, School of Medicine, Fukuoka University, Japan. 19. Jpn Heart J. 1983 Jan;24(1):91-102. Decrease of urinary taurine in essential hypertension. Kohashi N, Katori R. 20. Amino Acids. 2002;22(1):27-38. Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats. Nandhini AT, Anuradha CV. Department of Biochemistry, Faculty of Science, Annamalai University, Tamil Nadu, India. 21. Drug Chem Toxicol. 2001 Nov;24(4):429-37.
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Protective role of vitamin E, 2-deoxy-D-glucose, and taurine on perchloroethylene induced alterations in ATPases. Ebrahim AS, Babu E, Thirunavukkarasu C, Sakthisekaran D. Department of Medical Biochemistry, Dr. ALM Post-Graduate Institute of Basic Medical Sciences, University of Madras, Taramani, Chennai 600113, India. 22. Diabetes. 2003 Feb;52(2):499-505. (Animal Study) Comparative trial of N-acetyl-cysteine, taurine, and oxerutin on skin and kidney damage in long-term experimental diabetes. Odetti P, Pesce C, Traverso N, Menini S, Maineri EP, Cosso L, Valentini S, Patriarca S, Cottalasso D, Marinari UM, Pronzato MA. Department of Internal Medicine, University of Genova, Italy. 23. Diabetes Metab Res Rev. 2001 Sep-Oct;17(5):330-46. The role of taurine in diabetes and the development of diabetic complications. Hansen SH. Department of Clinical Biochemistry, Rigshospitalet, Copenhagen University Hospital, Denmark. shhansen@rh.dk 24. Cardiovasc Res. 2000 Jun;46(3):393-402. The role of taurine in the pathogenesis of the cardiomyopathy of insulin-dependent diabetes mellitus. Militante JD, Lombardini JB, Schaffer SW. Department of Pharmacology, Texas Tech University, Health Sciences Center, Lubbock 79430, USA. 25. Adv Exp Med Biol. 2000;483:497-501. (Animal Study) Taurine fluxes in insulin dependent diabetes mellitus and rehydration in streptozotocin treated rats. Rose SJ, Bushi M, Nagra I, Davies WE. Department of Paediatrics, Heartlands Hospital, Birmingham, England.
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26. Am J Clin Nutr. 2000 Jan;71(1):54-8. (Animal Study) Taurine improves insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous type 2 diabetes. Nakaya Y, Minami A, Harada N, Sakamoto S, Niwa Y, Ohnaka M. Department of Nutrition, Tokushima University, School of Medicine, Tokushima, Japan. nakaya@nutr.med.tokushima-u.ac.jp 27. Adv Exp Med Biol. 1998;442:163-8. (Animal Study) Effects of taurine supplementation on lipid peroxidation, blood glucose and blood lipid metabolism in streptozotocin-induced diabetic rats. You JS, Chang KJ. Department of Food Nutrition, Inha University, Inchon, Korea. 28. Eur J Pharmacol. 1996 May 6;303(1-2):47-53. (Animal Study) Restoration of endothelium-dependent relaxation in both hypercholesterolemia and diabetes by chronic taurine. Kamata K, Sugiura M, Kojima S, Kasuya Y. Department of Physiology and Morphology, Hoshi University, Tokyo, Japan. 29. Am J Physiol. 1995 Sep;269(3 Pt 2):F429-38. (Animal Study) Taurine ameliorates chronic streptozocin-induced diabetic nephropathy in rats. Trachtman H, Futterweit S, Maesaka J, Ma C, Valderrama E, Fuchs A, Tarectecan AA, Rao PS, Sturman JA, Boles TH, et al. Department of Pediatrics, Schneider Children's Hospital, Long Island Jewish Medical Center, Albert Einstein College of Medicine, New Hyde Park, New York 11040, USA. 30. Biochem Biophys Res Commun. 1993 Mar 15;191(2):759-65. (Animal Study) Taurine prevents glucose-induced lipid peroxidation and increased collagen production in cultured rat mesangial cells. Trachtman H, Futterweit S, Bienkowski RS. Division of Nephrology, Schneider Children's Hospital, New Hyde Park, NY 11042. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 254
31. Biochem Med Metab Biol. 1990 Feb;43(1):1-9. (Animal Study) Supplemental taurine in diabetic rats: effects on plasma glucose and triglycerides. Goodman HO, Shihabi ZK. Department of Pediatrics, Bowman Gray School of Medicine, Winston-Salem, North Carolina 27103. 32. Probl Endokrinol (Mosk). 1987 Mar-Apr;33(2):63-6. [Effect of taurine on the functional status of the insular apparatus and adrenal cortex of the rat with experimental diabetes] [Article in Russian] Mizina TIu, Dokshina GA. 33. Psychopharmacology (Berl). 1989;98(3):316-20. (Animal Study) Effect of ICV taurine on the impairment of learning, convulsions and death caused by hypoxia. Malcangio M, Bartolini A, Ghelardini C, Bennardini F, Malmberg-Aiello P, Franconi F, Giotti A. Department of Preclinical and Clinical Pharmacology, University of Florence, Firenze, Italy. 34. Eur J Pharmacol. 1986 Jan 21;120(2):235-9. Protective effect of taurine against decline of cardiac slow action potentials during hypoxia. Sawamura A, Sperelakis N, Azuma J. 35. The protective effects of taurine on hypoxia (performed in the absence of glucose) and on reoxygenation (in the presence of glucose) in guinea-pig heart. Franconi F, Stendardi I, Failli P, Matucci R, Baccaro C, Montorsi L, Bandinelli R, Giotti A. 36. Indian J Exp Biol. 2002 Oct;40(10):1169-72. Antiatherogenic effect of taurine in high fat diet fed rats.
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Sethupathy S, Elanchezhiyan C, Vasudevan K, Rajagopal G. Division of Biochemistry, Rajah Muthiah Medical College, Annamalai University, Annamalai Nagar 608 002, India. drsethupathy@rediffmail.com 37. J Nutr Sci Vitaminol (Tokyo). 1995 Dec;41(6):627-34. Effects of taurine on depletion of erythrocyte membrane Na-K ATPase activity due to ozone exposure or cholesterol enrichment. Qi B, Yamagami T, Naruse Y, Sokejima S, Kagamimori S. Department of Community Health and Preventive Medicine, Toyama Medical and Pharmaceutical University, Japan. 38. Adv Exp Med Biol. 2003;526:515-25. (Animal Study) Prevention of epileptic seizures by taurine. El Idrissi A, Messing J, Scalia J, Trenkner E. New York State Institute for Basic Research in Developmental Disabilities and The Center for Developmental Neuroscience, The City University of New York, Staten Island, NY 10314, USA. 39. Amino Acids. 1999;16(2):133-47. (Animal Study) Kainic acid (KA)-induced seizures in Sprague-Dawley rats and the effect of dietary taurine (TAU) supplementation or deficiency. Eppler B, Patterson TA, Zhou W, Millard WJ, Dawson R Jr. Department of Pharmacodynamics, University of Florida, Gainesville, USA. 40. Yakubutsu Seishin Kodo. 1991 Aug;11(4):257-60. (Animal Study) [Drug-induced seizures in taurine-deficient mice] [Article in Japanese] Shimada C, Tanaka S, Sano M, Araki H. Research and Development Center, Fuso Pharmaceutical Industries, Ltd., Osaka, Japan. 41. Neuropharmacology. 1987 Dec;26(12):1721-5.
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Higher susceptibility of taurine-deficient rats to seizures induced by 4-aminopyridine. Pasantes-Morales H, Arzate ME, Quesada O, Huxtable RJ. Instituto de Fisiologia Celular, Universidad Nacional Autonoma de Mexico, D.F. 42. Med Hypotheses. 1985 Dec;18(4):411-5. Could supplementary dietary tryptophan and taurine prevent epileptic seizures? Maurizi CP. 43. J Neurosci Res. 1981;6(4):465-74. Effect of taurine on seizures induced by 4-aminopyridine. Pasantes-Morales H, Arzate ME. 44. J Neural Transm. 1980;48(4):311-6. (Animal Study) Taurine selectivity antagonizes L-kynurenine-produced seizures in mice. Lapin IP. 45. Can J Physiol Pharmacol. 1978 Jun;56(3):497-500. (Animal Study) The effect of taurine on kindled seizures in the rat. Burnham WM, Albright P, Racine RJ. 46. Epilepsia. 1975 Jun;16(2):229-34. Effects of taurine on kindled amygdaloid seizures in rats, cats, and photosensitive baboons. Wada JA, Osawa T, Wake A, Corcoran ME. 47. Neural Plast. 2000;7(4):245-59. (Animal Study) Improvement of impaired memory in mice by taurine. Vohra BP, Hui X. Department of Biotechnology, School of Life Sciences, Sun-Yat-Sen University, Guangzhou, China-510 275. Vohra001@tc.umn.edu
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48. Environ Res. 2000 Jan;82(1):7-17. Effects of taurine on ozone-induced memory deficits and lipid peroxidation levels in brains of young, mature, and old rats. Rivas-Arancibia S, Dorado-Martinez C, Borgonio-Perez G, Hiriart-Urdanivia M, Verdugo-Diaz L, Duran-Vazquez A, Colin-Baranque L, Avila-Costa MR. Departamento de Fisiologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico, Mexico. 49. Arch Dis Child. 1992 Sep;67(9):1082-5. Effect of taurine supplementation on fat and energy absorption in cystic fibrosis. De Curtis M, Santamaria F, Ercolini P, Vittoria L, De Ritis G, Garofalo V, Ciccimarra F. Department of Paediatrics, 2nd School of Medicine, University of Naples, Italy. 50. Am J Dis Child. 1991 Dec;145(12):1401-4. Taurine decreases fecal fatty acid and sterol excretion in cystic fibrosis. A randomized double-blind trial. Smith LJ, Lacaille F, Lepage G, Ronco N, Lamarre A, Roy CC. Department of Pediatrics, Hopital Ste-Justine, Montreal, Quebec, Canada. 51. Klin Padiatr. 1991 Jan-Feb;203(1):28-32. [Taurine supplementation in cystic fibrosis (CF): effect on vitamin E absorption kinetics] [Article in German] Skopnik H, Kusenbach G, Bergt U, Friedrichs F, Stuhlsatz H, Dohmen H, Heimann G. Kinderklinik, RWTH Aachen. 52. Acta Univ Carol [Med] (Praha). 1990;36(1-4):152-6. Effect of taurine supplements on growth, fat absorption and bile acid on cystic fibrosis. Carrasco S, Codoceo R, Prieto G, Lama R, Polanco I. Department of Pediatrics, Children's Hospital La Paz, Autonoma University, Madrid, Spain. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 258
53. Biochem Cell Biol. 1988 Jul;66(7):702-6. Taurine uptake by normal and cystic fibrosis fibroblasts. Thompson GN. Department of Chemical Pathology, Adelaide Children's Hospital, North Adelaide, Australia. 54. J Pediatr Gastroenterol Nutr. 1988 Mar-Apr;7(2):214-9. Excessive fecal taurine loss predisposes to taurine deficiency in cystic fibrosis. Thompson GN. Department of Chemical Pathology, Adelaide Children's Hospital, South Australia. 55. Scand J Gastroenterol Suppl. 1988;143:151-6. Effect of taurine supplementation on fat and bile acid absorption in patients with cystic fibrosis. Colombo C, Arlati S, Curcio L, Maiavacca R, Garatti M, Ronchi M, Corbetta C, Giunta A. Dept. of Pediatrics, University of Milan, Italy. 56. Am J Clin Nutr. 1987 Oct;46(4):606-13. Protein metabolism in cystic fibrosis: responses to malnutrition and taurine supplementation. Thompson GN, Tomas FM. Department of Chemical Pathology, Adelaide Children's Hospital, South Australia. 57. Pediatrics. 1987 Oct;80(4):517-23. Taurine improves the absorption of a fat meal in patients with cystic fibrosis. Belli DC, Levy E, Darling P, Leroy C, Lepage G, Giguere R, Roy CC. Department of Pediatrics, Hopital Ste-Justine, Montreal, Quebec, Canada. 58. Pediatr Res. 1985 Jun;19(6):578-82.
259
Effect of taurine supplements on fat absorption in cystic fibrosis. Darling PB, Lepage G, Leroy C, Masson P, Roy CC. 59. Invest Ophthalmol Vis Sci. 2002 Feb;43(2):425-33. (Animal Study) Osmoregulatory alterations in taurine uptake by cultured human and bovine lens epithelial cells. Cammarata PR, Schafer G, Chen SW, Guo Z, Reeves RE. Department of Pathology and Anatomy, Division of Cell Biology and Genetics, University of North Texas Health Science Center at Fort Worth and the North Texas Eye Research Institute, Fort Worth, Texas 76107, USA. pcammara@hsc.unt.edu 60. Zhonghua Yan Ke Za Zhi. 2000 Jul;36(4):272-4, 17. (Animal Study) [An experimental research of taurine on H2O2-induced bovine lens epithelial cell apoptosis] [Article in Chinese] Chen F, Chen C. Beijing Institute of Ophthalmology, Beijing 100005, China. 61. Invest Ophthalmol Vis Sci. 1999 Mar;40(3):680-8. (Animal Study) Effect of dietary taurine supplementation on GSH and NAD(P)-redox status, lipid peroxidation, and energy metabolism in diabetic precataractous lens. Obrosova IG, Stevens MJ. Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, USA. 62. Free Radic Res. 1998 Sep;29(3):189-95. (Animal Study) Oxidative stress to rat lens in vitro: protection by taurine. Devamanoharan PS, Ali AH, Varma SD. Department of Ophthalmology, University of Maryland, Baltimore 21201, USA. 63. Mol Cell Biochem. 1997 Dec;177(1-2):245-50.
260
Prevention of lens protein glycation by taurine. Devamanoharan PS, Ali AH, Varma SD. Department of Ophthalmology, University of Maryland School of Medicine, Baltimore 21201, USA. 64. Invest Ophthalmol Vis Sci. 1993 Jul;34(8):2512-7. Hypertonic stress increases NaK ATPase, taurine, and myoinositol in human lens and retinal pigment epithelial cultures. Yokoyama T, Lin LR, Chakrapani B, Reddy VN. Eye Research Institute, Oakland University, Rochester, Michigan. 65. Neurochem Res. 1986 Apr;11(4):535-42. (Animal Study) Taurine and other free amino acids in the retina, vitreous, lens, iris-ciliary body, and cornea of the rat eye. Heinamaki AA, Muhonen AS, Piha RS. 66. Exp Eye Res. 1983 Oct;37(4):379-84. Distribution of taurine in the crystalline lens of vertebrate species and in cataractogenesis. Gupta K, Mathur RL. Cardiac Lesions 67. Can J Neurol Sci. 1980 Nov;7(4):435-40. (Animal Study) Taurine decreases lesion severity in the hearts of cardiomyopathic hamsters. Azari J, Brumbaugh P, Barbeau A, Huxtable R. 68. Gen Pharmacol. 1998 Apr;30(4):451-63. Review of some actions of taurine on ion channels of cardiac muscle cells and others. Satoh H, Sperelakis N. Department of Pharmacology, Nara Medical University, Japan. 69. Arzneimittelforschung 1998 Apr;48(4):360-4 (Animal Study) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 261
Protective effects of taurine against reperfusion-induced arrhythmias in isolated ischemic rat heart. Chahine R, Feng J Laboratory of Physiology, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon. 70. Ann Acad Med Stetin. 1997;43:129-42. (Animal Study) [Taurine as a regulator of fluid-electrolyte balance and arterial pressure] [Article in Polish] Ciechanowska B. Z Katedry Chorob Dzieci Pomorskiej Akademii Medycznej w Szczecinie, Szczecin. 71. Am J Vet Res. 1992 Feb;53(2):237-41. (Animal Study) Myocardial taurine concentrations in cats with cardiac disease and in healthy cats fed taurine-modified diets. Fox PR, Sturman JA. Department of Medicine, Animal Medical Center, New York, NY 10021. 72. Eur J Pharmacol. 1986 May 13;124(1-2):129-33. (Animal Study) Positive inotropic effect of some taurine-related compounds on guinea-pig ventricular strips perfused with low calcium medium. Franconi F, Failli P, Stendardi I, Matucci R, Bennardini F, Baccaro C, Giotti A. 73. Proc Soc Exp Biol Med. 1984 Oct;177(1):143-50. (Animal Study) Taurine in hearts and bodies of embryonic through early postpartum CF1 mice. Quilligan CJ, Hilton FK, Hilton MA. 74. Eur J Pharmacol. 1984 Feb 17;98(2):269-73. (Animal Study) TAG antagonises the central cardiovascular effects of taurine. Bousquet P, Feldman J, Bloch R, Schwartz J. 75. Res Commun Chem Pathol Pharmacol. 1984 Feb;43(2):343-6. (Animal Study)
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Further evidence of the antiarrhythmic efficacy of taurine in the rat heart. Hernandez J, Artillo S, Serrano MI, Serrano JS.
76. The role of taurine in developing rat retina Ophtalmologie (France), 1995, 9/3 (283-286)
77. Supplemental taurine in diabetic rats: Effects on plasma glucose and triglycerides BIOCHEM. MED. METAB. BIOL. (USA), 1990, 43/1 (1-9+8) 78. Taurine deficiency retinopathy in the cat J. SMALL ANIM. PRACT. (ENGLAND), 1980, 21/10 (521-534) 79. Taurine: A therapeutic agent in experimental kidney disease Amino Acids (Austria), 1996, 11/1 (1-13) 80. Effects of taurine and guanidinoethane sulfonate on toxicity of the pyrrolizidine alkaloid monocrotaline Biochemical Pharmacology (USA), 1996, 51/3 (321-329) 81. Fish oil and other nutritional adjuvants for treatment of congestive heart failure Medical Hypotheses (United Kingdom), 1996, 46/4 (400-406) 82. Usefulness of TAURINE in chronic congestive heart failure and its prospective application. Jpn Circ J (JAPAN) Jan 1992, 56 (1) p95-9 83. Platelet TAURINE in patients with arterial hypertension, myocardial failure or infarction.
263
Acta Med Scand Suppl (SWEDEN) 1980, 642 p79-84 84. Physiological and experimental regulation of TAURINE content in the heart. Fed Proc (UNITED STATES) Jul 1980, 39 (9) p2685-90 85. A relation between myocardial TAURINE contest and pulmonary wedge pressure in dogs with heart failure. Physiol Chem Phys (UNITED STATES) 1977, 9 (3) p259-63 86. Adrenergic stimulation of TAURINE transport by the heart. Science (UNITED STATES) Oct 28 1977, 198 (4315) p409-11 87. Taurine and serine supplementation modulates the metabolic response to tumor necrosis factor alpha in rats fed a low protein diet J. NUTR. (USA), 1992, 122/7 (1369-1375) 88. Taurine deficiency after intensive chemotherapy and/or radiation Am J Clin Nutr; 55(3):708-11 1992 89. Effect of glutaurine and its derivatives and their combinations with radiation protective substances upon irradiated mice Acta Radiol Oncol Radiat Phys Biol; 20(5):319-324 1981 90. [Effect of mixed gamma-neutron irradiation on taurine penetration through cellular membranes of rat peripheral blood leukocytes] Res. Inst. Biology and Biophysics, V. V. Kuibyshev Tomsk State Univ., Tomsk, USSR 91. [Sources of taurine hyperexcretion in irradiated rats] Radiobiologiia; 20(3):455-459 1980 92. [Taurine and sh-group content in the platelets of irradiated rats]
264
Radiobiologiia; 18(2):271-274 93. Prophylactic effects of taurine and diltiazem, alone or combined, on reperfusion arrhythmias in rats Acta Pharmacologica Sinica (China), 1996, 17/2 (122-124) 94. The antiarrhythmic effects of taurine alone and in combination with magnesium sulfate on ischemia/reperfusion arrhythmia Chinese Pharmacological Bulletin (China), 1994, 10/5 (358-362)
Choline Bitartrate 63 Studies

1. Blusztajn, J.K. Choline, a vital amine. Science. 1998; volume 281: pages 794-795. 2. Zeisel, S.H. Choline and phosphatidylcholine. In Shils, M. et al. Eds. Nutrition in Health and Disease, 9th Edition. Baltimore: Williams & Wilkins, 1999: pages 513-523. 3. Institute of Medicine, Food and Nutrition Board. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press, 1998: pages 390-422. 4. Zeisel, S.H. Choline: an essential nutrient for humans. Nutrition. 2000; volume 16: pages 669-671. 5. Jacob, R.A. et al. Folate nutriture alters choline status of women and men fed low choline diets. Journal of Nutrition. 1999; volume 129: pages 712-717. 6. Zeisel, S.H. & Blusztajn, J.K. Choline and human nutrition. Annual Review of Nutrition. 1994; volume 14: pages 269-296. 7. Gerhard, G.T. & Duell, P.B. Homocysteine and atherosclerosis. Current Opinion in Lipidology. 1999; volume 10: pages 417-428. 8. Lundberg, P. et al. 1H NMR determination of urinary betaine in patients with premature vascular disease and mild hyperhomocysteinemia. Clinical Chemistry. 1995; volume 41: pages 275-283. 9. Blom, H. Determinants of plasma homocysteine. American Journal of Clinical Nutrition. 1998; volume 68: pages 919-921. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 265
10. Whitehouse, P.J. The cholinergic deficit in Alzheimer's disease. Journal of Clinical Psychiatry. 1998; volume 59 (supplement 13): pages 19-22. 11. Higgins, J.P. & Flicker, L. Lecithin for dementia and cognitive impairment. Cochrane Database of Systematic Reviews. 2000. 2:CD001015. 12. Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr. 2003;133(5):1302-1307. 13. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 14. Dietary precursors and brain neurotransmitter formation. Fernstrom JD. Annu Rev Med (UNITED STATES) 1981, 32 p413-25 15. Behavioral effects of dietary neurotransmitter precursors: Basic and clinical aspects Young SN. Neuroscience and Biobehavioral Reviews (USA), 1996, 20/2 (313 323) 16. Precursor control of neurotransmitter synthesis. Wurtman RJ, Hefti F, Melamed E. Pharmacol Rev. 1980 Dec;32(4):315-35. 17. Nutrition 4. Choline and human nutrition Zeisel SH, Blusztajn JK. ANNU. REV. NUTR. (USA), 1994, 14:269-296 18. Choline may be an essential nutrient in malnourished patients with cirrhosis Chawla RK, Wolf DC, Kutner MH, Bonkovsky HL. GASTROENTEROLOGY (USA), 1989, 97/6 (1514-1520) 19. Male rats fed methyl and folate deficient diets with or without niacin develop hepatic carcinomas associated with decreased tissue NAD concentrations and altered poly(ADP ribose) polymerase activity Henning SM, Swendseid ME, Coulson WF. Journal of Nutrition (USA), 1997, 127/1 (30 36) 20. Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes. Platel A, Jalfre M, Pawelec C, Roux S, Porsolt RD. Pharmacol Biochem Behav (UNITED STATES) Aug 1984, 21 (2) p209-12 21. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Bartus RT, Dean RL 3rd, Sherman KA, Friedman E, Beer B. Neurobiol Aging (UNITED STATES) Summer 1981, 2 (2) p105-11 22. Verbal and visual memory improve after choline supplementation in long-term total parenteral nutrition: a pilot study.
266
Buchman AL, Sohel M, Brown M, Jenden DJ, Ahn C, Roch M, Brawley TL. Division of Gastroenterology and Hepatology, Northwestern University, Chicago, Illinois 60611, USA. a-buchman@nwu.edu JPEN J Parenter Enteral Nutr. 2001 Jan-Feb;25(1):30-5.
23. Dietary precursors and brain neurotransmitter formation. Annu Rev Med (UNITED STATES) 1981, 32 p413-25 24. Choline and human nutrition ANNU. REV. NUTR. (USA), 1994, 14/- (269-296) 25. Choline may be an essential nutrient in malnourished patients with cirrhosis GASTROENTEROLOGY (USA), 1989, 97/6 (1514-1520)
26. Behavioral effects of dietary neurotransmitter precursors: Basic and clinical aspects Neuroscience and Biobehavioral Reviews (USA), 1996, 20/2 (313-323) 27. Habituation of exploratory activity in mice: effects of combinations of piracetam and choline on memory processes. Pharmacol Biochem Behav (UNITED STATES) Aug 1984, 21 (2) p209-12 28. Profound effects of combining choline and piracetam on memory enhancement and cholinergic function in aged rats. Neurobiol Aging (UNITED STATES) Summer 1981, 2 (2) p105-11 29. Male rats fed methyl- and folate-deficient diets with or without niacin develop hepatic carcinomas associated with decreased tissue NAD concentrations and altered poly(ADPribose) polymerase activity Journal of Nutrition (USA), 1997, 127/1 (30-36)
267
30. Choline and cholinergic neurons. Blusztajn JK, Wurtman RJ. Science. 1983 Aug 12;221(4611):614-20. 31. Free choline and choline metabolites in rat brain and body fluids: sensitive determination and implications for choline supply to the brain. Klein J, Gonzalez R, Koppen A, Loffelholz K. Department of Pharmacology, University of Mainz, Germany. Neurochem Int. 1993 Mar;22(3):293-300. 32. Brain acetylcholine: control by dietary choline. Cohen EL, Wurtman RJ. Science. 1976 Feb 13;191(4227):561-2. 33. Neurochemical effects of choline supplementation. Wecker L. Can J Physiol Pharmacol. 1986 Mar;64(3):329-33. 34. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. Cohen BM, Renshaw PF, Stoll AL, Wurtman RJ, Yurgelun-Todd D, Babb SM. Brain Imaging Center, McLean Hospital, Belmont, MA 02178, USA. JAMA. 1995 Sep 20;274(11):902-7. 35. Metabolic imprinting of choline by its availability during gestation: implications for memory and attentional processing across the lifespan. Meck WH, Williams CL. Department of Psychological and Brain Sciences, Duke University, 9 Flowers Drive, Box 90086, 27708-0086, Durham, NC, USA Neurosci Biobehav Rev. 2003 Jun;27(4):385-99. 36. Choline supplementation reduces urinary carnitine excretion in humans. Dodson WL, Sachan DS. Department of Nutrition, University of Tennessee, Knoxville 37996-1900, USA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 268
Am J Clin Nutr. 1996 Jun;63(6):904-10. Comment in: Am J Clin Nutr. 1997 Feb;65(2):574-5. 37. J Nutr. 2003 Jan;133(1):84-9. Carnitine and choline supplementation with exercise alter carnitine profiles, biochemical markers of fat metabolism and serum leptin concentration in healthy women. Hongu N, Sachan DS. Department of Nutrition and Agricultural Experiment Station, The University of Tennessee, Knoxville, TN 379961900, USA. 38. 1_ J Nutr Biochem. 1992 Jun;3(6):3135. Effects of orally administered cytidine 5'diphosphate choline on brain phospholipid content. Lopez GCoviella I, Agut J, Ortiz JA, Wurtman RJ. 39. Arch Neurol. 1996 May;53(5):4418. Citicoline improves verbal memory in aging. Spiers PA, Myers D, Hochanadel GS, Lieberman HR, Wurtman RJ. 40. Methods Find Exp Clin Pharmacol. 1997 Apr;19(3):20110. Citicoline improves memory performance in elderly subjects. Alvarez XA, Laredo M, Corzo D, FernandezNovoa L, Mouzo R, Perea JE, Daniele D, Cacabelos R. 41. Psychopharmacology (Berl). 2002 May;161(3):24854. Epub 2002 Mar 22. Chronic citicoline increases phosphodiesters in the brains of healthy older subjects: an in vivo phosphorus magnetic resonance spectroscopy study. Babb SM, Wald LL, Cohen BM, Villafuerte RA, Gruber SA, YurgelunTodd DA, Renshaw PF. 42. Clin Ter. 1991 Jun 30;137(6):40313. [Citicoline in the treatment of cognitive and behavioral disorders in pathologic senile decline] Di Trapani G, Fioravanti M. 43. Prog Neuropsychopharmacol Biol Psychiatry. 2003 Jun;27(4):7117.
269
Dietary cytidine (5')diphosphocholine supplementation protects against development of memory deficits in aging rats. Teather LA, Wurtman RJ. 44. Arzneimittelforschung. 1993 Aug;43(8):8228. Effects of cytidine diphosphate choline on rats with memory deficits. Petkov VD, Kehayov RA, Mosharrof AH, Petkov VV, Getova D, Lazarova MB, Vaglenova J. 45. Minerva Med. 1990 Jun;81(6):46570. [Effect of CDPcholine on senile mental deterioration. Multicenter experience on 237 cases] Serra F, Diaspri GP, Gasbarrini A, Giancane S, Rimondi A, Tame MR, Sakellaridis E, Bernardi M, Gasbarrini G. 46. Naturforsch [C]. 2003 MarApr;58(34):27781. Effect of CDPcholine on hippocampal acetylcholinesterase and Na+,K(+)ATPase in adult and aged rats. Plataras C, Angelogianni P, Tsakiris S. 47. Methods Find Exp Clin Pharmacol. 1994 Apr;16(3):2118. Effects of CDPcholine on cognition and cerebral hemodynamics in patients with Alzheimer's disease. Caamano J, Gomez MJ, Franco A, Cacabelos R. 48. Methods Find Exp Clin Pharmacol. 1999 Nov;21(9):63344. Doubleblind placebocontrolled study with citicoline in APOE genotyped Alzheimer's disease patients. Effects on cognitive performance, brain bioelectrical activity and cerebral perfusion. Alvarez XA, Mouzo R, Pichel V, Perez P, Laredo M, FernandezNovoa L, Corzo L, Zas R, Alcaraz M, Secades JJ, Lozano R, Cacabelos R. 49. Ann N Y Acad Sci. 1996 Jan 17;777:399403.
270
Therapeutic effects of CDPcholine in Alzheimer's disease. Cognition, brain mapping, cerebrovascular hemodynamics, and immune factors. Cacabelos R, Caamano J, Gomez MJ, FernandezNovoa L, FrancoMaside A, Alvarez XA. 50. Methods Find Exp Clin Pharmacol. 1994 May;16(4):27984. CDPcholine induced blood histamine changes in Alzheimer's disease. FernandezNovoa L, Alvarez XA, FrancoMaside A, Caamano J, Cacabelos R. 51. J Neurosurg. 2003 Apr;98(4):86773. Cytidinediphosphocholine treatment to decrease traumatic brain injury induced hippocampal neuronal death, cortical contusion volume, and neurological dysfunction in rats. Dempsey RJ, Raghavendra Rao VL. 52. J Neurol Sci. 1991 Jul;103 Suppl:S158. Effects of CDPcholine on the recovery of patients with head injury. Calatayud Maldonado V, Calatayud Perez JB, Aso Escario J. 53. J Mol Neurosci. 2003 Feb;20(1):5360. CDPcholine prevents glutamatemediated cell death in cerebellar granule neurons. Mir C, Clotet J, Aledo R, Durany N, Argemi J, Lozano R, CervosNavarro J, Casals N. 54. J Neurochem. 2002 Jan;80(1):1223. Citicoline: neuroprotective mechanisms in cerebral ischemia. Adibhatla RM, Hatcher JF, Dempsey RJ. 55. J Neurosci Res. 1999 Dec 1;58(5):697705. CDPcholine: neuroprotection in transient forebrain ischemia of gerbils. Rao AM, Hatcher JF, Dempsey RJ. 56. Folia Neuropathol. 2001;39(3):1415.
271
CDPcholine, but not cytidine, protects hippocampal CA1 neurones in the gerbil following transient forebrain ischaemia. Grieb P, Gadamski R, Wojda R, Janisz M. 57. Stroke. 2002 Dec;33(12):28507. Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials. Davalos A, Castillo J, AlvarezSabin J, Secades JJ, Mercadal J, Lopez S, Cobo E, Warach S, Sherman D, Clark WM, Lozano R. 58. Rev Neurol. 2001 May 115;32(9):81821. [Neuroprotection in acute ischemic stroke. Practicability of guidelines for treatment] 59. Ann Neurol. 2000 Nov;48(5):71322. Effect of citicoline on ischemic lesions as measured by diffusion weighted magnetic resonance imaging. Citicoline 010 Investigators. Warach S, Pettigrew LC, Dashe JF, Pullicino P, Lefkowitz DM, Sabounjian L, Harnett K, Schwiderski U, Gammans R. 60. Neurology. 1997 Sep;49(3):6718. A randomized dose response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Clark WM, Warach SJ, Pettigrew LC, Gammans RE, Sabounjian LA. 61. Arch Physiol Biochem. 2001 Apr;109(2):1617. Ischemic brain injury caused by interrupted versus uninterrupted occlusion in hypotensive rats with subarachnoid hemorrhage: neuroprotective effects of citicoline. Alkan T, Kahveci N, Goren B, Korfali E, Ozluk K. 62. J Neurosci Res. 2002 Jan 15;67(2):1438. Pharmacodynamics of citicoline relevant to the treatment of glaucoma. Grieb P, Rejdak R. 63. Ophthalmology. 1999 Jun;106(6):112634. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 272
Cytidine5'diphosphocholine (citicoline) improves retinal and cortical responses in patients with glaucoma. Parisi V, Manni G, Colacino G, Bucci MG.
Inositol 56 Studies
1. Benjamin, J. et al. 1995. Double-blind, placebo-controlled, crossover trial of inositol treatment of panic disorder. Am J Psychiatry 52: 1084-1086. 2. Fux, M. et al. 1996. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 153(9): 1219-1221. 3. Levine, J et al. 1997. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol 7(2): 147-155. 4. Mishori, et al. 1999. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 45: 270-273. 5. Palatnik, A. et al. 2001. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21(3): 335-339. 6. Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry. 1996 Sep;153(9):1219-21. 7. High-dose peripheral inositol raises brain inositol levels and reverses behavioral effects of inositol depletion by lithium. Pharmacol Biochem Behav 1994 Oct;49(2):341-3. Agam G, Shapiro Y, Bersudsky Y, Kofman O, Belmaker RH. Laboratory of Biochemistry, Soroka Medical Center, Beer-Sheva, Israel. 8. Inositol treatment in psychiatry. Psychopharmacol Bull 1995;31(1):167-75. Benjamin J, Agam G, Levine J, Bersudsky Y, Kofman O, Belmaker RH. Division of Psychiatry, Faculty of Health Sciences, Ben Gurion University of the Negev, Beersheva, Israel. 9. Barak Y, Levine J, Glassman A, et al. Inositol treatment of Alzheimer's disease: a double blind, cross-over placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry. 1996; 20:729-735. 10. Benjamin J, Levine J, Fox M, et al. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry. 1995; 152:1084-1086. 11. Cohen RA, MacGregory LC, Spokes KC, et al. Effect of myo-inositol on renal Na-KATPase in experimental diabetes. Metabol. 1990; 39:1026-1032. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 273
12. Colodny L, Hoffman RL. Inositol-clinical applications for exogenous use. Altern Med Rev. 1998; 3:432-447. 13. Downes CP. The cellular functions of myo-inositol. Biochem Soc Trans. 1989; 17:259-268. 14. Einat H, Belmaker RH, Kopilov M, et al. Rat brain monomines after acute and chronic myo-inositol treatment. Eur Neuropsychopharmacol. 1999; 10:27-30. 15. Einat H, Karbovski H, Korik J, et al. Inositol reduces depressive-like behaviors in two different models of depression. Psychopharmacology. 1999; 144:158-162. 16. Fox M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiat. 1996; 153:1219-1221. 17. Holub BJ. Metabolism and function of myo-inositol and inositol phospholipids. Annu Rev Nutr. 1986; 6:563-597. 18. Holub BJ. The cellular forms and functions of the inositol phospholipids and their metabolic derivates. Nutr Rev. 1987; 45:65-71. 19. Khandelwal M, Reece EA, Wu YK, Borenstein M. Dietary myo-inositol therapy in hyperglycemic-induced embryopathy. Teratology. 1998; 57:79-84. 20. Larner J, Allan G, Kessler C, et al. Phosphoinositol glycan derived mediators and insulin resistance. Prospects for diagnosis and therapy. J Basic Clin Physiol Pharmacol. 1998; 9:127-137. 21. Levine J. Controlled trials of inositol in psychiatry. Eur Neuropsychopharmacol. 1997; 7:147-155. 22. Levine J, Aviram A, Holan A, et al. Inositol treatment of action, J Neural Transm. 1997; 104:307-310. 23. Levine J, Barak Y, Gonzalues M, et al. Double-blind, controlled-trial of inositol treatment of depression. Am J Psychiatry. 1995; 152:792-794. 24. Levine J, Goldberger I, Rapaport A, et al. CSF inositol in schizophrenia and highdose inositol treatment of schizophrenic. Eur Neuropsychopharmacol. 1994; 4:487-490. 25. Levine J, Kurtzman L, Rapoport A, et al. CSF inositol does not predict antidepressant response to inositol. J Neural Transm. 1996; 103:1457-1462. 26. Nestler JE, Jakabowicz DJ, Reamer P, et al. Ovulatory and metabolic effects of Dchiro-inositol in the polycystic overary syndrome. N Engl J Med. 1999; 340:1314-1320.
274
27. Seedat S, Stein DJ. Inositol augmentation of serotonin reuptake inhibitors in treatment-refractory obsessive-compulsive disorder: an open trial. Int Clin Psychopharmacol. 1999; 14:353-356. 28. 1. Belmaker, R. H. et al. 1995. Manipulation of inositol-linked second messenger systems as a therapeutic strategy in psychiatry. Adv Biochem Psychopharmacol 49: 6784. 29. Hooper, N. 1997. Glycosyl-phosphatidylinositol anchored membrane enzymes. Clin Chim Acta 266(1): 3-12. 31. Levine, J. 1997. Controlled trials of inositol in psychiatry. Eur europsychopharmacol 7(2): 147-155. 32. Levine, J. et al. 1995. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 152(5): 792-794. 33. Benjamin, J. et al. 1995a. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 152(7): 1084-1086. 34. Benjamin, J. et al. 1995b. Inositol treatment in psychiatry. Psychopharmacol Bull 31(1): 167-175. 35. Gelber et al. 2001. Effect of inositol on bulimia nervosa and binge eating. Int J Eat Disord. 29(3):345-8. 36. Palatnik, A. et al., 2001. Double-blind, controlled, crossover trial of inositol versus fluvoxamine for the treatment of panic disorder. J Clin Psychopharmacol 21(3): 335-339. 37. Fux, M. et al. 1996. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 153(9): 1219-1221. 38. Levine, J. et al. 1999. Combination of inositol and serotonin reuptake inhibitors in the treatment of depression. Biol Psychiatry 45(3): 270-273.
275
39. Chengappa et al. 2000. Inositol as an add-on treatment for bipolar depression. Bipolar Disord. 2(1):47-55. 40. Rahman, S. and R. S. Neuman. 1993. Myo-inositol reduces serotonin (5-HT2) receptor induced homologous and heterologous desensitization. Brain Res 631(2): 349351. 41. Greist, J. H. et al. 1995. Efficacy and tolerability of serotonin transport inhibitors in obsessive-compulsive disorder. A meta-analysis. Arch Gen Psychiatry 52(1): 53-60. 42. Hefez, A. et al. 1987. Long-term effects of extreme situational stress on sleep and dreaming. Am J Psychiatry 144(3): 344-347. 43. Friedman CA, et al. 2000. Relationship between serum inositol concentration and development of retinopathy of prematurity: a prospective study. J Pediatr Ophthalmol Strabismus Mar-Apr;37(2): 79-86. 44. Greene, N. D. and A. J. Copp. 1997. Inositol prevents folate-resistant neural tube defects in the mouse. Nat Med 3(1): 60-66. 45. Reece, E. A. et al. 1997. Dietary intake of myo-inositol and neural tube defects in offspring of diabetic rats. Am J Obstet Gynecol 176(3): 536-539. 46. Khandelwal, M. et al. 1998. Dietary myo-inositol therapy in hyperglycemia-induced embryopathy. Teratology 57(2): 79-84. 47. Colodny, L. and R. L. Hoffman. 1998. Inositol--clinical applications for exogenous use. Altern Med Rev 3(6): 432-447. 48. Gill, D. L. et al. 1989. Calcium signalling mechanisms in endoplasmic reticulum activated by inositol 1,4,5-trisphosphate and GTP. Cell Calcium 10(5):363-374. 49. Graf, E. and J. W. Eaton. 1993. Suppression of colonic cancer by dietary phytic acid. Nutr Cancer 19(1): 11-19. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 276
50. Graf, E. et al. 1987. Phytic acid. A natural antioxidant. J Biol Chem 262(24): 116471150. 51. Zhou, J. R. and J. W. Erdman. 1995. Phytic acid in health and disease. Crit Rev Food Sci Nutr 35(6): 495-508. 52. Carey et al. 2004. Single photon emission computed tomography (SPECT) in obsessive-compulsive disorder before and after treatment with inositol. Metab Brain Dis. 19(1-2):125-34. 53. Brink CB et al. 2004. Effects of myo-inositol versus fluoxetine and imipramine pretreatments on serotonin 5HT2A and muscarinic acetylcholine receptors in human neuroblastoma cells. Metab Brain Dis. 19(1-2):51-70. 54. Cai, F. et al. 1990. Preliminary report of efficacy of diabetic polyneuropathy treated with large dose inositol. Hua Xi Yi Ke Da Xue Xue Bao 21(2): 201-203. 55. Barak, Y. et al. 1996. Inositol treatment of Alzheimer's disease: A double blind, crossover placebo controlled trial. Prog Neuropsychopharmacol Biol Psychiatry 20(4): 729-735. 56. Nemets et al. 2002. Myo-inositol has no beneficial effect on premenstrual dysphoric disorder. World J Biol Psychiatry. 3(3):147-9.
L- Carnitine 93 Studies
1. Li B, Lloyd ML, Gudjonsson H, et al. The effect of enteral carnitine administration in humans. Am J Clin Nutr 1992;55:838-845. 2. Harper P, Elwin CE, Cederblad G. Pharmacokinetics of intravenous and oral bolus doses of L-carnitine in healthy subjects. Eur J Clin Pharmacol 1988;35:555-562. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 277
3. Sahajwalla CG, Helton ED, Purich ED, et al. Multiple-dose pharmacokinetics and bioequivalence of L-carnitine 330-mg tablet versus 1-g chewable tablet versus enteral solution in healthy adult male volunteers. J Pharm Sci 1995;84:627-633. 4. Bach AC, Schirardin H, Sihr MO, Storck D. Free and total camitine in human serum after oral ingestion of L-carnitine. Diabete Metab 1983;9:121-124. 5. Rebouche CJ, Chenard CA. Metabolic fate of dietary carnitine in human adults: identification and quantification of urinary and fecal metabolites. J Nutr 1991;121:539546. 6. Baker H, Frank O, DeAngelis B, Baker ER. Absorption and excretion of L-carnitine during single or multiple dosings in humans. Int J Vitam Nutr Res 1993;63:22-26. 7. Jogl G, Hsiao YS, Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci 2004;1033:17-29. 8. Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids 2004;70:243-251. 9. Platell C, Kong SE, McCauley R, Hall JC. Branched-chain amino acids. J Gastroenterol Hepatol 2000; 15:706-717. 10. Stanley CA. Carnitine deficiency disorders in children. Ann N Y Acad Sci 2004; 1033:42-51. 11. Evangeliou A, Vlassopoulos D. Carnitine metabolism and deficit--when supplementation is necessary? Curr Pharm Biotechnol 2003;4:211-219. 12. Cruciani RA, Dvorkin E, Homel P, et al. L-carnitine supplementation for the treatment of fatigue and depressed mood in cancer patients with carnitine deficiency: a preliminary analysis. Ann N Y Acad Sci 2004;1033:168-176. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 278
13. Korkina MB, Korchak GM, Medvedev DI. Clinico-experimental substantiation of the use of carnitine and cobalamin in the treatment of anorexia nervosa. Zh Nevropatol Psikhiatr Im S S Korsakova 1989;89:82-87. [Article in Russian] 14. Korkina MV, Korchak GM, Kareva MA. Effects of carnitine and cobamamide on the dynamics of mental work capacity in patients with anorexia nervosa. Zh Nevropatol Psikhiatr Im S S Korsakova 1992;92:99-102. [Article in Russian] 15. Giordano C, Perrotti G. Clinical studies of the effects of treatment with a combination of carnitine and cobamamide in infantile anorexia. Clin Ter 1979;88:51-60. [Article in Italian] 16. Swart I, Rossouw J, Loots JM, Kruger MC. The effect of L-carnitine supplementation on plasma carnitine levels and various performance parameters of male marathon athletes. Nutr Res 1997;17:405-414. 17. Vecchiet L, Di Lisa F, Pieralisi G, et al. Influence of L-carnitine administration on maximal physical exercise. Eur J Appl Physiol Occup Physiol 1990;61:486-490. 18. Volek JS, Kraemer WJ, Rubin MR, et al. L-carnitine L-tartrate supplementation favorably affects markers of recovery from exercise stress. Am J Physiol Endocrinol Metab 2002;282:E474-E482. 19. Vukovich MD, Costill DL, Fink WJ. Carnitine supplementation: effect on muscle carnitine and glycogen content during exercise. Med Sci Sports Exerc 1994;26:11221129. 20. Cooper MB, Jones DA, Edwards RH, et al. The effect of marathon running on carnitine metabolism and on some aspects of muscle mitochondrial activities and antioxidant mechanisms. J Sports Sci 1986;4:79-87.
279
21. Colombani P, Wenk C, Kunz I, et al. Effects of L-carnitine supplementation on physical performance and energy metabolism of endurance-trained athletes: a doubleblind crossover field study. Eur J Appl Physiol Occup Physiol 1996;73:434-439. 22. Kamikawa T, Suzuki Y, Kobayashi A, et al. Effects of L-carnitine on exercise tolerance in patients with stable angina pectoris. Jpn Heart J 1984;25:587-597. 23. Canale C, Terrachini V, Biagini A, et al. Bicycle ergometer and echocardiographic study in healthy subjects and patients with angina pectoris after administration of Lcarnitine: semiautomatic computerized analysis of M-mode tracing. Int J Clin Pharmacol Ther Toxicol 1988;26:221-224. 24. Cherchi A, Lai C, Angelino F, et al. Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomized, placebo controlled crossover study. Int J Clin Pharmacol Ther Toxicol 1985;23:569-572. 25. Iyer RN, Khan AA, Gupta A, et al. L-carnitine moderately improves the exercise tolerance in chronic stable angina. J Assoc Physicians India 2000;48:1050-1052. 26. Cacciatore L, Cerio R, Ciarimboli M, et al. The therapeutic effect of L-carnitine in patients with exercise-induced stable angina: a controlled study. Drugs Exp Clin Res 1991;17:225-235. 27. Loster H, Miehe K, Punzel M, et al. Prolonged oral L-carnitine substitution increases bicycle ergometer performance in patients with severe, ischemically induced cardiac insufficiency. Cardiovasc Drugs Ther 1999;13:537-546. 28. Brevetti G, Chiariello M, Ferulano G, et al. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation 1988;77:767-773. 29. Shankar SS, Mirzamohammadi B, Walsh JP, Steinberg HO. L-carnitine may attenuate free fatty acid-induced endothelial dysfunction. Ann N Y Acad Sci 2004;1033:189-197. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 280
30. Corbucci GG, Lettieri B. Cardiogenic shock and L-carnitine: clinical data and therapeutic perspectives. Int J Clin Pharmacol Res 1991;11:283-293. 31. Corbucci GG, Loche F. L-carnitine in cardiogenic shock therapy: pharmacodynamic aspects and clinical data. Int J Clin Pharmacol Res 1993; 13:87-91. 32. Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration. Am Heart J 2000; 139: S120-S123. 33. Gurlek A, Tutar E, Akcil E, et al. The effects of L-carnitine treatment on left ventricular function and erythrocyte superoxide dismutase activity in patients with ischemic cardiomyopathy. Eur J Heart Fail 2000;2:189-193. 34. Davini P, Bigalli A, Lamanna F, Boem A. Controlled study on L-carnitine therapeutic efficacy in post-infarction. Drugs Exp Clin Res 1992;18:355-365. 35. De Pasquale B, Righetti G, Menotti A. L-carnitine for the treatment of acute myocardial infarct. Cardiologia 1990;35:591-596. [Article in Italian] 36. Singh RB, Niaz MA, Agarwal P, et al. A randomised, double-blind, placebocontrolled trial of L-carnitine in suspected acute myocardial infarction. Postgrad Med J 1996;72:45-50. 37. Iliceto S, Scrutinio D, Bruzzi P, et al. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial. J Am Coll Cardiol 1995;26:380-387. 38. Stefanutti C, Vivenzio A, Lucani G, et al. Effect of L-carnitine on plasma lipoprotein fatty acids pattern in patients with primary hyperlipoproteinemia. Clin Ter 1998;149:115119.
281
39. Fernandez C, Proto C. L-carnitine in the treatment of chronic myocardial ischemia. An analysis of 3 multicenter studies and a bibliographic review. Clin Ter 1992;140:353377. [Article in Italian] 40. Digiesi V, Cantini F, Bisi G, et al. L-carnitine adjuvant therapy in essential hypertension. Clin Ter 1994; 144:391-395. 41. Kosan C, Sever L, Arisoy N, et al. Carnitine supplementation improves apolipoprotein B levels in pediatric peritoneal dialysis patients. Pediatr Nephrol 2003;18:1184-1188. 42. Sirtori CR, Calabresi L, Ferrara S, et al. L-carnitine reduces plasma lipoprotein(a) levels in patients with hyper Lp(a). Nutr Metab Cardiovasc Dis 2000;10:247-251. 43. Derosa G, Cicero AF, Gaddi A, et al. The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. Clin Ther 2003;25:1429-1439. 44. Mingrone G, Greco AV, Capristo E, et al. L-carnitine improves glucose disposal in type 2 diabetic patients. J Am Coll Nutr 1999; 18:77-82. 45. Cakir N, Yetkin I, Karakoc A, et al. L-carnitine in the treatment of painful diabetic neuropathy and its effect on plasma beta-endorphin levels. Curr Ther Res Clin Exp 2000;61:871-876. 46. Plioplys AV, Plioplys S. Serum levels of carnitine in chronic fatigue syndrome: clinical correlates. Neuropsychobiology 1995;32:132-138. 47. Plioplys AV, Plioplys S. Amantadine and L-carnitine treatment of chronic fatigue syndrome. Neuropsychobiology 1997;35:16-23. 48. Sachan DS, Rhew TH, Ruark RA. Ameliorating effects of carnitine and its precursors on alcohol-induced fatty liver. Am J Clin Nutr 1984;39:738-744. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 282
49. Selimoglu MA, Yagci RV. Plasma and liver carnitine levels of children with chronic hepatitis B. J Clin Gastroenterol 2004;38:130-133. 50. DaVanzo WJ, Ullian ME. L-carnitine administration reverses acute mental status changes in a chronic hemodialysis patient with hepatitis C infection. Clin Nephrol 2002;57:402-405. 51. Malaguarnera M, Pistone G, Astuto M, et al. L-carnitine in the treatment of mild or moderate hepatic encephalopathy. Dig Dis 2003;21:271-275. 52. Moretti S, Alesse E, Di Marzio L, et al. Effect of L-carnitine on human immunodeficiency virus-1 infection-associated apoptosis: a pilot study. Blood 1998;91:3817-3824. 53. De Simone C, Tzantzoglou S, Famularo G, et al. High dose L-carnitine improves immunologic and metabolic parameters in AIDS patients. Immunopharmacol Immunotoxicol 1993;15:1-12. 54. Moretti S, Famularo G, Marcellini S, et al. L-carnitine reduces lymphocyte apoptosis and oxidant stress in HIV-1-infected subjects treated with zidovudine and didanosine. Antioxid Redox Signal 2002;4:391-403. 55. Benvenga S, Ruggeri RM, Russo A, et al. Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 2001;86:3579-3594. 56. Costa M, Canale D, Filicori M, et al. L-carnitine in idiopathic asthenozoospermia: a multicenter study. Italian Study Group on Carnitine and Male Infertility. Andrologia 1994;26:155-159. 57. Vitali G, Parente R, Melotti C. Carnitine supplementation in human idiopathic asthenospermia: clinical results. Drugs Exp Clin Res 1995;21:157-159. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 283
58. Lenzi A, Lombardo F, Sgro P, et al. Use of carnitine therapy in selected cases of male factor infertility: a double-blind crossover trial. Fertil Steril 2003;79:292-300. 59. Lenzi A, Sgro P, Salacone P, et al. A placebo-controlled double-blind randomized trial of the use of combined L-carnitine and L-acetyl-camitine treatment in men with asthenozoospermia. Fertil Steril 2004;81:1578-1584. 60. Gunal AI, Celiker H, Donder E, Gunal SY. The effect of L-carnitine on insulin resistance in hemodialysed patients with chronic renal failure. J Nephrol 1999;12:38-40. 61. Vesela E, Racek J, Trefil L, et al. Effect of L-carnitine supplementation in hemodialysis patients. Nephron 2001;88:218-223. 62. Matsumoto Y, Amano I, Hirose S, et al. Effects of L-carnitine supplementation on renal anemia in poor responders to erythropoietin. Blood Purif 2001;19:24-32. 63. Elisaf M, Bairaktari E, Katopodis K, et al. Effect of L-carnitine supplementation on lipid parameters in hemodialysis patients. Am J Nephrol 1998;18:416-421. 64. Romagnoli GF, Naso A, Carraro G, Lidestri V. Beneficial effects of L-carnitine in dialysis patients with impaired left ventricular function: an observational study. Curr Med Res Opin 2002;18:172-175. 65. Golper TA, Goral S, Becker BN, Langman CB. L-carnitine treatment of anemia. Am J Kidney Dis 2003;41:S27-S34. 66. Kurz C, Arbeiter K, Obermair A, et al. L-carnitine-betamethasone combination therapy versus betamethasone therapy alone in prevention of respiratory distress syndrome. Z Geburtshilfe Perinatol 1993;197:215-219. [Article in German] 67. O'Donnell J, Finer NN, Rich W, et al. Role of L-carnitine in apnea of prematurity: a randomized, controlled trial. Pediatrics 2002;109:622-626.
284
68. Whitfield J, Smith T, Sollohub H, et al. Clinical effects of L-carnitine supplementation on apnea and growth in very low birth weight infants. Pediatrics 2003;111:477-482. 69. Iafolla AK, Browning IB 3rd, Roe CR. Familial infantile apnea and immature beta oxidation. Pediatr Pulmonol 1995;20:167-171. 70. Villani RG, Gannon J, Self M, Rich PA. L-Carnitine supplementation combined with aerobic training does not promote weight loss in moderately obese women. Int J Sport Nutr Exerc Metab 2000;10:199-207. 71. Johnston CS, Solomon RE, Cone C. Vitamin C depletion is associated with alterations in blood histamine and plasma free carnitine in adults. J Am Coil Nutr 1996;15:586-591. 72. Ha TY, Otsuka M, Arakawa N. The effect of graded doses of ascorbic acid on the tissue carnitine and plasma lipid concentrations. J Nutr Sci Vitaminol (Tokyo) 1990;36:227-234. 73. Otsuka M, Matsuzawa M, Ha TY, Arakawa N. Contribution of a high dose of Lascorbic acid to carnitine synthesis in guinea pigs fed high-fat diets. J Nutr Sci Vitaminol (Tokyo) 1999;45:163-171. 74. Triggs WJ, Roe CR, Rhead WJ, et al. Neuropsychiatric manifestations of defect in mitochondrial beta oxidation response to riboflavin. J Neurol Neurosurg Psychiatry 1992;55:209-211. 75. Podlepa EM, Gessler NN, Bykhovskii Via. The effect of methylation on the carnitine synthesis. Prikl Biokhim Mikrobiol 1990;26:179-183. [Article in Russian] 76. Dodson WL, Sachan DS. Choline supplementation reduces urinary carnitine excretion in humans. Am J Clin Nutr 1996;63:904-910.
285
77. Hug G, McGraw CA, Bates SR, Landrigan EA. Reduction of serum carnitine concentrations during anticonvulsant therapy with phenobarbital, valproic acid, phenytoin, and carbamazepine in children. J Pediatr 1991;119:799-802. 78. Melegh B, Pap M, Molnar D, et al. Carnitine administration ameliorates the changes in energy metabolism caused by short-term pivampicillin medication. Eur J Pediatr 1997;156:795-799. 79. Herink J. Enhancing effect of L-carnitine on some abnormal signs induced by pentylenetetrazol. Acta Medica (Hradec Kralove) 1996;39:63-66. 80. Lissoni P, Galli MA, Tancini G, Barni S. Prevention by L-carnitine of interleukin-2 related cardiac toxicity during cancer immunotherapy. Tumori 1993;79:202-204. 81. Kawasaki N, Lee JD, Shimizu H, Ueda T. Long-term L-carnitine treatment prolongs the survival in rats with adriamycin-induced heart failure. J Card Fail 1996;2:293-299. 82. Semino-Mora MC, Leon-Monzon ME, Dalakas MC. Effect of L-carnitine on the zidovudine-induced destruction of human myotubes. Part I: L-carnitine prevents the myotoxicity of AZT in vitro. Lab Invest 1994;71:102-112. 83. Georgala S, Schulpis KH, Georgala C, Michas T. L-carnitine supplementation in patients with cystic ache on isotretinoin therapy. J Eur Acad Dermatol Venereol 1999; 13:205-209. 84. Kuntzer T, Reichmann H, Bogousslavsky J, Regli F. Emetine-induced myopathy and carnitine deficiency. J Neurol 1990;237:495-496. 85. Sekas G, Paul HS. Hyperammonemia and carnitine deficiency in a patient receiving sulfadiazine and pyrimethamine. Am J Med 1993;95:112-113.
286
86. Mondillo S, Faglia S, D'Aprile N, et al. Therapy of arrhythmia induced by myocardial ischemia. Association of L-carnitine, propafenone and mexiletine. Clin Ter 1995;146:769-774. [Article in Italian] 87. Cavallini G, Caracciolo S, Vitali G, Modenini F, Biagiotti G. Carnitine versus androgen administration in the treatment of sexual dysfunction, depressed mood, and fatigue associated with male aging. Urology. 2004 Apr;63(4):641-6. 88. Vermeulen RC, Scholte HR. Exploratory open label, randomized study of acetyl- and propionylcarnitine in chronic fatigue syndrome. Psychosom Med. 2004 Mar;66(2):27682. 89. Bertelli A, Conte A, Ronca G, Segnini D, Yu G. Protective effect of propionyl carnitine against peroxidative damage to arterial endothelium membranes. Int J Tissue React. 1991;13(1):41-3. 90. Amico-Roxas M, Caruso A, Cutuli VM, de Bernardis E, Leonardi G. Inhibitory effects of propionyl-L-carnitine on plasma extravasation induced by irritants in rodents. Drugs Exp Clin Res. 1993;19(5): 213-7. 91. Bertelli A, Conte A, Palmieri L, et al. Effect of propionyl carnitine on energy charge and adenine nucleotide content of cardiac endothelial cells during hypoxia. Int J Tissue React. 1991;13(1):37-40. 92. Wiseman LR, Brogden RN. Propionyl-L-carnitine. Drugs Aging. 1998 Mar;12(3):243-8. 93. Ferrari R, Merli E, Cicchitelli G, et al. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann NY Acad Sci. 2004 Nov;1033:79-91.
L-Cysteine 50 Studies
1. Neurosci Lett. 2003 Jul 31;346(1-2):97-100. L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II. Kocki T, Luchowski P, Luchowska E, Wielosz M, Turski WA, Urbanska EM. Department of Pharmacology and Toxicology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland. 2. Biochem Biophys Res Commun. 2003 May 23;305(1):94-100. L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 287
activation. Horie T, Sakaida I, Yokoya F, Nakajo M, Sonaka I, Okita K. Pharmaceuticals Research Laboratories, Ajinomoto Co, Inc, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki 210-8681, Japan. 3. Russ J Immunol. 2002 Apr;7(1):48-56. Up-regulation of interferon-gamma production by reduced glutathione, anthocyane and L-cysteine treatment in children with allergic asthma and recurrent respiratory diseases. Chernyshov VP, Omelchenko LI, Treusch G, Vodyanik MA, Pochinok TV, Gumenyuk ME, Zelinsky GM. Institute of Pediatrics, Obstetrics and Gynecology, Academy of Medical Sciences, Kiev, Ukraine. chernyshov@ukr.net 4. Proc Nutr Soc. 2000 Nov;59(4):595-600. Glutathione and immune function. Droge W, Breitkreutz R. Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. W.Droege@dkfz-heidelberg.de 5. Toxicol Appl Pharmacol. 2000 Oct 1;168(1):72-8. gamma-Glutamyl transpeptidase and L-cysteine regulate methylmercury uptake by HepG2 cells, a human hepatoma cell line. Wang W, Clarkson TW, Ballatori N. Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA. 6. Amino Acids. 2000;18(4):319-27. Polyamines and thiols in the cytoprotective effect of L-cysteine and L-methionine on carbon tetrachloride-induced hepatotoxicity. Chen W, Kennedy DO, Kojima A, Matsui-Yuasa I. Department of Food and Nutrition, Faculty of Human Life Science, Osaka City University, Osaka, Japan. 7. Z Naturforsch [C]. 2000 Mar-Apr;55(3-4):271-7. Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase inhibition induced by free radicals. Tsakiris S, Angelogianni P, Schulpis KH, Behrakis P. Department of Experimental Physiology, University of Athens, Medical School, Greece. stsakir@cc.uoa.gr 8. Comp Biochem Physiol B Biochem Mol Biol. 1997 Feb;116(2):223-6. L-cysteine metabolism in guinea pig and rat tissues. Wrobel M, Ubuka T, Yao WB, Abe T. Department of Biochemistry, Okayama University Medical School, Japan. 9. Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIV-infected rhesus macaques. Gross A, Hack V, Stahl-Hennig C, Droge W. AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1639-41. 10. Biochem Pharmacol. 1996 May 3;51(9):1111-6. Maintenance of hepatic glutathione homeostasis and prevention of acetaminophen-induced cataract in mice by L-cysteine prodrugs. Rathbun WB, Killen CE, Holleschau AM, Nagasawa HT. Department of Ophthalmology, University of Minnesota, Minneapolis, USA.
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11. Jpn J Physiol. 1995;45(5):771-83. The central effect of L-cysteine on cardiovascular system of the conscious rat. Takemoto Y. Department of Physiology, Hiroshima University School of Medicine, Minami-ku, Japan. 12. Eur Surg Res. 1995;27(6):363-70. Effect of the combination of human thioredoxin and L-cysteine on ischemia-reperfusion injury in isolated rat lungs. Wada H, Hirata T, Decampos KN, Hitomi S, Slutsky AS. Department of Thoracic Surgery, Kyoto University, Japan. 13. FASEB J. 1994 Nov;8(14):1131-8. Functions of glutathione and glutathione disulfide in immunology and immunopathology. Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmunder H. Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany. 14. Pharmacology. 1993;46(2):61-5. Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with N-acetyL-cysteine. Droge W. Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, BRD. 15. Cysteine and glutathione deficiency in HIV-infected patients. The basis for treatment with N-acetyL-cysteine Droge W. AIDS-FORSCHUNG (Germany), 1992, 7/4 (197-199) 16. Biochem Pharmacol. 1992 Jul 7;44(1):129-35. Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. Richie JP Jr, Lang CA, Chen TS. American Health Foundation, Valhalla, NY 10595. 17. Biochem Pharmacol. 1992 Feb 4;43(3):483-8. Cysteine isopropylester protects against paracetamol-induced toxicity. Butterworth M, Upshall DG, Smith LL, Cohen GM. Toxicology Unit, School of Pharmacy, University of London, U.K. 18. Blood. 1992 Sep 1;80(5):1247-53. Antithrombotic properties of L-cysteine, N(mercaptoacetyl)-D-Tyr-Arg-Gly-Asp-sulfoxide (G4120) in a hamster platelet-rich femoral vein thrombosis model. Imura Y, Stassen JM, Bunting S, Stockmans F, Collen D. Center for Thrombosis and Vascular Research, University of Leuven, Belgium. 19. Effects of amino acids on acute alcohol intoxication in mice--concentrations of ethanol, acetaldehyde, acetate and acetone in blood and tissues. Tsukamoto S, Kanegae T, Nagoya T, Shimamura M, Mieda Y, Nomura M, Hojo K, Okubo H. Arukoru Kenkyuto Yakubutsu Ison. 1990 Oct;25(5):429-40. 20. Jpn J Cancer Res. 1989 Feb;80(2):182-7. Enhanced antitumor effect of 5'-deoxy-5fluorouridine by oral administration with L-cysteine. Iigo M, Nakajima Y, Araki E, Hoshi A. Chemotherapy Division, National Cancer Center Research Institute, Tokyo. 21. Am Rev Respir Dis. 1985 Nov;132(5):1049-54. Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro. Theron A, Anderson R. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 289
22. J Biol Chem. 1984 May 10;259(9):5606-11. Free radical metabolites of L-cysteine oxidation. Harman LS, Mottley C, Mason RP. 23. Preventing Hypoglycemia Anti-Aging News, January 1982 Vo.2, No. 1 pg 6-7 24. Hum Genet. 1979;50(1):51-7. Chromosomal breakage in Crohn's disease: anticlastogenic effect of D-penicillamine and L-cysteine. Emerit I, Emerit J, Levy A, Keck M. 25. Annu Rev Plant Biol. 2002;53:159-82. Phytochelatins and metallothioneins: roles in heavy metal detoxification and homeostasis. Cobbett C, Goldsbrough P. Department of Genetics, University of Melbourne, Parkville, Australia 3052. ccobbett@unimelb.edu.au 26. J Biol Chem. 2001 Jun 15;276(24):20817-20. Epub 2001 Apr 19. A new pathway for heavy metal detoxification in animals. Phytochelatin synthase is required for cadmium tolerance in Caenorhabditis elegans. Vatamaniuk OK, Bucher EA, Ward JT, Rea PA. Department of Biology, Plant Science Institute, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6018, USA. 27. Biol Trace Elem Res. 2000 Jul;76(1):19-30. Study of the effect of the administration of Cd(II), cysteine, methionine, and Cd(II) together with cysteine or methionine on the conversion of xanthine dehydrogenase into xanthine oxidase. Esteves AC, Felcman J. Department of Chemistry, Pontificia Universidade Catolica do Rio de Janeiro, Rio de Janeiro, Brazil. 28. Altern Med Rev. 1998 Aug;3(4):262-70. Cysteine metabolism and metal toxicity. Quig D. Doctor's Data, Inc., West Chicago, IL, USA. dquig@doctorsdata.com 29. J Nutr. 1987 Jun;117(6):1003-10. Pharmacologic role of cysteine in ameliorating or exacerbating mineral toxicities. Baker DH, Czarnecki-Maulden GL. 30. J Infect Dis. 2000 Sep;182 Suppl 1:S81-4. Regulation of cysteine-rich intestinal protein, a zinc finger protein, by mediators of the immune response. Cousins RJ, Lanningham-Foster L. Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611-0370, USA. 31. Am J Med. 1991 Sep 30;91(3C):140S-144S. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Droge W, Eck HP, Gmunder H, Mihm S. Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, F.R.G. 32. Salim AS. Sulfhydryl-containing agents in the treatment of gastric bleeding induced by nonsteroidal anti-inflammatory drugs. Can J Surgery 1993;36:5358.
290
33. Droge W, Eck HP, Gander H, Mihm S. Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Am J Med 1991;91(suppl 3C):140S44S. 34. Umbach, JA & Gundersen CB Evidence that cysteine string proteins regulate an early step in the Ca++-dependent secretion of transmitter at Drosophila neuromuscular junctions.. J. Neuroscience 1997; 17: 7203-7209. 35. Coppola,T & Gundersen, CB Widespread expression of human cysteine string proteins.. FEBS Letters 1996; 391: 269-272. 36. Kohan,SA, Pescatori,M, Brecha,N, Mastrogiacomo,A, Umbach,JA & Gundersen, CB Cysteine string protein immunoreactivity in the nervous system and adrenal gland of the rat.. J. Neuroscience 1995; 15: 6230-6238. 37.Gundersen, CB, Mastrogiacomo,A, & Umbach, JA Cysteine string proteins as templates for membrane fusion: models of synaptic vesicle exocytosis.. J. Theoretical Biology 1995; 172: 269-277. 38. Mastrogiacomo,A & Gundersen, CB The nucleotide and deduced amino acid sequence of a rat cysteine string protein.. Mol. Brain Research 1995; 28: 12-18. 39. Mastrogiacomo,A., Parsons,S.M., Zampighi,G.A., Jenden,D.J. Umbach, J.A. & Gundersen, C.B. Cysteine string proteins: a potential link between synaptic vesicles and presynaptic calcium channels.. Science 1994; 263: 981-982. 40. Gundersen,CB, Mastrogiacomo,A, Faull, K, & Umbach, JA Extensive lipidation of a Torpedo cysteine string protein.. J. Biol. Chem. 1994; 269: 19197-19199. 41. Umbach,JA, Zinsmaier,KE, Eberle,KK, Buchner,E, Benzer, S & Gundersen CB Presynaptic dysfunction in Drosophila csp mutants.. Neuron 1994; 13: 899-907. 42.Gundersen, C.B. and J.A. Umbach Suppression cloning of the cDNA for a candidate subunit of a presynaptic calcium channel.. Neuron 1992; 9: 527-537. 43. Anderson R, Lukey PT, Theron AJ, Dippenaar U. Ascorbate and cysteine-mediated selective neutralization of extracellular oxidants during N-formyl peptide activation of human phagocytes. Agents Actions. 1987;20:77-86. 44. Anderson R, Theron AJ, Ras GJ. Regulation by the antioxidants ascorbate, cysteine, and dapsone of the increased extracellular and intracellular generation of reactive oxidants by activated phagocytes from cigarette smokers. Am Rev Respir Dis. 1987; 135:1027-1032 45. Asper R, Schmucki O. Cystinuric therapy by ascorbic acid. Urol Int. 1982;37:91-109.
291
46. Campbell NR, Reade PC, Radden BG. Effect of cysteine on the survival of mice with transplanted malignant lymphoma. Nature. 1974;251:158-159. 47. Csako G. False-positive results for ketone with the drug mensa and other freesulfhydryl compounds. Clin Chem. 1987;33(2 pt 1):289-292. 48. Fettman MJ, Valerius KD, Ogilvie GK. Effects of dietary cysteine on blood sulfur amino acid, glutathione, and malondialdehyde concentrations in cats. Am J Vet Res. 1999;60:328-333. 49. Oeriu S, Vachitu E. The effect of the administration of compounds which contain sulfhydryl groups on the survival rate of mice, rats and guinea pigs. Journ Geront. 1965;20;47. 50. Stipanuk MH. Homocysteine, cysteine and taurine. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern Nutrition in Health and Disease. Ninth edition. Baltimore, MD: Williams & Wilkins; 1999:543-558.
Blue Cohosh Root 2 Studies

1. Castleman M. The Healing Herbs. New York: Bantam Books, 1991, 1203. 2. Foster S. Herbal Renaissance. Salt Lake City: Gibbs-Smith Publisher, 1993, 4850.
Siberian Ginseng Root 40 Studies

1. Blumenthal M, ed. The Complete German Commission E Monographs. Boston, Mass: Integrative Medicine Communications; 1998:124-125. 2. Bucci LR. Selected herbals and human exercise performance. Am J Clin Nutr. 2000;72(suppl):624S-636S. 3. Fugh-Berman A. Herb-drug interactions. Lancet. 2000;355:134-138. 4. Glatthaar-Saalmuller B, Sacher F, Esperester A. Antiviral activity of an extract derived from roots of Eleutherococcus senticosus. Antiviral Res. 2001;50(3):223-8. 5. Gyllenhaal C, Merritt SL, Peterson SD, Block KI, Gochenour T. Efficacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Med Rev. 2000;4(2):229-251.
292
6. Harkey MR, Henderson GL, Gershwin ME, Stern JS, Hackman RM. Variability in commercial ginseng products: an analysis of 25 preparations. Am J Clin Nutr. 2001;73:1101-1106. 7. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Alt Med Rev. 1999;4(4):249-265. 8. Koren G, Randor S, Martin S, Danneman D. Maternal ginseng use associated with neonatal androgenization [letter]. JAMA. 1990;264(22):2866. 9. McRae S. Elevated serum digoxin levels in a patient taking digoxin and Siberian ginseng. Can Med Assoc J. 1996;155:293295. 10. Miller LG. Herbal medicinals: selected clinical considerations focusing on known or potential drug-herb interactions. Arch Intern Med. 1998;158(20):22002211. 11. Newall CA, Anderson LA, Phillipson JD. Herbal Medicines: A Guide for Health Care Professionals. London, England: The Pharmaceutical Press; 1996:141-144. 12. Ott BR, Owens NJ. Complementary and alternative medicines for Alzheimer's disease. J Geriatr Psychiatry Neurol. 1998;11:163-173. 13. Pizzorno JE, Murray MT, eds. Textbook of Natural Medicine. New York, NY: Churchill-Livingstone; 1999:433-434;531-532;713-717;1385-1386. 14. Sinclair S. Male infertility: nutritional and environmental considerations. Alt Med Rev. 2000;5(1):28-38. 15. Vogler BK, Pittler MH, Ernst E. The efficacy of ginseng. A systematic review of randomized clinical trials. Eur J Clin Pharmacol. 1999;55:567-575. 16. White L, Mavor S. Kids, Herbs, Health. Loveland, Colo: Interweave Press; 1998:22, 40. 17. Williams M. Immuno-protection against herpes simplex type II infection by eleutherococcus root extract. Int J Alt Comp Med. 1995;13:9-12. 18. Winther K, Ranlov C, Rein E, Mehlsen J. Russian root (Siberian ginseng) improves cognitive functions in middle-aged people, whereas Ginkgo biloba seems effective only in the elderly. J Neurol Sci. 1997;150:S90. 19. Wong AHC, Smith M, Boon HS. Herbal remedies in psychiatric practice. Arch Gen Psychiatry. 1998;55:1033-1044. 20. Awang, D.V.C. 1991a. Maternal Use of Ginseng and Neonatal Androgenization. JAMA, April 10, 265(14):1828. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 293
21. Awang, D.V.C. 1991b. Maternal Use of Ginseng and Neonatal Androgenization. JAMA, July 17, 266(3):363. 22. Blumenthal, M., T. Hall, R. Rister, B Steinhoff (eds.), S. Klein, R. Rister (trans.). 1996. The German Commission E Monographs. Austin, Texas: American Botanical Council. 23. Baranov, A.I. 1979. "On a Technical English Name for Eleutherococcus" Taxon 28:586-587. 24. Duke, J. A. and E.S. Ayensu. 1985. Medicinal Plants of China. 2 vols. Algonac, MI: Reference Publications. 25. Farnsworth, N.R., A. D. Kinghorn, D.D. Soejarto and D. P. Waller. 1985. "Siberian Ginseng (Eleutherococcus senticosus): Current Status as an Adaptogen" pp. 155-215. In H. Wagner, H.Hikino and N.R. Farnsworth (eds.). Economic and Medicinal Plant Research. Vol. 1. Orlando, FL: Academic Press. 26. Foster, S. and C. X. Yue. 1992. Herbal Emmissaries: Bringing Chinese Herbs to the West. Rochester, Vt: Healing Arts Press. 27. Fulder, S. 1980. "The Drug That Builds Russians" New Sci. 21:576-579. 28. Halstead, BW. and L.L. Hood. 1984. Eleutherococcus senticosus Siberian Ginseng: An Introduction to the Concept of Adaptogenic Medicine. Long Beach, CA: Oriental Healing Arts Institute. 29. Hu, S.Y. 1979. (letter to S. Foster) p. 44 In S. Foster. "Ginseng: Are You Confused: A Look at Controversy in the Herb World" Well-Being No. 46: 43-50 (October, 1979). 30. Hu, S.Y. 1980. "Eleutherococcus vs. Acanthopanax. " Journ. Arn. Arb. 61: 107-111. 31. Hu, S.Y. 1980b. An Enumeration of Chinese Materia Medica. Hong Kong: The Chinese University Press. 32. Koren, G. S. Randor, S. Martin, and D. Danneman. 1990. Maternal Use of Ginseng and Neonatal Androgenization. JAMA, Dec. 12, 264(22):2866. 33. Lucas R. 1973. Eleuthero (Siberian Ginseng) Health Herb of Russia. Spokane WA: R&M Books. 34. McCaleb, R. 1988. "Dr. I.I. Brekhman (interview)." HerbalGram 16:11-12. 35. Ohwi, J. 1965. Flora of Japan. Washington, D.C.: Smithsonian Institution.
294
36. Pharmacopeia Committee of the Ministry of Health. 1985. Pharmacopeia of the People's Republic of China (Zhong Hua Ren Min Gong He Guo Yao, Dian, Ti Bu). Part 1. Beijing: People's Health Publishing House and Chemical Industry Publishing House. 37. Poyarkova, A.I. 1973. Eleutherococcus pp. 16-23. In B.K. Shishkin. Flora of the U.S.S.R. (1950) Translated from Russian. Jerusalem: Israel Program for Scientific Translations. 38. Soejarto, D.D. and N. R. Farnsworth. 1978. "The Correct Name for Siberian Ginseng" Bot. Mus. Leafl., Harv. Univ. 26 (9-10): 339-341. 39. Wagner, H. and A. Proksch. 1985. "Immunostimulatory Drugs of Fungi and Higher Plants" pp. 111- 153. In H. Wagner, H. Hikino and N.R. Farnsworth (eds.). Economic and Medicinal Plant Research. Vol. 1. Orlando, FL: Academic Press. 40. Waller, D. P., A. M. Martin, N. R. Farnsworth, and D.V.C. Awang. 1992. Lack of Androgenicity of Siberian ginseng. JAMA, May 6, 267(17):2329.
Rosemary Leaves 17 Studies

1. Masuda T et al. J Agric Food Chem 2002;50(21):5863-5869 2. al-Sereiti MR et al. Indian J Exp Biol 1999; 37(2):124-130 3. Saen-Lopez R et al. J Chromatogr A 2002953(1-2):251-256 4. Lee KG, Shibamoto T. J Agric Food Chem 2002; 50(17):4947-4952 5. Torre J et al. J Chromatogr A 2001;919(2):305-311 6. Slamenova D et al. Cancer Lett 2002;177(2):145-153 7. Zhu BT et al. Carcinogenesis 1998:19(10):1821-1827 8. Calabrese V et al. Int J Tissue React 2000;22(1):5-13
295
9. Calabrese V et al. Int J Tissue React 2001;23(2):51-58 10. Debersac P et al. Food Chem Toxicol 2001:39(9):907-918 11. Halaoui M et al. J Ethnopharmacol 2000; 71(3):465-472 12. Int J Tissue React. 2000;22(1):5-13. 13. Biochemical studies of a natural antioxidant isolated from rosemary and its application in cosmetic dermatology. Calabrese V, Scapagnini G, Catalano C, Dinotta F, Geraci D, Morganti P. Department of Biochemistry, Faculty of Medicine, University of Catania, Italy. Calabrese@mbox.Unict.it. 14. Zhu BT, Loder DP, Cai MX, Ho CT, Huang MT, Conney AH. Dietary administration of an extract from rosemary leaves enhances the liver microsomal metabolism of endogenous estrogens and decreases their uterotropic action in CD-1 mice. Carcinogenesis. 1998 Oct;19(10):1821-7 15. Inoue K, Takano H, Shiga A, Fujita Y, Makino H, Yanagisawa R, Ichinose T, Kato Y, Yamada T, Yoshikawa T. Effects of volatile constituents of a rosemary extract on allergic airway inflammation related to house dust mite allergen in mice. Int J Mol Med. 2005 Aug;16(2):315-9. 16. Hsu S. Green tea and the skin. J Am Acad Dermatol. 2005 Jun;52(6):1049-59. 17. Samman S, Sandstrom B, Toft MB, Bukhave K, Jensen M, Sorensen SS, Hansen M. Green tea or rosemary extract added to foods reduces nonheme-iron absorption. Am J Clin Nutr. 2001 Mar;73(3):607-12.
Apsartic Acid 21 Studies

1. H G Pandya, S C Coley, I D Wilkinson, and P D Griffiths. Magnetic resonance spectroscopic abnormalities in sporadic and variant Creutzfeldt-Jakob disease. Clin Radiol, 58(2):148-53, February 2003. 2. D Galanaud, D Dormont, D Grabli, P Charles, J J Hauw, C Lubetzki, J P Brandel, C Marsault, and P J Cozzone. MR spectroscopic pulvinar sign in a case of variant Creutzfeldt-Jakob disease. J Neuroradiol, 29(4):285-7, December 2002. 3. Oncol Rep. 2006 Jan;15(1):113-7. Inhibition of proliferative and invasive capacities of breast cancer cells by arginine-glycine-aspartic acid peptide in vitro. Yang W, Meng L, Wang H, Chen R, Wang R, Ma X, Xu G, Zhou J, Wang S, Lu Y, Ma D. Cancer Biology Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 296
Research Center, Tongji Hospital, Tongji Medical School, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China.. 4. Appl Microbiol. 1972 April; 23(4): 758764. Effect of L-Aspartic Acid and LGlutamic Acid on Production of L-Proline. Jyoji Kato, Masahiko Kisumi, and Ichiro Chibata. Department of Applied Biochemistry, Chemical Research Laboratory, Tanabe Seiyaku Co., Ltd., Kashimacho, Higashiyodogawa-ku, Osaka, Japan. Bac P, Pages N, Herrenknecht CLA, Teste JF. Magnes Res. 1995; 8:37-45.
5. de Haan A, van Doorn JE, Westra HG. Effects of potassium + magnesium aspartate on muscle metabolism and force development during short static exercise. Int J Sports Med. 1985; 6:44-49. 6. Hagan RD, Upton SJ, Duncan JJ, et al. Absence of effect of potassium- magnesium aspartate on physiologic responses to prolonged work in aerobically trained men. Int J Sports Med. 1982; 3:177-181. 7. Hicks JT. Treatment of fatigue in general practice: a double-blind study. Clinical Medicine. 1964; 71:85-90. 8. Maughan RJ, Sadler DJ. The effects of oral administration of salts of aspartic acid on the metabolic response to prolonged exhausting exercise in man. Int J Sports Med. 1983; 4:119-123.
9. Trudeau F, Murphy R. Effects of potassium-aspartate salt administration on glycogen use in the rat during a swimming stress. Physiol Behav. 1993; 54:7-12.
10. Tuttle JL, Potteiger JA, Evans BW, Ozmun JC. Effects of acute potassiummagnesium aspartate supplementation on ammonia concentrations during and after resistance training. Int J Sport Nutr. 1995; 5:102-109. 11. I . H. Koyuncuoglu and others, "The antagonizing effect of aspartic acid on the brain levels of monoamines and free amino acids during the development of tolerance to and physical dependence on morphine", Psychopharmacology, vol. 54, 1977, pp. 187 - 191. 12. H. Koyuncuoglu and M. Gungor, "Effect of nialamaide and reserpine on brain free amino acids of rats dependent on and withdrawn from morphine", Drug Research ,vol. 25, 1975, pp. 1762 - 1766.
297
13. H. Koyuncuoglu and others, "The antagonizing effect of aspartic acid on morphine withdrawal and levallorphan-precipitated abstinence syndrome signs and on associated changes in brain levels of free amino acids in the rat", Psychopharmacology ,vol. 62, 1979, pp. 89 - 95. 14. L. Eroglu and H. Koyuncuoglu, "The effect of aspartic acid on the intensity of physical dependence in morphine dependent mice", Polish Journal of Pharmacology ,vol. 31 , 1979, pp. 83 - 88. 15. E. Genc, L. Eroglu and H. Koyuncuoglu, "Further hints on morphine - aspartic acid interaction", Medical Bulletin of Istanbul University, vol. 11, 1978, pp. 137 - 141. 16. H. Koyuncuoglu, L. Eroglu and T. Altug, "Effects of aspartic acid, asparagine and/or L-asparaginase on forced swimming-induced immobility, analgesia and decrease in rectal temperature in rats", Experientia ,vol. 38, 1982, pp. 117 - 118. 17. H. Koyuncuoglu and E. Genc, "The antagonizing effect of aspartic acid on morphine physical dependence in mice: its relation to brain biogenic monoamines and cAMP", Medical Bulletin of Istanbul University ,vol. 12, 1979, pp. 27 - 36. 18. H. Koyuncuoglu and others, "Mutual effects of morphine and aspartic acid on brain levels in mice", Psychopharmacology ,vol. 52, 1977, pp. 181 - 184. 19. H. Koyuncuoglu and others, "The antagonistic effects of aspartic acid on some effects of morphine on rats", European Journal of Pharmacology ,vol. 27, 1974, pp. 148 - 150. 20. H. Koyuncuoglu and others, "The relationship between morphine, aspartic acid and L-asparaginase in rats", European Journal of Pharmacology ,vol. 60, 1979, pp. 369 - 372. 21. H. Koyuncuoglu and others, "Antagonizing effect of aspartic acid on the development of physical dependence on and tolerance to morphine in the rat", Drug Research ,vol. 27, 1977, pp. 1676 - 1679.
L-Glutamine 58 Studies
1. Tischler, ME et al. J Biol Chem 1982; 257:1613-21 2. Jepson, MM et al. Am J. Physiol 1988; 255 3. Maclennan, PA et al. FEBS, Letters 1987; 215:187-191 4. Max, SR et al. Med Sci Sports Exerc 1990; 22:325-330 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 298
5. Stehle, P. et al. Lancet 1989; 231-233 6. Hammarquist, F. et al. Ann Surgery 1989; 209:455-61 7. Werneman, J. et al. Metabolism 1989;(suppl 1):63-66 8. Werneman, J. et al. Lancet 1990; 335:701-3 9.Cerra, FB et al. Ann Surgery 1984; 199:288-91 10. Bonau, RA et al. Surgery 1987; 101:400-7 11. Bonau, RA et al. JPEN 1984; 8:622-27 12. Vinnars, E. et al. Ann Surgery 1975; 163:665-70 13. Carli, F. et al. Clin Sci 1990; 78:6231-8 14. Askanazi, J. et al. Ann Surgery 1980; 192:78-85 15. Furst, P. et al. In Clinical Nutrition 1981; 10-17 16. Muhlbacher, F. et al. Am J Physiol 1984; 14 17. Rennie, MJ et al. Clin Sci 1981; 61:627-39 18. Vinnars, E. et al. JPEN 1990; 14:1258-9 19. Wernerman, J. et al. Clin Nutr 1987; 6(suppl):33 20. Rennie, MJ et al. Lancet 1986; ii:1008-12 21. Furst, P. Proc. 6th Congr. ESPEN, Milan 1984; 21-53 22. Bulus, N. et al. Metabolism 1989; 38(8, suppl 1):1-15 23. Stryer, L. Biochemistry (3rd edition) 1988 24. Shabert, J., MD et al. The Ultimate Nutrient: Glutamine, 1994 25. Cooper, K. Anti-Oxidant Revolution, 1994 26.Lowe, DK et al. Glutamine-Enriched Parenteral Nutrition Is Safe in Normal Humans, Surg Forum 40 1989; 9-11
299
27. Ziegler, TR et al. Safety and Metabolic Effects of L-Glutamine Administration in Hunians, JPEN 14 1990; 137S-146S 28. Emery, AEH et al. Antenatal Diagnosis and Amino Acid Composition of Amniotic Fluid, Lancet I 1970: 1307-1308 29. Hawkins, RA Hyperammenomia Does Not Impair Brain Function in the Absence of Net Glutamine Synthesis, Biochem J 277 1991: 697-703 30. Gant, C., MD Interview on Ammonia Clearance and Liver Dysfunction, April 5, 1995. 31. Souba WW. Glutamine Physiology, Biochemistry, and Nutrition in Critical Illness. Austin, TX: R.G. Landes Co.; 1992. 32. Askanazi J, Carpenter YA, Michelsen CB, et al. Muscle and plasma amino acids following injury: Influence of intercurrent infection. Ann Surg 1980;192:78-85. 33. O'Dwyer ST, Smith RJ, Hwang TL, Wilmore DW. Maintenance of small bowel mucosa with glutamine-enriched parenteral nutrition. J Parent Enteral Nutr 1989;13:579585. 34. Hwang TL, O'Dwyer ST, Smith RJ, et al. Preservation of small bowel mucosa using glutamine-enriched parenteral nutrition. Surg Forum 1987;38:56. 35. Li J, Langkamp-Henken B, Suzuki K, Stahlgren LH. Glutamine prevents parenteral nutrition-induced increases in intestinal permeability. J Parent Enteral Nutr 1994;18:303307. 36. Barber AE, Jones WG, Minei JP, et al. Glutamine or fiber supplementation of a defined formula diet. Impact on bacterial translocation, tissue composition, and response to endotoxin. J Parent Enteral Nutr 1990;14:335-343. 37. Khan J, Iiboshi Y, Cui L, et al. Alanyl-glutamine-supplemented parenteral nutrition increased luminal mucus gel and decreased permeability in the rat small intestine. J Parent Enteral Nutr 1999;23:24-31. 38. Kanuchi O, Iwanaga T, Mitsuyama K. Germinated barley foodstuff feeding. A novel neutraceutical therapeutic strategy for ulcerative colitis. Digestion 2001;63:60-67. 39. Slotwinski R, Pertkiewicz M, Lech G, Szczygiel B. Cellular immunity changes after total parenteral nutrition enriched with glutamine in patients with sepsis and malnutrition. Pol Merkuriusz Lek 2000;8:405-408. [Article in Polish] 40. O'Flaherty L, Bouchier-Hayes DJ. Immunonutrition and surgical practice. Proc Nutr Soc 1999;58:831-837. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 300
41. Jian ZM, Cao JD, Zhu XG, et al. The impact of alanyl-glutamine on clinical safety, nitrogen balance, intestinal permeability, and clinical outcome in postoperative patients; a randomized, double-blind, controlled study of 120 patients. J Parenter Enteral Nutr 1999;23:S62-S66. 42. Barbosa E, Moreira EA, Goes JE, Faintuch J. Pilot study with a glutaminesupplemented enteral formula in critically ill infants. Rev Hosp Clin Fac Med Sao Paulo 1999;54:21-24. 43. Castell LM, Poortmans JR, Newsholme EA. Does glutamine have a role in reducing infections in athletes? Eur J Appl Physiol Occup Physiol 1996;73:488-490. 44. Shabert JK, Wilmore DW. Glutamine deficiency as a cause of human immunodeficiency virus wasting. Med Hypotheses 1996;46:252-256. 45. Noyer CM, Simon D, Borczuk A, et al. A double-blind placebo-controlled pilot study of glutamine therapy for abnormal intestinal permeability in patients with AIDS. Am J Gastroenterol 1998;93:972-975. 46. Clark RH, Feleke G, Din M, et al. Nutritional treatment for acquired immunodeficiency virus-associated wasting using beta-hydroxy beta-methylbutyrate, glutamine, and arginine: a randomized, double-blind, placebo-controlled study. J Parenter Enteral Nutr 2000;24:133-139. 47. Klimberg VS, McClellan JL. Glutamine, cancer, and its therapy. Am J Surg 1996;172:418-424. 48. Ollenschlager G, Simmel A, Roth E. Availability of glutamine from peptides and acetylglutamine for human tumor-cell cultures. Metabolism 1989;38:S40-S42. 49. Moyer MP, Armstrong A, Aust JB, et al. Effects of gastrin, glutamine, and somatostatin on the in vitro growth of normal and malignant human gastric mucosal cells. Arch Surg 1986;121:285-288. 50. Fahr MJ, Kombluth J, Blossom S, et al. Harry M. Vars Research Award. Glutamine enhances immunoregulation of tumor growth. J Parenter Enteral Nutr 1994;18:471-476. 51. van der Hulst RR, yon Meyenfeldt MF, Deutz NE, Soeters PB. Glutamine extraction by the gut is reduced in patients with depleted gastrointestinal cancer. Ann Surg 1997;225:112-121. 52. Daniele B, Perrone F, Gallo C, et al. Oral glutamine in the prevention of fluorouracil induced intestinal toxicity: a double blind, placebo controlled, randomised trial. Gut 2001;48:28-33.
301
53. Yoshida S, Matsui M, Shirouzu Y, et al. Effects of glutamine supplements and radiochemotherapy on systemic immune and gut barrier function in patients with advanced esophageal cancer. Ann Surg 1998;227:485-491. 54. Anderson PM, Ramsay NK, Shu XO, et al. Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant 1998;22:339-344. 55. Brown SA, Goringe A, Fegan C, et al. Parenteral glutamine protects hepatic function during bone marrow transplantation. Bone Marrow Transplant 1998;22:281-284. 56. Ziegler TR, Bye RK, Persinger RL. Effects of glutamine supplementation on circulating lymphocytes after bone marrow transplantation: a pilot study. Am J Med Sci 1998;315:4-10. 57. Coghlin Dickson TM, Wong RM, Offrin RS, et al. Effect of oral glutamine supplementation during bone marrow transplantation. J Parenter Enteral Nutr 2000;24:61-66. 58. Schloerb PR, Skikne BS. Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study. J Parenteral Enteral Nutr 1999;23:117122.
L-Tyrosine 53 Studies
1. Kearns LR, Phillips MC, Ness-Abramof R, et al: Update on parenteral amino acids. Nutr Clin Pract 16:219-225, 2002 2. Moller N, Meek S, Bigelow M, et al: The kidney is an important site for in vivo phenylalanine-to-tyrosine conversion in adult humans: A metabolic role of the kidney. Proc Natl Acad Sei USA 97:1242-1246, 2000 3. Panel on Macronutrients, Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes: Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids (Macronutrients). Food and Nutrition Board, Institute of Medicine, National Academy Press, Washington DC, 2002 4. Basile-Filho A, El-Khoury AE, Beaumier L, et al: Continuous 24-h L-[1-^sup 13^C] phenylalanine and L-[3, 3-^sup 2^H^sub 2^] tyrosine oral-tracer studies at an intermediate phenylalanine intake to estimate requirements in adults. Am J CHn Nutr 65:473-488, 1998 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 302
5. Im HA, Meyer PD, Stegink LD: N-acetyl-L-tyrosine as a tyrosine source during total parenteral nutrition in adult rats. Pediatr Res 19:514-518, 1985 6. Frst P: New developments in glutamine delivery. J Nutr 131: 2562S-2568S, 2001 7. Heird WC, Dell RB, Helms RA, et al: Amino acid mixture designed to maintain normal plasma amino acid patterns in infants and children requiring parenteral nutrition. Pediatrics 80:401-408, 1987 8. Heird WC, Hay W, Helms RA, et al: Pediatric parenteral amino acid mixture in low birth weight infants. Pediatrics 81:41-50, 1988 9. Christensen ML, Helms RA, Veal DF, et al: Clearance of N-acetyl-L-tyrosine in infants receiving a pediatrie amino acid solution. Clin Pharmacol 12:606-609, 1993 10. Van Goudoever JB, Sulkers EJ, Timmerman M, et al: Amino acid solutions for premature neonates during the first week of life: The role of N-acetyl-L-cysteine and Nacetyl-L-tyrosine. JPEN 18:404-408, 1994 11. Druml W, Hubl W, Roth E, et al: Utilization of tyrosine-containing dipeptides and Nacetyl-tyrosine in hepatic failure. Hepatology 21:923-928, 1985 12. Druml W, Roth E, Lenz K, et al: Phenylalanine and tyrosine metabolism in renal failure: Dipeptides as tyrosine source. Kidney Int 27:8282-8286, 1989 13. Druml W, Lochs H, Roth E, et al: Utilization of tyrosine dipeptides and acetyltyrosine in normal and uremic humans. Am J Physiol 260:E280-E285, 1991 14. Magnusson I, Ekman L, Wangdahl M, et al: N-acetyl-L-tyrosine and N-acetyl-Lcysteine as tyrosine and cysteine precursors during intravenous infusion in humans. Metabolism 38:957-961, 1989 15. Gazzaniga AB, Waxman K, Day AT, et al: Nitrogen balance in adult hospitalized patients with the use of a pediatrie amino acid model. Arch Surg 123:1275-1279, 1988 16. Ogwu V, Cohen G: A simple colorimetric method for the simultaneous determination of N-acetylcysteine and cysteine. Free Rad Biol Med 25:362-364, 1998 17. Robitaille L, Hoffer LJ: Measurement of branched chain amino acids in blood plasma by high-performance liquid chromatography. Can J Physiol Pharmacol 66:613-617, 1988 18. Mackenzie TA, Clark NG, Bistrian BR, et al: A simple method for estimating nitrogen balance in hospitalized patients: A review and supporting data for a previously proposed technique. J Am Coll Nutr 4:575-581, 1985
303
19. Venta R: Year-long validation study and reference values for urinary amino acids using a reversed-phase HPLC method. Clin Chem 47:575-583, 2001 20. Rudman D, Kutner M, Ansley J, et al: Hypotyrosinemia, hypocystinemia, and failure to retain nitrogen during total parenteral nutrition of cirrhotic patients. Gastroenterology 81:1025-1035, 1981 21. Garibotto G, Tessari P, Verzola D, et al: The metabolic conversion of phenylalanine into tyrosine in the human kidney: Does it have nutritional implications in renal patients? J Renal Nutr 12:8-16, 2002 22. Rieck J, Halkin H, Almog S, et al: Urinary loss of thiamine is increased by low doses of furosemide in healthy volunteers. J Lab CHn Med 134:238-243, 1999 23. Liu W, Lopez JM, VanderJagt DJ, et al: Evaluation of aminoaciduria in severely traumatized patients. Clin Chim Acta 316:123128, 2002 24. Roberts SA, Ball RO, Moore AM, et al: The effect of graded intake of glycyl-Ltyrosine on phenylalanine and tyrosine metabolism in parenterally fed neonates with an estimation of tyrosine requirement. Pediatr Res 49:111-119, 2001 25. JPEN J Parenter Enteral Nutr. 2003 Nov-Dec;27(6):419-22. N-acetyl-L-tyrosine as a tyrosine source in adult parenteral nutrition. Hoffer LJ, Sher K, Saboohi F, Bernier P, MacNamara EM, Rinzler D. 26. Am J Psychiatry. 2003 Oct;160(10):1887-9. Reduction of brain dopamine concentration with dietary tyrosine plus phenylalanine depletion: an [11C]raclopride PET study. Montgomery AJ, McTavish SF, Cowen PJ, Grasby PM. 27. Nutr Neurosci. 2003 Aug;6(4):237-46. Effects of tyrosine, phentermine, caffeine Damphetamine, and placebo on cognitive and motor performance deficits during sleep deprivation. Magill RA, Waters WF, Bray GA, Volaufova J, Smith SR, Lieberman HR, McNevin N, Ryan DH. 28. Nutr Neurosci. 2003 Aug;6(4):221-35. A comparison of tyrosine against placebo, phentermine, caffeine, and D-amphetamine during sleep deprivation. Waters WF, Magill RA, Bray GA, Volaufova J, Smith SR, Lieberman HR, Rood J, Hurry M, Anderson T, Ryan DH. 29. Awad AG. Diet and drug interactions in the treatment of mental illness a review. Can J Psychiatry. 1984;29:609-613. 30. Camacho F, Mazuecos J. Treatment of vitiligo with oral and topical phenylalanine: 6 years of experience. Arch Dermatol. 1999;135:216-217
304
31. Chakraborty DP, Roy S, Chakroborty AK. Vitiligo, psoralen, and meanogenesis: some observations and understanding. Pigment Cell Res. 1996;9(3):107-116. 32. Chiaroni P, Azorin JM, Bovier P, et al. A multivariate analysis of red blood cell membrane transports and plasma levels of L-tyrosine and L-tryptophan in depressed patients before treatment and after clinical improvement. Neuropsychobiology. 1990;23(1):1-7. 33. Deijen JB, Orlebeke JF. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull. 1994;33(3):319-323. 34. Fernstrom JD. Can nutrient supplements modify brain function? Am J Clin Nutr. 2000;71(6 Suppl):1669S-1675S. 35. Fugh-Berman A, Cott JM. Dietary supplements and natural products as psychotherapeutic agents. Psychosom Med. 1999;61:712-728. 36. Gelenberg AJ, Wojcik JD, Falk WE, et al. Tyrosine for depression: a double-blind trial. J Affect Disord. 1990;19:125-132. 37. Growdon JH, Melamed E, Logue M, et al. Effects of oral L-tyrosine administration on CSF tyrosine and homovanillic acid levels in patients with Parkinson's disease. Life Sci. 1982;30:827-832, 38. Hull KM, Maher TJ. L-Tyrosine potentiates the anorexia induced by mixed-acting sympathomimetic drugs in hyperphagic rats. J Pharmacol Exp Ther. 1990;255(2):403409. 39. Hull KM, Tolland DE, Maher TJ. L-tyrosine potentiation of opioid-induced analgesia utilizing the hot-plate test. J Pharmacol Exp Ther. 1994;269(3):1190-1195. 40. Kelly GS. Nutritional and botanical interventions to assist with the adaptation to stress. Altern Med Rev. 1999;4940;249-265. 41. Kirschmann GJ and Kirschmann JD. Nutrition Almanac, 4th ed. New York, NY: McGraw-Hill;1966:304. 42. Koch R. Tyrosine supplementation for phenylketonuria treatment. Am J Clin Nutr. 1996;64(6):974-975. 43. Menkes DB, Coates DC, Fawcett JP. Acute tryptophan depletion aggravates premenstrual syndrome. J Affect Disord. 1994;3291):37-44. 44. Meyers S. Use of neurotransmitter precursors for treatment of depression. Altern Med Rev. 2000;5(1):64-71.
305
45. Neri DF, Wiegmann D, Stanny RR, Shappell SA, McCardie A, McKay DL. The effects of tyrosine on cognitive performance during extended wakefulness. Aviat Space Environ Med. 1995;66(4):313-319. 46. Parry BL. The role of central serotonergic dysfunction in the aetiology of premenstrual dysphoric disorder: therapeutic implications. CNS Drugs. 2001;15(4):277285. 47. Pizzorno JE and Murray MT. Textbook of Natural Medicine, Vol 2. New York, NY: Churchill Livingstone; 1999:1049-1059. 48. Poustie VJ, Rutherford P. Tyrosine supplementation for phenylketonuria. Cochrane Database Syst Rev. 2000;(2):CD001507. 49. Riederer P. L-Dopa competes with tyrosine and tryptophan for human brain uptake. Nutr Metab. 1980;24(6):417-423. 50. Smith ML, Hanley WB, Clarke JT, et al. Randomised controlled trial of tyrosine supplementation on neuropsychological performance in phenylketonuria. Arch Dis Child. 1998;78(2):116-121. 51. van Spronsen FJ, van Rijn M, Bekhof J, Koch R, Smit PG. Phenylketonuria: tyrosine supplementation in phenylalanine-restricted diets. Am J Clin Nutr. 2001;73(2):153-157. 52. Wagenmakers AJ. Amino acid supplements to improve athletic performance. Curr Opin Clin Nutr Metab Care. 1999;2(6):539-544. 53. Yehuda S. Possible anti-Parkinson properties of N-(alpha-linolenoyl) tyrosine. A new molecule. Pharmacol Biochem Behav. 2002;72(1-2):7-11.
Linoleic Acid 56 Studies

1. Conjugated linoleic acid: A powerful anticarcinogen from animal fat sources. Ip C.; Scimeca J.A.; Thompson H.J. CANCER (USA) , 1994, 74/3 (1050-1054). 2. Conjugated linoleic acid and atherosclerosis in rabbits. Lee K.N.; Kritchevsky D.; Pariza M.W. Atherosclerosis (Ireland), 1994, 108/1 (19-25). 3. Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid. Chin S.F.; Storkson J.M.; Liu W.; Albright K.J.; Pariza M.W. J. NUTR. (USA) , 1994, 124/5 (694-701)
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4. Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells. Shultz TD; Chew BP; Seaman WR; Luedecke LO. Cancer Lett (NETHERLANDS) Apr 15 1992, 63 (2) p125-33, 5. Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat. Ip C; Singh M; Thompson HJ; Scimeca JA. Cancer Res (UNITED STATES) Mar 1 1994, 54 (5) p1212-5. 6. Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat. CANCER RES. (USA) , 1994, 54/5 (1212-1215) 7. Effect of cheddar cheese consumption on plasma conjugated linoleic acid concentrations in men. NUTR. RES. (USA) , 1994, 14/3 (373-386) 8. Differential stimulatory and inhibitory responses of human MCF-7 breast cancer cells to linoleic acid and conjugated linoleic acid in culture. ANTICANCER RES. (Greece), 1992, 12/6 B (2143-2145). 9. Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells. CANCER LETT. (Ireland), 1992, 63/2 (125133) 10. Inhibition of Listeria monocytogenes by fatty acids and monoglycerides. APPL. ENVIRON. MICROBIOL. (USA) , 1992, 58/2 (624-629) 11. Recognition of cervical neoplasia by the estimation of a free-radical reaction product (octadeca-9,11-dienoic acid) in exfoliated cells. CLIN. CHIM. ACTA (NETHERLANDS) , 1987, 163/2 (149-152). 12. Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection. BIOCHEM. BIOPHYS. RES. COMMUN. (USA) , 1994, 198/3 (1107-1112). 13. Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid. J. NUTR. (USA) , 1994, 124/5 (694701). 14. Conjugated linoleic acid and atherosclerosis in rabbits. ATHEROSCLEROSIS (Ireland) , 1994, 108/1 (19-25). 15. Conjugated linoleic acid is a growth factor for rats as shown by enhanced weight gain and improved feed efficiency. J. NUTR. (USA) , 1994, 124/12 (2344-2349) 16. Cows' milk fat components as potential anticarcinogenic agents. Journal of Nutrition (USA) , 1997, 127/6 (1055-1060).
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17. Effects of dietary conjugated linoleic acid on lymphocyte function and growth of mammary tumors in mice. Anticancer Research (Greece) , 1997, 17/2 A (987-993). 18. Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice. Anticancer Research (Greece) , 1997, 17/2 A (969-973).
19. Lymphatic recovery, tissue distribution, and metabolic effects of conjugated lioleic
acid in rats. Journal of Nutritional Biochemistry (USA) , 1997, 8/1 (38-43). 20. Proliferative responses of normal human mammary and MCF-7 breast cancer cells to linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture. Anticancer Research (Greece) , 1997, 17/1 A (197-203) 21. Conjugated linoleic acid modulates hepatic lipid composition in mice. Lipids (USA) , 1997, 32/2 (199-204). 22. Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion. Nutrition and Cancer (USA) , 1996, 26/2 (149-157). 23. The efficacy of conjugated linoleic acid in mammary cancer prevention is independent of the level or type of fat in the diet. Carcinogenesis (United Kingdom) , 1996, 17/5 (1045-1050). 24. Dietary modifiers of carcinogenesis. Environmental Health Perspectives (USA) , 1995, 103/SUPPL. 8 (177-184). 25. Effects of C18 fatty acid isomers on DNA synthesis in hepatoma and breast cancer cells. Anticancer Research (Greece) , 1995, 15/5 B (2017-2021). 26. Effect of timing and duration of dietary conjugated linoleic acid on mammary cancer prevention. Nutrition and Cancer (USA) , 1995, 24/3 (241-247). 27. The role of phenolics, conjugated linoleic acid, carnosine, and pyrroloquinoline quinone as nonessential dietary antioxidants. Nutrition Reviews (USA) , 1995, 53/3 (4958). 28. Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atharosclerosis in hypercholasterolemic hamsters. Artery (USA) , 1997, 22/5 (266-277). 29. Cesano A, Visonneau S, Scimeca JA, et al. Opposite effects of linoleic acid and conjugated linoleic acid on human prostatic cancer in SCID mice. Anticancer Res 1998;18(3A):142934. 30. Thompson H, Zhu Z, Banni S, et al. Morphological and biochemical status of the mammary gland as influenced by conjugated linoleic acid: implication for a reduction in Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 308
mammary cancer risk. Cancer Res 1997;57:506772. 31. Ip C. Review of the effects of trans fatty acids, oleic acid, n-3 polyunsaturated fatty acids, and conjugated linoleic acid on mammary carcinogenesis in animals. Am J Clin Nutr 1997;66(suppl):1523S29S [review]. 32. Parodi PW. Cows' milk fat components as potential anticarcinogenic agents. J Nutr 1997;127:105560 [review]. 33. West DB, Delany JP, Camet PM, et al. Effects of conjugated linoleic acid on body fat and energy metabolism in the mouse. Am J Physiol 1998;275:R66772. 34. Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic acid on body composition in mice. Lipids 1997;32:85358. 35. Sugano M, Tsujita A, Yamasaki M, et al. Conjugated linoleic acid modulates tissue levels of chemical mediators and immunoglobulins in rats. Lipids 1998;33:52127. 36. Nicolosi RJ, Rogers EJ, Kritchevsky D, et al. Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atherosclerosis in hypercholesterolemic hamsters. Artery 1997;22:26677. 37. Lee KN, Kritchevsky D, Pariza MW, et al. Conjugated linoleic acid and atherosclerosis in rabbits. Atherosclerosis 1994;108:1925. 38. Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et al. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys Res Commun 1998;244:67882. 39. Herbel BK, McGuire MK, McGuire MA, et al. Safflower oil consumption does not increase plasma conjugated linoleic acid concentrations in humans. Am J Clin Nutr 1998;67:33237. 40. Thom E. A pilot study with the aim of studying the efficacy and tolerability of Tonalin CLA on the body composition in humans. Medstat Research Ltd., Lillestrom, Norway, July 1997[unpublished]. 41. Banni S, Angioni E, Stefania M, et al. Conjugated linoleic acid and oxidative stress. J Am Oil Chem Soc. 1998; 75:261-267. 42. Belury MA. Conjugated linoleate: a polyunsaturated fatty acid with unique chemopreventive properties. Nutr Rev. 1995; 53:83-89.
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43. Cesano A, Visonneau S, Scimeca JA, et al. Opposite effects of linoleic acid and conjugated linoleic acid on human prostate cancer in SCID mice. Anticanc Res. 1998; 18:833-38. 44. de Deckere EA, van Amelsvoort JM, Mc Neill GP, Jones P. Effects of conjugated linoleic acid (CLA) isomers on lipid levels and peroxisome proliferation in the hamster. Br J Nutr. 1999; 82:309-17. 45. Gavino VC, Gavino G, Leblanc MJ, Tuchweber B. An isomeric mixture of conjugated linoleic acids but not pure cis-9, trans-11-octadecadienoic acid affects body weight gain and plasma lipids in hamsters. J Nutr. 2000; 130:27-29. 46. Houseknecht KL, Vanden Heuvel JP, Moya-Camarena SY, et al. Dietary conjugated linoleic acid normalizes impaired glucose tolerance in the Zucker diabetic fatty fa/fa rat. Biochem Biophys Res Commun. 1998; 244:678-682. 47. Lee KN, Pariza MW, Ntambi JM. Conjugated linoleic acid decreases hepatic stearoyl-CoA desaturase mRNA expression. Biochem Biophys Res Commun. 1998; 248:817-821. 48. McCarty MF. Downregulaton of macrophage activation by PPAR gamma suggests a role for conjugated linoleic acid in prevention of Alzheimer's disease. J Med Food. 1998; 1:217-226. 49. Moya-Camarena SY, Belury MA. Species differences in the metabolism and regulation of gene expression by conjugated linoleic acid. Nutr Rev. 1999; 57:336-340. 50. Ostrowski E, Muralitharan M, Cross RF. Dietary conjugated linoleic acids increase lean tissue and decrease fat deposition in growing pigs. J Nutr. 1999; 129:2037-2042. 51. Pariza MW, Park Y, Cook ME. Mechanisms of action of conjugated linoleic acid: evidence and speculation. Proc Soc Exp Biol Med. 2000; 223: 8-13. 52. Pariza MW, Parks Y, Cook ME. Conjugated linoleic acid and the control of cancer and obesity. Toxicol Sci. 1999; 51 (2 Suppl):107-110. 53. Pariza MW, Park Y, Kim S, et al. Mechanism of body fat reduction by conjugated linoleic acid. FASEB J. 1997; 11:A139. 54. Park Y, Albright KJ, Liu W, et al. Effect of conjugated linoleic acid on body composition in mice. Lipids. 1997; 32:853-858. 55. van den Berg JJ, Cook NE, Tribble DL. Reinvestigation of the antioxidant properties of conjugated linoleic acid. Lipids. 1995; 30:599-605.
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56. Yurawecz MP, Mossoba MM, Kramer JKG, Pariza MW, Nelson GJ, eds. Advances in Conjugated Linoleic Acid Research. Volume 1. Champaign, IL: AOCS Press; 1999.
Linolenic Acid 10 Studies

1. Botha JH, Robinson KM, Leary WP. The response of human carcinoma cell lines to gamma-linolenic acid with special reference to the effects of agents which influence prostaglandin and thromboxane syntheses. Prostaglandins Leukot Med. 1985; 19:63-77. 2. de Antueno R, Elliot M, Ells G, et al. In vivo and in vitro biotransformation of the lithium salt of gamma-linolenic acid by three human carcinomas. Br J Cancer. 1997; 75:1812-1818. 3. Fearon KC, Falconer JS, Ross JA, et al. An open-label phase I/II dose escalation study of the treatment of pancreatic cancer using lithium gammalinolenate. Anticancer Res. 1996; 16; 867-874. 4. Ferguson PJ. Synergistic cytotoxicity between gamma-linolenic acid and the flavonoid naringenin against a human oral squamous carcinoma cell line (Meeting abstract). Proc Annu Meet Am Assoc Cancer Res. 1997; 38:A2148. 5. Ilc K, Ferrero JM, Fischel JL, et al. Cytotoxic effects of two gamma linolenic salts (lithium gammalinolenate or meglumine gammalinolenate) alone or associated with a nitrosourea: an experimental study on human glioblastoma cell lines. Anticancer Drugs. 1999; 10:413-417. 6. Kairemo KJ, Jekunen AP, Korppi-Tommola ET, Pyrhonen SO. The effect of lithium gamma-linolenate therapy of pancreatic cancer on perfusion in liver and pancreatic tissues. Pancreas. 1998; 16:105-106. 7. Kinchington D, Randall S, Winther M, Horrobin D. Lithium gamma-linolenateinduced cytotoxicity against cells chronically infected with HIV-1. FEBS Lett. 1993; 330:219-221. 8. Ravichandran D, Cooper A, Johnson CD. Effect of lithium gamma-linoenate on the growth of experimental human pancreatic carcinoma. Br J Surg. 1998; 85:1201-1205. 9. Ravichandran D, Cooper A, Johnson CD. Growth inhibitory effect of lithium gammalinolenate on pancreatic cancer cell lines: the influence of albumin and iron. Eur J Cancer. 1998; 34:188-192.
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10. Seegers JC, Lotterling ML, Panzer A, et al. Comparative anti-mitotic effects of lithium gamma-linolenate, gamma-linolenic acid and arachidonic acid, on transformed and embryonic dells. Prostaglandins Leukot Essent Fatty Acids. 1998; 59:285-291.
Caprylic Acid - 9 Studies

1. Abate MA, Moore TL. Monooctanin use for gallstone dissolution. Drug Intell Clin Pharm. 1985; 19:708-713. 2. Kabara JJ. Fatty acids and derivatives as antimicrobial agents. In: Kabara JJ, ed. The Pharmacological Effect of Lipids I. Champaign, IL: American Oil Chemists' Society; 1978; 1-14. 3. Wyss O, Ludwig BJ, Joiner RR. The fungistatic and fungicidal action of fatty acids and related compounds. Arch Biochem. 1943;7,415. 4. Effect of Caprylic Acid on Performance and Mortality of Growing Rabbits.Skivanov V., M. Marounek: Effect of Caprylic Acid on Performance and Mortality of Growing Rabbits. Acta Vet. Brno 71, 2002: 435-439. 5. Enig MG. Lauric Oils as Antimicrobial Agents: Theory of Effect, Scientific Rationale, and Dietary Application as Adjunct Nutritional Support for HIV-Infected Individuals. in Watson R ed. Food and Nutrients in AIDS. CRC Press. Florida, pp81-97. 1999. 6. Isaacs CE, Kim KS and Thormar H. Inactivation of Enveloped Viruses in Human Bodily Fluids by Purified Lipids. Annal NY Acad Sci. 724: 457. 1994. 7. Sadeghi S et al. Dietary Lipids Modify the Cytokine Response to Bacterial Lipopolysaccharide in Mice. Immunology. 96(3): 404-10. 1999. 8. J Dairy Sci. 2005 Oct;88(10):3488-95. Antibacterial effect of caprylic acid and monocaprylin on major bacterial mastitis pathogens. Nair MK, Joy J, Vasudevan P, Hinckley L, Hoagland TA, Venkitanarayanan KS. Department of Animal Science, Unit 4040, University of Connecticut, Storrs 06269, USA. 9. Final report of the safety assessment for Caprylic/Capric Triglyceride.Anonymous J ENV PATH TOX Vol:4, 4 (1980) pp 105-20.
Glycerophosphorylcholine 11 Studies
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1. Pflgers Archiv European Journal of Physiology (Historical Archive). Publisher: Springer-Verlag GmbH. ISSN: 0031-6768 (Paper) 1432-2013 (Online) DOI: 10.1007/BF00583795. Issue: Volume 409, Numbers 4-5. Date:August 1987. Pages: 411 - 415 2. Transport Processes, Metabolism and Endocrinology; Kidney, Gastrointestinal Tract, and Exocrine Glands. Role and regulation of glycerophosphorylcholine in rat renal papilla. Gabriele Wirthensohn, Franz-X. Beck and Walter G. Guder. Biochim Biophys Acta. 1993 Jul 25;1150(1):25-34.Metabolism of the 'organic osmolyte' glycerophosphorylcholine in isolated rat inner medullary collecting duct cells. II. Regulation by extracellular osmolality. Bauernschmitt HG, Kinne RK. 3. Biochim Biophys Acta. 1985 Jan 9;833(1):111-8. 1-O-alkyl-2-acyl-sn-glycero-3phosphorylcholine is the precursor of platelet-activating factor in stimulated rabbit platelets. Evidence for an alkylacetyl-glycerophosphorylcholine cycle. Touqui L, Jacquemin C, Dumarey C, Vargaftig BB. 4. Biochim Biophys Acta. 1982 Mar 12;710(3):370-6. Phosphatidylcholine of blood lipoprotein is the precursor of glycerophosphorylcholine found in seminal plasma. Hammerstedt RH, Rowan WA. 5. Med Biol. 1985;63(2):81-7. Impaired glycerophosphorylcholine synthesis in murine muscular dystrophy. Infante JP.
6. FEBS Lett. 1985 Jul 8;186(2):205-10. Defective synthesis of glycerophosphorylcholine in murine muscular dystrophy; the primary molecular lesion? Infante JP.
7. Dev Neurosci. 1989;11(1):26-9. Regional and developmental estimations of glycerophosphorylcholine phosphodiesterase activities in rat brain. Kanfer JN, McCartney DG.
8. J Parasitol. 1995 Jun;81(3):335-40. Glycerophosphorylcholine, a component of both Ascaris suum muscle and Caenorhabditis elegans. Arevalo JI, Saz HJ, Nowak T, Larry JP.
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9. Kidney Cell Survival in High Tonicity - osmotic regulation of GPC: choline phosphodiesterase.Handler J.S.1; Kwon H.M. Comparative Biochemistry and Physiology -- Part A: Physiology, Volume 117, Number 3, July 1997, pp. 301306(6). Elsevier Science.
10. Glycerophosphorylcholine phosphocholine phosphodiesterase activity in cultured oligodendrocytes, astrocytes, and central nervous tissue of dysmyelinating rodent mutants. J. Yuan, D. G. McCartney, M. Monge, A. Espinosa de Los Monteros, B. Zalc, J. de Vellis, J. N. Kanfer. Journal of Neuroscience Research. Volume 31, Issue 1, 1992. Pages 68-74
Phosphatidylserine 13 Studies
1. Amaducc L, SMID Group. Phosphatidylserine in the treatment of Alzheimer's disease. Results of a multicenter study. Psychopharmacol Bull. 1988; 24:130-134. 2. Baer E, Maurukas J. Phosphatidyl serine. J Biol Chem. 1955; 212:25-38. 3. Blokland A, Honig W, Brouns F, Jolles J. Cognition-enhancing properties of subchronic phosphatidylserine (PS) treatment in middle-aged rats: comparison of bovine cortex PS with eggs PS and soybean PS. Nutr. 1999; 15: 778-783. 4. Casamenti F, Scali C, Pepeu G. Phosphatidylserine reverses the age-development decrease in cortical acetylcholine release: a microdialysis study. Eur J Pharmac. 1991; 194:11-16. 5. Crook T, Petrie W, Wells C, et al. Effects of phosphatidylserine in Alzheimer's disease. Psychopharmacol Bull. 1992; 28:61-66. 6. Crook TH, Tinklenberg J, Yesavage J, et al. Effects of phosphatidylserine in ageassociated memory impairment. Neurol. 1991; 41:644-649. 7. Folch J. Brain cephalin, a mixture of phosphatides. Separation from it of phosphatidyl serine, phosphatidyl ethanolamine, and a fraction containing an inositol phosphatide. J Biol Chem. 1942; 146:35-41. 8. Monteleleone P, Maj M, Reinat L, et al. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J Pharmacol. 1992; 41:385-388.
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9. Nunzi MG, Milan F, Guidolin D, Toffano G. Dendritic spine loss in hippocampus of aged rats. Effect of brain phosphatidylserine. Neurobiol Aging. 1987; 8:501-510. 10. Pepeu G, Marconcini Pepeu I, Amaducc L. A review of phosphatidylserine pharmacological and clinical effects. Is phosphatidylserine a drug for the ageing brain? Pharmacol Res. 1996; 33:73-80. 11. Phosphatidylserine- a novel pharmacological approach to brain ageing. Clin Trials J. 1987; 24:1-130. 12. Villardita C, Grioli S, Salmeri G, et al. Multicentre clinical trial of brain phophatidylserine in elderly patients with intellectual deterioration. Clinic Trials J. 1987; 24:84-93. 13. Zanott A, Valzelli L, Toffano G. Chronic phosphatidylserine treatment improves spatial memory and passive avoidance in aged rats. Psychopharmacol. 1989; 99:316-321.
Pregenolone -23 Studies

1. Sahelian, Ray, M.D. Pregnenolone: Nature's Feel Good Hormone. (Garden City Park, New York: Avery Publishing Group, 1997), 57. 2. Roberts, E. (1995) "Pregnenolone-From Selye to Alzheimer and a Model of the Pregnenolone Sulfate Binding Binding Site on the GABAA Receptor," Biochemical Pharmacology 49:1 (1995): 1-16. 3. Regelson, William, M.D., and Carol Colman, The Super-Hormone Promise: Nature's Antidote to Aging. (New York: Pocket Books, 1996), 79. 4. Young, D. Gary, Pregnenolone: A Radical New Approach to Health, Longevity, and Emotional Well-Being. (Salem, Utah: Essential Science Publishing, 2000), 21. 5. Lee, John R., M.D. "Natural" vs. "Synthetic" Hormones, A Question of Semantics. (3 July 1998). 6. Flood, et al., "Memory-enhancing effects in male mice of pregnenolone and steroids metabolically derived from it." Proc Natl Acad Sci USA, (Mar 1, 1992): 1567-71. 7. Mathis, C, et al., "The neurosteroid pregnenolone sulfate blocks NMDA antagonistinduced deficits in a passive avoidance memory task." Psychopharmacology (Berl). (Oct. 1993): 201-6.
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8. Flood JF, et al., "Age related decrease of plasma testosterone in SAMPX mice: replacement improved age related impairment of learning and memory." Physiol Behav (Apr 1995): 669-73. 9. Rebel, P et al., "Biosynthesis and assay of neurosteroid in rats and mice: functional correlates." J Steroid Biochem Mol Biol, (June 1995), 355-60. 10. George, MS et al., "CSF neuroactive steroids in affective disorders: pregnenolone. progesterone, and DBI." Biol Psychiatry, (May 1994), 775-80. 11. Guth et al.. "Key role for pregnenolone in combination therapy that promotes recovery after spinal cord injury." Proc Natl Acad Sci USA (Dec 6, 1994), 12308-12. 12. Shiraki M1 et al., "The effect of estrogen and sex steroids and thyroid hormone preparation on bone mineral density in senile osteoporosis--a comparative study of the effect of 1 alphahydroxycholecalciferol on senile osteoporosis." Nippon Naibunpi Gakkai Zasshi (Feb 199 1)84-95. 13. Sahelian, Ray, MD, pregnenolone: A Practical Guide Melatonin/DHEA Research. 14. 1. Akwa Y, Young J, Kabbadj K, et al. Neurosteroids: biosynthesis, metabolism and function of pregnenolone and dehydroepiandrosterone in the brain. J Steroid Biochem Mol Biol. 1991;40(1-3):71-81. 15. Havlikova H, Hill M, Hampl R, Starka L. Sex- and age-related changes in epitestosterone in relation to pregnenolone sulfate and testosterone in normal subjects. J Clin Endocrinol Metab. 2002 May;87(5):2225-31. 16. Araghiniknam M, Chung S, Nelson-White T, Eskelson C, Watson RR. Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans. Life Sci. 1996;59(11):L147-57. 17. Darnaudery M, Pallares M, Piazza PV, Le Moal M, Mayo W. The neurosteroid pregnenolone sulfate infused into the medial septum nucleus increases hippocampal acetylcholine and spatial memory in rats. Brain Res. 2002 Oct 4;951(2):237-42. 18. Mayo W, Lemaire V, Malaterre J, et al. Pregnenolone sulfate enhances neurogenesis and PSA-NCAM in young and aged hippocampus. Neurobiol Aging. 2005 Jan;26(1):10314. 19. Jaliffa CO, Howard S, Hoijman E, et al. Effect of neurosteroids on the retinal gabaergic system and electroretinographic activity in the golden hamster. J Neurochem. 2005 Jul 11. 20. Roberts E. Pregneolonefrom Selye to Alzheimer and a model of the pregnenolone sulfate binding site on the GABAA receptor. Biochem Pharmacol. 1995 Jan 6;49(1):1-16. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 316
21. McGavack TH, Chevalley J, Weissberg J. The use of delta 5-pregnenolone in various clinical disorders. J Clin Endocrinol Metab. 1951 Jun;11(6):559-77. 22. Dzugan SA, Arnold SR. Hypercholesterolemia treatment: a new hypothesis or just an accident? Med Hypotheses. 2002 Dec;59(6):751-6. 23.George MS, Guidotti A, Rubinow D, Pan B, Mikalauskas K, Post RM. CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI. Biol Psychiatry. 1994 May 15;35(10):775-80.
Benfotiamine 32 Studies
1. Stracke H, Lindemann A, Federlin K. A benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes. 1996;104(4):311-6. 2. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9. Epub 2003 Feb 18. 3. Hammes HP, Du X, Edelstein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar;9(3):294-9. 4. 1. Bitsch R, Wolf M, Mller J. Bioavailability assessment of the lipophilic benfotiamine as compared to a water-soluble thiamin derivative. Ann Nutr Metab 1991;35(2):292-6. 5. Schreeb KH, Freudenthaler S, Vormfelde SV, et al. Comparative bioavailability of two vitamin B1 preparations: benfotiamine and thiamine mononitrate. Eur J Clin Pharmacol 1997; 52(4):319-20. 6. Loew D. Pharmacokinetics of thiamine derivatives especially of benfotiamine. Int J Clin Pharmacol Ther 1996;34(2):47-50. 7. Frank T, Bitsch R, Maiwald J, Stein G. High thiamine diphosphate concentrations in erythrocytes can be achieved in dialysis patients by oral administration of benfontiamine. Eur J Clin Pharmacol. 2000;56(3):251-7.
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8. Pike RL, Brown ML. Nutrition, An Integrated Approach, 3rd Ed. New York:MacMillan; 1986:467. 9. Hammes H-P, Du X, Edlestein D, et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic neuropathy. Nat Med 2003;9(3):294-99. 10. Monnier VM, Kohn RR, Cerami A. Accelerated age-related browning of human collagen in diabetes mellitus. Proc Natl Acad Sci 1984;81(2):583-7. 11. Brownlee M. The pathological implications of protein glycation. Clin Invest Med 1995;18(4):275-81. 12. Pomero F, Molinar Min A, La Selva M, et al. Benfotiamine is similar to thiamine in correcting endothelial cell defects induced by high glucose. Acta Diabetol 2001;38(3):135-8. 13. Stracke H, Hammes HP, Werkman D, et al. Efficacy of benfotiamine versus thiamine on function and glycation products of peripheral nerves in diabetic rats. Exp Clin Endocrinol Diabetes 2001;109(6):300-6. 14. Babaei-Jadidi R, Karachalias N, Ahmed N, et al. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Diabetes 2003;52(8):2110-20. 15. Bergfeld R, MatsumaraT, Du X, Brownlee M. Benfotiamin prevents the consequences of hyperglycemia induced mitochondrial overproduction of reactive oxygen specifies and experimental diabetic neuropathy (Abstract) Diabetologia 2001; 44(Suppl1):A39. 16. 1996 Feb; 34(2): 47-50. Loew D. Pharmacokinetics of thiamine derivatives especially of Benfotiamine. Int J Clin Pharmacol Ther. 17. Stracke H, Lindemann A, Federlin K. A Benfotiamine-vitamin B combination in treatment of diabetic polyneuropathy. Exp Clin Endocrinol Diabetes 1996; 104(4): 3116. 18. Lin J, Alt A, Liersch J, Bretzel RG, Brownlee MA, Hammes HP. Benfotiamine inhibits intracellular formation of advanced glycation endproducts in vivo. Diabetes. 2000 May; 49(Suppl1): A143 (P583).
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19. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Nat Med. 2003 Mar; 9(3): 294-9. 20. Winkler G, Pal B, Nagybeganyi E, Ory I, Porochnavec M, Kempler P. Effectiveness of different Benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung. 1999 Mar; 49(3): 220-4. 21. Koltai MZ. Prevention of cardiac autonomic neuropathy in dogs with Benfotiamine. In Gries FA, Federlin K. Benfotiamine in the Therapy of Polyneuropathy. New York: Georg Thieme Verlag, 1998; 45-9. 22. Ann N Y Acad Sci. 2005 Jun;1043:784-92. Inhibitors of advanced glycation end product formation and neurovascular dysfunction in experimental diabetes. Cameron NE, Gibson TM, Nangle MR, Cotter MA. School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK. n.e.cameron@abdn.ac.uk 23. High-dose thiamine therapy counters dyslipidemia and advanced glycation of plasma protein in streptozotocin-induced diabetic rats. Karachalias N, Babaei-Jadidi R, Kupich C, Ahmed N, Thornalley PJ.Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, UK. thorp@essex.ac.uk. 24. Curr Drug Targets. 2005 Jun;6(4):453-74. The role of AGEs and AGE inhibitors in diabetic cardiovascular disease. Thomas MC, Baynes JW, Thorpe SR, Cooper ME. 25. Clin Lab. 2005;51(5-6):257-73. Mutations in the transketolase-like gene TKTL1: clinical implications for neurodegenerative diseases, diabetes and cancer. Coy JF, Dressler D, Wilde J, Schubert P.R-Biopharm AG, Landwehrstrasse 54, 64293 Darmstadt, Germany. j.coy@r-biopharm.de 26. Int J Clin Pharmacol Ther. 2005 Feb;43(2):71-7. Erratum in: Int J Clin Pharmacol Ther. 2005 Jun;43(6):304. Benfotiamine in the treatment of diabetic polyneuropathy--a three-week randomized, controlled pilot study (BEDIP study). Haupt E, Ledermann H, Kopcke W. Saale-Klinik, Bad Kissingen, Lindenfels, Germany. BfA.Saaleklinik@tonline.de 27. Diabetologia. 2004 Dec;47(12):2235-46. Epub 2004 Dec 11. High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats.Babaei-Jadidi R, Karachalias N, Kupich C, Ahmed N, Thornalley PJ.Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex, CO4 3SQ, UK. 28. Diabetes Metab Res Rev. 2004 Jul-Aug;20(4):330-6. Thiamine and benfotiamine prevent increased apoptosis in endothelial cells and pericytes cultured in high glucose.
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Beltramo E, Berrone E, Buttiglieri S, Porta M. Department of Internal Medicine, University of Turin, Italy. elena.beltramo@unito.it 29. Diabetes. 2003 Aug;52(8):2110-20. Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine. Babaei-Jadidi R, Karachalias N, Ahmed N, Battah S, Thornalley PJ. Department of Biological Sciences, University of Essex, Central Campus, Wivenhoe Park, Colchester, Essex, UK. 30. Nat Med. 2003 Mar;9(3):294-9. Epub 2003 Feb 18. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents experimental diabetic retinopathy. Hammes HP, Du X, Edelstein D, Taguchi T, Matsumura T, Ju Q, Lin J, Bierhaus A, Nawroth P, Hannak D, Neumaier M, Bergfeld R, Giardino I, Brownlee M. Medical Clinic V, School of Clinical Medicine, Mannheim, Germany. 31. Eksp Klin Farmakol. 2002 Jul-Aug;65(4):37-41. [The immunometaboic effects of benfotiamine and riboxine on hemolytic anemia] [Article in Russian] Uteshev BS, Lazareva GA, Prokopenko LG.Pharmacology Department, State Medical University, ul. Ostrovityanova 1, Moscow, 117437 Russia. 32. MMW Fortschr Med. 2001 Apr 19;143(16):53. [Chronic alcohol abuse. Benfotiamine in alcohol damage is a must] [Article in German] Ayazpoor U.
SUPER ANTIOXIDANTS Vitamin A 41 STUDIES

1. Groff JL. Advanced Nutrition and Human Metabolism. 2nd ed. St Paul: West Publishing; 1995. 2. Ross AC. Vitamin A and retinoids. In: Shils M, ed. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:305-327. 3. Semba RD. The role of vitamin A and related retinoids in immune function. Nutr Rev. 1998;56(1 Pt 2):S38-48.
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4. Semba RD. Impact of vitamin A on immunity and infection in developing countries. In: Bendich A, Decklebaum RJ, eds. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2nd ed. Totowa: Humana Press Inc; 2001:329-346. 5. McCullough, F. et al. The effect of vitamin A on epithelial integrity. Proceedings of the Nutrition Society. 1999; volume 58: pages 289-293. (PubMed) 6. Olson JA. Vitamin A. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed. Washington D.C.: ILSI Press; 1996:109-118. 7. Lynch SR. Interaction of iron with other nutrients. Nutr Rev. 1997;55(4):102-110. (PubMed) 8. Brody T. Nutritional Biochemistry. 2nd ed. San Diego: Academic Press; 1999. 9. Russell RM. The vitamin A spectrum: from deficiency to toxicity. Am J Clin Nutr. 2000;71(4):878-884. (PubMed) 10. Christian P, West KP, Jr. Interactions between zinc and vitamin A: an update. Am J Clin Nutr. 1998;68(2 Suppl):435S-441S. (PubMed) 11. Suharno D, West CE, Muhilal, Karyadi D, Hautvast JG. Supplementation with vitamin A and iron for nutritional anaemia in pregnant women in West Java, Indonesia. Lancet. 1993;342(8883):1325-1328. (PubMed) 12. Underwood BA, Arthur P. The contribution of vitamin A to public health. FASEB J. 1996;10(9):1040-1048. (PubMed) 13. Semba RD. Vitamin A and human immunodeficiency virus infection. Proc Nutr Soc. 1997;56(1B):459-469. 14. Field CJ, Johnson IR, Schley PD. Nutrients and their role in host resistance to infection. J Leukoc Biol. 2002;71(1):16-32. (PubMed) 15. West CE. Vitamin A and measles. Nutr Rev. 2000;58(2 Pt 2):S46-54. 16. Semba RD, Miotti PG, Chiphangwi JD, et al. Maternal vitamin A deficiency and mother-to-child transmission of HIV-1. Lancet. 1994;343(8913):1593-1597. (PubMed) 17. Thurnham DI, Northrop-Clewes CA. Optimal nutrition: vitamin A and the carotenoids. Proc Nutr Soc. 1999;58(2):449-457. (PubMed) 18. Food and Nutrition Board, Institute of Medicine. Vitamin A. Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington D.C.: National Academy Press; 2001:65-126. (National Academy Press) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 321
19. Comstock GW, Helzlsouer KJ. Preventive nutrition and lung cancer. In: Bendich A, Decklebaum RJ, eds. Preventive Nutrition: The Comprehensive Guide for Health Professionals. 2nd ed. Totowa: Humana Press Inc; 2001:97-129. 20. Omenn GS, Goodman GE, Thornquist MD, et al. Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease. N Engl J Med. 1996;334(18):1150-1155. (PubMed) 21. Prakash P, Krinsky NI, Russell RM. Retinoids, carotenoids, and human breast cancer cell cultures: a review of differential effects. Nutr Rev. 2000;58(6):170-176. (PubMed) 22. Bohlke K, Spiegelman D, Trichopoulou A, Katsouyanni K, Trichopoulos D. Vitamins A, C and E and the risk of breast cancer: results from a case-control study in Greece. Br J Cancer. 1999;79(1):23-29 (PubMed) 23. Franceschi S. Micronutrients and breast cancer. Eur J Cancer Prev. 1997;6(6):535539. (PubMed) 24. Longnecker MP, Newcomb PA, Mittendorf R, Greenberg ER, Willett WC. Intake of carrots, spinach, and supplements containing vitamin A in relation to risk of breast cancer. Cancer Epidemiol Biomarkers Prev. 1997;6(11):887-892. (PubMed) 25. Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int J Cancer. 2001;91(4):563-567. (PubMed) 26. Zhang S, Hunter DJ, Forman MR, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;91(6):547-556. (PubMed) 27. Ching S, Ingram D, Hahnel R, Beilby J, Rossi E. Serum levels of micronutrients, antioxidants and total antioxidant status predict risk of breast cancer in a case control study. J Nutr. 2002;132(2):303-306. (PubMed) 28. Dorgan JF, Sowell A, Swanson CA, et al. Relationships of serum carotenoids, retinol, alpha-tocopherol, and selenium with breast cancer risk: results from a prospective study in Columbia, Missouri (United States). Cancer Causes Control. 1998;9(1):89-97. (PubMed) 29. Hulten K, Van Kappel AL, Winkvist A, et al. Carotenoids, alpha-tocopherols, and retinol in plasma and breast cancer risk in northern Sweden. Cancer Causes Control. 2001;12(6):529-537. (PubMed) 30. van Soest S, Westerveld A, de Jong PT, Bleeker-Wagemakers EM, Bergen AA. Retinitis pigmentosa: defined from a molecular point of view. Surv Ophthalmol. 1999;43(4):321-334. (PubMed)
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31. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761772. (PubMed) 32. Sibulesky L, Hayes KC, Pronczuk A, Weigel-DiFranco C, Rosner B, Berson EL. Safety of <7500 RE (<25000 IU) vitamin A daily in adults with retinitis pigmentosa. Am J Clin Nutr. 1999;69(4):656-663. (PubMed) 33. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 34. March of Dimes. Accutane and Other Retinoids [Web page]. April, 2002. Available at: http://www.marchofdimes.com/professionals/681_1168.asp. Accessed December 12, 2003. 35. Michaelsson K, Lithell H, Vessby B, Melhus H. Serum retinol levels and the risk of fracture. N Engl J Med. 2003;348(4):287-294. (PubMed) 36. Promislow JH, Goodman-Gruen D, Slymen DJ, Barrett-Connor E. Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study. J Bone Miner Res. 2002;17(8):1349-1358. (PubMed) 37. Feskanich D, Singh V, Willett WC, Colditz GA. Vitamin A intake and hip fractures among postmenopausal women. JAMA. 2002;287(1):47-54. (PubMed) 38. Rohde CM, DeLuca H. Bone resorption activity of all-trans retinoic acid is independent of vitamin D in rats. J Nutr. 2003;133(3):777-783. (PubMed) 39. Johansson S, Melhus H. Vitamin A antagonizes calcium response to vitamin D in man. J Bone Miner Res. 2001;16(10):1899-1905. (PubMed) 40. Wang XD. Chronic alcohol intake interferes with retinoid metabolism and signaling. Nutr Rev. 1999;57(2):51-59. (PubMed) 41. Leo MA, Lieber CS. Alcohol, vitamin A, and beta-carotene: adverse interactions, including hepatotoxicity and carcinogenicity. Am J Clin Nutr. 1999;69(6):1071-1085. (PubMed)
Vitamin C 51 STUDIES
1. Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999;69(6):1086-1107. (PubMed)
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2. Simon JA, Hudes ES. Serum ascorbic acid and gallbladder disease prevalence among US adults: the Third National Health and Nutrition Examination Survey (NHANES III). Arch Intern Med. 2000;160(7):931-936. (PubMed) 3.Sauberlich, HE. A history of scurvy and vitamin C. In Packer, L. and Fuchs, J. Eds. Vitamin C in health and disease. New York: Marcel Decker Inc. 1997: pages 1-24. 4. Stephen R, Utecht T. Scurvy identified in the emergency department: a case report. J Emerg Med. 2001;21(3):235-237. (PubMed) 5. Weinstein M, Babyn P, Zlotkin S. An orange a day keeps the doctor away: scurvy in the year 2000. Pediatrics. 2001;108(3):E55. (PubMed) 6. Food and Nutrition Board, Institute of Medicine. Vitamin C. Dietary Reference Intakes for Vitamin C, Vitamin E, Selenium, and Carotenoids. Washington D.C.: National Academy Press; 2000:95-185. (National Academy Press) 7. Losonczy KG, Harris TB, Havlik RJ. Vitamin E and vitamin C supplement use and risk of all-cause and coronary heart disease mortality in older persons: the Established Populations for Epidemiologic Studies of the Elderly. Am J Clin Nutr. 1996;64(2):190196. (PubMed) 8. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334(18):1156-1162. (PubMed) 9. Enstrom JE, Kanim LE, Klein MA. Vitamin C intake and mortality among a sample of the United States population. Epidemiology. 1992;3(3):194-202. (PubMed) 10. Enstrom JE. Counterpoint--vitamin C and mortality. Nutr Today. 1993;28:28-32. 11. Osganian SK, Stampfer MJ, Rimm E, et al. Vitamin C and risk of coronary heart disease in women. J Am Coll Cardiol. 2003;42(2):246-252. (PubMed) 12. Khaw KT, Bingham S, Welch A, et al. Relation between plasma ascorbic acid and mortality in men and women in EPIC-Norfolk prospective study: a prospective population study. European Prospective Investigation into Cancer and Nutrition. Lancet. 2001;357(9257):657-663. (PubMed) 13. Levine M, Wang Y, Padayatty SJ, Morrow J. A new recommended dietary allowance of vitamin C for healthy young women. Proc Natl Acad Sci U S A. 2001;98(17):98429846. (PubMed) 14. Frei B. To C or not to C, that is the question! J Am Coll Cardiol. 2003;42(2):253255.
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15. Yokoyama T, Date C, Kokubo Y, Yoshiike N, Matsumura Y, Tanaka H. Serum vitamin C concentration was inversely associated with subsequent 20-year incidence of stroke in a Japanese rural community. The Shibata study. Stroke. 2000;31(10):22872294. (PubMed) 16. Steinmetz KA, Potter JD. Vegetables, fruit, and cancer prevention: a review. J Am Diet Assoc. 1996;96(10):1027-1039. (PubMed) 17. Kromhout D. Essential micronutrients in relation to carcinogenesis. Am J Clin Nutr. 1987;45(5 Suppl):1361-1367. 18. Zhang S, Hunter DJ, Forman MR, et al. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999;91(6):547-556. (PubMed) 19. Michels KB, Holmberg L, Bergkvist L, Ljung H, Bruce A, Wolk A. Dietary antioxidant vitamins, retinol, and breast cancer incidence in a cohort of Swedish women. Int J Cancer. 2001;91(4):563-567. (PubMed) 20. Feiz HR, Mobarhan S. Does vitamin C intake slow the progression of gastric cancer in Helicobacter pylori-infected populations? Nutr Rev. 2002;60(1):34-36. (PubMed) 21. Jacques PF. The potential preventive effects of vitamins for cataract and age-related macular degeneration. Int J Vitam Nutr Res. 1999;69(3):198-205. (PubMed) 22. Jacques PF, Chylack LT, Jr., Hankinson SE, et al. Long-term nutrient intake and early age-related nuclear lens opacities. Arch Ophthalmol. 2001;119(7):1009-1019. (PubMed) 23. Simon JA, Hudes ES. Serum ascorbic acid and other correlates of self-reported cataract among older Americans. J Clin Epidemiol. 1999;52(12):1207-1211. (PubMed) 24. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119(10):1439-1452. (PubMed) 25. Cheng Y, Willett WC, Schwartz J, Sparrow D, Weiss S, Hu H. Relation of nutrition to bone lead and blood lead levels in middle-aged to elderly men. The Normative Aging Study. Am J Epidemiol. 1998;147(12):1162-1174. (PubMed) 26. Simon JA, Hudes ES. Relationship of ascorbic acid to blood lead levels. JAMA. 1999;281(24):2289-2293. (PubMed) 27. Dawson EB, Evans DR, Harris WA, Teter MC, McGanity WJ. The effect of ascorbic acid supplementation on the blood lead levels of smokers. J Am Coll Nutr. 1999;18(2):166-170. (PubMed)
325
28. Gokce N, Keaney JF, Jr., Frei B, et al. Long-term ascorbic acid administration reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation. 1999;99(25):3234-3240. (PubMed) 29. Duffy SJ, Gokce N, Holbrook M, et al. Treatment of hypertension with ascorbic acid. Lancet. 1999;354(9195):2048-2049. (PubMed) 30. Cameron E, Pauling L. Supplemental ascorbate in the supportive treatment of cancer: Prolongation of survival times in terminal human cancer. Proc Natl Acad Sci U S A. 1976;73(10):3685-3689. 31. Creagan ET, Moertel CG, O'Fallon JR, et al. Failure of high-dose vitamin C (ascorbic acid) therapy to benefit patients with advanced cancer. N Engl J Med. 1979;301(13):687-690. (PubMed) 32. Moertel CG, Fleming TR, Creagan ET, Rubin J, O'Connell MJ, Ames MM. Highdose vitamin C versus placebo in the treatment of patients with advanced cancer who have had no prior chemotherapy. A randomized double-blind comparison. N Engl J Med. 1985;312(3):137-141. (PubMed) 33. Padayatty SJ, Sun H, Wang Y, et al. Vitamin C pharmacokinetics: implications for oral and intravenous use. Ann Intern Med. 2004;140(7):533-537. (PubMed) 34. Kaegi E, Task Force on Alternative Therapeuties of the Canadian Breast Cancer Research Initiative. Unconventional therapies for cancer: 5. Vitamins A, C, and E. CMAJ. 1998;158(11):1483-1488. (PubMed) 35. Lee DH, Folsom AR, Harnack L, Halliwell B, Jacobs DR, Jr. Does supplemental vitamin C increase cardiovascular disease risk in women with diabetes? Am J Clin Nutr. 2004;80(5):1194-1200. (PubMed) 36. MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326):2333. (PubMed) 37. Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal women: a randomized controlled trial. JAMA. 2002;288(19):2432-2440. (PubMed) 38. Levy AP, Friedenberg P, Lotan R, et al. The effect of vitamin therapy on the progression of coronary artery atherosclerosis varies by haptoglobin type in postmenopausal women. Diabetes Care. 2004;27(4):925-930. (PubMed) 39. Hemila H. Vitamin C intake and susceptibility to the common cold. Br J Nutr. 1997;77(1):59-72. (PubMed)
326
40. Johnston CS, Martin LJ, Cai X. Antihistamine effect of supplemental ascorbic acid and neutrophil chemotaxis. J Am Coll Nutr. 1992;11(2):172-176. (PubMed) 41. Gregory JF, 3rd. Ascorbic acid bioavailability in foods and supplements. Nutr Rev. 1993;51(10):301-303. 42. Johnston CS, Luo B. Comparison of the absorption and excretion of three commercially available sources of vitamin C. J Am Diet Assoc. 1994;94(7):779-781. 43. Austria R, Semenzato A, Bettero A. Stability of vitamin C derivatives in solution and topical formulations. J Pharm Biomed Anal. 1997;15(6):795-801. (PubMed) 44. DeRitter E. Physiologic availability of dehydro-L-ascorbic acid and palmitoyl-Lascorbic acid. Science. 1951;113:628-631. 45. Lee SH, Oe T, Blair IA. Vitamin C-induced decomposition of lipid hydroperoxides to endogenous genotoxins. Science. 2001;292(5524):2083-2086. (PubMed) 46. Podmore ID, Griffiths HR, Herbert KE, Mistry N, Mistry P, Lunec J. Vitamin C exhibits pro-oxidant properties. Nature. 1998;392(6676):559. 47. Carr A, Frei B. Does vitamin C act as a pro-oxidant under physiological conditions? FASEB J. 1999;13(9):1007-1024. (PubMed) 48. Basu TK. Vitamin C-aspirin interactions. Int J Vitam Nutr Res Suppl. 1982;23:8390. (PubMed) 49. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 50. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592. (PubMed) 51. Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract. 2002;56(1):53-56 (PubMed).
Vitamin E
- 78 Studies
1. Traber MG. Utilization of vitamin E. Biofactors. 1999;10(2-3):115-120. (PubMed)
327
2. Traber MG. Vitamin E. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:347-362. 3. Food and Nutrition Board, Institute of Medicine. Vitamin E. Dietary reference intakes for vitamin C, vitamin E, selenium, and carotenoids. Washington D.C.: National Academy Press; 2000:186-283. (National Academy Press) 4. Traber MG. Does vitamin E decrease heart attack risk? summary and implications with respect to dietary recommendations. J Nutr. 2001;131(2):395S-397S. (PubMed) 5. Traber MG, Elsner A, Brigelius-Flohe R. Synthetic as compared with natural vitamin E is preferentially excreted as alpha-CEHC in human urine: studies using deuterated alpha-tocopheryl acetates. FEBS Lett. 1998;437(1-2):145-148. (PubMed) 6. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Proc Natl Acad Sci U S A. 1997;94(7):3217-3222. (PubMed) 7. Li D, Saldeen T, Mehta JL. gamma-tocopherol decreases ox-LDL-mediated activation of nuclear factor-kappaB and apoptosis in human coronary artery endothelial cells. Biochem Biophys Res Commun. 1999;259(1):157-161. (PubMed) 8. Helzlsouer KJ, Huang HY, Alberg AJ, et al. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000;92(24):2018-2023. (PubMed) 9. Jiang Q, Christen S, Shigenaga MK, Ames BN. gamma-tocopherol, the major form of vitamin E in the US diet, deserves more attention. Am J Clin Nutr. 2001;74(6):714-722. (PubMed) 10. Sokol R. Vitamin E. In: Ziegler EE, Filer LJ, eds. Present Knowledge in Nutrition. 7th ed: ILSI Press; 1996:130-136. 11. Ford ES, Sowell A. Serum alpha-tocopherol status in the United States population: findings from the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 1999;150(3):290-300. (PubMed) 12. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Am J Epidemiol. 1994;139(12):1180-1189. (PubMed) 13. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. N Engl J Med. 1996;334(18):1156-1162. (PubMed)
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14. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Vitamin E consumption and the risk of coronary heart disease in men. N Engl J Med. 1993;328(20):1450-1456. (PubMed) 15. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Vitamin E consumption and the risk of coronary disease in women. N Engl J Med. 1993;328(20):1444-1449. (PubMed) 16. Cherubini A, Zuliani G, Costantini F, et al. High vitamin E plasma levels and low low-density lipoprotein oxidation are associated with the absence of atherosclerosis in octogenarians. J Am Geriatr Soc. 2001;49(5):651-654. (PubMed) 17. Gale CR, Ashurst HE, Powers HJ, Martyn CN. Antioxidant vitamin status and carotid atherosclerosis in the elderly. Am J Clin Nutr. 2001;74(3):402-408. (PubMed) 18. McQuillan BM, Hung J, Beilby JP, Nidorf M, Thompson PL. Antioxidant vitamins and the risk of carotid atherosclerosis. The Perth Carotid Ultrasound Disease Assessment study (CUDAS). J Am Coll Cardiol. 2001;38(7):1788-1794. (PubMed) 19. Simon E, Gariepy J, Cogny A, Moatti N, Simon A, Paul JL. Erythrocyte, but not plasma, vitamin E concentration is associated with carotid intima-media thickening in asymptomatic men at risk for cardiovascular disease. Atherosclerosis. 2001;159(1):193200. (PubMed) 20. Jacques PF. The potential preventive effects of vitamins for cataract and age-related macular degeneration. Int J Vitam Nutr Res. 1999;69(3):198-205. (PubMed) 21. Gale CR, Hall NF, Phillips DI, Martyn CN. Plasma antioxidant vitamins and carotenoids and age-related cataract. Ophthalmology. 2001;108(11):1992-1998. (PubMed) 22. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9. Arch Ophthalmol. 2001;119(10):1439-1452. (PubMed) 23. Teikari JM, Rautalahti M, Haukka J, et al. Incidence of cataract operations in Finnish male smokers unaffected by alpha tocopherol or beta carotene supplements. J Epidemiol Community Health. 1998;52(7):468-472. (PubMed) 24. Meydani SN, Meydani M, Blumberg JB, et al. Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial. Jama. 1997;277(17):1380-1386. (PubMed) 25. Han SN, Meydani SN. Vitamin E and infectious diseases in the aged. Proc Nutr Soc. 1999;58(3):697-705. (PubMed)
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26. Heinonen OP, Albanes D, Virtamo J, et al. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998;90(6):440-446. (PubMed) 27. Klein EA, Thompson IM, Lippman SM, et al. SELECT: the next prostate cancer prevention trial. Selenum and Vitamin E Cancer Prevention Trial. J Urol. 2001;166(4):1311-1315. (PubMed) 28. Azen SP, Qian D, Mack WJ, et al. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation. 1996;94(10):2369-2372. (PubMed) 29. Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS). Lancet. 1996;347(9004):781-786. (PubMed) 30. Boaz M, Smetana S, Weinstein T, et al. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebocontrolled trial. Lancet. 2000;356(9237):1213-1218. (PubMed) 31. Rapola JM, Virtamo J, Ripatti S, et al. Randomised trial of alpha-tocopherol and betacarotene supplements on incidence of major coronary events in men with previous myocardial infarction. Lancet. 1997;349(9067):1715-1720. (PubMed) 32. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342(3):154-160. (PubMed) 33. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet. 1999;354(9177):447-455. (PubMed) 34. Davi G, Ciabattoni G, Consoli A, et al. In vivo formation of 8-iso-prostaglandin f2alpha and platelet activation in diabetes mellitus: effects of improved metabolic control and vitamin E supplementation. Circulation. 1999;99(2):224-229. (PubMed) 35. Jain SK, McVie R, Jaramillo JJ, Palmer M, Smith T. Effect of modest vitamin E supplementation on blood glycated hemoglobin and triglyceride levels and red cell indices in type I diabetic patients. J Am Coll Nutr. 1996;15(5):458-461. (PubMed) 36. Paolisso G, D'Amore A, Galzerano D, et al. Daily vitamin E supplements improve metabolic control but not insulin secretion in elderly type II diabetic patients. Diabetes Care. 1993;16(11):1433-1437. (PubMed)
330
37. Reaven PD, Herold DA, Barnett J, Edelman S. Effects of Vitamin E on susceptibility of low-density lipoprotein and low-density lipoprotein subfractions to oxidation and on protein glycation in NIDDM. Diabetes Care. 1995;18(6):807-816. (PubMed) 38. Meydani M. Antioxidants and cognitive function. Nutr Rev. 2001;59(8 Pt 2):S75-80; discussion S80-72. 39. Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alphatocopherol, or both as treatment for Alzheimer's disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336(17):1216-1222. (PubMed) 40. Masaki KH, Losonczy KG, Izmirlian G, et al. Association of vitamin E and C supplement use with cognitive function and dementia in elderly men. Neurology. 2000;54(6):1265-1272. (PubMed) 41. Yu W, Sanders BG, Kline K. RRR-alpha-tocopheryl succinate-induced apoptosis of human breast cancer cells involves Bax translocation to mitochondria. Cancer Res. 2003;63(10):2483-2491. (PubMed) 42. You H, Yu W, Munoz-Medellin D, Brown PH, Sanders BG, Kline K. Role of extracellular signal-regulated kinase pathway in RRR-alpha-tocopheryl succinate-induced differentiation of human MDA-MB-435 breast cancer cells. Mol Carcinog. 2002;33(4):228-236. (PubMed) 43. Neuzil J, Weber T, Schroder A, et al. Induction of cancer cell apoptosis by alphatocopheryl succinate: molecular pathways and structural requirements. FASEB J. 2001;15(2):403-415. (PubMed) 44. Brigelius-Flohe R, Kelly FJ, Salonen JT, Neuzil J, Zingg JM, Azzi A. The European perspective on vitamin E: current knowledge and future research. Am J Clin Nutr. 2002;76(4):703-716. (PubMed) 45. Weber T, Lu M, Andera L, et al. Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosisinducing ligand (Apo2 ligand) in vivo. Clin Cancer Res. 2002;8(3):863-869. (PubMed) 46. Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. Vitamin E inhibits melanoma growth in mice. Surgery. 2002;131(1):85-91. (PubMed) 47. Malafa MP, Neitzel LT. Vitamin E succinate promotes breast cancer tumor dormancy. J Surg Res. 2000;93(1):163-170. (PubMed) 48. Cheeseman KH, Holley AE, Kelly FJ, Wasil M, Hughes L, Burton G. Biokinetics in humans of RRR-alpha-tocopherol: the free phenol, acetate ester, and succinate ester forms of vitamin E. Free Radic Biol Med. 1995;19(5):591-598. (PubMed)
331
49. Larry King leads $6 million advertising blitz for Ester-E. Phosphagenics Newsletter: Phosphagenics; October, 2004:6. http://www.phosphagenics.com/files/55VYK670JY/POH%20newsletter%20FINAL.pdf 50. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 51. Berson EL, Rosner B, Sandberg MA, et al. A randomized trial of vitamin A and vitamin E supplementation for retinitis pigmentosa. Arch Ophthalmol. 1993;111(6):761772. (PubMed) 52. Miller ER, Pastor-Barriuso R, Dalal D, Riemersma RA, Appel LJ, Guallar E. Metaanalysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):xx-xx. http://www.annals.org/cgi/content/full/0000605200501040-00110v1 53. Shekelle PG, Morton SC, Jungvig LK, et al. Effect of supplemental vitamin E for the prevention and treatment of cardiovascular disease. J Gen Intern Med. 2004;19(4):380389. (PubMed) 54. Eidelman RS, Hollar D, Hebert PR, Lamas GA, Hennekens CH. Randomized trials of vitamin E in the treatment and prevention of cardiovascular disease. Arch Intern Med. 2004;164(14):1552-1556. (PubMed) 55. Vivekananthan DP, Penn MS, Sapp SK, Hsu A, Topol EJ. Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomised trials. Lancet. 2003;361(9374):2017-2023. (PubMed) 56. Brown BG, Zhao XQ, Chait A, et al. Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease. N Engl J Med. 2001;345(22):1583-1592. (PubMed) 57. Collins R, Peto R, Armitage J. The MRC/BHF Heart Protection Study: preliminary results. Int J Clin Pract. 2002;56(1):53-56. (PubMed) 58. Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot WJ, Dong ZW, Mark SD. Prospective study of serum vitamin E levels and esophageal and gastric cancers. J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6. PMID: 13130117 59. Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003 Aug;38(2):413-9. PMID: 12883485
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60. Fariss MW, Zhang JG. Vitamin E therapy in Parkinson's disease. Toxicology. 2003 Jul 15;189(1-2):129-46. Review. PMID: 12821288
61. Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, Griffin M, Ippolito E, Bavera P. Evaluation of the local effects of vitamin E (E-Mousse) on free radicals in diabetic microangiopathy: a randomized, controlled trial. Angiology. 2003 Jul-Aug;54(4):415-21. PMID: 12934761 62. Jessup JV, Horne C, Yarandi H, Quindry J. The effects of endurance exercise and vitamin E on oxidative stress in the elderly. Biol Res Nurs. 2003 Jul;5(1):47-55. PMID: 12886670 63. Canbaz S, Duran E, Ege T, Sunar H, Cikirikcioglu M, Acipayam M. The effects of intracoronary administration of vitamin E on myocardial ischemia-reperfusion injury during coronary artery surgery. Thorac Cardiovasc Surg. 2003 Apr;51(2):57-61. PMID: 12730811 64. Manson JE, Bassuk SS, Stampfer MJ. Does vitamin E supplementation prevent cardiovascular events? J Womens Health (Larchmt). 2003 Mar;12(2):123-36. Review. PMID: 12741415 65. Chang CW, Chu G, Hinz BJ, Greve MD. Current use of dietary supplementation in patients with age-related macular degeneration. Can J Ophthalmol. 2003 Feb;38(1):27-32. PMID: 12608514 66. Letur-Konirsch H, Delanian S. Successful pregnancies after combined pentoxifylline-tocopherol treatment in women with premature ovarian failure who are resistant to hormone replacement therapy. Fertil Steril. 2003 Feb;79(2):439-41. PMID: 12568863 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 333
67. Olanow CW. Dietary vitamin E and Parkinson's disease: something to chew on. Lancet Neurol. 2003 Feb;2(2):74. PMID: 12849259 68. Martin A. Antioxidant vitamins E and C and risk of Alzheimer's disease. Nutr Rev. 2003 Feb;61(2):69-73. Review. PMID: 12674439 69. Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, Takata J, Karube Y, Fujiwara M. Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosci Lett. 2003 Jan 30;337(1):56-60. PMID: 12524170 70. Rehim WM, Sharaf IA, Hishmat M, el-Toukhy MA, Rawash NA, Fouad HN. Antioxidant capacity in Fasciola hepatica patients before and after treatment with triclabendazole alone or in combination with ascorbic acid (vitamin C) and tocofersolan (vitamin E). Arzneimittelforschung. 2003;53(3):214-20. PMID: 12705178 71. Brockes C, Buchli C, Locher R, Koch J, Vetter W. Vitamin E prevents extensive lipid peroxidation in patients with hypertension. Br J Biomed Sci. 2003;60(1):5-8. PMID: 12680623 72. Lin Y, Huang R, Santanam N, Liu YG, Parthasarathy S, Huang RP. Profiling of human cytokines in healthy individuals with vitamin E supplementation by antibody array. Cancer Lett. 2002 Dec 10;187(1-2):17-24. PMID: 12359346 73. Scorolli L, Scalinci SZ, Limoli PG, Morara M, Vismara S, Scorolli L, Corazza D, Meduri R. [Photodynamic therapy for age related macular degeneration with and without antioxidants] Can J Ophthalmol. 2002 Dec;37(7):399-404. French. PMID: 12518724 74. Malafa MP, Fokum FD, Smith L, Louis A. Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate.
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Ann Surg Oncol. 2002 Dec;9(10):1023-32. PMID: 12464597
75. Ghosh D, Das UB, Misro M. Protective role of alpha-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress. Free Radic Res. 2002 Nov;36(11):1209-18. PMID: 12592673 76. Liu L, Meydani M. Combined vitamin C and E supplementation retards early progression of arteriosclerosis in heart transplant patients. Nutr Rev. 2002 Nov;60(11):368-71. Review. PMID: 12462519 77. Boshtam M, Rafiei M, Sadeghi K, Sarraf-Zadegan N. Vitamin E can reduce blood pressure in mild hypertensives. Int J Vitam Nutr Res. 2002 Oct;72(5):309-14. PMID: 12463106 78. Jialal I, Devaraj S, Venugopal SK. Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res. 2002 Dec;36(12):1331-6. Review. PMID: 12607825
Vitamin B6 - 28 STUDIES
1. Leklem JE. Vitamin B-6. In: Machlin L, ed. Handbook of Vitamins. New York: Marcel Decker Inc; 1991:341-378. 2. Leklem JE. Vitamin B-6. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:413-422. 3. Hansen CM, Leklem JE, Miller LT. Vitamin B-6 status of women with a constant intake of vitamin B-6 changes with three levels of dietary protein. J Nutr. 1996;126(7):1891-1901. (PubMed) 4. Food and Nutrition Board, Institute of Medicine. Vitamin B6. Dietary Reference Intakes: Thiamin, Riboflavin, Niacin, Vitamin B-6, Vitamin B-12, Pantothenic Acid,
335
Biotin, and Choline. Washington D.C.: National Academy Press; 1998:150-195. (National Academy Press) 5. Boushey CJ, Beresford SA, Omenn GS, Motulsky AG. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995;274(13):1049-1057. (PubMed) 6. Rimm EB, Willett WC, Hu FB, et al. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women. JAMA. 1998;279(5):359-364. (PubMed) 7. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998;98(3):204-210. (PubMed) 8. Ubbink JB, Vermaak WJ, van der Merwe A, Becker PJ, Delport R, Potgieter HC. Vitamin requirements for the treatment of hyperhomocysteinemia in humans. J Nutr. 1994;124(10):1927-1933. (PubMed) 9. Meydani SN, Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B-6 deficiency impairs interleukin 2 production and lymphocyte proliferation in elderly adults. Am J Clin Nutr. 1991;53(5):1275-1280. (PubMed) 10. Talbott MC, Miller LT, Kerkvliet NI. Pyridoxine supplementation: effect on lymphocyte responses in elderly persons. Am J Clin Nutr. 1987;46(4):659664. (PubMed) 11. Selhub J, Bagley LC, Miller J, Rosenberg IH. B vitamins, homocysteine, and neurocognitive function in the elderly. Am J Clin Nutr. 2000;71(2):614S-620S. (PubMed) 12. Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr. 1996;63(3):306-314. (PubMed) 13. Curhan GC, Willett WC, Speizer FE, Stampfer MJ. Intake of vitamins B6 and C and the risk of kidney stones in women. J Am Soc Nephrol. 1999;10(4):840-845. (PubMed) 14. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of the intake of vitamins C and B6, and the risk of kidney stones in men. J Urol. 1996;155(6):18471851. (PubMed) 15. Bender DA. Non-nutritional uses of vitamin B6. Br J Nutr. 1999;81(1):7-20 (PubMed)
336
16. Villegas-Salas E, Ponce de Leon R, Juarez-Perez MA, Grubb GS. Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive. Contraception. 1997;55(4):245-248. (PubMed) 17. Kleijnen J, Ter Riet G, Knipschild P. Vitamin B6 in the treatment of the premenstrual syndrome--a review. Br J Obstet Gynaecol. 1990;97(9):847-852. (PubMed) 18. Wyatt KM, Dimmock PW, Jones PW, Shaughn O'Brien PM. Efficacy of vitamin B-6 in the treatment of premenstrual syndrome: systematic review. Bmj. 1999;318(7195):1375-1381. (PubMed) 19. Vutyavanich T, Wongtra-ngan S, Ruangsri R. Pyridoxine for nausea and vomiting of pregnancy: a randomized, double-blind, placebo-controlled trial. Am J Obstet Gynecol. 1995;173(3 Pt 1):881-884. (PubMed) 20. Sahakian V, Rouse D, Sipes S, Rose N, Niebyl J. Vitamin B6 is effective therapy for nausea and vomiting of pregnancy: a randomized, double-blind placebo-controlled study. Obstet Gynecol. 1991;78(1):33-36. (PubMed) 21. Jewell D, Young G. Interventions for nausea and vomiting in early pregnancy. Cochrane Database Syst Rev. 2002(1):CD000145. (PubMed) 22. Ellis JM, Kishi T, Azuma J, Folkers K. Vitamin B6 deficiency in patients with a clinical syndrome including the carpal tunnel defect. Biochemical and clinical response to therapy with pyridoxine. Res Commun Chem Pathol Pharmacol. 1976;13(4):743-757. (PubMed) 23. Ellis J, Folkers K, Watanabe T, et al. Clinical results of a cross-over treatment with pyridoxine and placebo of the carpal tunnel syndrome. Am J Clin Nutr. 1979;32(10):2040-2046. (PubMed) 24. Keniston RC, Nathan PA, Leklem JE, Lockwood RS. Vitamin B6, vitamin C, and carpal tunnel syndrome. A cross-sectional study of 441 adults. J Occup Environ Med. 1997;39(10):949-959. (PubMed) 25. Spooner GR, Desai HB, Angel JF, Reeder BA, Donat JR. Using pyridoxine to treat carpal tunnel syndrome. Randomized control trial. Can Fam Physician. 1993;39:21222127. (PubMed) 26. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001 27. Hansen CM, Shultz TD, Kwak HK, Memon HS, Leklem JE. Assessment of vitamin B-6 status in young women consuming a controlled diet containing four levels of vitamin B-6 provides an estimated average requirement and recommended dietary allowance. J Nutr. 2001;131(6):1777-1786. (PubMed) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 337
28. Kretsch MJ, Sauberlich HE, Skala JH, Johnson HL. Vitamin B-6 requirement and status assessment: young women fed a depletion diet followed by a plant- or animalprotein diet with graded amounts of vitamin B-6. Am J Clin Nutr. 1995;61(5):1091-1101. (PubMed) 29. Ribaya-Mercado JD, Russell RM, Sahyoun N, Morrow FD, Gershoff SN. Vitamin B6 requirements of elderly men and women. J Nutr. 1991;121(7):1062-1074. (PubMed).
Magnesium - 86 Studies
1. Bucca C, Rolla G. Nebulised magnesium in asthma: the right solution for an old remedy? Lancet. 2003 Jun 21;361(9375):2095-6. PMID: 12826427 2. Jian W, Su L, Yiwu L. The effects of magnesium prime solution on magnesium levels and potassium loss in open heart surgery. Anesth Analg. 2003 Jun;96(6):1617-20, table of contents. PMID: 12760983 3. Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen. Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. PMID: 12730554 4. Geleijnse JM, Grobbee DE. Nutrition and healthhypertension. Ned Tijdschr Geneeskd. 2003 May 24;147(21):996-1000. PMID: 12811968 5. Suresh S, Lozono S, Hall SC. Large-dose intravenous methotrexate-induced cutaneous toxicity: can oral magnesium oxide reduce pain? Anesth Analg. 2003 May;96(5):1413-4, table of contents. PMID: 12707144 6. Sigman-Grant M, Warland R, Hsieh G. Selected lower-fat foods positively impact nutrient quality in diets of free-living Americans. J Am Diet Assoc. 2003 May;103(5):570-6. PMID: 12728214
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7.Haupt H, Scheibe F, Mazurek B. Therapeutic efficacy of magnesium in acoustic trauma in the guinea pig. ORL J Otorhinolaryngol Relat Spec. 2003 May-Jun;65(3):134-9. PMID: 12925813 8. Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat. Brain Res Bull. 2003 Apr 15;60(1-2):105-14. PMID: 12725898 9. Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya T, Okamura M, Kim S, Iwao H, Miura K. Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation. Transplantation. 2003 Apr 15;75(7):1040-4. PMID: 12698095 10. Sharkey JR, Giuliani C, Haines PS, Branch LG, Busby-Whitehead J, Zohoori N. Summary measure of dietary musculoskeletal nutrient (calcium, vitamin D, magnesium, and phosphorus) intakes is associated with lower-extremity physical performance in homebound elderly men and women. Am J Clin Nutr. 2003 Apr;77(4):847-56. PMID: 12663282 11. Seguro AC, de Araujo M, Seguro FS, Rienzo M, Magaldi AJ, Campos SB. Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) nephrotoxicity in rats. Clin Nephrol. 2003 Apr;59(4):267-72. PMID: 12708566 12. Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. Development of ionized hypomagnesemia is associated with higher mortality rates. Crit Care Med. 2003 Apr;31(4):1082-7. PMID: 12682476 13. Ilich JZ, Brownbill RA, Tamborini L. Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density. Eur J Clin Nutr. 2003 Apr;57(4):554-65. PMID: 12700617 14. Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider M, Chachashvily S, Averbukh Z, Golik A, Chen-Levy Z, Modai D. Serum magnesium aberrations in furosemide (frusemide) treated patients with congestive heart failure: pathophysiological correlates and prognostic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 339
evaluation. Heart. 2003 Apr;89(4):411-6. PMID: 12639869 15. Lin PH, Aickin M, Champagne C, Craddick S, Sacks FM, McCarron P, MostWindhauser MM, Rukenbrod F, Haworth L; Dash-Sodium Collaborative Research Group. Food group sources of nutrients in the dietary patterns of the DASH-Sodium trial. J Am Diet Assoc. 2003 Apr;103(4):488-96. PMID: 12669013 16. Onagawa T, Ohkuchi A, Ohki R, Izumi A, Matsubara S, Sato I, Suzuki M, Minakami H. Woman with postpartum ventricular tachycardia and hypomagnesemia. J Obstet Gynaecol Res. 2003 Apr;29(2):92-5. PMID: 12755529 17. Singhi SC, Singh J, Prasad R. Hypo- and hypermagnesemia in an Indian Pediatric Intensive Care Unit. J Trop Pediatr. 2003 Apr;49(2):99-103. PMID: 12729292 18. van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. Acta Neurochir (Wien). 2003 Mar;145(3):195-9; discussion 199. Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for long term treatment. PMID: 12632115 19. Higgins JC. The 'crashing astimatic.' Am Fam Physician. 2003 Mar 1;67(5):997-1004. PMID: 12643359 20. Roy SR, Milgrom H. Managing outpatient asthma exacerbations. Curr Allergy Asthma Rep. 2003 Mar;3(2):179-89. PMID: 12562559 21. Cappell MS. Gastric and duodenal ulcers during pregnancy. Gastroenterol Clin North Am. 2003 Mar;32(1):263-308. PMID: 12635419 22. Igondjo-Tchen S, Pages N, Bac P, Godeau G, Durlach J. Marfan syndrome, magnesium status and medical prevention of cardiovascular complications by hemodynamic treatments and antisense gene therapy. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 340
Magnes Res. 2003 Mar;16(1):59-64. PMID: 12735484 23. Caron MF, Kluger J, Tsikouris JP, Ritvo A, Kalus JS, White CM. Pharmacotherapy. 2003 Mar;23(3):296-300. Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide. PMID: 12627926 24. Ferrari L, Meschi M, Musini S, Frattini A, Savazzi GM. Recenti Prog Med. 2003 Mar;94(3):136-41. Etiopathogenesis and clinical aspects of nephrolithiasis--at present. PMID: 12677782 25. Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Aspects Med. 2003 Feb 6;24(1-3):107-36. PMID: 12537992 26. Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. Effect of intra-operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia. 2003 Feb;58(2):131-5. PMID: 12562408 27. Pamnani MB, Bryant HJ, Clough DL, Schooley JF. Increased dietary potassium and magnesium attenuate experimental volume dependent hypertension possibly through endogenous sodium-potassium pump inhibitor. Clin Exp Hypertens. 2003 Feb;25(2):103-15. PMID: 12611422 28. Czajkowski K, Wojcicka-Bentyn J, Grymowicz M, Smolarczyk R, MalinowskaPolubiec A, Romejko E. Calcium-phosphorus-magnesium homeostasis in pregnant women after renal transplantation. Int J Gynaecol Obstet. 2003 Feb;80(2):111-6. PMID: 12566182 29. Hata M, Miyao M, Mizuno Y. Osteoporosis as a lifestyle-related disease. Nippon Rinsho. 2003 Feb;61(2):305-13. PMID: 12638226 30. Zhang Y, Davies LR, Martin SM, Bawaney IM, Buettner GR, Kerber RE. Magnesium reduces free radical concentration and preserves left ventricular Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 341
function after direct current shocks. Resuscitation. 2003 Feb;56(2):199-206. PMID: 12589995 31. Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003 Jan 23;348(4):304-11. PMID: 12540643 32. Vink R, O'Connor CA, Nimmo AJ, Heath DL. Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats. Neurosci Lett. 2003 Jan 9;336(1):41-4. PMID: 12493598 33. Averbukh Z, Rosenberg R, Galperin E, Berman S, Cohn M, Cohen N, Modai D, Efrati S, Weissgarten J. Cell-associated magnesium and QT dispersion in hemodialysis patients. Am J Kidney Dis. 2003 Jan;41(1):196-202. PMID: 12500237 34. Meram I, Balat O, Tamer L, Ugur MG. Trace elements and vitamin levels in menopausal women receiving hormone replacement therapy. Clin Exp Obstet Gynecol. 2003;30(1):32-4. PMID: 12731741 35. Duley L, Gulmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev. 2003;(2):CD000025. PMID: 12804383 36. Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. Adenosine triphosphate-magnesium chloride: relevance for intensive care. Intensive Care Med. 2003 Jan;29(1):10-8. Epub 2002 Nov 02. PMID: 12528016 37. Margolin A, Kantak K, Copenhaver M, Avants SK. A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. J Addict Dis. 2003;22(2):49-61. PMID: 12703668 38. Egami I, Wakai K, Kunitomo H, Tamakoshi A, Ando M, Nakayama T, Ohno Y. Associations of lifestyle factors with bone mineral density among male Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 342
university students in Japan. J Epidemiol. 2003 Jan;13(1):48-55. PMID: 12587613 39. Cisse CT, Faye Dieme ME, Ngabo D, Mbaye M, Diagne PM, Moreau JC. Therapeutics indications and prognosis of eclampsia at Dakar University Teaching Hospital. J Gynecol Obstet Biol Reprod (Paris). 2003;32(3 Pt 1):239-45. PMID: 12773926 40. Darvish D. Magnesium may help patients with recessive hereditary inclusion body myopathy, a pathological review. Med Hypotheses. 2003 Jan;60(1):94-101. PMID: 12450772 41. Kato Y, Tamaki G, Tokumitsu M, Yamaguchi S, Yachiku S, Okuyama M. A case of urolithiasis associated with short bowel syndrome. Nippon Hinyokika Gakkai Zasshi. 2003 Jan;94(1):33-6. PMID: 12638204 42. Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. The use of magnesium to prevent laryngospasm after tonsillectomy and adenoidectomy: a preliminary study. Paediatr Anaesth. 2003 Jan;13(1):43-7. PMID: 12535038 43. Byrd RP Jr, Roy TM. Magnesium: its proven and potential clinical significance. South Med J. 2003 Jan;96(1):104. PMID: 12602735 44.: Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99. PMID: 12495373 45. Carlin Schooley M, Franz KB. Magnesium deficiency during pregnancy in rats increases systolic blood pressure and plasma nitrite. Am J Hypertens. 2002 Dec;15(12):1081-6. PMID: 12460704 46. Imazu M. Hypertension and insulin disorders. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 343
Curr Hypertens Rep. 2002 Dec;4(6):477-82. PMID: 12419178 47. Grzybek A, Klosiewicz-Latoszek L, Targosz U. Changes in the intake of vitamins and minerals by men and women with hyperlipidemia and overweight during dietetic treatment. Eur J Clin Nutr. 2002 Dec;56(12):1162-8. PMID: 12494300 48. Gryspeerdt S, Lefere P, Dewyspelaere J, Baekelandt M, van Holsbeeck B. Optimisation of colon cleansing prior to computed tomographic colonography. JBR-BTR. 2002 Dec;85(6):289-96. PMID: 12553658 49. Bhatia R, Prabhakar S, Grover VK. Tetanus. Neurol India. 2002 Dec;50(4):398-407. PMID: 12577086 50. Murck H. Magnesium and affective disorders. Nutr Neurosci. 2002 Dec;5(6):375-89. PMID: 12509067 51. Haas KM, Suzuki S, Yamaguchi N, Kato I, Ban K, Tanaka T, Fukuda S, Togari H. Nitric oxide further attenuates pulmonary hypertension in magnesium-treated piglets. Pediatr Int. 2002 Dec;44(6):670-4. PMID: 12421268 52. Minami T, Adachi T, Fukuda K. An effective use of magnesium sulfate for intraoperative management of laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient. Anesth Analg. 2002 Nov;95(5):1243-4, table of contents. PMID: 12401602 53. Nakatani T, Asai T. Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity. Hinyokika Kiyo. 2002 Nov;48(11):699-705. PMID: 12512145 54. Blackwell SC, Redman ME, Whitty JE, Refuerzo JS, Berry SM, Sorokin Y, Russell E, Cotton DB. The effect of intrapartum magnesium sulfate therapy on fetal cardiac Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 344
troponin I levels at delivery. J Matern Fetal Neonatal Med. 2002 Nov;12(5):327-31. PMID: 12607765 55. Unachak K, Louthrenoo O, Katanyuwong K. Primary hypomagnesemia in Thai infants: a case report with 7 years follow-up and review of literature. J Med Assoc Thai. 2002 Nov;85(11):1226-31. PMID: 12546321 56. Berger R, Garnier Y, Jensen A. Perinatal brain damage: underlying mechanisms and neuroprotective strategies. J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28. PMID: 12445595 57. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. New migraine preventive options: an update with pathophysiological considerations. Rev Hosp Clin Fac Med Sao Paulo. 2002 Nov-Dec;57(6):293-8. Epub 2003 Feb 17. PMID: 12612763 58. Milionis HJ, Rizos E, Liamis G, Nikas S, Siamopoulos KC, Elisaf MS. Acid-base and electrolyte disturbances in patients with hypercalcemia. South Med J. 2002 Nov;95(11):1280-7. PMID: 12539994 59. Rao GN. Diet and kidney diseases in rats. Toxicol Pathol. 2002 Nov-Dec;30(6):651-6. PMID: 12512864 60. Anderson RA. A complementary approach to urolithiasis prevention. World J Urol. 2002 Nov;20(5):294-301. Epub 2002 Oct 17. PMID: 12522585 61. Paskitti M, Reid KH. Use of an adenosine triphosphate-based 'cocktail' early in reperfusion substantially improves brain protein synthesis after global ischemia in rats. Neurosci Lett. 2002 Oct 18;331(3):147-50. PMID: 12383918
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62. Gaby AR. Intravenous nutrient therapy: the "Myers' cocktail". Altern Med Rev. 2002 Oct;7(5):389-403. PMID: 12410623 63.Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia. Anesth Analg. 2002 Oct;95(4):828-34, table of contents. PMID: 12351253 64. Davis GK, Homer CS, Brown MA. Hypertension in pregnancy: do consensus statements make a difference? Aust N Z J Obstet Gynaecol. 2002 Oct;42(4):369-73. PMID: 12403283 65. Ichiba H, Tamai H, Negishi H, Ueda T, Kim TJ, Sumida Y, Takahashi Y, Fujinaga H, Minami H; Kansai Magnesium Study Group. Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia. Pediatr Int. 2002 Oct;44(5):505-9. PMID: 12225549 66. Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation. 2002 Sep 27;74(6):784-91. PMID: 12364856 67. Plasma exchange in severe postpartum HELLP syndrome. Forster JG, Peltonen S, Kaaja R, Lampinen K, Pettila V. Acta Anaesthesiol Scand. 2002 Sep;46(8):955-8. PMID: 12190795 68. Kantas E, Cetin A, Kaya T, Cetin M. Effect of magnesium sulfate, isradipine, and ritodrine on contractions of myometrium: pregnant human and rat. Acta Obstet Gynecol Scand. 2002 Sep;81(9):825-30. PMID: 12225296 69. Memis D, Turan A, Karamanlioglu B, Sut N, Pamukcu Z. The use of magnesium sulfate to prevent pain on injection of propofol. Anesth Analg. 2002 Sep;95(3):606-8, table of contents. PMID: 12198045
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70. Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg. 2002 Sep;95(3):661-6, table of contents. PMID: 12198056 71. Forlani S, De Paulis R, de Notaris S, Nardi P, Tomai F, Proietti I, Ghini AS, Chiariello L. Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg. 2002 Sep;74(3):720-5; discussion 725-6. PMID: 12238830 72. Tramer MR, Glynn CJ. Magnesium Bier's block for treatment of chronic limb pain: a randomised, double-blind, cross-over study. Pain. 2002 Sep;99(1-2):235-41. PMID: 12237201 73. Patrick L. Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Altern Med Rev. 2002 Aug;7(4):276-91. PMID: 12197781 74. Attygalle D, Rodrigo N. Magnesium as first line therapy in the management of tetanus: a prospective study of 40 patients. Anaesthesia. 2002 Aug;57(8):811-7. PMID: 12133096 75. Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S; Acute Asthma/Magnesium Study Group. IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest. 2002 Aug;122(2):489-97. PMID: 12171821 76. Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. Effect of formulation variables on the floating properties of gastric floating drug delivery system. Drug Dev Ind Pharm. 2002 Aug;28(7):783-93. PMID: 12236064
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77. van den Bergh WM, Zuur JK, Kamerling NA, van Asseldonk JT, Rinkel GJ, Tulleken CA, Nicolay K. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage. J Neurosurg. 2002 Aug;97(2):416-22. PMID: 12186471 78. Garcia MC, Byrd RP Jr, Roy TM. Lethal iatrogenic hypermagnesemia. Tenn Med. 2002 Aug;95(8):334-6. PMID: 12174756 79. Patel S, Martinez-Ripoll M, Blundell TL, Albert A. J Mol Biol. 2002 Jul 26;320(5):1087-94. Structural enzymology of Li(+)-sensitive/Mg(2+)-dependent phosphatases. PMID: 12126627 80. Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. Combined systemic administration of morphine and magnesium sulfate attenuates painrelated behavior in mononeuropathic rats. Brain Res. 2002 Jul 5;943(1):101-4. PMID: 12088843 81. Dagdelen S, Toraman F, Karabulut H, Alhan C. The value of P dispersion on predicting atrial fibrillation after coronary artery bypass surgery: effect of magnesium on P dispersion. Ann Noninvasive Electrocardiol. 2002 Jul;7(3):211-8. PMID: 12167181 82. Streetman DD, Bhatt-Mehta V, Johnson CE. Management of acute, severe asthma in children. Ann Pharmacother. 2002 Jul-Aug;36(7-8):1249-60. PMID: 12086560 83. Kaye P, O'Sullivan I. The role of magnesium in the emergency department. Emerg Med J. 2002 Jul;19(4):288-91. PMID: 12101132 84. Yamori Y, Liu L, Mu L, Zhao H, Pen Y, Hu Z, Kuga S, Negishi H, Ikeda K; Japan-China Cooperative Study Group: Chongqing Project. Diet-related factors, educational levels and blood pressure in a Chinese population sample: findings from the Japan-China Cooperative Research Project. Hypertens Res. 2002 Jul;25(4):559-64. PMID: 12358141 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 348
85. Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic liver cirrhosis -- relation to spironolactone. J Intern Med. 2002 Jul;252(1):56-63. PMID: 12074739 86. Malluche HH, Mawad H. Management of hyperphosphataemia of chronic kidney disease: lessons from the past and future directions. Nephrol Dial Transplant. 2002 Jul;17(7):1170-5. PMID: 12105237
Zinc 50 STUDIES
1: Nowak G, Szewczyk B, Wieronska JM, Branski P, Palucha A, Pilc A, Sadlik K, Piekoszewski W. Antidepressant-like effects of acute and chronic treatment with zinc in forced swim test and olfactory bulbectomy model in rats. Brain Res Bull. 2003 Jul 15;61(2):159-64. PMID: 12832002 2: Lambert JC, Zhou Z, Wang L, Song Z, McClain CJ, Kang YJ. Prevention of alterations in intestinal permeability is involved in zinc inhibition of acute ethanol-induced liver damage in mice. J Pharmacol Exp Ther. 2003 Jun;305(3):880-6. Epub 2003 Mar 06. PMID: 12626662 3: Roldan S, Winkel EG, Herrera D, Sanz M, Van Winkelhoff AJ. The effects of a new mouthrinse containing chlorhexidine, cetylpyridinium chloride and zinc lactate on the microflora of oral halitosis patients: a dual-centre, double-blind placebo-controlled study. J Clin Periodontol. 2003 May;30(5):427-34. PMID: 12716335 4: Winkel EG, Roldan S, Van Winkelhoff AJ, Herrera D, Sanz M. Clinical effects of a new mouthrinse containing chlorhexidine, cetylpyridinium chloride and zinc-lactate on oral halitosis. A dual-center, double-blind placebo-controlled study. J Clin Periodontol. 2003 Apr;30(4):300-6. PMID: 12694427 5: Orbak R, Cicek Y, Tezel A, Dogru Y. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 349
Effects of zinc treatment in patients with recurrent aphthous stomatitis. Dent Mater J. 2003 Mar;22(1):21-9. PMID: 12790293 6: Mossad SB. Effect of zincum gluconicum nasal gel on the duration and symptom severity of the common cold in otherwise healthy adults. QJM. 2003 Jan;96(1):35-43. PMID: 12509647 7: McElroy BH, Miller SP. Effectiveness of zinc gluconate glycine lozenges (Cold-Eeze) against the common cold in school-aged subjects: a retrospective chart review. Am J Ther. 2002 Nov-Dec;9(6):472-5. PMID: 12424502 8: Nowak G, Szewczyk B. Mechanisms contributing to antidepressant zinc actions. Pol J Pharmacol. 2002 Nov-Dec;54(6):587-92. Review. PMID: 12866713 9: Putt MS, Yu D, Kohut BE. Inhibition of calculus formation by dentifrice formulations containing essential oils and zinc. Am J Dent. 2002 Oct;15(5):335-8. PMID: 12537346 10: Rostan EF, DeBuys HV, Madey DL, Pinnell SR. Evidence supporting zinc as an important antioxidant for skin. Int J Dermatol. 2002 Sep;41(9):606-11. Review. PMID: 12358835 11: Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, Sommerfelt H, Bhan MK. Effect of routine zinc supplementation on pneumonia in children aged 6 months to 3 years: randomised controlled trial in an urban slum. BMJ. 2002 Jun 8;324(7350):1358. PMID: 12052800 12: Oken E, Duggan C. Update on micronutrients: iron and zinc. Curr Opin Pediatr. 2002 Jun;14(3):350-3. Review. PMID: 12011679 13: Cho YH, Lee SJ, Lee JY, Kim SW, Lee CB, Lee WY, Yoon MS. Antibacterial effect of intraprostatic zinc injection in a rat model of chronic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 350
bacterial prostatitis. Int J Antimicrob Agents. 2002 Jun;19(6):576-82. PMID: 12135851 14: Bhandari N, Bahl R, Taneja S, Strand T, Molbak K, Ulvik RJ, Sommerfelt H, Bhan MK. Substantial reduction in severe diarrheal morbidity by daily zinc supplementation in young north Indian children. Pediatrics. 2002 Jun;109(6):e86. PMID: 12042580 15: Strand TA, Chandyo RK, Bahl R, Sharma PR, Adhikari RK, Bhandari N, Ulvik RJ, Molbak K, Bhan MK, Sommerfelt H. Effectiveness and efficacy of zinc for the treatment of acute diarrhea in young children. Pediatrics. 2002 May;109(5):898-903. PMID: 11986453 16: Lowe NM, Lowe NM, Fraser WD, Jackson MJ. Is there a potential therapeutic value of copper and zinc for osteoporosis? Proc Nutr Soc. 2002 May;61(2):181-5. Review. PMID: 12133199 17: Karyadi E, West CE, Schultink W, Nelwan RH, Gross R, Amin Z, Dolmans WM, Schlebusch H, van der Meer JW. A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status. Am J Clin Nutr. 2002 Apr;75(4):720-7. PMID: 11916759 18: Afonne OJ, Orisakwe OE, Obi E, Dioka CE, Ndubuka GI. Nephrotoxic actions of low-dose mercury in mice: protection by zinc. Arch Environ Health. 2002 Mar-Apr;57(2):98-102. PMID: 12194165 19: Hwang IK, Go VL, Harris DM, Yip I, Song MK. Effects of arachidonic acid plus zinc on glucose disposal in genetically diabetic (ob/ob) mice. Diabetes Obes Metab. 2002 Mar;4(2):124-31. PMID: 11940110 20: Su JC, Birmingham CL. Zinc supplementation in the treatment of anorexia nervosa. Eat Weight Disord. 2002 Mar;7(1):20-2. Review. PMID: 11930982 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 351
21: Tsocheva-Gaitandjieva NT, Gabrashanska MP, Tepavitcharova S. Trace element levels in the liver of rats with acute and chronic fascioliasis and after treatment with zinc-copper hydroxochloride mixed crystals. J Helminthol. 2002 Mar;76(1):87-90. PMID: 12018202 22: Zemel BS, Kawchak DA, Fung EB, Ohene-Frempong K, Stallings VA. Effect of zinc supplementation on growth and body composition in children with sickle cell disease. Am J Clin Nutr. 2002 Feb;75(2):300-7. PMID: 11815322 23: Yoshida S, Tomita H. A case of Cronkhite-Canada syndrome whose major complaint, taste disturbance, was improved by zinc therapy. Acta Otolaryngol Suppl. 2002;(546):154-8. PMID: 12132614 24: Rahman MM, Wahed MA, Fuchs GJ, Baqui AH, Alvarez JO. Synergistic effect of zinc and vitamin A on the biochemical indexes of vitamin A nutrition in children. Am J Clin Nutr. 2002 Jan;75(1):92-8. PMID: 11756065 25: Prasad AS, Kucuk O. Zinc in cancer prevention. Cancer Metastasis Rev. 2002;21(3-4):291-5. Review. PMID: 12549767 26: Yoshida Y, Higashi T, Nouso K, Nakatsukasa H, Nakamura SI, Watanabe A, Tsuji T. Effects of zinc deficiency/zinc supplementation on ammonia metabolism in patients with decompensated liver cirrhosis. Acta Med Okayama. 2001 Dec;55(6):349-55. PMID: 11779097 27: Jampol LM, Ferris FL 3rd. Antioxidants and zinc to prevent progression of age-related macular degeneration. JAMA. 2001 Nov 21;286(19):2466-8. No abstract available. PMID: 11759670 28: Dijkhuizen MA, Wieringa FT, West CE, Martuti S, Muhilal. Effects of iron and zinc supplementation in Indonesian infants on micronutrient status and growth. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 352
J Nutr. 2001 Nov;131(11):2860-5. PMID: 11694609 29: Fong LY, Nguyen VT, Farber JL. Esophageal cancer prevention in zinc-deficient rats: rapid induction of apoptosis by replenishing zinc. J Natl Cancer Inst. 2001 Oct 17;93(20):1525-33. PMID: 11604475 30: Takagi H, Nagamine T, Abe T, Takayama H, Sato K, Otsuka T, Kakizaki S, Hashimoto Y, Matsumoto T, Kojima A, Takezawa J, Suzuki K, Sato S, Mori M. Zinc supplementation enhances the response to interferon therapy in patients with chronic hepatitis C. J Viral Hepat. 2001 Sep;8(5):367-71. PMID: 11555194 31: Christian P, Khatry SK, Yamini S, Stallings R, LeClerq SC, Shrestha SR, Pradhan EK, West KP Jr. Zinc supplementation might potentiate the effect of vitamin A in restoring night vision in pregnant Nepalese women. Am J Clin Nutr. 2001 Jun;73(6):1045-51. PMID: 11382658 32: Najda J, Stella-Holowiecka B, Machalski M. Low-dose zinc administration as an effective Wilson's disease treatment. Biol Trace Elem Res. 2001 Jun;80(3):281-4. PMID: 11508632 33: Iitaka M, Kakinuma S, Fujimaki S, Oosuga I, Fujita T, Yamanaka K, Wada S, Katayama S. Induction of apoptosis and necrosis by zinc in human thyroid cancer cell lines. J Endocrinol. 2001 May;169(2):417-24. PMID: 11312158 34: Yang HM, Chai JK, Guo ZR. [Effect of improved topical agents on healing time of deep second-degree burn wound] Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi. 2001 May;15(3):162-4. Chinese. PMID: 11393958 35: Khatun UH, Malek MA, Black RE, Sarkar NR, Wahed MA, Fuchs G, Roy SK. A randomized controlled clinical trial of zinc, vitamin A or both in undernourished children with persistent diarrhea in Bangladesh. Acta Paediatr. 2001 Apr;90(4):376-80. PMID: 11332926
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36: Yoshikawa Y, Ueda E, Miyake H, Sakurai H, Kojima Y. Insulinomimetic bis(maltolato)zinc(II) complex: blood glucose normalizing effect in KK-A(y) mice with type 2 diabetes mellitus. Biochem Biophys Res Commun. 2001 Mar16;281(5):1190-3. PMID: 11243860 37: Hotz C, Brown KH. Identifying populations at risk of zinc deficiency: the use of supplementation trials. Nutr Rev. 2001 Mar;59(3 Pt 1):80-4. Review. PMID: 11330625 38: Ho E, Quan N, Tsai YH, Lai W, Bray TM. Dietary zinc supplementation inhibits NFkappaB activation and protects against chemically induced diabetes in CD1 mice. Exp Biol Med (Maywood). 2001 Feb;226(2):103-11. PMID: 11446433 39: Dreno B, Moyse D, Alirezai M, Amblard P, Auffret N, Beylot C, Bodokh I, Chivot M, Daniel F, Humbert P, Meynadier J, Poli F; Acne Research and Study Group. Multicenter randomized comparative double-blind controlled clinical trial of the safety and efficacy of zinc gluconate versus minocycline hydrochloride in the treatment of inflammatory acne vulgaris. Dermatology. 2001;203(2):135-40. PMID: 11586012 40: Bhutta ZA, Bird SM, Black RE, Brown KH, Gardner JM, Hidayat A, Khatun F, Martorell R, Ninh NX, Penny ME, Rosado JL, Roy SK, Ruel M, Sazawal S, Shankar A. Therapeutic effects of oral zinc in acute and persistent diarrhea in children in developing countries: pooled analysis of randomized controlled trials. Am J Clin Nutr. 2000 Dec;72(6):1516-22. PMID: 11101480 41: Saple DG, Ravichandran G, Desai A. Evaluation of safety and efficacy of ketoconazole 2% and zinc pyrithione 1% shampoo in patients with moderate to severe dandruff--a postmarketing study. J Indian Med Assoc. 2000 Dec;98(12):810-1. PMID: 11394481 42: Hirt M, Nobel S, Barron E. Zinc nasal gel for the treatment of common cold symptoms: a double-blind, placebo-controlled trial. Ear Nose Throat J. 2000 Oct;79(10):778-80, 782. PMID: 11055098
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43: Sayeg Porto MA, Oliveira HP, Cunha AJ, Miranda G, Guimaraes MM, Oliveira WA, dos Santos DM. Linear growth and zinc supplementation in children with short stature. J Pediatr Endocrinol Metab. 2000 Sep-Oct;13(8):1121-8. PMID: 11085191 44: Umeta M, West CE, Haidar J, Deurenberg P, Hautvast JG. Zinc supplementation and stunted infants in Ethiopia: a randomised controlled trial. Lancet. 2000 Jun 10;355(9220):2021-6. PMID: 10885352 45: Goel A, Chauhan DP, Dhawan DK. Protective effects of zinc in chlorpyrifos induced hepatotoxicity: a biochemical and trace elemental study. Biol Trace Elem Res. 2000 May;74(2):171-83. PMID: 11051590 46: Mocchegiani E, Muzzioli M. Therapeutic application of zinc in human immunodeficiency virus against opportunistic infections. J Nutr. 2000 May;130(5S Suppl):1424S-31S. Review. PMID: 10801955 47: Williams DR. Chemical speciation applied to bio-inorganic chemistry. J Inorg Biochem. 2000 Apr;79(1-4):275-83. Review. PMID: 10830878 48: Tahmaz L, Gokalp A, Kibar Y, Kocak I, Yalcin O, Ozercan Y. Effect of hypothyroidism on the testes in mature rats and treatment with levothyroxine and zinc. Andrologia. 2000 Mar;32(2):85-9. PMID: 10755190 49: Cacic M, Percl M, Jadresin O, Kolacek S. [The role of zinc in the initial treatment of Wilson's disease in children] Lijec Vjesn. 2000 Mar;122(3-4):77-81. Serbo-Croatian (Roman). PMID: 10932534 50: Penland JG. Behavioral data and methodology issues in studies of zinc nutrition in humans. J Nutr. 2000 Feb;130(2S Suppl):361S-364S. Review. PMID: 10721907
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Selenium 50 STUDIES
1: Santamaria A, Salvatierra-Sanchez R, Vazquez-Roman B, Santiago-Lopez D, Villeda-Hernandez J, Galvan-Arzate S, Jimenez-Capdeville ME, Ali SF. Protective effects of the antioxidant selenium on quinolinic acid-induced neurotoxicity in rats: in vitro and in vivo studies. J Neurochem. 2003 Jul;86(2):479-88. PMID: 12871589 2: Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, Zghal K, Fki H, Damak J, Bahloul A. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003 Mar-Apr;49(2):83-94. PMID: 12623744 3: Di Leo MA, Ghirlanda G, Gentiloni Silveri N, Giardina B, Franconi F, Santini SA. Potential therapeutic effect of antioxidants in experimental diabetic retina: a comparison between chronic taurine and vitamin E plus selenium supplementations. Free Radic Res. 2003 Mar;37(3):323-30. PMID: 12688428 4: Xu J, Yang F, Chen L, Hu Y, Hu Q. Effect of selenium on increasing the antioxidant activity of tea leaves harvested during the early spring tea producing season. J Agric Food Chem. 2003 Feb 12;51(4):1081-4. PMID: 12568576 5: Kalinina EP, Zhuravskaia NS, Tsyvkina GI, Koziavina NV. [Correction of immune disorders with neoselenium in patients with chronic bronchitis] Klin Med (Mosk). 2003;81(3):43-6. Russian. PMID: 12698851 6: Chow CK, Hong CB. Dietary vitamin E and selenium and toxicity of nitrite and nitrate. Toxicology. 2002 Nov 15;180(2):195-207. Review. PMID: 12324194 7: El-Bayoumy K, Richie JP Jr, Boyiri T, Komninou D, Prokopczyk B, Trushin N, Kleinman W, Cox J, Pittman B, Colosimo S. Influence of selenium-enriched yeast supplementation on biomarkers of oxidative damage and hormone status in healthy adult males: a clinical pilot study. Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1459-65. PMID: 12433727 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 356
8: Burbano X, Miguez-Burbano MJ, McCollister K, Zhang G, Rodriguez A, Ruiz P, Lecusay R, Shor-Posner G. Impact of a selenium chemoprevention clinical trial on hospital admissions of HIV-infected participants. HIV Clin Trials. 2002 Nov-Dec;3(6):483-91. PMID: 12501132 9: Zuberbuehler CA, Messikommer RE, Wenk C. Choice feeding of selenium-deficient laying hens affects diet selection, selenium intake and body weight. J Nutr. 2002 Nov;132(11):3411-7. PMID: 12421860 10: Arai T, Magori E, Morimoto Y. Changes in activities of enzymes in erythrocytes from ddY mice supplemented with dietary selenium. Exp Anim. 2002 Oct;51(5):517-9. PMID: 12451715 11: Shor-Posner G, Lecusay R, Morales G, Campa A, Miguez-Burbano MJ. Neuroprotection in HIV-positive drug users: implications for antioxidant therapy. J Acquir Immune Defic Syndr. 2002 Oct 1;31 Suppl 2:S84-8. Review. PMID: 12394787 12: Dylewski ML, Mastro AM, Picciano MF. Maternal selenium nutrition and neonatal immune system development. Biol Neonate. 2002 Aug;82(2):122-7. PMID: 12169835 13: Holben DH, Smith AM, Ilich JZ, Landoll JD, Holcomb JP, Matkovic V. Selenium intakes, absorption, retention, and status in adolescent girls. J Am Diet Assoc. 2002 Aug;102(8):1082-7. PMID: 12171452 14: Hintze KJ, Lardy GP, Marchello MJ, Finley JW. Selenium accumulation in beef: effect of dietary selenium and geographical area of animal origin. J Agric Food Chem. 2002 Jul 3;50(14):3938-42. PMID: 12083862 15: Duffield-Lillico AJ, Reid ME, Turnbull BW, Combs GF Jr, Slate EH, Fischbach LA, Marshall JR, Clark LC. Baseline characteristics and the effect of selenium supplementation on cancer incidence in a randomized clinical trial: a summary report of the Nutritional Prevention of Cancer Trial. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 357
Cancer Epidemiol Biomarkers Prev. 2002 Jul;11(7):630-9. PMID: 12101110 16: Popova NV. Perinatal selenium exposure decreases spontaneous liver tumorogenesis in CBA mice. Cancer Lett. 2002 May 8;179(1):39-42. PMID: 11880180 17: Murphy J, Hannon EM, Kiely M, Flynn A, Cashman KD. Selenium intakes in 18-64-y-old Irish adults. Eur J Clin Nutr. 2002 May;56(5):402-8. PMID: 12001010 18: Gierus M, Schwarz FJ, Kirchgessner M. Selenium supplementation and selenium status of dairy cows fed diets based on grass, grass silage or maize silage. J Anim Physiol Anim Nutr (Berl). 2002 Apr;86(3-4):74-82. PMID: 11972675 19: Gartner R, Gasnier BC, Dietrich JW, Krebs B, Angstwurm MW. Selenium supplementation in patients with autoimmune thyroiditis decreases thyroid peroxidase antibodies concentrations. J Clin Endocrinol Metab. 2002 Apr;87(4):1687-91. PMID: 11932302 20: Mehta U, Kang BP, Bansal G, Bansal MP. Studies of apoptosis and bcl-2 in experimental atherosclerosis in rabbit and influence of selenium supplementation. Gen Physiol Biophys. 2002 Mar;21(1):15-29. PMID: 12168721 21: Kurz B, Jost B, Schunke M. Dietary vitamins and selenium diminish the development of mechanically induced osteoarthritis and increase the expression of antioxidative enzymes in the knee joint of STR/1N mice. Osteoarthritis Cartilage. 2002 Feb;10(2):119-26. PMID: 11869071 22: Huang K, Yang S. Inhibitory effect of selenium on Cryptosporidium parvum infection in vitro and in vivo. Biol Trace Elem Res. 2002 Winter;90(1-3):261-72. PMID: 12666840
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23: Gazdik F, Horvathova M, Gazdikova K, Jahnova E. The influence of selenium supplementation on the immunity of corticoid-dependent asthmatics. Bratisl Lek Listy. 2002;103(1):17-21. PMID: 12061081 24: Gazdik F, Kadrabova J, Gazdikova K. Decreased consumption of corticosteroids after selenium supplementation in corticoid-dependent asthmatics. Bratisl Lek Listy. 2002;103(1):22-5. PMID: 12061082 25: Sepulveda RT, Zhang J, Watson RR. Selenium supplementation decreases coxsackievirus heart disease during murine AIDS. Cardiovasc Toxicol. 2002;2(1):53-61. PMID: 12189280 26: Miyazaki Y, Koyama H, Nojiri M, Suzuki S. Relationship of dietary intake of fish and non-fish selenium to serum lipids in Japanese rural coastal community. J Trace Elem Med Biol. 2002;16(2):83-90. PMID: 12195730 27: Muller AS, Pallauf J, Most E. Parameters of dietary selenium and vitamin E deficiency in growing rabbits. J Trace Elem Med Biol. 2002;16(1):47-55. PMID: 11878752 28: de Lorgeril M, Salen P, Accominotti M, Cadau M, Steghens JP, Boucher F, de Leiris J. Dietary and blood antioxidants in patients with chronic heart failure. Insights into the potential importance of selenium in heart failure. Eur J Heart Fail. 2001 Dec;3(6):661-9. PMID: 11738217 29: Sjunnesson H, Sturegard E, Willen R, Wadstrom T. High intake of selenium, beta-carotene, and vitamins A, C, and E reduces growth of Helicobacter pylori in the guinea pig. Comp Med. 2001 Oct;51(5):418-23. PMID: 11924801 30: Kang BP, Mehta U, Bansal MP. Selenium supplementation protects from high fat diet-induced atherogenesis in rats: role of mitogen stimulated lymphocytes and macrophage NO production.
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Indian J Exp Biol. 2001 Aug;39(8):793-7. PMID: 12018582 31: Vinceti M, Wei ET, Malagoli C, Bergomi M, Vivoli G. Adverse health effects of selenium in humans. Rev Environ Health. 2001 Jul-Sep;16(4):233-51. Review. PMID: 12041880 32: Zhang ZW, Shimbo S, Qu JB, Watanabe T, Nakatsuka H, Matsuda-Inoguchi N, Higashikawa K, Ikeda M. Dietary selenium intake of Chinese adult women in the 1990s. Biol Trace Elem Res. 2001 May;80(2):125-38. PMID: 11437178 33: Combs GF Jr. Selenium in global food systems. Br J Nutr. 2001 May;85(5):517-47. Review. PMID: 11348568 34: Finley JW, Ip C, Lisk DJ, Davis CD, Hintze KJ, Whanger PD. Cancer-protective properties of high-selenium broccoli. J Agric Food Chem. 2001 May;49(5):2679-83. PMID: 11368655 35: Federico A, Iodice P, Federico P, Del Rio A, Mellone MC, Catalano G, Federico P. Effects of selenium and zinc supplementation on nutritional status in patients with cancer of digestive tract. Eur J Clin Nutr. 2001 Apr;55(4):293-7. PMID: 11360134 36: Chanoine JP, Neve J, Wu S, Vanderpas J, Bourdoux P. Selenium decreases thyroglobulin concentrations but does not affect the increased thyroxine-to-triiodothyronine ratio in children with congenital hypothyroidism. J Clin Endocrinol Metab. 2001 Mar;86(3):1160-3. PMID: 11238502 37: Naziroglu M, Cay M. Protective role of intraperitoneally administered vitamin E and selenium on the antioxidative defense mechanisms in rats with diabetes induced by streptozotocin. Biol Trace Elem Res. 2001 Feb;79(2):149-59. PMID: 11330521
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38: Kiremidjian-Schumacher L, Roy M. Effect of selenium on the immunocompetence of patients with head and neck cancer and on adoptive immunotherapy of early and established lesions. Biofactors. 2001;14(1-4):161-8. Review. PMID: 11568453 39: Gartner R, Albrich W, Angstwurm MW. The effect of a selenium supplementation on the outcome of patients with severe systemic inflammation, burn and trauma. Biofactors. 2001;14(1-4):199-204. Review. PMID: 11568457 40: Abdollahi M, Rahmat-Jirdeh N, Soltaninejad K. Protection by selenium of lead-acetate-induced alterations on rat submandibular gland function. Hum Exp Toxicol. 2001 Jan;20(1):28-33. PMID: 11339622 41: Berger MM, Reymond MJ, Shenkin A, Rey F, Wardle C, Cayeux C, Schindler C, Chiolero RL. Influence of selenium supplements on the post-traumatic alterations of the thyroid axis: a placebo-controlled trial. Intensive Care Med. 2001 Jan;27(1):91-100. PMID: 11280679 42: Combs GF Jr. Impact of selenium and cancer-prevention findings on the nutrition-health paradigm. Nutr Cancer. 2001;40(1):6-11. Review. PMID: 11799925 43: Kim YS, Milner J. Molecular targets for selenium in cancer prevention. Nutr Cancer. 2001;40(1):50-4. Review. PMID: 11799923 44: Francescato HD, Costa RS, Rodrigues Camargo SM, Zanetti MA, Lavrador MA, Bianchi MD. Effect of oral selenium administration on cisplatin-induced nephrotoxicity in rats. Pharmacol Res. 2001 Jan;43(1):77-82. PMID: 11207069 45: Tutel'ian VA, Khotimchenko SA. [Selenium as an essential and deficient factor in the nutrition of Russian population] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 361
Vestn Ross Akad Med Nauk. 2001;(6):31-4. Russian. PMID: 11517874 46: Shakhovskaia AK, Gmoshinskii IV, Vasil'ev AV, Loranskaia TI, Ovchinnikova IV, Orlova LA, Mazo VK. [Use of organic forms of selenium in nutrition of patients with gastrointestinal diseases] Vopr Pitan. 2001;70(3):22-4. Russian. PMID: 11517685 47: Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris JS, Comstock GW. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23. PMID: 11121464 48: Djujic IS, Jozanov-Stankov ON, Milovac M, Jankovic V, Djermanovic V. Bioavailability and possible benefits of wheat intake naturally enriched with selenium and its products. Biol Trace Elem Res. 2000 Dec;77(3):273-85. PMID: 11204469 49: Sieja K. Protective role of selenium against the toxicity of multi-drug chemotherapy in patients with ovarian cancer. Pharmazie. 2000 Dec;55(12):958-9. No abstract available. PMID: 11189880 50: McKenzie RC. Selenium, ultraviolet radiation and the skin. Clin Exp Dermatol. 2000 Nov;25(8):631-6. Review. PMID: 11167979
Copper 60 Studies
1. Linder MC, Hazegh-Azam M. Copper biochemistry and molecular biology. Am J Clin Nutr. 1996;63(5):797S-811S. (PubMed) 2. Turnlund JR. Copper. In: Shils M, Olson JA, Shike M, Ross AC, eds. Nutrition in Health and Disease. 9th ed. Baltimore: Williams & Wilkins; 1999:241-252.
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3. Uauy R, Olivares M, Gonzalez M. Essentiality of copper in humans. Am J Clin Nutr. 1998;67(5 Suppl):952S-959S. (PubMed) 4. Harris ED. Copper. In: O'Dell BL, Sunde RA, eds. Handbook of nutritionally essential minerals. New York: Marcel Dekker, Inc; 1997:231-273. 5. Food and Nutrition Board, Institute of Medicine. Copper. Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academy Press; 2001:224-257. (National Academy Press) 6. Johnson MA, Fischer JG, Kays SE. Is copper an antioxidant nutrient? Crit Rev Food Sci Nutr. 1992;32(1):1-31. 7. Finley EB, Cerklewski FL. Influence of ascorbic acid supplementation on copper status in young adult men. Am J Clin Nutr. 1983;37(4):553-556. (PubMed) 8. Jacob RA, Skala JH, Omaye ST, Turnlund JR. Effect of varying ascorbic acid intakes on copper absorption and ceruloplasmin levels of young men. J Nutr. 1987;117(12):2109-2115. (PubMed) 9. Percival SS, Kauwell GP, Bowser E, Wagner M. Altered copper status in adult men with cystic fibrosis. J Am Coll Nutr. 1999;18(6):614-619. (PubMed) 10. Fox PL, Mazumder B, Ehrenwald E, Mukhopadhyay CK. Ceruloplasmin and cardiovascular disease. Free Radic Biol Med. 2000;28(12):1735-1744. (PubMed) 11. Jones AA, DiSilvestro RA, Coleman M, Wagner TL. Copper supplementation of adult men: effects on blood copper enzyme activities and indicators of cardiovascular disease risk. Metabolism. 1997;46(12):1380-1383. (PubMed) 12. Ford ES. Serum copper concentration and coronary heart disease among US adults. Am J Epidemiol. 2000;151(12):1182-1188. (PubMed) 13. Klevay LM. Cardiovascular disease from copper deficiency--a history. J Nutr. 2000;130(2S Suppl):489S-492S. (PubMed) 14. Kinsman GD, Howard AN, Stone DL, Mullins PA. Studies in copper status and atherosclerosis. Biochem Soc Trans. 1990;18(6):1186-1188. (PubMed) 15. Mielcarz G, Howard AN, Mielcarz B, et al. Leucocyte copper, a marker of copper body status is low in coronary artery disease. J Trace Elem Med Biol. 2001;15(1):31-35. (PubMed) 16. Wang XL, Adachi T, Sim AS, Wilcken DE. Plasma extracellular superoxide dismutase levels in an Australian population with coronary artery disease. Arterioscler Thromb Vasc Biol. 1998;18(12):1915-1921. (PubMed) 17. Klevay LM. Lack of a recommended dietary allowance for copper may be hazardous to your health. J Am Coll Nutr. 1998;17(4):322-326. (PubMed) 18. Milne DB, Nielsen FH. Effects of a diet low in copper on copper-status indicators in postmenopausal women. Am J Clin Nutr. 1996;63(3):358-364. (PubMed)
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19. Medeiros DM, Milton A, Brunett E, Stacy L. Copper supplementation effects on indicators of copper status and serum cholesterol in adult males. Biol Trace Elem Res. 1991;30(1):19-35. (PubMed) 20. Turley E, McKeown A, Bonham MP, et al. Copper supplementation in humans does not affect the susceptibility of low density lipoprotein to in vitro induced oxidation (FOODCUE project). Free Radic Biol Med. 2000;29(11):1129-1134. (PubMed) 21. Rock E, Mazur A, O'Connor J M, Bonham MP, Rayssiguier Y, Strain JJ. The effect of copper supplementation on red blood cell oxidizability and plasma antioxidants in middle-aged healthy volunteers. Free Radic Biol Med. 2000;28(3):324-329. (PubMed) 22. Percival SS. Copper and immunity. Am J Clin Nutr. 1998;67(5 Suppl):1064S-1068S. (PubMed) 23. Failla ML, Hopkins RG. Is low copper status immunosuppressive? Nutr Rev. 1998;56(1 Pt 2):S59-64.
24. Heresi G, Castillo-Duran C, Munoz C, Arevalo M, Schlesinger L. Phagocytosis and immunoglobulin levels in hypocupremic children. Nutr Res. 1985;5:1327-1334. 25. Kelley DS, Daudu PA, Taylor PC, Mackey BE, Turnlund JR. Effects of low-copper diets on human immune response. Am J Clin Nutr. 1995;62(2):412-416. (PubMed) 26. Conlan D, Korula R, Tallentire D. Serum copper levels in elderly patients with femoral-neck fractures. Age Ageing. 1990;19(3):212-214. (PubMed) 27. Eaton-Evans J, Mellwrath EM, Jackson WE, McCartney H, Strain JJ. Copper supplementation and the maintenance of bone mineral density in middle-aged women. J Trace Elem Exp Med. 1996;9:87-94. 28. Baker A, Harvey L, Majask-Newman G, Fairweather-Tait S, Flynn A, Cashman K. Effect of dietary copper intakes on biochemical markers of bone metabolism in healthy adult males. Eur J Clin Nutr. 1999;53(5):408-412. (PubMed) 29. Baker A, Turley E, Bonham MP, et al. No effect of copper supplementation on biochemical markers of bone metabolism in healthy adults. Br J Nutr. 1999;82(4):283-290. (PubMed) 30. Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001. 31. Bremner I. Manifestations of copper excess. Am J Clin Nutr. 1998;67(5 Suppl):1069S-1073S. (PubMed) 32. Fitzgerald DJ. Safety guidelines for copper in water. Am J Clin Nutr. 1998;67(5 Suppl):1098S-1102S. (PubMed) 33. Wood RJ, Suter PM, Russell RM. Mineral requirements of elderly people. Am J Clin Nutr. 1995;62(3):493-505. (PubMed)
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34. Br J Nutr. 2003 Jul;90(1):161-8. Adaptive responses in men fed low- and high-copper diets. Majsak-Newman G, Dainty JR, Lewis DJ, Langford NJ, Crews HM, Fairweather-Tait SJ. PMID: 12844388 35. Eur J Clin Nutr. 2003 May;57(5):706-12. Copper and zinc intake and serum levels in patients with juvenile rheumatoid arthritis. Silverio Amancio OM, Alves Chaud DM, Yanaguibashi G, Esteves Hilario MO. PMID: 12771972 36. J Dairy Sci. 2003 Apr;86(4):1240-9. Role of dietary copper in enhancing resistance to Escherichia coli mastitis. Scaletti RW, Trammell DS, Smith BA, Harmon RJ. PMID: 12741549 37. Contraception. 2003 Feb;67(2):161-3. Human spermatozoa motility analysis in a Ringer's solution containing cupric ions. Araya R, Gomez-Mora H, Vera R, Bastidas JM. PMID: 12586326 38. J Nutr. 2003 Feb;133(2):522-7. Low dietary copper increases fecal free radical production, fecal water alkaline phosphatase activity and cytotoxicity in healthy men. Davis CD. PMID: 12566494 39. J Nutr. 2002 Oct;132(10):3142-5. The timing of perinatal copper deficiency in mice influences offspring survival. Prohaska JR, Brokate B. PMID: 12368408 40. Am J Clin Nutr. 2002 Sep;76(3):687-8; author reply 688. Extra dietary copper inhibits LDL oxidation. Klevay LM. PMID: 12198019 41. Vet Rec. 2002 Jul 13;151(2):50-3. Effects of copper supplementation on the copper status of peripartum beef cows and their calves. Enjalbert F, Lebreton P, Salat O, Meschy F, Schelcher F. PMID: 12148603 42. Ceska Slov Farm. 2002 Jul;51(4):205-7. Anti-inflammatory activity of (o-cresotinate) copper and zinc aquacomplexes Sokolik J, Tumova I, Blahova M, Bernathova M, Svec P. PMID: 12183910 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 365
43. J Anim Sci. 2002 Jul;80(7):1999-2005. Effects of dietary copper on the expression of lipogenic genes and metabolic hormones in steers. Lee SH, Engle TE, Hossner KL. PMID: 12162670 44. J Nutr. 2002 May;132(5):1018-25. Dietary copper affects azoxymethane-induced intestinal tumor formation and protein kinase C isozyme protein and mRNA expression in colon of rats. Davis CD, Johnson WT. PMID: 11983831 45. Proc Nutr Soc. 2002 May;61(2):181-5. Is there a potential therapeutic value of copper and zinc for osteoporosis? Lowe NM, Lowe NM, Fraser WD, Jackson MJ. PMID: 12133199 46. Bull Exp Biol Med. 2002 Apr;133(4):334-5. Protective effect of copper-rutin complex in animals with experimental epilepsy. Tsaryuk VV, Potapovich AI, Kostyuk VA. PMID: 12124637 47. J Nutr. 2002 Feb;132(2):190-6. Skeletal unloading and dietary copper depletion are detrimental to bone quality of mature rats. Smith BJ, King JB, Lucas EA, Akhter MP, Arjmandi BH, Stoecker BJ. PMID: 11823577 48. Trop Anim Health Prod. 2002 Feb;34(1):75-80. A possible association between dietary intake of copper, zinc and phosphate and delayed puberty in heifers in Sudan. Ahmed MM, Fadlalla IM, Barri ME. PMID: 11887424 49. J Exp Biol. 2002 Jan;205(Pt 2):279-90. Copper metabolism in actively growing rainbow trout (Oncorhynchus mykiss): interactions between dietary and waterborne copper uptake. Kamunde C, Grosell M, Higgs D, Wood CM. PMID: 11821494 50. Nutrition. 2001 Sep;17(9):701-8. Low dietary zinc alters indices of copper function and status in postmenopausal women. Milne DB, Davis CD, Nielsen FH. PMID: 11527655
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51. J Nutr. 2001 Aug;131(8):2171-6. A longitudinal investigation of aggregate oral intake of copper. Pang Y, MacIntosh DL, Ryan PB. PMID: 11481413 52. J Anim Physiol Anim Nutr (Berl). 2001 Feb;85(1-2):29-37. The lowering effect of high copper intake on selenium retention in weanling rats depends on the selenium concentration of the diet. Yu S, Beynen AC. PMID: 11686770 53. Gig Sanit. 2001 Jan-Feb;(1):54-7. Providing athletes with trace elements during intensive exercise Nasolodin VV, Gladkikh IP, Meshcheriakov SI. PMID: 11236477 54. Biol Trace Elem Res. 2000 Dec;77(3):241-9. Effect of dietary copper on selenium toxicity in Fischer 344 rats. Tatum L, Shankar P, Boylan LM, Spallholz JE. PMID: 11204466 55. J Nutr. 2000 Nov;130(11):2838-43. Zinc and copper intakes and their major food sources for older adults in the 1994-96 continuing survey of food intakes by individuals (CSFII). Ma J, Betts NM. PMID: 11053529 56. Cancer Lett. 2000 Oct 16;159(1):57-62. Inadequate dietary copper increases tumorigenesis in the Min mouse. Davis CD, Newman S. PMID: 10974406 57. Inflamm Res. 2000 May;49(5):214-23. Nutritional supplementation with copper in the rat. I. Effects on adjuvant arthritis development and on some in vivo- and ex vivo-markers of blood neutrophils. Milanino R, Marrella M, Crivellente F, Benoni G, Cuzzolin L. PMID: 10893044 58. Nippon Ronen Igakkai Zasshi. 2000 Apr;37(4):304-8. Copper supplement with cocoa for copper deficiency in patients with long-term enteral nutrition Wakugami K, Suenaga H, Egashira A, Taira T, Tokashiki T, Yamazaki T, Maehara A, Uechi K. PMID: 10917028
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59. Proc Soc Exp Biol Med. 2000 Mar;223(3):282-7. Alterations in hypertrophic gene expression by dietary copper restriction in mouse heart. Kang YJ, Wu H, Saari JT. PMID: 10719841 60. Ann Nutr Metab. 2000;44(3):129-34. Plasma copper concentration as marker of copper intake from food. Konig JS, Elmadfa I. PMID: 11053900
Quercetin 20 STUDIES
1. Pharmacology. 2003 Oct;69(2):59-67. Protective Effect of Flavonoids against Agingand Lipopolysaccharide-Induced Cognitive Impairment in Mice. Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, Kulkarni SK. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 2. Clin Pharmacokinet. 2003;42(5):437-59. Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress. Schwedhelm E, Maas R, Troost R, Boger RH. Institute of Experimental and Clinical Pharmacology, Clinical Pharmacology Unit, University Hospital of Hamburg-Eppendorf, Hamburg, Germany. schwedhelm@ukehamburg.de 3. Neurobiol Aging. 2002 Sep-Oct;23(5):891-97. Natural extracts as possible protective agents of brain aging. Bastianetto S, Quirion R. Department of Psychiatry and Pharmacology and Therapeutics, Douglas Hospital Research Centre, McGill University, 6875 LaSalle Boulevard, Verdun, Que, Canada H4H 1R3. 4. Mol Biol Cell. 2002 Jul;13(7):2502-17. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Volonte D, Zhang K, Lisanti MP, Galbiati F. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. 5. Mech Ageing Dev. 2000 Dec 20;121(1-3):217-30. Antioxidants may contribute in the fight against ageing: an in vitro model. Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar P, Powell JR. Molecular Physiology, Unilever Research Laboratory Colworth, Sharnbrook, Bedford MK44 1LQ, UK. 6. Eur J Clin Nutr. 2000 May;54(5):415-7. Quercetin intake and the incidence of cerebrovascular disease. Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 368
Hakkinen S, Aromaa A, Reunanen A. National Public Health Institute, Helsinki, Finland. paul.knekt@ktl.fi 7. Free Radic Biol Med. 1997;22(4):669-78. Quercetin protects cutaneous tissueassociated cell types including sensory neurons from oxidative stress induced by glutathione depletion: cooperative effects of ascorbic acid. Skaper SD, Fabris M, Ferrari V, Dalle Carbonare M, Leon A. Researchlife S.c.p.A., Castelfranco Veneto, Italy. 8. Exp Gerontol. 1982;17(3):213-7. Quercetin, flavonoids and the life-span of mice. Jones E, Hughes RE. 9. Biochem Pharmacol. 1992 Mar 17;43(6):1167-79. Effects of flavonoids on immune and inflammatory cell functions. Middleton E Jr, Kandaswami C. Department of Medicine, State University of New York, Buffalo 14203. 10. Lancet. 1993 Oct 23;342(8878):1007-11. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. National Institute of Public Health and Environment Protection, Bilthoven, Netherlands. 11. Surgery. 2002 Feb;131(2):198-204. Quercetin inhibits human vascular smooth muscle cell proliferation and migration. Alcocer F, Whitley D, Salazar-Gonzalez JF, Jordan WD, Sellers MT, Eckhoff DE, Suzuki K, Macrae C, Bland KI. Department of Surgery, University of Alabama at Birmingham, 35294-0007, USA. 12. Res Commun Chem Pathol Pharmacol. 1992 Nov;78(2):211-8. Changes in the xanthine dehydrogenase/xanthine oxidase ratio in the rat kidney subjected to ischemiareperfusion stress: preventive effect of some flavonoids. Sanhueza J, Valdes J, Campos R, Garrido A, Valenzuela A. Unidad de Bioquimica Farmacologica y Lipidos, INTA, Universidad de Chile, Santiago. 13. Methods Find Exp Clin Pharmacol. 2001 May;23(4):175-81. Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats. Satyanarayana PS, Singh D, Chopra K. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 14. Free Radic Biol Med. 2002 Jul 1;33(1):63-70. Quercetin metabolism in the lens: role in inhibition of hydrogen peroxide induced cataract. Cornish KM, Williamson G, Sanderson J. School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK. 15. Zhongguo Yao Li Xue Bao. 1999 May;20(5):426-30. Quercetin decreased heart rate and cardiomyocyte Ca2+ oscillation frequency in rats and prevented cardiac hypertrophy in mice. Wang Y, Wang HY, Yuan ZK, Zhao XN, Wang JX, Zhang ZX. School of Medicine, State Key Laboratory of Coordination Chemistry, Nanjing University, China.
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16. Preferential requirement for protein tyrosine phosphatase activity in the 12-Otetradecanoylphorbol-13-acetate-induced differentiation of human colon cancer cells. Kuo ML, Huang TS, Lin JK. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei. Biochem Pharmacol; 50(8):1217-22 1995 17. Effect of Quercitrin on acute and chronic experimental colitis in the rat De Medina F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A. F.S. De Medina, Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada Spain Journal of Pharmacology and Experimental Therapeutics (USA) , 1996, 278/2 (771-779) 18. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada. Nutrition and Cancer (USA) , 1996, 26/2 (167 181) 19. Gitika B, Sai Ram M, Sharma SK, Ilavazhagan G, Banerjee PK. Quercetin protects C6 glial cells from oxidative stress induced by tertiarybutylhydroperoxide. Free Radic Res. 2006 Jan;40(1):95-102. PMID: 16298764 20. Yang JH, Hsia TC, Kuo HM, Lee Chao PD, Chou CC, Wei YH, Chung JG. Inhibition of Lung Cancer Cell Growth by Quercetin Glucuronides via G2/M Arrest and Induction of Apoptosis. Drug Metab Dispos. 2005 Nov 9; [Epub ahead of print] PMID: 16280456 [PubMed - as supplied by publisher]
Astaxanthin 20 STUDIES
1. Mol Cells. 2003 Aug 31;16(1):97-105. Astaxanthin inhibits nitric oxide production and inflammatory gene expression by suppressing I(kappa)B kinase-dependent NF-kappaB activation. Lee SJ, Bai SK, Lee KS, Namkoong S, Na HJ, Ha KS, Han JA, Yim SV, Chang K, Kwon YG, Lee SK, Kim YM. Vascular System Research Center and Department of Molecular and Cellular Biochemistry, Kangwon National University Biology, Chunchon 200-701, Korea. 2. Biochem Biophys Res Commun. 2003 Aug 1;307(3):704-12.
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Direct superoxide anion scavenging by a disodium disuccinate astaxanthin derivative: Relative efficacy of individual stereoisomers versus the statistical mixture of stereoisomers by electron paramagnetic resonance imaging. Cardounel AJ, Dumitrescu C, Zweier JL, Lockwood SF. Davis Heart and Lung Research Institute, 473 West 12th Avenue, Columbus, OH 432101252, USA. 3. Eur J Pharm Sci. 2003 Jul;19(4):299-304. Oral bioavailability of the antioxidant astaxanthin in humans is enhanced by incorporation of lipid based formulations. Mercke Odeberg J, Lignell A, Pettersson A, Hoglund P. Department of Clinical Pharmacology, Lund University Hospital, S-221 85 Lund, Sweden. johanna.odeberg@klinfarm.lu.se 4. J Med Food. 2003 Spring;6(1):51-6. Safety of an astaxanthin-rich Haematococcus pluvialis algal extract: a randomized clinical trial. Spiller GA, Dewell A. Health Research and Studies Center, Los Altos, CA 94023, USA. spiller@sphere.org 5. Invest Ophthalmol Vis Sci. 2003 Jun;44(6):2694-701. Effects of astaxanthin on lipopolysaccharide-induced inflammation in vitro and in vivo. Ohgami K, Shiratori K, Kotake S, Nishida T, Mizuki N, Yazawa K, Ohno S. Department of Ophthalmology and Visual Sciences, Hokkaido University Graduate School of Medicine, Sapporo, Japan. kohgami@med.hokudai.ac.jp 6. Trends Biotechnol. 2003 May;21(5):210-6. Haematococcus astaxanthin: applications for human health and nutrition. Guerin M, Huntley ME, Olaizola M. Mera Pharmaceuticals Inc., 73-4460 Queen Kaahumanu Hwy, Suite 110, Kailua-Kona, 96740, Hawaii, USA 7. Redox Rep. 2002;7(5):290-3. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 371
Astaxanthin protects beta-cells against glucose toxicity in diabetic db/db mice. Uchiyama K, Naito Y, Hasegawa G, Nakamura N, Takahashi J, Yoshikawa T. First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan. 8. J Pharm Sci. 2003 Apr;92(4):922-6. Improved aqueous solubility of crystalline astaxanthin (3,3'-dihydroxy-beta, betacarotene-4,4'-dione) by Captisol (sulfobutyl ether beta-cyclodextrin). Lockwood SF, O'Malley S, Mosher GL. Hawaii Biotech, Inc., 99-193 Aiea Heights Drive, Suite 200, Aiea, Hawaii 96701, USA. slockwood@hibiotech.com 9. Antioxid Redox Signal. 2003 Feb;5(1):139-44. Astaxanthin limits exercise-induced skeletal and cardiac muscle damage in mice. Aoi W, Naito Y, Sakuma K, Kuchide M, Tokuda H, Maoka T, Toyokuni S, Oka S, Yasuhara M, Yoshikawa T. Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, 602-0841. 10. Comp Biochem Physiol C Toxicol Pharmacol. 2002 Nov;133(3):443-51. Astaxanthin and canthaxanthin do not induce liver or kidney xenobiotic-metabolizing enzymes in rainbow trout (Oncorhynchus mykiss Walbaum). Page GI, Davies SJ. Fish Nutrition Unit, Department of Biological Sciences, University of Plymouth, Drake Circus, Plymouth PL4 8AA, UK. pagegi@mapleleaf.ca 11. J Dermatol Sci. 2002 Oct;30(1):73-84. Modulatory effects of an algal extract containing astaxanthin on UVA-irradiated cells in culture. Lyons NM, O'Brien NM. Department of Food Science, Food Technology and Nutrition, University College Cork, Cork, Ireland. nob@ucc.ie 12. Life Sci. 2002 Apr 21;70(21):2509-20. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 372
Contribution of the antioxidative property of astaxanthin to its protective effect on the promotion of cancer metastasis in mice treated with restraint stress. Kurihara H, Koda H, Asami S, Kiso Y, Tanaka T. Institute for Health Care Science, Suntory Ltd., 1-1-1 Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka 618-8503, Japan. Hiroshi_Kurihara@suntory.co.jp 13. Arch Toxicol. 2002 Jan;75(11-12):665-75. Metabolism and CYP-inducer properties of astaxanthin in man and primary human hepatocytes. Kistler A, Liechti H, Pichard L, Wolz E, Oesterhelt G, Hayes A, Maurel P. Vitamins and Fine Chemicals, Human Nutrition and Health, F. Hoffmann-La Roche Ltd, Basel, Switzerland. kistlera@bluewin.ch 14. J Reprod Fertil Suppl. 2001;57:331-4. Effect of supplementation with the antioxidant astaxanthin on reproduction, pre-weaning growth performance of kits and daily milk intake in mink. Hansen KB, Tauson AH, Inborr J. Department of Animal Science and Animal Health, Royal Veterinary and Agricultural University, Gronnegardsvej 3, 1870 Frederiksberg C, Denmark. 15. Biochem Biophys Res Commun. 2001 Oct 19;288(1):225-32. Astaxanthin and peridinin inhibit oxidative damage in Fe(2+)-loaded liposomes: scavenging oxyradicals or changing membrane permeability? Barros MP, Pinto E, Colepicolo P, Pedersen M. Department of Botany, Stockholm University, SE-10691 Stockholm, Sweden. mpbarros@botan.su.se 16. J Atheroscler Thromb. 2000;7(4):216-22. Inhibition of low-density lipoprotein oxidation by astaxanthin. Iwamoto T, Hosoda K, Hirano R, Kurata H, Matsumoto A, Miki W, Kamiyama M, Itakura H, Yamamoto S, Kondo K. National Institute of Health and Nutrition, Tokyo, Japan. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 373
17. Methods Find Exp Clin Pharmacol. 2001 Mar;23(2):79-84. Effect of astaxanthin on the hepatotoxicity, lipid peroxidation and antioxidative enzymes in the liver of CCl4-treated rats. Kang JO, Kim SJ, Kim H. Department of Food and Nutrition, College of Human Ecology, Seoul National University, Korea. 18. Biochim Biophys Acta. 2001 Jun 6;1512(2):251-8. Efficient radical trapping at the surface and inside the phospholipid membrane is responsible for highly potent antiperoxidative activity of the carotenoid astaxanthin. Goto S, Kogure K, Abe K, Kimata Y, Kitahama K, Yamashita E, Terada H. Faculty of Pharmaceutical Sciences, University of Tokushima, Japan. Kogure@ph.tokushima-u.ac.jp 19. 0955-2863. 2000 Oct;11(10):482-490. Plasma appearance and distribution of astaxanthin E/Z and R/S isomers in plasma lipoproteins of men after single dose administration of astaxanthin(1). Osterlie M, Bjerkeng B, Liaaen-Jensen S. HIST, Department of Food Science, N-7004, Trondheim, Norway 20. Antimicrob Agents Chemother. 2000 Sep;44(9):2452-7. Astaxanthin-rich algal meal and vitamin C inhibit Helicobacter pylori infection in BALB/cA mice. Wang X, Willen R, Wadstrom T. Department of Infectious Diseases and Medical Microbiology, University of Lund, Sweden.
L-Carnosine - 28 Studies
1. Stadtman ER. Protein oxidation and aging. Science. 1992; 257(5074):1220-4. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 374
2. Preston JE, Hipkiss AR, Himsworth DT, et al. Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and betaalanine. Neurosci Lett. 1998; 242(2):105-8. 3. Stadtman ER, Levine RL. Protein oxidation. Ann NY Acad Sci. 2000; 899:191-208. 4. Bierhaus A, Hofmann MA, Ziegler R, et al. AGEs and their interaction with AGEreceptors in vascular disease and diabetes mellitus. I. The AGE concept. Cardiovascular Research. 1998; 37(3):586-600. 5. Munch G, Schinzel R, Loske C, et al. Alzheimer's disease-synergistic effects of glucose deficit, oxidative stress and advanced glycation endproducts. Journal of Neural Transmission. 1998; 105(4-5):439-61. 6. Hipkiss AR, Michaelis J, Syrris P. Non-enzymatic glycosylation of the dipeptide Lcarnosine, a potential anti-protein-cross-linking agent. FEBS Lett. 1995; 371(1):81-5. 7. Munch G, Mayer S, Michaelis J, et al. Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Biochim Biophys Acta. 1997; 1360(1):17-29. 8. Hipkiss AR, Chana H. Carnosine protects proteins against methylglyoxal-mediated modifications. Biochem Biophys Res Commun. 1998; 248(1):28-32. 9. Brownson C, Hipkiss AR. Carnosine reacts with a glycated protein. Free Radic Biol Med. 2000; 28(10):1564-70. 10. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci Lett. 1997; 238(3):135-8. 11. Boldyrev AA, Stvolinsky SL, Tyulina OV, et al. Biochemical and physiological evidence that carnosine is an endogenous neuroprotector against free radicals. Cell Mol Neurobiol. 1997; 17(2):259-71. 12. Hipkiss AR, Preston JE, Himsworth DT, et al. Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Ann NY Acad Sci. 1998; 854:37-53. 13. McFarland GA, Holliday R. Retardation of the senescence of cultured human diploid fibroblasts by carnosine. Exp Cell Res. 1994; 212(2):167-75. 14. McFarland GA, Holliday R. Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts. Exp Gerontol. 1999; 34(1):35-45.
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15. Yuneva MO, Bulygina ER, Gallant SC, et al. Effect of carnosine on age-induced changes in senescence-accelerated mice. J Anti-Aging Med. 1999; 2(4):337-42. 16. Horning MS, Blakemore LJ, Trombley PQ. Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. Brain Res. 2000; 852(1):56-61. 17. Huang X, Cuajungco MP, Atwood CS, et al. Cu(II) potentiation of alzheimer Ab neurotoxicity. Correlation with cell-free hydrogen peroxide production and metal reduction. J Biol Chem. 1999; 274(52):37111-6. 18. Atwood CS, Moir RD, Huang X, et al. Dramatic aggregation of Alzheimer Ab by Cu(II) is induced by conditions representing physiological acidosis. J Biol Chem. 1998; 273(21):12817-26. 19. Cherny RA, Legg JT, McLean CA, et al. Aqueous dissolution of Alzheimer's disease Ab amyloid deposits by biometal depletion. J Biol Chem. 1999; 274(33):23223-8. 20. Gulyaeva NV. Superoxide-scavenging activity of carnosine in the presence of copper and zinc ions. Biochemistry (Moscow). 1987; 52(7 Part 2):1051-4. 21. de la Torre JC. Cerebromicrovascular pathology in Alzheimer's disease compared to normal aging. Gerontology. 1997; 43(1-2):26-43. 22. Hipkiss AR, Preston JE, Himswoth DT, et al. Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Neurosci Lett. 1997; 238(3):135-8. 23. Doble A. The role of excitotoxicity in neurodegenerative disease: implications for therapy. Pharmacol Ther. 1999; 81(3):163-221. 24. Boldyrev A, Song R, Lawrence D, et al. Carnosine protects against excitotoxic cell death independently of effects on reactive oxygen species. Neuroscience. 1999; 94(2):571-7. 25. Stvolinsky SL, Kukley ML, Dobrota D, et al. Carnosine: an endogenous neuroprotector in the ischemic brain. Cell Mol Neurobiol. 1999; 19(1):45-56. 26. Nagai K, Suda T, Kawasaki K, et al. Action of carnosine and beta-alanine on wound healing. Surgery. 1986;100(5):815-21. 27. Vizioli MR, Blumen G, Almeida OP, et al. Effects of carnosine on the development of rat sponge-induced granulation tissue. II. Histoautoradiographic observations on collagen biosynthesis. Cell Mol Biol. 1983; 29(1):1-9. 28. Ikeda D, Wada S, Yoneda C, et al. Carnosine stimulates vimentin expression in cultured rat fibroblasts. Cell Struct Funct. 1999; 24(2):79-87. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 376
Lycopene
50 Studies
1:Agarwal, S., and Rao A.V.; Tomato lycopene and low-density lipoprotein oxidation: a human dietary intervention study. Lipids, 33, 981-984 (1998). 2: Batieha, A.M,, Armenian, H.K., Norkus, E.P., Morris, J.,S., Spate, V.E., and Comstock, G.W. Serum micronutrients and subsequent risk of cervical cancer in a population-based nested case-control study. Cancer Epiderniol. Biomarkers Prev, 2: 335339 (1993.). 3: Belakbir, A., Ruiz, J.M., and Romero, L.; Yield and fruit quality of pepper (Capsicum annuum L.) in response to bioregulators. HortScience. 33(l): 85-87 (1998). 4: Ben-Shaul, Y. and Naftali, Y.; The development and ultrastructure of lycopene bodies in chromoplasts of Lycopersicum esculentum. Protoplasma 67: 333-344 (1969) 5: Bien, J.G., Brown, E.D., and Smith, J.C.; Determination of individual carotenoids in human plasma by high performance liquid chromatography. J. Liq. Chromatog. 8: 473484 (1985). 6: Bjelke, F.; Case-control study in Norway, Scand. J. Gastroenterol. 9: 42-49 (1974). 7: Block, G., Patterson, B., and Subar, A.; Fruit, vegetables, and cancer prevention: A review of the epidemi-ological evidence. Nutr. Cancer 18: 1-29 (1992). 8: Boskovic, M.A.; 1979. Fate of lycopene in dehydrated tomato products: Carotenoid isomerization in food systems. J. Food Sci. 44: 84-86 (1979). 9: Brady, W.E., Mares-Perlman, J.A., Bowen, R. and Stacewicz-Sapuntzakis, M.; Human serum carotenoid concentrations are related to physiologic and lifestyle factors. J. Nutr. 1 26(l): 129-137 (1996). 10: Britton, G.; "Carotenoids: Spectroscopy," 1B: pp, 57. Birkhauser Verlag, Boston, (1995). 11: Bushway, R.J.; Separation of carotenoids in fruits and vegetables by high performance liquid chromatography. J. Liq. Chromatog, 8: 1527-1547 (1985). 12: Cano, M, P., Ancos, B., Lobo, G., Monreal, M., and De-Ancos, B.; Effects of freezing and canning of papaya slices on their carotenoid composition. Z. Lebensmittel Unters. Forsch. 202(4): 279-284 (1996).
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13: Chandler, L.A. and Schwartz, S.J.; Isomerization and losses of trans-beta-carotene in sweet potatoes as affected by processing treatments. J. Agric Food Chem. 36:129-133 (1988). 14: Choo, YM., Yap, S.C., Ooi, C.X., Ma, A.X., Goh, S.H., and Ong, S.H.; Recovered oil from palm-pressed fiber: A good source of natural carotenoids, vitamin E, and sterols. JAOCS 73: 599-602 (1996). 15: Clinton, S.K., Emenhiser, C., Schwartz, S.J., Bostwick, D.G., Williams, A.W., Moore, B.J., and Erdman, J.W.; Cis-trans lycopene isomers, carotenoids, and retinol in the human prostate. Cancer Epidemiol. Biomarkers Prev. 5: 823-833 (1996). 16: Clinton, S.K.; Lycopene: Chemistry. biology, and implications for human health and disease. Nutr. Rev. 56(2): 35-51 (1998). 17: Colditz, G.A., Branch, L,G., and Lipnick, R.J.; Increased green and yellow vegetable intake and lowered cancer deaths in an elderly population. Am. Clin. Nutr. 41: 32-36 (1985). 18: Cole, E.R. and Kapur, N.S. ; The stability of lycopene. II. Oxidation during heating of tomato pulps. J. Sci. Food Agric. 8: 366-368 (1957). 19: Cole, E.R., and Kapur, N.S.; The stability of lycopene. I. Degradation by oxygen. J. Sci. Food Agric. 8: 360-365 (1957). 20: Cook-Mozaffari, P.J., Azordegan, F., and Day, N.E.; Oseophageal cancer studies in the Caspian Litoral of Iran: Results of a case-control study. Brit. J. Cancer 39: 292-309 (1979). 21: Countryman, C., Bankson, D., Collins, S., Man, B., and Lin, W.; Lycopene inhibits the growth of the HL-60 promyelocylic leukemia cell line. Clin. Chem. 37:1056 (1991). 22: Craft, N.E.; Carotenoid reversed-phase high-performance liquid chromatography methods: Reference compendium. Meth. Enzymol. 213: 185-205 (1992). 23: Crouzet, J., and Kanasawud, P.; . Formation of volatile compounds by thermal degradation of carotenoids. Meth. Enzymol. 213: 54-62 (1992). 24: Davies, B.H.; Carotenoids, In "Chemistry and Biochemistry of Plant Pigments," Vol. 2, 2nd ed., ed. T.W. Goodwin, pp. 38-165. Academic Press, New York (1976). 25: Di Mascio, P., Kaiser, S., and Sies, H.; Lycopene as the most efficient biological carotenoid singlet oxygen quencher. Arch. Biochem. Biophys. 274: 532-538 (1989). 26: Diaz, M.N., Frei, B., Vita, J.A., and Keaney, J.F.; Antioxidants and atherosclerotic heart disease. New Eng. J. Med. 337: 408-416 (1997).. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 378
27: Duggar, B.M.; Lycopersicon: The red pigment of the tomato and the effects of conditions on its development. Washington Univ. Stud., 1: 22-45 (1913). 28: Duke, J.A. and Beckstrom-Stemberg, S.M.; Plants containing lycopene. Phytochemical database. USDA NCI Carotencid Food Composition Database. Agric. Res, Service, U.S. Dept. of Agriculture, Beltsville, Md. (1998). 29: Duke, J.A.; "Handbook of Phytochemical Constituents of GRAS Herbs and Other Economic Plants." CRC Press, Boca Raton, Fla.(1992). 30: Emenhiser, C., Sander, L.C., and Schwartz, S J.; Capabilitry of a polymeric C30 stationary phase to resolve cis-trans carotenoid isomers in reversed-phase liquid chromatography J. Chromatog A 707: 205 216 (1995). 31: Emenhiser, C., Simunovic, N, Sander, L. C., and Schwartz, S.J.; Separation of geometric isomers in biological extracts using a polymeric C 30 column in reversedphase liquid chromatography. J. Agric. Food Chem. 44: 3887-3893 (1996). 32: Epler, K,S., Sander, L.G, Ziegler, R.G., Wise, S.A., and Craft, N.E.; Evaluation of reversed-phase liquid chromatographic columns for recovery and selectivity ofselected carotenoids. J. Chromatog. 595: 89-101 (1992). 33: Ferruzzi, M.G., Sander, L.C., Rock, C.L., and Schwartz. S J.; Carotenoid determination in biological microsamples using liquid chromatography with a coulometric electrochemical array detector. Anal. Biochem. 256: 74-81 (1998). 34: Forman. M.R., et.al.; The correlation between two dietary assessments of carotenoid intake and plasma Garotenoid concentrations: Application of a carotenoid food composition database. Am. J. Clin, Nutr 58: 519-24 (1993). 35: Franceschi, S., Bidoli, E., La Vecchia, G., Talamini, R., D'Avanzo, B., and Negri, E.; Tomatoes and risk of digestive-tract cancers. Intl. J. Cancer 59(2): 181-184 ( 1994). 36: Gartner, C., Stahl, W, and Sies, H.; Lycopene is more bioavailable from tomato paste than from fresh tomatoes, Am. J. Clin. Nutr. 66: 116-122 (1997). 37: Gester, H.; The potential role of lycopene for human health. J. Am. Col. Nutr. 16(2): 109-126 (1997). 38: Giovannucci, E. L., Ascherio, A., Rimm, E. B., Stampfer, M.J., Colditz, G.A., and Willett, W.C.; Intake of carotenoids and retinol in relationship to risk of prostate cancer. J. NatI. Cancer Inst. 87: 1767-1776 (1995). 39: Godoy, H.T. and Rodriguez-Amaya, D.B.; Changes in individual carotenoids on processing and storage of mango (Mangifera indica) slices and puree. Intl. J. Food Sci. Technol. 22: 451-460 (1987).. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 379
40: Gross, J.; "Pigments in Vegetables: Chlorophylls and Carotenoids. pp. 148-249. Van Nostrand Reinhold, New York (1991). 41: Ha, T.K.K., Saffar, N., Talwar, D., Cooney, J., Simpson, K., O'-Reilly D., and Lean, M.E.J.; Abnormal antioxidant vitamin and carotenoid status in chronic renal failure. Q.J.M. 89: 765-769 (1996). 42: Harborne, J.B. and Baxter, H.; "Phytochemical Dictionary. A Handbook of Bioactive Compounds from Plants," Taylor & Frost, London (1983). 43: Henry, L,K., Catignani, G.L., and Schwartz, S.J.; Oxidative degradation kinetics of lycopene. lutein, 9-cis and all-trans beta-carotene. J. Am. Oil Chem. Soc, 75: 823-829 (1998). 44: Jarvinen, R,, Knekt, P., Seppanen, R., and Teppo, L.; Diet and breast cancer risk in a cohort of Finnish women. Cancer Lett. 114: 251-253 (1997). 45: Joyce, E.; Carotenoids of Brassica napus. J. Sci. Food Agric. 10: 342-348 ( 1959). 46: Joyce, E.; Some polyenes of Brassica rutabaga. Nature, 173: 311-312 (1954). 47: Kaplan, L.A., Lau, J.M., and Stein, E.A.; Carotenoid composition, concentrations, and relationships in various human organs. Clin. Physiol. Biochem, 8: 1-10 (1990). 48: Karrer, P, Helfenstein, A., Wehri, H., and Wettstein, A.; Pflanzenfarbstoffe. XXV. Leber die Konstitution des Lycopins und Carotins, Acta 14: 154-162 (1930). 49: Khachik, F, Beecher, G.R., and Smith, J.C. Jr.; Lutein, lycopene, and their oxidative metabolites in chemoprevention of cancer J. Cell Biochem, Suppl. 22: 236-246 (1995.) 50: Khachik, F., et.al.; Effect of food preparation on qualitative and quantitative distribution of major carotenoid constituents of tomatoes and several green vegetables, J. Agric. Food Chem, 40: 390-398 (1992).
Rosemary Leaf Powder - 20 STUDIES

1. Chemical composition, plant genetic differences, antimicrobial and antifungal activity investigation of the essential oil of Rosmarinus officinalis L. J Agric Food Chem. 2004 Jun 2;52(11):3530-5. 2. Effects of a novel gaseous antioxidative system containing a rosemary extract on the oxidation induced by nitrogen dioxide and ultraviolet radiation. Biosci Biotechnol Biochem. 2004 Apr;68(4):781-6.. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 380
3. Carnosic acid, a component of rosemary (Rosmarinus officinalis L.), promotes synthesis of nerve growth factor in T98G human glioblastoma cells. Biol Pharm Bull. 2003 Nov;26(11):1620-2. 4. Antioxidant activities of rosemary, sage, and sumac extracts and their combinations on stability of natural peanut oil. J Med Food. 2003 Fall;6(3):267-70. 5. Phenolic diterpenes, flavones, and rosmarinic acid distribution during the development of leaves, flowers, stems, and roots of Rosmarinus officinalis. Antioxidant activity. J Agric Food Chem. 2003 Jul 16;51(15):4247-53. 6. Quantitative determination of phenolic diterpenes in rosemary extracts. Aspects of accurate quantification. J Chromatogr A. 2003 May 2;995(1-2):119-25. 7. Aromas of rosemary and lavender essential oils differentially affect cognition and mood in healthy adults. Int J Neurosci. 2003 Jan;113(1):15-38. 8. Suppressive effects of rosmarinic acid on mesangioproliferative glomerulonephritis in rats. Nephron. 2002 Dec;92(4):898-904. 9. Carnosic acid inhibits proliferation and augments differentiation of human leukemic cells induced by 1,25-dihydroxyvitamin D3 and retinoic acid. Nutr Cancer. 2001;41(1-2):135-44. 10. Carnosol, an antioxidant in rosemary, suppresses inducible nitric oxide synthase through down-regulating nuclear factor-kappaB in mouse macrophages. Carcinogenesis. 2002 Jun;23(6):983-91. 11. Evaluation of the effectiveness of Rosmarinus officinalis (Lamiaceae) in the alleviation of carbon tetrachloride-induced acute hepatotoxicity in the rat. J Ethnopharmacol. 2002 Jul;81(2):145-54.
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12. Rosemary-stimulated reduction of DNA strand breaks and FPG-sensitive sites in mammalian cells treated with H2O2 or visible light-excited Methylene Blue. Cancer Lett. 2002 Mar 28;177(2):145-53. 13. Antioxidant properties of phenolic diterpenes from Rosmarinus officinalis. Acta Pharmacol Sin. 2001 Dec;22(12):1094-8. 14. Carnosol-induced apoptosis and downregulation of Bcl-2 in B-lineage leukemia cells. Cancer Lett. 2001 Sep 10;170(1):33-9. 15. Chemistry and antioxidative factors in rosemary and sage. Biofactors. 2000;13(1-4):161-6. 16. Inhibitory effects of rosmarinic acid on the proliferation of cultured murine mesangial cells. Nephrol Dial Transplant. 2000 Aug;15(8):1140-5. 17. Allied studies on the effect of Rosmarinus officinalis L. on experimental hepatotoxicity and mutagenesis. Int J Food Sci Nutr. 1999 Nov;50(6):413-27. 18. Pharmacology of rosemary (Rosmarinus officinalis Linn.) and its therapeutic potentials. Indian J Exp Biol. 1999 Feb;37(2):124-30. 19. Flavonoids in Rosmarinus officinalis leaves. Phytochemistry. 1994 Nov;37(5):1463-6. 20. Rosmarinic Acid Research Rosmarinic acid. Institut fur Pharmazeutische Biologie, Philipps-Universitat Marburg, Deutschhausstr. Marburg, Germany.
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Tocotrienols 40 STUDIES
1. J Gerontol A Biol Sci Med Sci 2000 Jun;55(6):B280-5 Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. Adachi H, Ishii N. Life Science Research Center, Lion Corporation, Kanagawa, Japan. hadachi@lion.co.jp 2. N Engl J Med 1993 May 20;328(20):1450-6 Vitamin E consumption and the risk of coronary heart disease in men. Rimm EB, Stampfer MJ, Ascherio A, Giovannucci E, Colditz GA, Willett WC. Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115. 3. N Engl J Med 1993 May 20;328(20):1444-9 Vitamin E consumption and the risk of coronary disease in women. Stampfer MJ, Hennekens CH, Manson JE, Colditz GA, Rosner B, Willett WC. Channing Laboratory, Boston, MA 02115. 4. Lancet 1996 Mar 23;347(9004):781-6 Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS) Stephens NG, Parsons A, Schofield PM, Kelly F, Cheeseman K, Mitchinson MJ. Department of Medicine, Cambridge University. 5. JAMA 2001 Mar 7;285(9):1178-82 Effects of vitamin E on lipid peroxidation in healthy persons. Meagher EA, Barry OP, Lawson JA, Rokach J, FitzGerald GA. Center for Experimental Therapeutics, 811 Biomedical Research Bldg II/III, University of Pennsylvania, 421 Curie Blvd, Philadelphia, PA 19104-6160, USA. 6. JAMA 1995 Jun 21;273(23):1849-54 Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis. Hodis HN, Mack WJ, LaBree L, Cashin-Hemphill L, Sevanian A, Johnson R, Azen SP. Atherosclerosis Research Unit, University of Southern California School of Medicine, Los Angeles 90033, USA. 7. Eur Heart J 2001 Jan;22(2):103-4 Clinical, public health, and research implications of the Heart Outcomes Prevention Evaluation (HOPE) Study. Yusuf S. 8. Am J Clin Nutr 1996 Mar;63(3):377-85 Inverse relation between the concentration of low-density-lipoprotein vitamin E and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 383
severity of coronary artery disease. Regnstrom J, Nilsson J, Moldeus P, Strom K, Bavenholm P, Tornvall P, Hamsten A. Department of Medicine, the King Gustaf V Research Institute, Karolinska Hospital, Stockholm, Sweden. 9. N Engl J Med 1996 May 2;334(18):1156-62 Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women. Kushi LH, Folsom AR, Prineas RJ, Mink PJ, Wu Y, Bostick RM. Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis 55454-1015, USA. 10. Am J Epidemiol 1994 Jun 15;139(12):1180-9 Antioxidant vitamin intake and coronary mortality in a longitudinal population study. Knekt P, Reunanen A, Jarvinen R, Seppanen R, Heliovaara M, Aromaa A. Social Insurance Institution, Helsinki, Finland. 11. Sources And Consumption Of Antioxidants In The Diet Bieri J G J Am Oil Chem Soc 61 (12). 1984. 1917-1918. 1984 12. J Nutr 1985 Jun;115(6):807-13 Oral alpha-tocopherol supplements decrease plasma gamma-tocopherol levels in humans. Handelman GJ, Machlin LJ, Fitch K, Weiter JJ, Dratz EA. 13. J Intern Med 1996 Feb;239(2):111-7 Gamma, but not alpha, tocopherol levels in serum are reduced in coronary heart disease patients. Ohrvall M, Sundlof G, Vessby B. Department of Geriatrics, University of Uppsala, Sweden. 14. Proc Natl Acad Sci U S A 1997 Apr 1;94(7):3217-22 Gamma-tocopherol traps mutagenic electrophiles such as NO(X) and complements alpha-tocopherol: physiological implications. Christen S, Woodall AA, Shigenaga MK, Southwell-Keely PT, Duncan MW, Ames BN. Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720, USA. 15. Proc Natl Acad Sci U S A 1993 Mar 1;90(5):1771-5 Gamma-tocopherol detoxification of nitrogen dioxide: superiority to alpha-tocopherol. Cooney RV, Franke AA, Harwood PJ, Hatch-Pigott V, Custer LJ, Mordan LJ. Cancer Research Center of Hawaii, University of Hawaii, Honolulu 96813. 16. J Gerontol A Biol Sci Med Sci 2000 Jun;55(6):B280-5 Effects of tocotrienols on life span and protein carbonylation in Caenorhabditis elegans. Adachi H, Ishii N. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 384
Life Science Research Center, Lion Corporation, Kanagawa, Japan. hadachi@lion.co.jp 17. Lipids 1995 Dec;30(12):1179-83 Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis. Tomeo AC, Geller M, Watkins TR, Gapor A, Bierenbaum ML. Kenneth L. Jordan Research Group, Montclair, New Jersey 07042, USA. 18. J Biol Chem 1993 May 25;268(15):11230-8 Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase. Parker RA, Pearce BC, Clark RW, Gordon DA, Wright JJ. Department of Metabolic Diseases, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543. 19. Am J Clin Nutr 1991 Apr;53(4 Suppl):1021S-1026S Lowering of serum cholesterol in hypercholesterolemic humans by tocotrienols (palmvitee). Qureshi AA, Qureshi N, Wright JJ, Shen Z, Kramer G, Gapor A, Chong YH, DeWitt G, Ong A, Peterson DM, et al. Advanced Medical Research, Madison, WI 53719. 20. Novel tocotrienols of rice bran modulate cardiovascular disease risk parameters of hypercholesterolomic humans Qureshi A.A.; Bradlow B.A.; Salser W.A.; Brace L.D. Dr. A.A. Qureshi, Advance Medical Research, 8251 Raymond Road, Madison, WI 53719 United States Journal of Nutritional Biochemistry ( J. NUTR. BIOCHEM. ) ( United States ) 1997 , 8/5 (290-298) 21. N Engl J Med 1990 Nov 8;323(19):1289-98 Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B. Brown G, Albers JJ, Fisher LD, Schaefer SM, Lin JT, Kaplan C, Zhao XQ, Bisson BD, Fitzpatrick VF, Dodge HT. Department of Medicine, University of Washington School of Medicine, Seattle. 22. N Engl J Med 1983 Aug 18;309(7):385-9 Apolipoprotein A-I as a marker of angiographically assessed coronary-artery disease. Maciejko JJ, Holmes DR, Kottke BA, Zinsmeister AR, Dinh DM, Mao SJ. 23. Br Heart J 1988 Nov;60(5):397-403 High prevalence of hypertriglyceridaemia and apolipoprotein abnormalities in coronary artery disease. Barbir M, Wile D, Trayner I, Aber VR, Thompson GR. Department of Medicine, Royal Postgraduate Medical School, Hammersmith Hospital, London. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 385
24. Proc Natl Acad Sci U S A 2000 Oct 10;97(21):11494-9 Gamma-tocopherol and its major metabolite, in contrast to alpha-tocopherol, inhibit cyclooxygenase activity in macrophages and epithelial cells. Jiang Q, Elson-Schwab I, Courtemanche C, Ames BN. Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA. 25. J Am Coll Cardiol 1999 Oct;34(4):1208-15 Differential effects of alpha- and gamma-tocopherol on low-density lipoprotein oxidation, superoxide activity, platelet aggregation and arterial thrombogenesis. Saldeen T, Li D, Mehta JL. Department of Forensic Medicine, University of Uppsala, Sweden. . 26. J Nutr Biochem 2001 Jun;12(6):318-329 Synergistic effect of tocotrienol-rich fraction (TRF(25)) of rice bran and lovastatin on lipid parameters in hypercholesterolemic humans. Qureshi AA, Sami SA, Salser WA, Khan FA. Advanced Medical Research, 8251 Raymond Road, 53719, Madison, WI, USA 27. Lipids 1993 Dec;28(12):1113-8 gamma-Tocotrienol as a hypocholesterolemic and antioxidant agent in rats fed atherogenic diets. Watkins T, Lenz P, Gapor A, Struck M, Tomeo A, Bierenbaum M. Kenneth L. Jordan Heart Fund, Montclair, New Jersey 07042. 28. J Nutr 2001 Jan;131(1):161S-163S Vitamin E: mechanisms of action as tumor cell growth inhibitors. Kline K, Yu W, Sanders BG. Division of Nutrition and. School of Biological Sciences, The University of Texas at Austin, Austin, TX 78712, USA. k.kline@mail.utexas.edu 29. J Nutr 1994 May;124(5):607-14 The chemoprevention of cancer by mevalonate-derived constituents of fruits and vegetables. Elson CE, Yu SG. Department of Nutritional Sciences, University of Wisconsin, Madison 53706-1571. 30. J Nutr 1999 Apr;129(4):804-13 Apoptosis and cell-cycle arrest in human and murine tumor cells are initiated by isoprenoids. Mo H, Elson CE. Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
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31. J Nutr 1997 May;127(5):668-74 Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE. Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA. 32. Nutr Cancer 1992;18(1):1-29 Fruit, vegetables, and cancer prevention: a review of the epidemiological evidence. Block G, Patterson B, Subar A. Dept. of Social and Administrative Health Sciences, School of Public Health, University of California, Berkeley 94720. 33. Proc Soc Exp Biol Med 1999 Sep;221(4):294-311 Isoprenoid-mediated inhibition of mevalonate synthesis: potential application to cancer. Elson CE, Peffley DM, Hentosh P, Mo H. Department of Nutritional Sciences, College of Agricultural and Life Sciences, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA. 34. J Nutr 1995 Jun;125(6 Suppl):1666S-1672S Suppression of mevalonate pathway activities by dietary isoprenoids: protective roles in cancer and cardiovascular disease. Elson CE. Department of Nutritional Sciences, University of Wisconsin-Madison 53706, USA. 35. Nutrition 1993 May-Jun;9(3):229-32 Long-term administration of tocotrienols and tumor-marker enzyme activities during hepatocarcinogenesis in rats. Rahmat A, Ngah WZ, Shamaan NA, Gapor A, Abdul Kadir K. Department of Biochemistry, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur. 36. Comp Biochem Physiol C 1993 Sep;106(1):237-40 Glutathione S-transferase and gamma-glutamyl transpeptidase activities in cultured rat hepatocytes treated with tocotrienol and tocopherol. Ong FB, Wan Ngah WZ, Shamaan NA, Md Top AG, Marzuki A, Khalid AK. Jabatan Biokimia, Fakulti Perubatan, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala, Lumpur. 37. J Nutr 1997 May;127(5):668-74 Isoprenoids suppress the growth of murine B16 melanomas in vitro and in vivo. He L, Mo H, Hadisusilo S, Qureshi AA, Elson CE. Department of Nutritional Sciences, University of Wisconsin, Madison 53706, USA. 38. Lipids 1995 Dec;30(12):1139-43 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 387
Effect of tocotrienols on the growth of a human breast cancer cell line in culture. Nesaretnam K, Guthrie N, Chambers AF, Carroll KK. Palm Oil Research Institute of Malaysia, Kuala Lumpur, Malaysia. 39. Lipids 1998 May;33(5):461-9 Tocotrienols inhibit the growth of human breast cancer cells irrespective of estrogen receptor status. Nesaretnam K, Stephen R, Dils R, Darbre P. Division of Cell and Molecular Biology, School of Animal and Microbial Sciences, The University of Reading, Whiteknights, England. sarnesar@porim.gov.my 40. Int J Food Sci Nutr 2000;51 Suppl:S95-103 Tocotrienols inhibit growth of ZR-75-1 breast cancer cells. Nesaretnam K, Dorasamy S, Darbre PD. Palm Oil Research Institute of Malaysia, PO Box 10620, Kuala Lumpur 50720, Malaysia.
Raspberry Leaf Powder - 10 Studies

1. Han C, Ding H, Casto B, Stoner GD, D'Ambrosio SM. Inhibition of the growth of premalignant and malignant human oral cell lines by extracts and components of black raspberries. Nutr Cancer. 2005;51(2):207-17. PMID: 15860443 2. Huang C, Huang Y, Li J, Hu W, Aziz R, Tang MS, Sun N, Cassady J, Stoner GD. Inhibition of benzo(a)pyrene diol-epoxide-induced transactivation of activated protein 1 and nuclear factor kappaB by black raspberry extracts. Cancer Res. 2002 Dec 1;62(23):6857-63. PMID: 124608993. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, Klaunig JE 3. Xue H, Aziz RM, Sun N, Cassady JM, Kamendulis LM, Xu Y, Stoner GD, Klaunig JE. Inhibition of cellular transformation by berry extracts. Carcinogenesis. 2001 Feb;22(2):351-6. Erratum in: Carcinogenesis 2001 May;22(5):8313. PMID: 11181460 4. J Agric Food Chem. 2005 Jul 27;53(15):5922-31. Preclinical evaluation of rapeseed, raspberry, and pine bark phenolics for health related effects.
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Vuorela S, Kreander K, Karonen M, Nieminen R, Hamalainen M, Galkin A, Laitinen L, Salminen JP, Moilanen E, Pihlaja K, Vuorela H, Vuorela P, Heinonen M. 5. Viljanen K, Kylli P, Kivikari R, Heinonen M. Inhibition of protein and lipid oxidation in liposomes by berry phenolics. J Agric Food Chem. 2004 Dec 1;52(24):7419-24. PMID: 15563229 6. Vuorela S, Salminen H, Makela M, Kivikari R, Karonen M, Heinonen M. Effect of plant phenolics on protein and lipid oxidation in cooked pork meat patties. J Agric Food Chem. 2005 Nov 2;53(22):8492-7. PMID: 16248543 7. Puupponen-Pimia R, Nohynek L, Hartmann-Schmidlin S, Kahkonen M, Heinonen M, Maatta-Riihinen K, Oksman-Caldentey KM. Berry phenolics selectively inhibit the growth of intestinal pathogens. J Appl Microbiol. 2005;98(4):991-1000. PMID: 15752346 8. Puupponen-Pimia R, Nohynek L, Meier C, Kahkonen M, Heinonen M, Hopia A, Oksman-Caldentey KM. Antimicrobial properties of phenolic compounds from berries. J Appl Microbiol. 2001 Apr;90(4):494-507. PMID: 11309059 9. Puupponen-Pimia R, Nohynek L, Alakomi HL, Oksman-Caldentey KM. Bioactive berry compounds-novel tools against human pathogens. Appl Microbiol Biotechnol. 2005 Apr;67(1):8-18. Epub 2004 Dec 2. Review. PMID: 15578177 10. Viljanen K, Kylli P, Kivikari R, Heinonen M. Inhibition of protein and lipid oxidation in liposomes by berry phenolics. J Agric Food Chem. 2004 Dec 1;52(24):7419-24. PMID: 15563229
Citrus Bioflavonoids 11 STUDIES

1. Tirkey N, Pilkhwal S, Kuhad A, Chopra K. Hesperidin, a citrus bioflavonoid, decreases the oxidative stress produced by carbon tetrachloride in rat liver and kidney. BMC Pharmacol. 2005 Jan 31;5(1):2. PMID: 15683547 2. Garg A, Garg S, Zaneveld LJ, Singla AK. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 389
Chemistry and pharmacology of the Citrus bioflavonoid hesperidin. Phytother Res. 2001 Dec;15(8):655-69. Review. PMID: 11746857 3. Emim JA, Oliveira AB, Lapa AJ. Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. J Pharm Pharmacol. 1994 Feb;46(2):118-22. PMID: 8021799 4. WILLIAMS HL, HEDGECOCK LD. Citrus bioflavonoid, ascorbic acid and the B Vitamins in treatment of certain types of neurosensory deafness: preliminary report. Mayo Clin Proc. 1962 Aug 29;37:474-83. No abstract available. PMID: 14007172 5. MARTIN WC. Treatment of capillary fragility with soluble citrus bioflavonoid complex. Int Rec Med Gen Pract Clin. 1955 Feb;168(2):66-9. No abstract available. PMID: 14353570 6. Treatment of capillary fragility with soluble citrus bioflavonoid complex. Int Rec Med Gen Pract Clin. 1955 Feb;168(2):66-9. No abstract available. PMID: 14353570 7. Emim JA, Oliveira AB, Lapa AJ. Pharmacological evaluation of the anti-inflammatory activity of a citrus bioflavonoid, hesperidin, and the isoflavonoids, duartin and claussequinone, in rats and mice. J Pharm Pharmacol. 1994 Feb;46(2):118-22. PMID: 8021799 8. WILLIAMS HL, HEDGECOCK LD. Citrus bioflavonoid, ascorbic acid and the B Vitamins in treatment of certain types of neurosensory deafness: preliminary report. Mayo Clin Proc. 1962 Aug 29;37:474-83. No abstract available. PMID: 14007172 9. FABRICANT ND. Therapeutic failure of citrus bioflavonoids in the common cold and nasal allergy. Eye Ear Nose Throat Mon. 1956 Nov;35(11):717-9. No abstract available. PMID: 13365639 10. MACON WL Jr. Citrus bioflavonoids in the treatment of the common cold. Ind Med Surg. 1956 Nov;25(11):525-7. No abstract available. PMID: 13366468 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 390
11. MENKIN V. Anti-inflammatory activity of some water-soluble bioflavonoids. Am J Physiol. 1959 Jun;196(6):1205-10. No abstract available. PMID: 13661342
Rutin 16 STUDIES
1. Anon: Natural Medicines Comprehensive Database, 4th ed. Therapeutic Research Faculty, Stockton, CA; 2002. 2. Wijayanegara H, Mose JC, Achmad L et al: A clinical trial of hydroxyethylrutosides in the treatment of haemorrhoids of pregnancy. J Int Med Res 1992; 20(1):54-60. 3. De Jongste AB, Jonker JJ, Huisman MV et al: A double-blind three center clinical trial on the short-term efficacy of O-(B-hydroxyethyl)-rutosides in patients with postthrombotic syndrome. Thromb Haemost 1989; 62(3):826-829. 4. Bergqvist D, Hallbook T, Lindblad B et al: A double-blind trial of O-(Bhydroxyethyl)-rutoside in patients with chronic venous insufficiency. VASA 1981; 10(3):253-260. 5. Mann RJ: A double-blind trial of O.B-hydroxyethyl rutosides for stasis leg ulcers. Br J Clin Pract 1981; 35(2):79-81. 6. Partial reversal by rutin and quercetin of impaired cardiac function in streptozotocininduced diabetic rats. Can J Physiol Pharmacol. 2005 Apr;83(4):343-355. 7. Effect of rutin on total antioxidant status of rats exposed to cigarette smoke. Pharmacol Rep. 2005 Jan-Feb;57(1):84-9. 8. Modulation of aberrant crypt foci and apoptosis by dietary herbal supplements (quercetin, curcumin, silymarin, ginseng and rutin). Carcinogenesis. 2005 Apr 14; 9. Dietary rutin, but not its aglycone quercetin, ameliorates dextran sulfate sodiuminduced experimental colitis in mice: attenuation of pro-inflammatory gene expression. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 391
Biochem Pharmacol. 2005 Feb 1;69(3):395-406. 10. [Inhibitory effect of quercetin, rutin and puerarin on HDL oxidation induced by Cu2+] Sichuan Da Xue Xue Bao Yi Xue Ban. 2004 Nov;35(6):836-8. 11. [Effect of hesperidin and rutin on oxidative modification of high density lipoprotein in vitro] 12. Mechanisms involved in the antiplatelet activity of rutin, a glycoside of the flavonol quercetin, in human platelets. J Agric Food Chem. 2004 Jul 14;52(14):4414-8. 13. The modulating effects of quercetin and rutin on the mitomycin C induced DNA damage. Toxicol Lett. 2004 Jun 15;151(1):143-9. 14. Synergistic inhibition of low-density lipoprotein oxidation by rutin, gamma-terpinene, and ascorbic acid. Phytomedicine. 2004 Feb;11(2-3):105-13. 15. Bioavailability and efficiency of rutin as an antioxidant: a human supplementation study. Eur J Clin Nutr. 2000 Oct;54(10):774-82. 16. Protective effects of N-acetylcysteine and rutin on the lipid peroxidation of the lung epithelium during the adult respiratory distress syndrome. Shock. 2000 Jan;13(1):14-8.
Billberry - 17 Studies
FILED ACCORDING TO CONDITION OR FUNCTION Anti-angiogenic
1. Free Radic Res. 2002 Sep;36(9):1023-31. Anti-angiogenic property of edible berries. Roy S, Khanna S, Alessio HM, Vider J, Bagchi D, Bagchi M, Sen CK. Laboratory of Molecular Medicine, Department of Surgery, 512 Heart and Lung Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 392
Research Institute, Ohio State University Medical Center, 473 W. 12th Avenue, Columbus, OH 43210, USA.
Cancer
2. J Agric Food Chem. 2003 Jan 1;51(1):68-75. Induction of apoptosis in cancer cells by Bilberry (Vaccinium myrtillus) and the anthocyanins. Katsube N, Iwashita K, Tsushida T, Yamaki K, Kobori M. Fruit Processing Research Center, AOHATA Corporation, Takehara, Hiroshima 729-2392, Japan. 3. J Agric Food Chem. 2003 Sep 24;51(20):5867-5870. Resveratrol in Raw and Baked Blueberries and Bilberries. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, Van Breemen RB. Food and Nutritional Science Division, California State University, Long Beach, Long Beach, California 90840; Department of Chemistry, University of Illinois at Chicago, Chicago, Illinois 60607; and Department of Medicinal Chemistry and Pharmacognosy, University of Illinois College of Pharmacy, Chicago, Illinois 60612. 4. Planta Med. 1996 Jun;62(3):212-6. In vitro anticancer activity of fruit extracts from Vaccinium species. Bomser J, Madhavi DL, Singletary K, Smith MA. Department of Food Science and Human Nutrition, University of Illinois, Urbana 61801, USA.
Capillary support
5. Pharmacol Res. 1995 Mar-Apr;31(3-4):183-7. (Animal Study) Effect of Vaccinium myrtillus anthocyanosides on ischaemia reperfusion injury in hamster cheek pouch microcirculation. Bertuglia S, Malandrino S, Colantuoni A. CNR Institute of Clinical Physiology, Pisa, Italy. 6. Arzneimittelforschung. 1976;26(5):832-5. (Animal Study) Studies on Vaccinium myrtillus anthocyanosides. II. Aspects of anthocyanins pharmacokinetics in the rat. Lietti A, Forni G. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 393
7. Arzneimittelforschung. 1976;26(5):829-32. Studies on Vaccinium myrtillus anthocyanosides. I. Vasoprotective and antiinflammatory activity. Lietti A, Cristoni A, Picci M.
Connective tissue
8. Klin Monatsbl Augenheilkd. 1996 Dec;209(6):368-72. [Effect of anthocyanins on human connective tissue metabolism in the human] [Article in German] Boniface R, Robert AM. Labor fur Bindegewebsbiochemie, Medizinische Fakultat, Universitat Paris, Val de Marne.
Dyslipidaemiae
9. Thromb Res. 1996 Dec 1;84(5):311-22. (Animal Study) Novel lipid-lowering properties of Vaccinium myrtillus L. leaves, a traditional antidiabetic treatment, in several models of rat dyslipidaemia: a comparison with ciprofibrate. Cignarella A, Nastasi M, Cavalli E, Puglisi L. Institute of Pharmacological Sciences, University of Milano, Italy.
Chronic Fatigue Syndrome

10. Altern Med Rev. 2001 Oct;6(5):450-9. Chronic fatigue syndrome: oxidative stress and dietary modifications. Logan AC, Wong C. CFS/FM Integrative Care Centre, Toronto, ON, Canada. alancloganND@excite.com
Cardiocascular and EYE

11. Curr Mol Med. 2003 Mar;3(2):149-59. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 394
Potential mechanisms of cancer chemoprevention by anthocyanins. Hou DX. Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima 890-0065, Japan. hou@chem.agri.kagoshima-u.ac.jp
EYE
12. J Biol Chem. 2003 May 16;278(20):18207-13. Epub 2003 Mar 19. A2E-epoxides damage DNA in retinal pigment epithelial cells. Vitamin E and other antioxidants inhibit A2E-epoxide formation. Sparrow JR, Vollmer-Snarr HR, Zhou J, Jang YP, Jockusch S, Itagaki Y, Nakanishi K. Department of Ophthalmology and Chemistry, Columbia University, New York, New York 10028, USA. jrs88@columbia.edu 13. Altern Med Rev. 2001 Apr;6(2):141-66. Natural therapies for ocular disorders, part two: cataracts and glaucoma. Head KA. Thorne Research, Inc., P.O. Box 25, Dover, ID 83825,USA. kathi@thorne.com
Ulcer
14. Arzneimittelforschung. 1988 May;38(5):686-90. (Animal Study) Antiulcer activity of an anthocyanidin from Vaccinium myrtillus. Magistretti MJ, Conti M, Cristoni A. Research and Development Laboratories, Inverni della Beffa S.p.A., Milan, Italy.
Bilberry High in Quercetin

15. Eur J Clin Nutr. 2003 Jan;57(1):37-42. Consumption of black currants, lingonberries and bilberries increases serum quercetin concentrations. Erlund I, Marniemi J, Hakala P, Alfthan G, Meririnne E, Aro A. Biomarker Laboratory, National Public Health Institute, Helsinki, Finland. iris.erlund@ktl.fi 16. J Agric Food Chem. 2000 Jul;48(7):2960-5. Influence of domestic processing and storage on flavonol contents in berries. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 395
Hakkinen SH, Karenlampi SO, Mykkanen HM, Torronen AR. Department of Clinical Nutrition, Department of Physiology, University of Kuopio, PO box 1627, FIN-70211 Kuopio, Finland.
RNA
17. Mol Biotechnol. 2001 Oct;19(2):201-3. Isolation of high quality RNA from bilberry (Vaccinium myrtillus L.) fruit. Jaakola L, Pirttila AM, Halonen M, Hohtola A. Department of Biology, University of Oulu, P.O. Box 3000, FIN-90014 Oulu, Finland. Laura.Jaakola@oulu.fi
Red Wine Concentrate 14 STUDIES

1. Resveratrol reduces oxidation and proliferation of human retinal pigment epithelial cells via extracellular signal-regulated kinase inhibition. Chem Biol Interact. 2005 Jan 15;151(2):143-9. King RE, Kent KD, Bomser JA. Department of Food Science and Technology, Ohio State University, Columbus, OH
2. Role of resveratrol in prevention and therapy of cancer: preclinical and clinical studies. Anticancer Res. 2004 Sep-Oct;24(5A):2783-840. Aggarwal BB, Bhardwaj A, Aggarwal RS, Seeram NP, Shishodia S, Takada Y. Cytokine Research Laboratory, Department of Bioimmunotherapy, The University of Texas M. D.
3. Resveratrol-induced cellular apoptosis and cell cycle arrest in neuroblastoma cells and antitumor effects on neuroblastoma in mice. Surgery. 2004 Jul;136(1):57-66. 4. Anti-inflammatory Effects of Resveratrol in Lung Epithelial Cells: Molecular Mechanisms. Am J Physiol Lung Cell Mol Physiol. 2004 Jun 4
5. Identification of a p53-dependent pathway in the induction of apoptosis of human breast cancer cells by the natural product, resveratrol. Laux MT, Aregullin M, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 396
J Altern Complement Med. 2004 Apr;10(2):235-9.
6. Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of p53 in human neuroblastoma. Anticancer Res. 2004 Mar-Apr;24(2B):987-98.
7. Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem. 2003 Sep 24;51(20):5867-70. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. Food and Nutritional Science Division, California State University-Long Beach, CA 90840
8. Wine and tumors: study of resveratrol. Drugs Exp Clin Res. 2003;29(5-6):257-61. dependent antiproliferative and antiapoptotic action on DHL-4 cells. These results confirm resveratrol's potential therapeutic role on tumors. 9. Potent induction of cellular antioxidants and phase 2 enzymes by resveratrol in cardiomyocytes: protection against oxidative and electrophilic injury. Cao Z, Li Y. St. John's University College of Pharmacy and Allied Health Professions, Jamaica, NY Eur J Pharmacol. 2004 Apr 5;489(1-2):39-48. 10. Modulation of androgen receptor-dependent transcription by resveratrol and genistein in prostate cancer cells. Gao S, Liu GZ, Wang Z. The University of Texas M. D. Anderson Cancer Center, Houston, Texas . Prostate. 2004 May 1;59(2):214-25.
11. Resveratrol suppresses the angiogenesis and tumor growth of gliomas in rats. Clin Cancer Res. 2004 Mar 15;10(6):2190-202.
12. Neuroprotective effects of resveratrol against beta-amyloid-induced neurotoxicity in rat hippocampal neurons: involvement of protein kinase C. Br J Pharmacol. 2004 Mar;141(6):997-1005.
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13. Resveratrol in raw and baked blueberries and bilberries. J Agric Food Chem. 2003 Sep 24;51(20):5867-70. Lyons MM, Yu C, Toma RB, Cho SY, Reiboldt W, Lee J, van Breemen RB. Food and Nutritional Science Division, California State University-Long Beach, CA 90840 14. Resveratrol protects myocardial ischemia-reperfusion injury through both NOdependent and NO-independent mechanisms. Free Radic Biol Med. 2004 Mar 15;36(6):774-81.
Grape Skin Extract 48 STUDIES
1. Rosenkranz S, Knirel D, Dietrich H, Flesch M, Erdmann E, Bohm M. Inhibition of the PDGF receptor by red wine flavonoids provides a molecular explanation for the French paradox. FASEB J. 2002 Dec;16(14):1958-60. 2. Criqui MH, Ringel BL. Does diet or alcohol explain the French paradox? Lancet. 1994 Dec 24-31;344(8939-8940):1719-23. 3. Burr ML. Explaining the French paradox. JR Soc Health. 1995 Aug;115(4):217-9. 4. Lavayssiere R, Cabee A. MRI in France: the French paradox. J Magn Reson Imaging. 2001 Apr;13(4):528-33. 5. Mar MH, Zeisel SH. Betaine in wine: answer to the French paradox? Med Hypotheses. 1999 Nov;53(5):383-5. 6. De Beer D, Joubert E, Gelderblom W, Manley M. Antioxidant activity of South African red and white cultivar wines: free radical scavenging. J Agric Food Chem. 2003 Feb 12;51(4):902-9. 7. Cui J, Tosaki A, Cordis GA, et al. Cardioprotective abilities of white wine. Ann NY Acad Sci. 2002 May;957:308-16. 8. Bertelli AA, Migliori M, Panichi V, et al. Oxidative stress and inflammatory reaction modulation by white wine. Ann NY Acad Sci. 2002 May;957:295-301. 9. Ariga T. The antioxidative function, preventive action on disease and utilization of proanthocyanidins. Biofactors. 2004 21(1-4):197-201. 10. Bagchi D, Garg A, Krohn RL, et al. Protective effects of grape seed proanthocyanidins and selected antioxidants against TPA-induced hepatic and brain lipid
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peroxidation and DNA fragmentation, and peritoneal macrophage activation in mice. Gen Pharmacol. 1998 May;30(5):771-6. 11. Ye X, Krohn RL, Liu W, et al. The cytotoxic effects of a novel IH636 grape seed proanthocyanidin extract on cultured human cancer cells. Mol Cell Biochem. 1999 Jun;196(1-2):99-108. 12.. Deshane J, Chaves L, Sarkikonda KV, et al. Proteomics analysis of rat brain protein modulations by grape seed extract. J Agric Food Chem. 2004 Dec 29;52(26):7872-83. 13.. Rababah TM, Hettiarachchy NS, Horax R. Total phenolics and antioxidant activities of fenugreek, green tea, black tea, grape seed, ginger, rosemary, gotu kola and ginkgo extracts, vitamin E and tert-butylhydroquinone. J Agric Food Chem. 2004 Aug 11;52(16):5183-6. 14. Shi J, Yu J, Pohorly JE, Kakuda Y. Polyphenolics in grape seedsbiochemistry and functionality. J Med Food. 2003 Winter;6(4):291-9. 15. Hagerman A, Riedl K, Jones GA, et al. High molecular weight plant polyphenolics (tannins) as biological antioxidants. J Agric Food Chem. 1998 46:1887-92. 16. Natella F, Belelli F, Gentili V, Ursini F, Scaccini C. Grape seed proanthocyanidins prevent plasma postprandial oxidative stress in humans. J Agric Food Chem. 2002 Dec 18;50(26):7720-5. 17. Choi SM, Lee BM. An alternative mode of action of endocrine-disrupting chemicals and chemoprevention. J Toxicol Environ Health B Crit Rev. 2004 Nov-Dec;7(6):451-63. 18. Delmas D, Jannin B, Latruffe N. Resveratrol: Preventing properties against vascular alterations and aging. Mol Nutr Food Res. 2005 Apr 14. 19. Granieri M, Bellisarii FI, De Caterina R. Group B vitamins as new variables related to the cardiovascular risk. Ital Heart J Suppl. 2005 Jan;6(1):1-16. 20. Hannon-Fletcher MP, Armstrong NC, Scott JM, et al. Determining bioavailability of food folates in a controlled intervention study. Am J Clin Nutr. 2004 Oct;80(4):911-8. 21. Weiswasser JM, Nylen E, Arora S, Wakefield M, Sidawy AN. Syndrome X and diabetes: what is the mystery? Semin Vasc Surg. 2002 Dec;15(4):216-24. 22. Al-Awwadi NA, Araiz C, Bornet A, et al. Extracts enriched in different polyphenolic families normalize increased cardiac NADPH oxidase expression while having differential effects on insulin resistance, hypertension, and cardiac hypertrophy in highfructose-fed rats. J Agric Food Chem. 2005 Jan 12;53(1):151-7.
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23. Al Awwadi NA, Bornet A, Azay J, et al. Red wine polyphenols alone or in association with ethanol prevent hypertension, cardiac hypertrophy, and production of reactive oxygen species in the insulin-resistant fructose-fed rat. J Agric Food Chem. 2004 Sep 8;52(18):5593-7. 24. Kokavec A, Crowe SF. Effect on plasma insulin and plasma glucose of consuming white wine alone after a meal. Alcohol Clin Exp Res. 2003 Nov;27(11):1718-23. 25. Auger C, Teissedre PL, Grain P, et al. Dietary wine phenolics catechin, quercetin, and resveratrol efficiently protect hypercholesterolemic hamsters against aortic fatty streak accumulation. J Agric Food Chem. 2005 Mar 23;53(6):2015-21. 26. Sano T, Oda E, Yamashita T, et al. Anti-thrombotic effect of proanthocyanidin, a purified ingredient of grape seed. Thromb Res. 2005;115(1-2):115-21. 27. Fragopoulou E, Antonopoulou S, Nomikos T, Demopoulos CA. Structure elucidation of phenolic compounds from red/white wine with antiatherogenic properties. Biochim Biophys Acta. 2003 Jun 10;1632(1-3):90-9. 28. Yamakoshi J, Kataoka S, Koga T, Ariga T. Proanthocyanidin-rich extract from grape seeds attenuates the development of aortic atherosclerosis in cholesterol-fed rabbits. Atherosclerosis. 1999 Jan;142(1):139-49. 29. Vinson JA, Mandarano MA, Shuta DL, Bagchi M, Bagchi D. Beneficial effects of a novel IH636 grape seed proanthocyanidin extract and a niacin-bound chromium in a hamster atherosclerosis model. Mol Cell Biochem. 2002 Nov;240(1-2):99-103. 30. Das S, Cordis GA, Maulik N, Das DK. Pharmacological preconditioning with resveratrol: role of CREB-dependent Bcl-2 signaling via adenosine A3 receptor activation. Am J Physiol Heart Circ Physiol. 2005 Jan;288(1):H328-35. 31. Inoue H, Jiang XF, Katayama T, Osada S, Umesono K, Namura S. Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor alpha in mice. Neurosci Lett. 2003 Dec 11;352(3):203-6. 32. Weinberger Z, Richter ED. Cellular telephones and effects on the brain: the head as an antenna and brain tissue as a radio receiver. Med Hypotheses. 2002 Dec;59(6):703-5. 33. Martinez-Burdalo M, Martin A, Anguiano M, Villar R. Comparison of FDTDcalculated specific absorption rate in adults and children when using a mobile phone at 900 and 1800 MHz. Phys Med Biol. 2004 Jan 21;49(2):345-54. 34. Jang M, Pezzuto JM. Effects of resveratrol on 12-O-tetradecanoylphorbol-13-acetateinduced oxidative events and gene expression in mouse skin. Cancer Lett. 1998 Dec 11;134(1):81-9.
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35. Saito M, Hosoyama M, Ariga T, Kataoka S, Yamaji N. Antiulcer activity of grape seed extract and procyanidins. J Agric Food Chem. 1998 March19;46(4):1460-64. 36. Mittal A, Elmets CA, Katiyar SK. Dietary feeding of proanthocyanidins from grape seeds prevents photocarcinogenesis in SKH-1 hairless mice: relationship to decreased fat and lipid peroxidation. Carcinogenesis. 2003 Aug;24(8):1379-88. 37. 59. Ishikawa M, Maki K, Tofani I, Kimura K, Kimura M. Grape seed proanthocyanidins extract promotes bone formation in rats mandibular condyle. Eur J Oral Sci. 2005 Feb;113(1):47-52. 38. Mizutani K, Ikeda K, Kawai Y, Yamori Y. Resveratrol attenuates ovariectomyinduced hyypertension and bone loss in stroke-prone spontaneously hypertensive rats. J Nutr Sci Vitaminol (Tokyo). 2000 Apr;46(2):78-83. 39. Fan PH, Lou HX. Isolation and structure identification of grape seed polyphenols and its effects on oxidative damage to cellular DNA. Yao Xue Xue Bao. 2004 Nov;39(11):869-75. 40. Grape seed extract prevents H(2)O(2)-induced chromosomal damage in human lymphoblastoid cells. Biol Pharm Bull. 2004 Sep;27(9):1459-61. 41. Oral intake of proanthocyanidin-rich extract from grape seeds improves chloasma. Phytother Res. 2004 Nov;18(11):895-9. . 42. Supplementation with grape seed polyphenols results in increased urinary excretion of 3-hydroxyphenylpropionic Acid, an important metabolite of proanthocyanidins in humans. J Agric Food Chem. 2004 Aug 25;52(17):5545-9. 43. Neuroprotective effects of grape seed extract on neuronal injury by inhibiting DNA damage in the gerbil hippocampus after transient forebrain ischemia. Life Sci. 2004 Sep 3;75(16):1989-2001. 44. Grape seed extract affects proliferation and differentiation of human intestinal Caco-2 cells.J Agric Food Chem. 2004 Jun 2;52(11):3301-8. 45. The effect of grape-seed extract on 24 h energy intake in humans. Eur J Clin Nutr. 2004 Apr;58(4):667-73.
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46. Effect of a standardized grape seed extract on low-density lipoprotein susceptibility to oxidation in heavy smokers. Vigna GB. University of Ferrara, Ferrara, Italy. Metabolism. 2003 Oct;52(10):1250-7. 47. Polyphenolics in grape seeds-biochemistry and functionality. J Med Food. 2003 Winter;6(4):291-9. 48. Grape seed extract activates Th1 cells in vitro. Clin Diagn Lab Immunol 2002 Mar;9(2):470-6.
China Green Tea Leaf Powder - 100 Studies
1. J Agric Food Chem. 2003 Oct 22;51(22):6627-34. A Combination of Tea (Camellia senensis) Catechins Is Required for Optimal Inhibition of Induced CYP1A Expression by Green Tea Extract. Williams SN, Pickwell GV, Quattrochi LC. Department of Medicine, Section of Medical Toxicology, University of Colorado Health Sciences Center, Denver, Colorado 80262.
2. Biochem Biophys Res Commun. 2003 Oct 24;310(3):715-719. Suppression of Helicobacter pylori-induced gastritis by green tea extract in Mongolian gerbils. Matsubara S, Shibata H, Ishikawa F, Yokokura T, Takahashi M, Sugimura T, Wakabayashi K. Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 11, Tsukiji 5-chome, Chuo-ku, 104-0045, Tokyo, Japan 3. Cell Mol Life Sci. 2003 Aug;60(8):1760-3. Green tea epigallocatechin-3-gallate is an inhibitor of mammalian histidine decarboxylase. Rodriguez-Caso C, Rodriguez-Agudo D, Sanchez-Jimenez F, Medina MA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 402
Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, Malaga, Spain. 4. Eur J Cancer Prev. 2003 Oct;12(5):391-5. Effects of green tea on carcinogen-induced hepatic CYP1As in C57BL/6 mice. Yang M, Yoshikawa M, Arashidani K, Kawamoto T. Department of Preventive Medicine/Cancer Research Institute, Seoul National University College of Medicine, 28 Yongon-Dong Chongno-Gu, 110-799 Seoul, Korea. 5. Eur J Cancer Prev. 2003 Oct;12(5):383-90. Protective effects of green tea extracts (polyphenon E and EGCG) on human cervical lesions. Ahn WS, Yoo J, Huh SW, Kim CK, Lee JM, Namkoong SE, Bae SM, Lee IP. Department of Obstetrics and Gynaecology. 6. Phytomedicine. 2003;10(6-7):517-22. Hydroxyl radical and hypochlorous acid scavenging activity of small centaury (Centaurium erythraea) infusion. A comparative study with green tea (Camellia sinensis). Valentao P, Fernandes E, Carvalho F, Andrade PB, Seabra RM, Bastos ML. CEQUP/Servico de Farmacognosia, Faculdade de Farmacia, Universidade do Porto, Porto, Portugal. 7. Phytomedicine. 2003;10(6-7):494-8. Enhancement of neutral endopeptidase activity in SK-N-SH cells by green tea extract. Melzig MF, Janka M. Institut fur Pharmazie, Freie Universitat Berlin, Germany. melzig@zedat.fu-berlin.de 8. Br J Pharmacol. 2003 Oct;140(3):487-499. Epub 2003 Aug 26. Interactions of androgens, green tea catechins and the antiandrogen flutamide with the external glucose-binding site of the human erythrocyte glucose transporter GLUT1. Naftalin RJ, Afzal I, Cunningham P, Halai M, Ross C, Salleh N, Milligan SR. New Hunt's House, King's College London, Guys Campus, London SE1 1UL. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 403
9. Clin Cancer Res. 2003 Aug 15;9(9):3312-9. Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals. Chow HH, Cai Y, Hakim IA, Crowell JA, Shahi F, Brooks CA, Dorr RT, Hara Y, Alberts DS. Arizona Cancer Center, The University of Arizona, Tucson, Arizona 85724, USA. 10. Clin Exp Allergy. 2003 Sep;33(9):1252-5. Green tea-induced asthma: relationship between immunological reactivity, specific and non-specific bronchial responsiveness. Shirai T, Reshad K, Yoshitomi A, Chida K, Nakamura H, Taniguchi M. Department of Internal Medicine, Fujinomiya City General Hospital, Fujinomiya, Japan. fmyhsp@lilac.ocn.ne.jp 11. J Pharmacol Exp Ther. 2003 Oct;307(1):230-6. Epub 2003 Sep 03. Green tea polyphenol causes differential oxidative environments in tumor versus normal epithelial cells. Yamamoto T, Hsu S, Lewis J, Wataha J, Dickinson D, Singh B, Bollag WB, Lockwood P, Ueta E, Osaki T, Schuster G. Kochi Medical School, Japan. 12. Biol Pharm Bull. 2003 Sep;26(9):1235-8. Inhibitory effect of green tea polyphenols on membrane-type 1 matrix metalloproteinase, MT1-MMP. Oku N, Matsukawa M, Yamakawa S, Asai T, Yahara S, Hashimoto F, Akizawa T. Department of Medical Biochemistry and COE Program in the 21st Century, University of Shizuoka, School of Pharmaceutical Sciences. 13. Sichuan Da Xue Xue Bao Yi Xue Ban. 2003 Apr;34(2):303-5. [Protective effects of green tea on mice with the irradiating damage induced by gammaray][Article in Chinese] Wang Z, Zeng L, Xiao Y, Lu S, Gao X. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 404
Department of Nutrition and Food Hygiene, West China School of Public Health, Sichuan University, Chengdu 610041, China. 14. Int J Cancer. 2003 Oct 10;106(6):871-8. Green tea catechins inhibit VEGF-induced angiogenesis in vitro through suppression of VE-cadherin phosphorylation and inactivation of Akt molecule. Tang FY, Nguyen N, Meydani M. Vascular Biology Laboratory, JM USDA-Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA.
15. J Urol. 2003 Sep;170(3):773-6. Inhibition of bladder tumor growth by the green tea derivative epigallocatechin-3-gallate. Kemberling JK, Hampton JA, Keck RW, Gomez MA, Selman SH. Department of Urology, Medical College of Ohio, 3065 Arlington Avenue, Dowling Hall 2170, Toledo, OH 43614-5807, USA. 16. J Neurochem. 2003 Sep;86(5):1189-200. Green tea polyphenols enhance sodium nitroprusside-induced neurotoxicity in human neuroblastoma SH-SY5Y cells. Zhang Y, Zhao B. Laboratory of Visual Information Processing, Institute of Biophysics, Academia Sinica, 15 Datun Road, Chaoyang District, Beijing 100101, China. 17. Brain Res Bull. 2003 Aug 30;61(4):399-406. Effects of delayed administration of (-)-epigallocatechin gallate, a green tea polyphenol on the changes in polyamine levels and neuronal damage after transient forebrain ischemia in gerbils. Lee SY, Kim CY, Lee JJ, Jung JG, Lee SR. Department of Pharmacology, Kyungpook National University, 700-422 Taegu, South Korea. 18. Recent Results Cancer Res. 2003;163:165-71; discussion 264-6. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 405
Chemoprevention of nonmelanoma skin cancer: experience with a polyphenol from green tea. Linden KG, Carpenter PM, McLaren CE, Barr RJ, Hite P, Sun JD, Li KT, Viner JL, Meyskens FL. Department of Dermatology, University of California, Irvine, 101 The City Drive, Orange, CA 92868, USA. 19. FASEB J. 2003 Oct;17(13):1913-5. Epub 2003 Aug 01. Dual mechanisms of green tea extract (EGCG)-induced cell survival in human epidermal keratinocytes. Chung JH, Han JH, Hwang EJ, Seo JY, Cho KH, Kim KH, Youn JI, Eun HC. Department of Dermatology, Seoul National University College of Medicine, and Laboratory of Cutaneous Aging Research, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea. 20. Biochem Biophys Res Commun. 2003 Aug 15;308(1):64-7. Effect of green tea polyphenols on angiogenesis induced by an angiogenin-like protein. Maiti TK, Chatterjee J, Dasgupta S. Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, West Bengal, India. 21. Eur J Epidemiol. 2003;18(5):401-5. Relation of coffee, green tea, and caffeine intake to gallstone disease in middle-aged Japanese men. Ishizuk H, Eguchi H, Oda T, Ogawa S, Nakagawa K, Honjo S, Kono S. Department of Preventive Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan. 22. Nutr Cancer. 2003;45(2):226-35. Catechin content of 18 teas and a green tea extract supplement correlates with the antioxidant capacity. Henning SM, Fajardo-Lira C, Lee HW, Youssefian AA, Go VL, Heber D. UCLA Center for Human Nutrition, School of Medicine, Warren Hall 14-166, 900 Veteran Avenue, Los Angeles, CA 90095, USA. shenning@mednet.ucla.edu Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 406
23. Zhonghua Yu Fang Yi Xue Za Zhi. 2003 May;37(3):171-3. [Study on the protective effect of green tea on gastric, liver and esophageal cancers] [Article in Chinese] Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Jiang QW, Yu SZ.School of Public Health, Fudan University, Shanghai 200032, China. 24. Drugs Aging. 2003;20(10):711-21. Potential therapeutic properties of green tea polyphenols in Parkinson's disease. Pan T, Jankovic J, Le W. Department of Neurology, Baylor College of Medicine, Houston, Texas 77030, USA. 25. Curr Drug Targets Immune Endocr Metabol Disord. 2003 Sep;3(3):234-42. Skin photoprotection by green tea: antioxidant and immunomodulatory effects. Katiyar SK. Department of Dermatology, University of Alabama at Birmingham, Birmingham, AL 35294, USA. skatiyar@uab.edu 26. Chem Res Toxicol. 2003 Jul;16(7):865-72. Identification of potential aryl hydrocarbon receptor antagonists in green tea. Palermo CM, Hernando JI, Dertinger SD, Kende AS, Gasiewicz TA. Department of Environmental Medicine, University of Rochester, Rochester, New York 14642, USA. 27. Life Sci. 2003 Aug 8;73(12):1479-89. Action of green tea catechin on bone metabolic disorder in chronic cadmium-poisoned rats. Choi JH, Rhee IK, Park KY, Park KY, Kim JK, Rhee SJ. Department of Food Science and Nutrition, Catholic University of Daegu, 712-702, South Korea. 28. Ann N Y Acad Sci. 2003 May;993:351-61; discussion 387-93. Gene and protein expression profiles of anti- and pro-apoptotic actions of dopamine, Rapomorphine, green tea polyphenol (-)-epigallocatechine-3-gallate, and melatonin. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 407
Weinreb O, Mandel S, Youdim MB. Eve Topf, Haifa, Israel. 29. Life Sci. 2003 Aug 1;73(11):1383-92. Stimulatory effect of oral administration of green tea and caffeine on locomotor activity in SKH-1 mice. Michna L, Lu YP, Lou YR, Wagner GC, Conney AH. Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey and The University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ, USA. 30. Life Sci. 2003 Jul 25;73(10):1299-313. Green tea extract inhibits angiogenesis of human umbilical vein endothelial cells through reduction of expression of VEGF receptors. Kojima-Yuasa A, Hua JJ, Kennedy DO, Matsui-Yuasa I. Department of Food and Human Health Sciences, Graduate School of Human Life Science, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan. kojma@life.osaka-cu.ac.jp 31. Int J Cancer. 2003 Sep 10;106(4):574-9. Green tea and risk of breast cancer in Asian Americans. Wu AH, Yu MC, Tseng CC, Hankin J, Pike MC. Department of Preventive Medicine, University of Southern California, Keck School of Medicine, Los Angeles, CA, USA. annawu@hsc.usc.edu 32. J Nutr. 2003 Jul;133(7 Suppl):2417S-2424S. Molecular targets for green tea in prostate cancer prevention. Adhami VM, Ahmad N, Mukhtar H. Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. 33. FEBS Lett. 2003 Jul 10;546(2-3):265-70. Complex effects of different green tea catechins on human platelets.
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Lill G, Voit S, Schror K, Weber AA. Institut fur Pharmakologie und Klinische Pharmakologie, Universitatsklinikum Dusseldorf, Moorenstr 5, D-40225 Dusseldorf, Germany. 34. Arch Intern Med. 2003 Jun 23;163(12):1448-53. Cholesterol-lowering effect of a theaflavin-enriched green tea extract: a randomized controlled trial. Maron DJ, Lu GP, Cai NS, Wu ZG, Li YH, Chen H, Zhu JQ, Jin XJ, Wouters BC, Zhao J. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232, USA. david.maron@vanderbilt.edu 35. Anticancer Res. 2003 Mar-Apr;23(2B):1533-9. Green tea polyphenol targets the mitochondria in tumor cells inducing caspase 3dependent apoptosis. Hsu S, Lewis J, Singh B, Schoenlein P, Osaki T, Athar M, Porter AG, Schuster G. Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443. Medical College of Georgia, Augusta, GA 30912-1126, USA. shsu@mail.mcg.edu 36. Zhonghua Liu Xing Bing Xue Za Zhi. 2003 Mar;24(3):192-5. [A case-control study on drinking green tea and decreasing risk of cancers in the alimentary canal among cigarette smokers and alcohol drinkers] [Article in Chinese] Mu LN, Zhou XF, Ding BG, Wang RH, Zhang ZF, Chen CW, Wei GR, Zhou XM, Jiang QW, Yu SZ. School of Public Health, Fudan University, Shanghai 200032, China. 37. Arch Dermatol Res. 2003 Jul;295(3):112-6. Epub 2003 Jun 13. Comparative effects of polyphenols from green tea (EGCG) and soybean (genistein) on VEGF and IL-8 release from normal human keratinocytes stimulated with the proinflammatory cytokine TNFalpha. Trompezinski S, Denis A, Schmitt D, Viac J.
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INSERM U 346, Clinique Dermatologique, Hopital E. Herriot, 69437 Lyon, France. 38. Carcinogenesis. 2003 Jun;24(6):1105-9. Epub 2003 Apr 24. Prevention of dual promoting effects of pentachlorophenol, an environmental pollutant, on diethylnitrosamine-induced hepato- and cholangiocarcinogenesis in mice by green tea infusion. Umemura T, Kai S, Hasegawa R, Kanki K, Kitamura Y, Nishikawa A, Hirose M. Division of Pathology, National Institute of Health Sciences, 1-18-1, Kamiyoga, Setagaya-ku, Tokyo 158-8501, Japan. umemura@nihs.go.jp 39. DNA Cell Biol. 2003 Mar;22(3):217-24. A major constituent of green tea, EGCG, inhibits the growth of a human cervical cancer cell line, CaSki cells, through apoptosis, G(1) arrest, and regulation of gene expression. Ahn WS, Huh SW, Bae SM, Lee IP, Lee JM, Namkoong SE, Kim CK, Sin JI. Department of Obstetrics and Gynecology, College of Medicine, The Catholic University of Korea, Seoul, Korea. 40. J Biochem (Tokyo). 2003 May;133(5):571-6. Inhibitory effects of green tea catechins on the activity of human matrix metalloproteinase 7 (matrilysin). Oneda H, Shiihara M, Inouye K. Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan. 41. Nutrition. 2003 Jun;19(6):536-40. Effect of green tea in the prevention and reversal of fasting-induced intestinal mucosal damage. Asfar S, Abdeen S, Dashti H, Khoursheed M, Al-Sayer H, Mathew T, Al-Bader A. Department of Surgery, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait. sami@hsc.kuniv.edu.kw 42. Carcinogenesis. 2003 May;24(5):927-36.
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Treatment of green tea polyphenols in hydrophilic cream prevents UVB-induced oxidation of lipids and proteins, depletion of antioxidant enzymes and phosphorylation of MAPK proteins in SKH-1 hairless mouse skin. Vayalil PK, Elmets CA, Katiyar SK. Department of Dermatology, University of Alabama at Birmingham, 1670 University Blvd, Volker Hall 557, 35294, USA. 43. Exp Mol Med. 2003 Apr 30;35(2):136-9. Epigallocatechin gallate, a constituent of green tea, suppresses cytokine-induced pancreatic beta-cell damage. Han MK. Department of Microbiology, Chonbuk National University Medical School and Institute for Medical Sciences, Jeonju 560-756, Korea. 44. Oral Microbiol Immunol. 2003 Jun;18(3):192-5. Inhibitory effects of green tea catechins on protein tyrosine phosphatase in Prevotella intermedia. Okamoto M, Leung KP, Ansai T, Sugimoto A, Maeda N. Department of Oral Bacteriology, Tsurumi University School of Dental Medicine, Yokohama, Japan. 45. Phytother Res. 2003 May;17(5):566-7. Superoxide dismutase activity enhanced by green tea inhibits lipid accumulation in 3T3L1 cells. Mori M, Hasegawa N. Department of Food and Nutrition, Nagoya Bunri College, Nagoya, Japan. 46. Phytother Res. 2003 May;17(5):477-80. Powdered green tea has antilipogenic effect on Zucker rats fed a high-fat diet. Hasegawa N, Yamda N, Mori M. Department of Food and Nutrition, Nagoya Bunri College, Nagoya, Japan. hsgwn@nagoya-bunri.ac.jp Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 411
47. J Agric Food Chem. 2003 May 21;51(11):3379-81. Effect of selenium on the yield and quality of green tea leaves harvested in early spring. Hu Q, Xu J, Pang G. Laboratory of Food Processing and Quality Control, College of Food Science and Technology, Nanjing Agricultural University, Nanjing 210095, People's Republic of China. 48. Antiviral Res. 2003 Apr;58(2):167-73. Inhibition of adenovirus infection and adenain by green tea catechins. Weber JM, Ruzindana-Umunyana A, Imbeault L, Sircar S. Departement de Microbiologie et d'Infectiologie, Faculte de Medecine, Universite de Sherbrooke, Que, Sherbrooke, Canada J1H 5N4. joseph.weber@usherbrooke.ca 49. Arch Pharm Res. 2003 Mar;26(3):214-23. Comparison of green tea extract and epigallocatechin gallate on blood pressure and contractile responses of vascular smooth muscle of rats. Lim DY, Lee ES, Park HG, Kim BC, Hong SP, Lee EB. Department of Pharmacology, College of Medicine, Chosun University, Gwangju 501759, Korea. dylim@chosun.ac.kr 50. Phytother Res. 2003 Apr;17(4):358-63. DNA degradation by water extract of green tea in the presence of copper ions: implications for anticancer properties. Malik A, Azam S, Hadi N, Hadi SM. Department of Biochemistry, Faculty of Life Science, AMU, Aligarh, India. 51. Thromb Haemost. 2003 May;89(5):866-74. Green tea epigallocatechin-3-gallate inhibits platelet signalling pathways triggered by both proteolytic and non-proteolytic agonists. Deana R, Turetta L, Donella-Deana A, Dona M, Maria Brunati A, De Michiel L, Garbisa S.
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Department of Biological Chemistry and Institute of the Neuroscience of the Italian National Research Council (CNR), University of Padova, Italy, E-mail: arianna.donella@unipd.it 52. J Immunol. 2003 Apr 15;170(8):4335-41. Neutrophil restraint by green tea: inhibition of inflammation, associated angiogenesis, and pulmonary fibrosis. Dona M, Dell'Aica I, Calabrese F, Benelli R, Morini M, Albini A, Garbisa S. Department of Experimental Biomedical Sciences, Medical School of Padova, Padova, Italy. 53. Curr Med Chem Anti-Canc Agents. 2002 Jul;2(4):441-63. Green tea catechins as novel antitumor and antiangiogenic compounds. Demeule M, Michaud-Levesque J, Annabi B, Gingras D, Boivin D, Jodoin J, Lamy S, Bertrand Y, Beliveau R. Laboratoire de Medecine Moleculaire, UQAM-Hocric;pital Sainte-Justine, Montreal, Canada. 54. Kidney Int. 2003 May;63(5):1785-90. Effect of green tea extract on cardiac hypertrophy following 5/6 nephrectomy in the rat. Priyadarshi S, Valentine B, Han C, Fedorova OV, Bagrov AY, Liu J, Periyasamy SM, Kennedy D, Malhotra D, Xie Z, Shapiro JI. The Department of Medicine, Medical College of Ohio, Toledo, Ohio 43614, USA. 55. Phytother Res. 2003 Mar;17(3):206-9. Protective effect of green tea polyphenol (-)-epigallocatechin gallate and other antioxidants on lipid peroxidation in gerbil brain homogenates. Lee SR, Im KJ, Suh SI, Jung JG. Department of Pharmacology, School of Medicine and Brain Research Institute, Keimyung University, Taegu, South Korea. srlee@dsmc.or.kr 56. FASEB J. 2003 May;17(8):952-4. Epub 2003 Mar 28.
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Neuroprotection and neurorescue against Abeta toxicity and PKC-dependent release of nonamyloidogenic soluble precursor protein by green tea polyphenol (-)epigallocatechin-3-gallate. Levites Y, Amit T, Mandel S, Youdim MB. Eve Topf and USA National Parkinson Foundation, Centers of Excellence for Neurodegenerative Diseases Research, Technion Faculty of Medicine, Haifa, Israel. 57. J Agric Food Chem. 2003 Apr 9;51(8):2421-5. Influence of green tea polyphenol in rats with arginine-induced renal failure. Yokozawa T, Cho EJ, Nakagawa T. Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Toyama 930-0194, Japan. yokozawa@ms.toyama-mpu.ac.jp 58. J Pharmacol Exp Ther. 2003 Jul;306(1):29-34. Epub 2003 Mar 27. Green tea polyphenols induce differentiation and proliferation in epidermal keratinocytes. Hsu S, Bollag WB, Lewis J, Huang Q, Singh B, Sharawy M, Yamamoto T, Schuster G. Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443. Medical College of Georgia, Augusta, GA 30912-1126, USA. shsu@mail.mcg.edu 59. Mutat Res. 2003 Feb-Mar;523-524:33-41. Anticlastogenic, antigenotoxic and apoptotic activity of epigallocatechin gallate: a green tea polyphenol. Roy M, Chakrabarty S, Sinha D, Bhattacharya RK, Siddiqi M. Department of Environmental Carcinogenesis and Toxicology, Chittaranjan National Cancer Institute, 37 SP Mukherjee Road, Kolkata 700 026, India. 60. Cancer. 2003 Mar 15;97(6):1442-6. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Jatoi A, Ellison N, Burch PA, Sloan JA, Dakhil SR, Novotny P, Tan W, Fitch TR, Rowland KM, Young CY, Flynn PJ.
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Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. jatoi.aminah@mayo.edu 61. Int J Urol. 2003 Mar;10(3):160-6. Preventive effects of urinary bladder tumors induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in rat by green tea leaves. Sato D, Matsushima M. Second Department of Urology, Toho University of Medicine, Tokyo, Japan. sai2uro@oha.toho-u.ac.jp 62. J Biomed Sci. 2003 Mar-Apr;10(2):219-27. Green Tea Constituent (-)-Epigallocatechin-3-Gallate Inhibits Hep G2 Cell Proliferation and Induces Apoptosis through p53-Dependent and Fas-Mediated Pathways. Kuo PL, Lin CC. Graduate Institute of Natural Products, Kaohsiung Medical University, Kaohsiung, Taiwan, ROC. 63. Oncogene. 2003 Feb 20;22(7):1035-44. Inhibition of ultraviolet B-mediated activation of nuclear factor kappaB in normal human epidermal keratinocytes by green tea Constituent (-)-epigallocatechin-3-gallate. Afaq F, Adhami VM, Ahmad N, Mukhtar H. Department of Dermatology, University of Wisconsin, Madison, WI 53706, USA. 64. FASEB J. 2003 Apr;17(6):702-4. Epub 2003 Feb 05. Green tea polyphenol epigallocatechin-3 gallate induces apoptosis of proliferating vascular smooth muscle cells via activation of p53. Hofmann CS, Sonenshein GE. Department of Biochemistry, Boston University School of Medicine, Massachusetts 02118, USA. 65. Yan Ke Xue Bao. 2000 Sep;16(3):194-8. Growth inhibition, induction of apoptosis by green tea constituent (-)-epigallocatechin-3gallate in cultured rabbit lens epithelial cells. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 415
Huang W, Li S, Zeng J, Liu Y, Wu M, Zhang M. Zhongshan Ophthalmic Center, Sun Yat-sen University of Medical Sciences, Guangzhou 510060, China. 66. Anticancer Res. 2002 Nov-Dec;22(6C):4115-20. Induction of p57 is required for cell survival when exposed to green tea polyphenols. Hsu S, Yu FS, Lewis J, Singh B, Borke J, Osaki T, Athar M, Schuster G. Department of Oral Biology and Maxillofacial Pathology, School of Dentistry, AD1443, Medical College of Georgia, Augusta, GA 30912-1126, USA. shsu@mail.mcg.edu 67. J Biochem Mol Biol. 2003 Jan 31;36(1):66-77. Signal transduction pathways: targets for green and black tea polyphenols. Park AM, Dong Z. The Hormel Institute, University of Minnesota, Austin, MN 55912, USA. 68. Clin Exp Pharmacol Physiol. 2003 Jan-Feb;30(1-2):88-95. Green tea catechins evoke a phasic contraction in rat aorta via H2O2-mediated multiplesignalling pathways. Shen JZ, Zheng XF, Wei EQ, Kwan CY. Department of Pharmacology, School of Medicine, Zhejiang University, Hubin Campus, Hangzhou, People's Republic of China. 69. Anticancer Res. 2002 Nov-Dec;22(6A):3373-8. Induction of apoptosis by the green tea flavonol (-)-epigallocatechin-3-gallate in human endothelial ECV 304 cells. Yoo HG, Shin BA, Park JC, Kim HS, Kim WJ, Chay KO, Ahn BW, Park RK, Ellis LM, Jung YD. Chonnam University Research Institute of Medical Sciences, Chonnam National University Medical School, Kwangju, Korea. 70. Cancer Detect Prev. 2002;26(6):411-8.
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Modification of lung cancer susceptibility by green tea extract as measured by the comet assay. Zhang H, Spitz MR, Tomlinson GE, Schabath MB, Minna JD, Wu X. Department of Epidemiology, The University of Texas M.D. Anderson Cancer Center Box 189 1515 Holcombe Blvd, Houston, TX 77030, USA 71. Biol Pharm Bull. 2002 Dec;25(12):1513-8. Neuroprotective effects of the green tea components theanine and catechins. Kakuda T. Central Research Institute, Itoen, Ltd, Shuzuoka, Japan. 72. Life Sci. 2003 Jan 17;72(9):1073-83. Effects of green tea polyphenols on dopamine uptake and on MPP+ -induced dopamine neuron injury. Pan T, Fei J, Zhou X, Jankovic J, Le W. Department of Neurology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. 73. Asia Pac J Clin Nutr. 2002;11(4):292-7. Effect of green tea catechin on arachidonic acid cascade in chronic cadmium-poisoned rats. Choi JH, Chang HW, Rhee SJ. Department of Food Science and Nutrition, Catholic University of Daegu, Kyongsan-si, Korea. 74. Antivir Chem Chemother. 2002 Jul;13(4):223-9. Antiviral properties of prodelphinidin B-2 3'-O-gallate from green tea leaf. Cheng HY, Lin CC, Lin TC. Graduate Institute of Pharmaceutical Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan, Republic of China. 75. Atherosclerosis. 2003 Jan;166(1):23-30. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 417
Green tea catechins inhibit the cultured smooth muscle cell invasion through the basement barrier. Maeda K, Kuzuya M, Cheng XW, Asai T, Kanda S, Tamaya-Mori N, Sasaki T, Shibata T, Iguchi A. 76. J Periodontal Res. 2002 Dec;37(6):433-8. Improvement of periodontal status by green tea catechin using a local delivery system: a clinical pilot study. Hirasawa M, Takada K, Makimura M, Otake S. Department of Microbiology, Nihon University School of Dentistry at Matsudo, Matsudo, Chiba Japan. masahira@mascat.nihon-u.ac.jp 77. Breast Cancer Res Treat. 2002 Dec;76(3):195-201. (-)-Epigallocatechin (EGC) of green tea induces apoptosis of human breast cancer cells but not of their normal counterparts. Vergote D, Cren-Olive C, Chopin V, Toillon RA, Rolando C, Hondermarck H, Le Bourhis X. Laboratoire de Biologic du Developpement (UPRES-EA 1033), Universite des Sciences et Technologies de Lille, Villeneuve d'Ascq, France. 78. Yakugaku Zasshi. 2002 Nov;122(11):995-9. [Glutamate transporter mediated increase of antitumor activity by theanine, an amino acid in green tea] [Article in Japanese] Sadzuka Y, Yamashita Y, Kishimoto S, Fukushima S, Takeuchi Y, Sonobe T. University of Shizuoka, 52-1 Yada, Shizuoka 422-8526, Japan. sadzuka@u-shizuokaken.ac.jp 79. Int J Cancer. 2002 Dec 10;102(5):439-44. The green tea polyphenol, epigallocatechin-3-gallate, protects against the oxidative cellular and genotoxic damage of UVA radiation. Tobi SE, Gilbert M, Paul N, McMillan TJ.
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Department of Biological Sciences, Institute of Environmental and Natural Sciences, Lancaster University, Lancaster, United Kingdom. 80. Int J Oncol. 2002 Dec;21(6):1307-15. Bioactivity of well-defined green tea extracts in multicellular tumor spheroids. Mueller-Klieser W, Schreiber-Klais S, Walenta S, Kreuter MH. Institute of Physiology and Pathophysiology, Johannes Gutenberg-University Mainz, 55099 Mainz, Germany. wolfgang.mueller-klieser@uni-mainz.de 81. Life Sci. 2002 Dec 6;72(3):257-68. Anti-proliferative and differentiation-inducing activities of the green tea catechin epigallocatechin-3-gallate (EGCG) on the human eosinophilic leukemia EoL-1 cell line. Lung HL, Ip WK, Wong CK, Mak NK, Chen ZY, Leung KN. Department of Biochemistry, The Chinese University of Hong Kong, Shatin, China. 82. Chem Phys Lipids. 2002 Dec;120(1-2):109-17. Antioxidant effects of green tea polyphenols on free radical initiated peroxidation of rat liver microsomes. Cai YJ, Ma LP, Hou LF, Zhou B, Yang L, Liu ZL. National Laboratory of Applied Organic Chemistry, Lanzhou University, Gansu 730000, Lanzhou, People's Republic of China 83. Food Chem Toxicol. 2002 Dec;40(12):1745-50. Direct scavenging of nitric oxide and superoxide by green tea. Nakagawa T, Yokozawa T. Institute of Natural Medicine, Toyama Medical and Pharmaceutical University, 2630 Sugitani, Japan. 84. J Ethnopharmacol. 2002 Nov;83(1-2):109-16. Anti-diabetic activity of green tea polyphenols and their role in reducing oxidative stress in experimental diabetes. M C S, K S, Kuttan R. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 419
Amala Cancer Research Centre, Amala Nagar,Trichur 680 553, Kerala, India. 85. Zhonghua Yu Fang Yi Xue Za Zhi. 2002 Jul;36(4):243-6. [Green tea extracts protected against carbon tetrachloride-induced chronic liver damage and cirrhosis] [Article in Chinese] Xiao J, Lu R, Shen X, Wu M. Department of Hutyition and Food Hygiene, School of Health, Fudan University, Shanghai 200032, China. 86. Cancer Lett. 2002 Dec 15;188(1-2):163-70. Lack of inhibitory effects of green tea catechins in 1,2-dimetylhydrazine-induced rat intestinal carcinogenesis model: comparison of the different formulations, administration routes and doses. Hirose M, Yamaguchi T, Mizoguchi Y, Akagi K, Futakuchi M, Shirai T. Division of Pathology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, 158-8501, Tokyo, Japan. m-hirose@nihs.go.jp 87. Cancer Lett. 2002 Dec 15;188(1-2):9-13. Green tea: cancer preventive beverage and/or drug. Fujiki H, Suganuma M, Imai K, Nakachi K. Department of Biochemistry, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, Yamashiro-cho, 770-8514, Tokushima, Japan. hfujiki@ph.bunri-u.ac.jp 88. Amino Acids. 2002;22(2):131-43. The specific anti-cancer activity of green tea (-)-epigallocatechin-3-gallate (EGCG). Wang YC, Bachrach U. Department of Molecular Biology, Hebrew University-Hadassah Medical School, Jerusalem, Israel. 89. Mol Med. 2002 Jul;8(7):382-92. Synthetic analogs of green tea polyphenols as proteasome inhibitors. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 420
Smith DM, Wang Z, Kazi A, Li LH, Chan TH, Dou QP. Drug Discovery Program, H Lee Moffitt Cancer Center & Research Institute, Departments of Interdisciplinary Oncology and Biochemistry & Molecular Biology, College of Medicine,University of South Florida, Tampa, FL 33612-9497, USA. 90. Neurotoxicology. 2002 Sep;23(3):289-300. Differential modulation of growth and glutathione metabolism in cultured rat astrocytes by 4-hydroxynonenal and green tea polyphenol, epigallocatechin-3-gallate. Ahmed I, John A, Vijayasarathy C, Robin MA, Raza H. Department of Anatomy, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates. 91. Drug Metab Dispos. 2002 Nov;30(11):1246-9. Contribution of presystemic hepatic extraction to the low oral bioavailability of green tea catechins in rats. Cai Y, Anavy ND, Chow HH. College of Pharmacy, University of Arizona, Tucson, Arizona 85724, USA. 92. Cancer Epidemiol Biomarkers Prev. 2002 Oct;11(10 Pt 1):1025-32. Pharmacokinetics of tea catechins after ingestion of green tea and (-)-epigallocatechin-3gallate by humans: formation of different metabolites and individual variability. Lee MJ, Maliakal P, Chen L, Meng X, Bondoc FY, Prabhu S, Lambert G, Mohr S, Yang CS. Laboratory for Cancer Research, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey 08854-8020, USA. 93. Free Radic Biol Med. 2002 Oct 15;33(8):1097-105. Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. Ahmed S, Rahman A, Hasnain A, Lalonde M, Goldberg VM, Haqqi TM. Department of Orthopedics, Case Western Reserve University, Cleveland, OH 441064946, USA.
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94. Ophthalmic Res. 2002 Jul-Aug;34(4):258-63. Green tea (Camellia sinensis) protects against selenite-induced oxidative stress in experimental cataractogenesis. Gupta SK, Halder N, Srivastava S, Trivedi D, Joshi S, Varma SD. Department of Pharmacology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India. skgup@hotmail.com 95. Inflammation. 2002 Oct;26(5):233-41. A green tea-derived polyphenol, epigallocatechin-3-gallate, inhibits IkappaB kinase activation and IL-8 gene expression in respiratory epithelium. Chen PC, Wheeler DS, Malhotra V, Odoms K, Denenberg AG, Wong HR. Division of Critical Care Medicine, Children's Hospital Medical Center and Children's Hospital Research Foundation, Cincinnati, OH 45244, USA. 96. Biochem Biophys Res Commun. 2002 Sep 20;297(2):412-8. Elevation of P-glycoprotein function by a catechin in green tea. Wang EJ, Barecki-Roach M, Johnson WW. Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Lafayette, NJ 07848, USA. 97. Asia Pac J Clin Nutr. 2002;11(3):232-6. Effects of green tea catechin on prostaglandin synthesis of renal glomerular and renal dysfunction in streptozotocin-induced diabetic rats. Rhee SJ, Kim MJ, Kwag OG. Department of Food Science and Nutrition, Catholic University of Daegu, Gyungsan-si, Gyungbuk, Korea. sjrhee@cataegu.ac.kr 98. Biol Pharm Bull. 2002 Sep;25(9):1238-40. Activity-guided fractionation of green tea extract with antiproliferative activity against human stomach cancer cells. Kinjo J, Nagao T, Tanaka T, Nonaka G, Okawa M, Nohara T, Okabe H.
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kinjojun@fukuoka-u.ac.jp 99. Am J Physiol Gastrointest Liver Physiol. 2002 Oct;283(4):G957-64. Prevention of hepatic ischemia-reperfusion injury by green tea extract. Zhong Z, Froh M, Connor HD, Li X, Conzelmann LO, Mason RP, Lemasters JJ, Thurman RG. Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill, 27599, USA. 100. Mutat Res. 2002 Sep;512(1):37-65. Comparative antimutagenic and anticlastogenic effects of green tea and black tea: a review. Gupta S, Saha B, Giri AK. Division of Human Genetics and Genomics, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Calcutta 700 032, India.
Reduced L-Glutathione - 13 CITATIONS
1: Kaposzta Z, Clifton A, Molloy J, Martin JF, Markus HS. S-nitrosoglutathione reduces asymptomatic embolization after carotid angioplasty. Circulation. 2002 Dec 10;106(24):3057-62. PMID: 12473551 2: Fraternale A, Casabianca A, Orlandi C, Cerasi A, Chiarantini L, Brandi G, Magnani M. Macrophage protection by addition of glutathione (GSH)-loaded erythrocytes to AZT and DDI in a murine AIDS model. Antiviral Res. 2002 Dec;56(3):263-72. PMID: 12406509 3: Knight TR, Ho YS, Farhood A, Jaeschke H. Peroxynitrite is a critical mediator of acetaminophen hepatotoxicity in murine livers: protection by glutathione. J Pharmacol Exp Ther. 2002 Nov;303(2):468-75. PMID: 12388625
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4: Usberti M, Gerardi G, Micheli A, Tira P, Bufano G, Gaggia P, Movilli E, Cancarini GC, De Marinis S, D'Avolio G, Broccoli R, Manganoni A, Albertin A, Di Lorenzo D. Effects of a vitamin E-bonded membrane and of glutathione on anemia and erythropoietin requirements in hemodialysis patients. J Nephrol. 2002 Sep-Oct;15(5):558-64. PMID: 12455724 5: Cascinu S, Catalano V, Cordella L, Labianca R, Giordani P, Baldelli AM, Beretta GD, Ubiali E, Catalano G. Neuroprotective effect of reduced glutathione on oxaliplatin-based chemotherapy in advanced colorectal cancer: a randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2002 Aug 15;20(16):3478-83. PMID: 12177109 6: Arosio E, De Marchi S, Zannoni M, Prior M, Lechi A. Effect of glutathione infusion on leg arterial circulation, cutaneous microcirculation, and pain-free walking distance in patients with peripheral obstructive arterial disease: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2002 Aug;77(8):754-9. PMID: 12173710 7: Ueno Y, Kizaki M, Nakagiri R, Kamiya T, Sumi H, Osawa T. Dietary glutathione protects rats from diabetic nephropathy and neuropathy. J Nutr. 2002 May;132(5):897-900. PMID: 11983810 8: Gao F, Yao CL, Gao E, Mo QZ, Yan WL, McLaughlin R, Lopez BL, Christopher TA, Ma XL. Enhancement of glutathione cardioprotection by ascorbic acid in myocardial reperfusion injury. J Pharmacol Exp Ther. 2002 May;301(2):543-50. PMID: 11961055 9: Inal ME, Akgun A, Kahraman A. Radioprotective effects of exogenous glutathione against whole-body gamma-ray irradiation: age- and gender-related changes in malondialdehyde levels, superoxide dismutase and catalase activities in rat liver. Methods Find Exp Clin Pharmacol. 2002 May;24(4):209-12. PMID: 12092007 10: Snyder AH, McPherson ME, Hunt JF, Johnson M, Stamler JS, Gaston B. Acute effects of aerosolized S-nitrosoglutathione in cystic fibrosis. Am J Respir Crit Care Med. 2002 Apr 1;165(7):922-6. PMID: 11934715
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11: Kaposzta Z, Martin JF, Markus HS. Switching off embolization from symptomatic carotid plaque using S-nitrosoglutathione. Circulation. 2002 Mar 26;105(12):1480-4. PMID: 11914258 12: Ortolani O, Conti A, De Gaudio AR, Moraldi E, Novelli GP. [Glutathione and N-acetylcysteine in the prevention of free-radical damage in the initial phase of septic shock] Recenti Prog Med. 2002 Feb;93(2):125-9. Italian. PMID: 11887346 13: Amer MA. Modulation of age-related biochemical changes and oxidative stress by vitamin C and glutathione supplementation in old rats. Ann Nutr Metab. 2002;46(5):165-8. PMID: 12378038
L-Cysteine 22 STUDIES
1. Neurosci Lett. 2003 Jul 31;346(1-2):97-100. L-cysteine sulphinate, endogenous sulphur-containing amino acid, inhibits rat brain kynurenic acid production via selective interference with kynurenine aminotransferase II. Kocki T, Luchowski P, Luchowska E, Wielosz M, Turski WA, Urbanska EM. Department of Pharmacology and Toxicology, Medical University, Jaczewskiego 8, 20090 Lublin, Poland. 2. Biochem Biophys Res Commun. 2003 May 23;305(1):94-100. L-cysteine administration prevents liver fibrosis by suppressing hepatic stellate cell proliferation and activation. Horie T, Sakaida I, Yokoya F, Nakajo M, Sonaka I, Okita K. Pharmaceuticals Research Laboratories, Ajinomoto Co, Inc, 1-1, Suzuki-cho, Kawasakiku, Kawasaki 210-8681, Japan. 3. Proc Nutr Soc. 2000 Nov;59(4):595-600. Glutathione and immune function. Droge W, Breitkreutz R. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 425
Department of Immunochemistry, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. W.Droege@dkfz-heidelberg.de 4. Toxicol Appl Pharmacol. 2000 Oct 1;168(1):72-8. gamma-Glutamyl transpeptidase and L-cysteine regulate methylmercury uptake by HepG2 cells, a human hepatoma cell line. Wang W, Clarkson TW, Ballatori N. Department of Environmental Medicine, University of Rochester School of Medicine, Rochester, New York 14642, USA. 5. Amino Acids. 2000;18(4):319-27. Polyamines and thiols in the cytoprotective effect of L-cysteine and L-methionine on carbon tetrachloride-induced hepatotoxicity. Chen W, Kennedy DO, Kojima A, Matsui-Yuasa I. Department of Food and Nutrition, Faculty of Human Life Science, Osaka City University, Osaka, Japan. 6. Z Naturforsch [C]. 2000 Mar-Apr;55(3-4):271-7. Protective effect of L-cysteine and glutathione on rat brain Na+,K+-ATPase inhibition induced by free radicals. Tsakiris S, Angelogianni P, Schulpis KH, Behrakis P. Department of Experimental Physiology, University of Athens, Medical School, Greece. stsakir@cc.uoa.gr 7. Comp Biochem Physiol B Biochem Mol Biol. 1997 Feb;116(2):223-6. L-cysteine metabolism in guinea pig and rat tissues. Wrobel M, Ubuka T, Yao WB, Abe T. Department of Biochemistry, Okayama University Medical School, Japan. 8. Gross A, Hack V, Stahl-Hennig C, Droge W. AIDS Res Hum Retroviruses. 1996 Nov 20;12(17):1639-41. Elevated hepatic gamma-glutamylcysteine synthetase activity and abnormal sulfate levels in liver and muscle tissue may explain abnormal cysteine and glutathione levels in SIVinfected rhesus macaques. 9. Biochem Pharmacol. 1996 May 3;51(9):1111-6.
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Maintenance of hepatic glutathione homeostasis and prevention of acetaminopheninduced cataract in mice by L-cysteine prodrugs. Rathbun WB, Killen CE, Holleschau AM, Nagasawa HT. Department of Ophthalmology, University of Minnesota, Minneapolis, USA. 10. Jpn J Physiol. 1995;45(5):771-83. The central effect of L-cysteine on cardiovascular system of the conscious rat. Takemoto Y. Department of Physiology, Hiroshima University School of Medicine, Minami-ku, Japan. 11. FASEB J. 1994 Nov;8(14):1131-8. Functions of glutathione and glutathione disulfide in immunology and immunopathology. Droge W, Schulze-Osthoff K, Mihm S, Galter D, Schenk H, Eck HP, Roth S, Gmunder H. Department of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, Germany. 12. Pharmacology. 1993;46(2):61-5. Cysteine and glutathione deficiency in AIDS patients: a rationale for the treatment with N-acetyL-cysteine. Droge W. Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, BRD. 13. Biochem Pharmacol. 1992 Jul 7;44(1):129-35. Acetaminophen-induced depletion of glutathione and cysteine in the aging mouse kidney. Richie JP Jr, Lang CA, Chen TS. American Health Foundation, Valhalla, NY 10595. 14. Biochem Pharmacol. 1992 Feb 4;43(3):483-8. Cysteine isopropylester protects against paracetamol-induced toxicity. Butterworth M, Upshall DG, Smith LL, Cohen GM. Toxicology Unit, School of Pharmacy, University of London, U.K. 15. Blood. 1992 Sep 1;80(5):1247-53. Antithrombotic properties of L-cysteine, N-(mercaptoacetyl)-D-Tyr-Arg-Gly-Aspsulfoxide (G4120) in a hamster platelet-rich femoral vein thrombosis model. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 427
Imura Y, Stassen JM, Bunting S, Stockmans F, Collen D. Center for Thrombosis and Vascular Research, University of Leuven, Belgium. 16. Jpn J Cancer Res. 1989 Feb;80(2):182-7. Enhanced antitumor effect of 5'-deoxy-5-fluorouridine by oral administration with Lcysteine. Iigo M, Nakajima Y, Araki E, Hoshi A. Chemotherapy Division, National Cancer Center Research Institute, Tokyo. 17. Am Rev Respir Dis. 1985 Nov;132(5):1049-54. Investigation of the protective effects of the antioxidants ascorbate, cysteine, and dapsone on the phagocyte-mediated oxidative inactivation of human alpha-1-protease inhibitor in vitro. Theron A, Anderson R. 18. J Biol Chem. 1984 May 10;259(9):5606-11. Free radical metabolites of L-cysteine oxidation. Harman LS, Mottley C, Mason RP. 19. Hum Genet. 1979;50(1):51-7. Chromosomal breakage in Crohn's disease: anticlastogenic effect of D-penicillamine and L-cysteine. Emerit I, Emerit J, Levy A, Keck M. 20. Biol Trace Elem Res. 2000 Jul;76(1):19-30. Study of the effect of the administration of Cd(II), cysteine, methionine, and Cd(II) together with cysteine or methionine on the conversion of xanthine dehydrogenase into xanthine oxidase. Esteves AC, Felcman J. Department of Chemistry, Pontificia Universidade Catolica do Rio de Janeiro, Rio de Janeiro, Brazil. 21. J Infect Dis. 2000 Sep;182 Suppl 1:S81-4. Regulation of cysteine-rich intestinal protein, a zinc finger protein, by mediators of the immune response. Cousins RJ, Lanningham-Foster L. Food Science and Human Nutrition Department, Center for Nutritional Sciences, University of Florida, Gainesville, FL 32611-0370, USA. 22. Am J Med. 1991 Sep 30;91(3C):140S-144S.
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Modulation of lymphocyte functions and immune responses by cysteine and cysteine derivatives. Droge W, Eck HP, Gmunder H, Mihm S. Division of Immunochemistry, Deutsches Krebsforschungszentrum, Heidelberg, F.R.G.
Coenzyme Q10 43 STUDIES

1: Muller T, Buttner T, Gholipour AF, Kuhn W. Coenzyme Q10 supplementation provides mild symptomatic benefit in patients with Parkinson's disease. Neurosci Lett. 2003 May 8;341(3):201-4. PMID: 12697283 [PubMed - indexed for MEDLINE] 2: Elshershari H, Ozer S, Ozkutlu S, Ozme S. Potential usefulness of coenzyme Q10 in the treatment of idiopathic dilated cardiomyopathy in children. Int J Cardiol. 2003 Mar;88(1):101-2. PMID: 12659993 [PubMed - indexed for MEDLINE] 3: Beal MF. Bioenergetic approaches for neuroprotection in Parkinson's disease. Ann Neurol. 2003;53 Suppl 3:S39-47; discussion S47-8. Review. PMID: 12666097 [PubMed - indexed for MEDLINE] 4: Lu WL, Zhang Q, Lee HS, Zhou TY, Sun HD, Zhang DW, Zheng L, Lee M, Wong SM. Total coenzyme Q10 concentrations in Asian men following multiple oral 50-mg doses administered as coenzyme Q10 sustained release tablets or regular tablets. Biol Pharm Bull. 2003 Jan;26(1):52-5. PMID: 12520172 [PubMed - indexed for MEDLINE] 5: Van Maldergem L, Trijbels F, DiMauro S, Sindelar PJ, Musumeci O, Janssen A, Delberghe X, Martin JJ, Gillerot Y. Coenzyme Q-responsive Leigh's encephalopathy in two sisters. Ann Neurol. 2002 Dec;52(6):750-4. PMID: 12447928 [PubMed - indexed for MEDLINE] 6: Ramadan LA, Abd-Allah AR, Aly HA, Saad-el-Din AA. Testicular toxicity effects of magnetic field exposure and prophylactic role of coenzyme Q10 and L-carnitine in mice.
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Pharmacol Res. 2002 Oct;46(4):363-70. PMID: 12361700 [PubMed - indexed for MEDLINE] 7: Turunen M, Wehlin L, Sjoberg M, Lundahl J, Dallner G, Brismar K, Sindelar PJ. beta2-Integrin and lipid modifications indicate a non-antioxidant mechanism for the antiatherogenic effect of dietary coenzyme Q10. Biochem Biophys Res Commun. 2002 Aug 16;296(2):255-60. PMID: 12163010 [PubMed - indexed for MEDLINE] 8: Sarter B. Coenzyme Q10 and cardiovascular disease: a review. J Cardiovasc Nurs. 2002 Jul;16(4):9-20. Review. PMID: 12597259 [PubMed - indexed for MEDLINE] 9: Koryagin AS, Krylova EV, Luk'yanova LD. Effect of ubiquinone-10 on the blood system in rats exposed to radiation. Bull Exp Biol Med. 2002 Jun;133(6):562-4. PMID: 12447465 [PubMed - indexed for MEDLINE] 10: Lamson DW, Plaza SM. Mitochondrial factors in the pathogenesis of diabetes: a hypothesis for treatment. Altern Med Rev. 2002 Apr;7(2):94-111. Review. PMID: 11991790 [PubMed - indexed for MEDLINE] 11: Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases. Free Radic Res. 2002 Apr;36(4):455-60. Review. PMID: 12069110 [PubMed - indexed for MEDLINE] 12: Rozen TD, Oshinsky ML, Gebeline CA, Bradley KC, Young WB, Shechter AL, Silberstein SD. Open label trial of coenzyme Q10 as a migraine preventive. Cephalalgia. 2002 Mar;22(2):137-41. PMID: 11972582 [PubMed - indexed for MEDLINE] 13: Watts GF, Playford DA, Croft KD, Ward NC, Mori TA, Burke V. Coenzyme Q(10) improves endothelial dysfunction of the brachial artery in Type II diabetes mellitus. Diabetologia. 2002 Mar;45(3):420-6. PMID: 11914748 [PubMed - indexed for MEDLINE] 14: Lister RE. An open, pilot study to evaluate the potential benefits of coenzyme Q10 combined with Ginkgo biloba extract in fibromyalgia syndrome. J Int Med Res. 2002 Mar-Apr;30(2):195-9. PMID: 12025528 [PubMed - indexed for MEDLINE] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 430
15: Huang CC, Kuo HC, Chu CC, Kao LY. Rapid visual recovery after coenzyme q10 treatment of leber hereditary optic neuropathy. J Neuroophthalmol. 2002 Mar;22(1):66. PMID: 11937918 [PubMed - indexed for MEDLINE] 16: Ferrante RJ, Andreassen OA, Dedeoglu A, Ferrante KL, Jenkins BG, Hersch SM, Beal MF. Therapeutic effects of coenzyme Q10 and remacemide in transgenic mouse models of Huntington's disease. J Neurosci. 2002 Mar 1;22(5):1592-9. PMID: 11880489 [PubMed - indexed for MEDLINE] 17: Brancato R, Fiore T, Papucci L, Schiavone N, Formigli L, Orlandini SZ, Gobbi PG, Carones F, Donnini M, Lapucci A, Capaccioli S. Concomitant effect of topical ubiquinone Q10 and vitamin E to prevent keratocyte apoptosis after excimer laser photoablation in rabbits. J Refract Surg. 2002 Mar-Apr;18(2):135-9. PMID: 11934201 [PubMed - indexed for MEDLINE] 18: Schilling G, Coonfield ML, Ross CA, Borchelt DR. Coenzyme Q10 and remacemide hydrochloride ameliorate motor deficits in a Huntington's disease transgenic mouse model. Neurosci Lett. 2001 Nov 27;315(3):149-53. PMID: 11716985 [PubMed - indexed for MEDLINE] 19: Burke BE, Neuenschwander R, Olson RD. Randomized, double-blind, placebo-controlled trial of coenzyme Q10 in isolated systolic hypertension. South Med J. 2001 Nov;94(11):1112-7. PMID: 11780680 [PubMed - indexed for MEDLINE] 20: Di Giovanni S, Mirabella M, Spinazzola A, Crociani P, Silvestri G, Broccolini A, Tonali P, Di Mauro S, Servidei S. Coenzyme Q10 reverses pathological phenotype and reduces apoptosis in familial CoQ10 deficiency. Neurology. 2001 Aug 14;57(3):515-8. PMID: 11502923 [PubMed - indexed for MEDLINE] 21: Tran MT, Mitchell TM, Kennedy DT, Giles JT. Role of coenzyme Q10 in chronic heart failure, angina, and hypertension. Pharmacotherapy. 2001 Jul;21(7):797-806. Review. PMID: 11444576 [PubMed - indexed for MEDLINE] 22: [No authors listed] Extra co-enzyme Q10 for statin-users?
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Treatmentupdate. 2001 Jun;13(2):4-7. PMID: 11570288 [PubMed - indexed for MEDLINE] 23: Gazdikova K, Gvozdjakova A, Kucharska J, Spustova V, Braunova Z, Dzurik R. [Effect of coenzyme Q10 in patients with kidney diseases] Cas Lek Cesk. 2001 May 24;140(10):307-10. Slovak. PMID: 11411060 [PubMed - indexed for MEDLINE] 24: Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 2001 Apr;21(4):585-93. PMID: 11304477 [PubMed - indexed for MEDLINE] 25: Rauchova H, Lenaz G. [Coenzyme Q and its therapeutic use] Ceska Slov Farm. 2001 Mar;50(2):78-82. Review. Czech. PMID: 11288594 [PubMed - indexed for MEDLINE] 26: Piotrowski P, Wierzbicka K, Smialek M. Neuronal death in the rat hippocampus in experimental diabetes and cerebral ischaemia treated with antioxidants. Folia Neuropathol. 2001;39(3):147-54. PMID: 11770125 [PubMed - indexed for MEDLINE] 27: Rauscher FM, Sanders RA, Watkins JB 3rd. Effects of coenzyme Q10 treatment on antioxidant pathways in normal and streptozotocin-induced diabetic rats. J Biochem Mol Toxicol. 2001;15(1):41-6. PMID: 11170314 [PubMed - indexed for MEDLINE] 28: Shinkai T, Nakashima M, Ohmori O, Terao T, Nakamura J, Hiramatsu N, Hashiguchi H, Tsuji S. Coenzyme Q10 improves psychiatric symptoms in adult-onset mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: a case report. Aust N Z J Psychiatry. 2000 Dec;34(6):1034-5. PMID: 11127618 [PubMed - indexed for MEDLINE] 29: Choi C, Sunwoo IN, Kim HS, Kim DI. Transient improvement of pyruvate metabolism after coenzyme Q therapy in KearnsSayre syndrome: MRS study. Yonsei Med J. 2000 Oct;41(5):676-9. PMID: 11079632 [PubMed - indexed for MEDLINE] 30: Kaikkonen J, Nyyssonen K, Tomasi A, Iannone A, Tuomainen TP, Porkkala-Sarataho E, Salonen JT. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 432
Antioxidative efficacy of parallel and combined supplementation with coenzyme Q10 and d-alpha-tocopherol in mildly hypercholesterolemic subjects: a randomized placebocontrolled clinical study. Free Radic Res. 2000 Sep;33(3):329-40. PMID: 10993487 [PubMed - indexed for MEDLINE] 31: Rotig A, Appelkvist EL, Geromel V, Chretien D, Kadhom N, Edery P, Lebideau M, Dallner G, Munnich A, Ernster L, Rustin P. Quinone-responsive multiple respiratory-chain dysfunction due to widespread coenzyme Q10 deficiency. Lancet. 2000 Jul 29;356(9227):391-5. PMID: 10972372 [PubMed - indexed for MEDLINE] 32: Raitakari OT, McCredie RJ, Witting P, Griffiths KA, Letters J, Sullivan D, Stocker R, Celermajer DS. Coenzyme Q improves LDL resistance to ex vivo oxidation but does not enhance endothelial function in hypercholesterolemic young adults. Free Radic Biol Med. 2000 Apr 1;28(7):1100-5. PMID: 10832071 [PubMed - indexed for MEDLINE] 33: Liou CW, Huang CC, Lin TK, Tsai JL, Wei YH. Correction of pancreatic beta-cell dysfunction with coenzyme Q(10) in a patient with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes syndrome and diabetes mellitus. Eur Neurol. 2000;43(1):54-5. PMID: 10601810 [PubMed - indexed for MEDLINE] 34: Overvad K, Diamant B, Holm L, Holmer G, Mortensen SA, Stender S. Coenzyme Q10 in health and disease. Eur J Clin Nutr. 1999 Oct;53(10):764-70. Review. PMID: 10556981 [PubMed - indexed for MEDLINE] 35: Svensson M, Malm C, Tonkonogi M, Ekblom B, Sjodin B, Sahlin K. Effect of Q10 supplementation on tissue Q10 levels and adenine nucleotide catabolism during high-intensity exercise. Int J Sport Nutr. 1999 Jun;9(2):166-80. PMID: 10362453 [PubMed - indexed for MEDLINE] 36: Abe K, Matsuo Y, Kadekawa J, Inoue S, Yanagihara T. Effect of coenzyme Q10 in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS): evaluation by noninvasive tissue oximetry. J Neurol Sci. 1999 Jan 1;162(1):65-8. PMID: 10064171 [PubMed - indexed for MEDLINE] 37: Piotrowski P, Ostrowski RP, Pankowska T, Smialek M. [The effect of coenzyme Q10 on lactate acidosis at the beginning of experimental Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 433
cerebral ischemia in rats after the use of endothelin 1 (preliminary results)] Neurol Neurochir Pol. 1998 Nov-Dec;32(6):1397-404. Polish. PMID: 10358830 [PubMed - indexed for MEDLINE] 38: Rowland MA, Nagley P, Linnane AW, Rosenfeldt FL. Coenzyme Q10 treatment improves the tolerance of the senescent myocardium to pacing stress in the rat. Cardiovasc Res. 1998 Oct;40(1):165-73. PMID: 9876329 [PubMed - indexed for MEDLINE] 39: Palomaki A, Malminiemi K, Solakivi T, Malminiemi O. Ubiquinone supplementation during lovastatin treatment: effect on LDL oxidation ex vivo. J Lipid Res. 1998 Jul;39(7):1430-7. PMID: 9684746 [PubMed - indexed for MEDLINE] 40: Singh RB, Niaz MA, Rastogi V, Rastogi SS. Coenzyme Q in cardiovascular disease. J Assoc Physicians India. 1998 Mar;46(3):299-306. Review. PMID: 11273351 [PubMed - indexed for MEDLINE] 41: Lund EL, Quistorff B, Spang-Thomsen M, Kristjansen PE. Effect of radiation therapy on small-cell lung cancer is reduced by ubiquinone intake. Folia Microbiol (Praha). 1998;43(5):505-6. PMID: 9821311 [PubMed - indexed for MEDLINE] 42: Ostrowski RP, Piotrowski P, Pankowska T, Smialek M. Evaluation of morphological changes after treatment with coenzyme Q10 (CoQ10) in endothelin-1 induced experimental ischemia in the rat. Folia Neuropathol. 1998;36(3):185-8. PMID: 9833395 [PubMed - indexed for MEDLINE] 43: Dlugosz A, Sawicka E. The chemoprotective effect of coenzyme Q on lipids in the paint and lacquer industry workers. Int J Occup Med Environ Health. 1998;11(2):153-63. PMID: 9753894 [PubMed - indexed for MEDLINE]
N-Acetylcysteine (NAC) - 40 STUDIES
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1. Hum Exp Toxicol. 2003 Aug;22(8):453-8. Successful treatment of acetaminophen overdose associated with hepatic failure. Pajoumand A, Jalali N, Abdollahi M, Shadnia S. Poison Centre, Loghman-Hakim Hospital, Faculty of Medicine, Shaheed-Beheshti University of Medical Science, Tehran, Iran. 2. Klin Med (Mosk). 2003;81(4):58-60. [Safety of paracetamol as a representative of nonprescription analgetics-antipyretics] [Article in Russian] Makar'iants ML. 3. Hepatology. 2002 Apr;35(4):876-82. Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity. Schmidt LE, Dalhoff K, Poulsen HE. Departments of Hepatology and Clinical Pharmacology, Rigshospitalet, University Hospital, Copenhagen, Denmark. lars.schmidt@dadlnet.dk 4. Exp Toxicol Pathol. 2002 Feb;53(6):489-500. Acetaminophen hepatotoxicity and mechanisms of its protection by N-acetylcysteine: a study of Hep3B cells. Manov I, Hirsh M, Iancu TC. Pediatric Research and Electron Microscopy Unit, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. 5. J Ocul Pharmacol Ther 1998 Aug;14(4):345-55 Prevention of acetaminophen-induced cataract by a combination of diallyl disulfide and N-acetylcysteine. Zhao C, Shichi H. Department of Ophthalmology, Kresge Eye Institute, Wayne State University School of Medicine, Detroit, Michigan, USA.
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6. Metabolic activation and paracetamol hepatotoxicity - An update on the management of paracetamol (acetaminophen) poisoning. Chan T.Y.K.; Critchley J.A.J.H.; Chan J.C.N.; Tomlinson B. Department of Clinical Pharmacology, Chinese University of Hong Kong, Prince of Wales Hospital,Shatin Hong Kong Journal of the Hong Kong Medical Association (J. HONG KONG MED. ASSOC. ) (Hong Kong) 1994, 46/1 (87-92) 7. Intravenous N-acetylcysteine, hepatotoxicity and plasma glutathione S-transferase in patients with paracetamol overdosage. Beckett GJ; Donovan JW; Hussey AJ; Proudfoot AT; Prescott LF University Department of Clinical Chemistry, Royal Infirmary, Edinburgh, Scotland, UK. Human & experimental toxicology (ENGLAND) May 1990, 9 (3) p183-6, 8. A comparison of the protective effects of N-acetyl-cysteine and Scarboxymethylcysteine against paracetamol-induced hepatotoxicity. Ioannides C; Hall DE; Mulder DE; Steele CM; Spickett J; Delaforge M; Parke DV Toxicology (NETHERLANDS) Nov 1983, 28 (4) p313-21, 9. Cimetidine protects against acetaminophen toxicity. Jackson J.E. Sect. Clin. Pharmacol., Dept. Pharmacol., Univ. Arizona Health Sci. Cent., Tucson, AZ 85724 United States Life Sciences ( LIFE SCI. ) (United Kingdom) 1982, 31/1 (31-35) 10. Effects of aspirin and acetaminophen on the liver. Zimmerman H.J. George Washington Univ. Med. Cent. Washington, D.C. 20037 United States Archives of Internal Medicine ( ARCH. INTERN. MED. ) (United States) 1981, 141/3 (333-342) 11. Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine. Prescott L.F.; Park J.; Ballantyne A.; et al. Reg. Poisoning Treatm. Cent., Roy. Infirm., Edinburgh United Kingdom Lancet ( LANCET ) (United Kingdom) 1977, 2/8035 (432-434) Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 436
12. The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage Prescott L.F.; Donovan J.W.; Jarvie D.R.; Proudfoot A.T. University Department of Clinical Pharmacology, Royal Infirmary, Edinburgh EH3 97W United Kingdom European Journal of Clinical Pharmacology ( EUR. J. CLIN. PHARMACOL. ) ( Germany) 1989, 37/5 (501-506) 13. Acetaminophen hepatotoxicity and malnutrition. Newman T.J.; Bargman G.J. Dept. Ped., Univ. Wisconsin Hosp., Madison, Wis. 53706 United States American Journal of Gastroenterology ( AM. J. GASTROENTEROL. ) (United States) 1979, 72/6 (647-650)
ALCOHOL
14. Protective effect of N-acetylcysteine on rat liver cell membrane during methanol intoxication. Dobrzynska I, Skrzydlewska E, Kasacka I, Figaszewski Z. Institute of Chemistry, University in Bialystok, Poland. J Pharm Pharmacol. 2000 May;52(5):547-52
ALS
15. Neurobiol Dis. 2003 Aug;13(3):213-21. Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine. Beretta S, Sala G, Mattavelli L, Ceresa C, Casciati A, Ferri A, Carri MT, Ferrarese C. Department of Neuroscience and Biomedical Technologies, University of MilanoBicocca, San Gerardo Hospital, via Donizetti, 106, 20052, Monza (MI), Italy. 16. Neurochem Int. 2001 Aug;39(2):141-9. Glutathione elevation and its protective role in acrolein-induced protein damage in synaptosomal membranes: relevance to brain lipid peroxidation in neurodegenerative disease.
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Pocernich CB, Cardin AL, Racine CL, Lauderback CM, Butterfield DA. Department of Chemistry, 125 Chemistry-Physics Building, University of Kentucky, Lexington, KY 40506, USA. 17. J Neurochem. 2001 Jan;76(1):224-33. N-acetyl-L-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: effects on beta-amyloid secretion and tau phosphorylation. Olivieri G, Baysang G, Meier F, Muller-Spahn F, Stahelin HB, Brockhaus M, Brack C. Neurobiology Laboratory, Psychiatric University Hospital, Basel, Switzerland. gianfranco.olivieri@pukbasel.ch 18. N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis. Andreassen OA, Dedeoglu A, Klivenyi P, Beal MF, Bush AI. Neurology Service, Massachusetts General Hospital and Harvard Medical School, Boston, USA. Neuroreport 2000 Aug 3;11(11):2491-3 19. Reduction of lower motor neuron degeneration in wobbler mice by N-acetyl-Lcysteine. Henderson JT, Javaheri M, Kopko S, Roder JC. Samuel Lunenfeld Research Institute, Program in Development and Fetal Health, Mount Sinai Hospital, Toronto, Ontario, Canada. J Neurosci 1996 Dec 1;16(23):7574-82
CANCER
20. Cancer Res. 2003 Jun 15;63(12):3413-7. 2-Deoxy-D-glucose-induced cytotoxicity and radiosensitization in tumor cells is mediated via disruptions in thiol metabolism. Lin X, Zhang F, Bradbury CM, Kaushal A, Li L, Spitz DR, Aft RL, Gius D. Section of Cancer Biology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri, USA. 21. Int J Biol Markers. 2003 Jan-Mar;18(1):70-4. Antiangiogenic activity of chemopreventive drugs.
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Pfeffer U, Ferrari N, Morini M, Benelli R, Noonan DM, Albini A. Laboratory of Molecular Oncology, National Cancer Research Institute, Genoa, Italy. ulrich.pfeffer@istge.it 22. J Environ Pathol Toxicol Oncol. 2003;22(1):17-28. Reactive oxygen species, antioxidant mechanisms, and serum cytokine levels in cancer patients: impact of an antioxidant treatment. Mantovani G, Maccio A, Madeddu C, Mura L, Massa E, Gramignano G, Lusso MR, Murgia V, Camboni P, Ferreli L. Department of Medical Oncology, University of Cagliari, Cagliari, Italy. mantovan@pacs.unica.it 23. Cell Mol Life Sci. 2003 Jan;60(1):6-20. Molecular mechanisms of N-acetylcysteine actions. Zafarullah M, Li WQ, Sylvester J, Ahmad M. Departement de Medecine, Centre de Recherche du Centre Hospitalier de l'Universite de Montreal, Lab. K-5255 Mailloux, Hopital Notre-Dame du CHUM, 1560 Sherbrooke est, Montreal, Quebec H2L 4M1, Canada. Muhammad.Zafarullah@umontreal.ca 24. Toxicol Pathol. 2003 Jan-Feb;31(1):39-51. Slowing tumorigenic progression in TRAMP mice and prostatic carcinoma cell lines using natural anti-oxidant from spinach, NAO--a comparative study of three antioxidants. Nyska A, Suttie A, Bakshi S, Lomnitski L, Grossman S, Bergman M, Ben-Shaul V, Crocket P, Haseman JK, Moser G, Goldsworthy TL, Maronpot RR. Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina 27709, USA. nyska@niehs.nih.gov 25. Toxicol Lett. 2003 Mar 3;138(3):243-51. Astroglial CYP1B1 up-regulation in inflammatory/oxidative toxic conditions: IL-1beta effect and protection by N-acetylcysteine. Malaplate-Armand C, Ferrari L, Masson C, Siest G, Batt AM. Centre du Medicament, Inserm U525, Faculte de Pharmacie, Universite Henri Poincare Nancy I, 30 rue Lionnois, 54000 Nancy, France. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 439
26. J Neurooncol. 2002 Jan;56(2):109-17. Mitogen activated protein kinase activation and oxidant signaling in astrocytoma cells. Kuruganti PA, Wurster RD, Lucchesi PA. Neuroscience Program, Department of Physiology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA. pkuruganti@yahoo.com 27. Ann N Y Acad Sci. 2002 Nov;973:555-8. Type I insulin-like growth factor receptor expression on colorectal adenocarcinoma cell lines is decreased in response to the chemopreventive agent N-acetyl-l-cysteine. Kelly RG, Nally K, Shanahan F, O'Connell J. Department of Medicine, University College Cork, Ireland. 28. Nutr Cancer. 2002;43(1):59-66. Timing of supplementation with the antioxidant N-acetyl-L-cysteine reduces tumor multiplicity in novel, cancer-prone p53 haploinsufficient Tg.AC (v-Ha-ras) transgenic mice but has no impact on malignant progression. Martin KR, Saulnier MJ, Kari FW, Barrett JC, French JE. Transgenic Carcinogenesis Unit, Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. krm12@psu.edu 29. Acta Biol Hung. 2002;53(3):293-8. N-acetil-l-cysteine and 2-amino-2-thiiazoline N-acetyl-l-cysteinate as a possible cancer chemopreventive agents in murine models. Simkeviciene V, Straukas J, Uleckiene S. Institute of Biochemistry, Vilnius, Lithuania. vitalija@bchi.lt 30. J Nutr. 2002 Aug;132(8):2151-6. N-acetylcysteine, vitamin C and vitamin E diminish homocysteine thiolactone-induced apoptosis in human promyeloid HL-60 cells. Huang RF, Huang SM, Lin BS, Hung CY, Lu HT. Department of Nutrition and Food Sciences, Fu-Jen University, Hsin-Chuang, Taiwan, ROC. rweifen@mails.fju.edu.tw 31. J Urol. 2002 Aug;168(2):780-5.
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N-acetylcysteine augments the cellular redox changes and cytotoxic activity of internalized mycobacterium bovis in human bladder cancer cells. Pook SH, Esuvaranathan K, Mahendran R. Department of Surgery, National University of Singapore, Singapore. 32. Carcinogenesis. 2002 Jun;23(6):993-1001. Inhibition of chronic ulcerative colitis-associated colorectal adenocarcinoma development in a murine model by N-acetylcysteine. Seril DN, Liao J, Ho KL, Yang CS, Yang GY. Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, College of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854-8020, USA. 33. Oncol Rep. 2002 Jul-Aug;9(4):887-96. Phase II study of subcutaneously administered interleukin-2 in combination with medroxyprogesterone acetate and antioxidant agents as maintenance treatment in advanced cancer responders to previous chemotherapy. Mantovani G, Maccio A, Madeddu C, Mulas C, Massa E, Astara G, Ferreli L, Mudu MC, Gramignano G, Murgia V, Lusso MR, Mocci M, Cardia A, Mura L. Department of Medical Oncology, University of Cagliari, Italy. mantovan@pacs.unica.it An open, non-randomized phase II study was carried out including patients with 34. Int J Cancer. 2002 Apr 1;98(4):493-7. Effects of N-acetylcysteine in an esophageal carcinogenesis model in rats treated with diethylnitrosamine and diethyldithiocarbamate. Balansky RM, Ganchev G, D'Agostini F, De Flora S. National Center of Oncology, Sofia, Bulgaria. 35. Cancer Epidemiol Biomarkers Prev. 2002 Feb;11(2):167-75. Effects of oral administration of N-acetyl-L-cysteine: a multi-biomarker study in smokers.
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Van Schooten FJ, Nia AB, De Flora S, D'Agostini F, Izzotti A, Camoirano A, Balm AJ, Dallinga JW, Bast A, Haenen GR, Van't Veer L, Baas P, Sakai H, Van Zandwijk N. Department of Health Risk Analysis and Toxicology, Maastricht University, The Netherlands. 36. Cancer Res. 2002 Jan 1;62(1):2-7. Inhibition of benzo(a)pyrene-induced lung tumorigenesis in A/J mice by dietary Nacetylcysteine conjugates of benzyl and phenethyl isothiocyanates during the postinitiation phase is associated with activation of mitogen-activated protein kinases and p53 activity and induction of apoptosis. Yang YM, Conaway CC, Chiao JW, Wang CX, Amin S, Whysner J, Dai W, Reinhardt J, Chung FL. Division of Carcinogenesis and Molecular Epidemiology, American Health Foundation, Valhalla, New York 10595, USA. 37. FASEB J. 2002 Jan;16(1):2-14. Angioprevention': angiogenesis is a common and key target for cancer chemopreventive agents. Tosetti F, Ferrari N, De Flora S, Albini A. Molecular Biology Laboratory, National Cancer Research Institute (IST), Genova, Italy. 38. Cancer Res. 2001 Nov 15;61(22):8171-8. Inhibition of angiogenesis-driven Kaposi's sarcoma tumor growth in nude mice by oral N-acetylcysteine. Albini A, Morini M, D'Agostini F, Ferrari N, Campelli F, Arena G, Noonan DM, Pesce C, De Flora S. National Institute for Cancer Research (IST), c/o Advanced Biotechnology Center, Largo R. Benzi 10, I-16132 Genoa, Italy. albini@vega.cba.unige.it 39. Biogerontology. 2001;2(1):55-60. N-Acetyl-L-Cystein downregulates beta-amyloid precursor protein gene transcription in human neuroblastoma cells. Studer R, Baysang G, Brack C.
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Laboratory of Molecular Gerontology, Basel University, Psychiatric University Clinic, Switzerland. Rolf.Studer@Actelion.Com 40. Cancer Res. 2001 Nov 1;61(21):7868-74. Therapeutic efficacy of aortic administration of N-acetylcysteine as a chemoprotectant against bone marrow toxicity after intracarotid administration of alkylators, with or without glutathione depletion in a rat model. Neuwelt EA, Pagel MA, Hasler BP, Deloughery TG, Muldoon LL.
Alpha Lipoic Acid 20 STUDIES
1. Endocr Rev. 2002 Oct;23(5):599-622. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. University of California at San Francisco, San Francisco, California 94143, USA. jevansphd@earthlink.net 2. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10. Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct interaction with DNA. Lee HA, Hughes DA. Immunology Group, Nutrition and Consumer Science Division, Institute of Food Research, Norwich Research Park, Colney, Norwich, Norfolk NR4 7UA, UK. 3. FASEB J. 2001 Nov;15(13):2423-32. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. Zhang WJ, Frei B. Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA. 4. Drug Metab Rev. 1998 May;30(2):245-75. alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Packer L. Department of Molecular and Cell Biology, University of California, Berkeley 947203200, USA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 443
5. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1709-15. Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. Suzuki YJ, Aggarwal BB, Packer L. Department of Molecular & Cell Biology, University of California, Berkeley 94720.
AGING
6. J Alzheimers Dis. 2003 Jun;5(3):229-39. Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. Lovell MA, Xie C, Xiong S, Markesbery WR. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. 7. Neurosci Lett. 2002 Aug 9;328(2):93-6. Alpha-lipoic acid prevents ethanol-induced protein oxidation in mouse hippocampal HT22 cells. Pirlich M, Kiok K, Sandig G, Lochs H, Grune T. Department of Gastroenterology and Hepatology, University Hospital Charite, Humboldt-University Berlin, Schumannstr. 20/21, 10098, Berlin, Germany. 8. Neurosci Lett. 2002 Mar 15;321(1-2):100-4. Beneficial effects of alpha-lipoic acid plus vitamin E on neurological deficit, reactive gliosis and neuronal remodeling in the penumbra of the ischemic rat brain. Gonzalez-Perez O, Gonzalez-Castaneda RE, Huerta M, Luquin S, Gomez-Pinedo U, Sanchez-Almaraz E, Navarro-Ruiz A, Garcia-Estrada J. Division de Neurociencias, Centro de Investigacion Biomedica de Occidente (CIBO) del Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Guadalajara Jalisco 44340, Mexico. 9. Free Radic Biol Med. 1997;22(1-2):359-78. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Packer L, Tritschler HJ, Wessel K. Department of Molecular and Cell Biology, University of California, Berkeley 947203200, USA.
CATARACTS
10. Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):44-50. Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gammalinolenic acid conjugate. Borenshtein D, Ofri R, Werman M, Stark A, Tritschler HJ, Moeller W, Madar Z. Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel. 11. Biochem Mol Biol Int. 1998 Oct;46(3):585-95. Modelling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathione Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 444
concentrations in lens in model diabetic cataractogenesis. Kilic F, Handelman GJ, Traber K, Tsang K, Packer L, Trevithick JR. Department of Biochemistry, University of Western Ontario, London, Canada. 12. Biochem Biophys Res Commun. 1996 Apr 16;221(2):422-9. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Maitra I, Serbinova E, Tritschler HJ, Packer L. Department of Molecular and Cell Biology, University of California, Berkeley, 947203200, USA. 13. Biochem Mol Biol Int. 1995 Oct;37(2):361-70. Modelling cortical cataractogenesis 17: in vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis. Kilic F, Handelman GJ, Serbinova E, Packer L, Trevithick JR. Dept. of Biochemistry, University of Western Ontario, London, Canada.
DIABETES
14. Vnitr Lek. 2002 Jun;48(6):534-41. [Autonomic neuropathy in diabetics, treatment possibilities] [Article in Czech] Lacigova S, Rusavy Z, Cechurova D, Jankovec Z, Zourek M. I. interni klinika Fakultni nemocnice, Plzen. 15. Diabetes Metab Res Rev. 2002 May-Jun;18(3):176-84. Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives. van Dam PS. Department of Internal Medicine and Endocrinology, University Medical Center, Utrecht, The Netherlands. P.S.vanDam@digd.azu.nl 16. Endocr Pract. 2002 Jan-Feb;8(1):29-35. Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlledrelease formulation of alpha-lipoic acid. Evans JL, Heymann CJ, Goldfine ID, Gavin LA. Northern California Diabetes Institute, Seton Medical Center, Dale City, CA 94015, USA. 16. Nutrition. 2001 Oct;17(10):888-95. Molecular aspects of lipoic acid in the prevention of diabetes complications. Packer L, Kraemer K, Rimbach G. Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90098-9121, USA. packerresearch@aol.com
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17. J Am Coll Nutr. 2001 Oct;20(5 Suppl):363S-369S; discussion 381S-383S. Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes. Ruhe RC, McDonald RB. Department of Nutrition, University of California, Davis 95616-8669, USA. 18. Metabolism. 2001 Aug;50(8):868-75. The effects of treatment with alpha-lipoic acid or evening primrose oil on vascular hemostatic and lipid risk factors, blood flow, and peripheral nerve conduction in the streptozotocin-diabetic rat. Ford I, Cotter MA, Cameron NE, Greaves M. Departments of Medicine & Therapeutics, University of Aberdeen, Aberdeen, Scotland. 19. Diabetes Technol Ther. 2000 Autumn;2(3):401-13. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Evans JL, Goldfine ID. Medical Research Institute, San Bruno, California 94066, USA. jevans@lipoic.com 20. Free Radic Biol Med. 2001 Jul 1;31(1):53-61. Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. Universitatsklinikum Hamburg-Eppendorf Klinik und Poliklinik fur Innere Medizin, Abteilung Kardiologie, Hamburg, Germany. heitzer@uke.uni-hamburg.de
Superroxide Dismutase 51 STUDIES

1. Cai Q, Shu XO, Wen W, et al. Genetic polymorphism in the manganese superoxide dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Breast Cancer Res. 2004;6(6):R647-R55. 2. Ough M, Lewis A, Zhang Y, et al. Inhibition of cell growth by overexpression of manganese superoxide dismutase (MnSOD) in human pancreatic carcinoma. Free Radic Res. 2004 Nov;38(11):1223-33. 3. Manju V, Balasubramanian V, Nalini N. Oxidative stress and tumor markers in cervical cancer patients. J Biochem Mol Biol Biophys. 2002 Dec;6(6):387-90. 4. Lund-Olesen K. Etiology of multiple sclerosis: role of superoxide dismutase. Med Hypotheses. 2000 Feb;54(2):321-2.
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5. Choi J, Rees HD, Weintraub ST, et al. Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol Chem. 2005 Mar 25;280(12):11648-55. 6. Hattori N. Etiology and pathogenesis of Parkinsons disease: from mitochondrial dysfunctions to familial Parkinsons disease. Rinsho Shinkeigaku. 2004 Apr;44(45):241-62. 7. Ueda K, Ogata M. Levels of erythrocyte superoxide dismutase activity in Japanese people. Acta Med Okayama. 1978 Dec;32(6):393-7. 8. Cutler RG. Antioxidants and longevity of mammalian species. Basic Life Sci. 1985;35:15-73. 9. Cutler RG. Antioxidants and aging. Am J Clin Nutr. 1991 Jan;53(1 Suppl):373S-9S. 10. Life Extension-sponsored study #1. Changes in serum levels of superoxide dismutase and catalase in humans after dietary SODzyme supplementation. 11. Knight JA. Free radicals: their history and current status in aging and disease. Ann Clin Lab Sci. 1998 Nov-Dec; 28(6):331-46. 12. Reedy EA. The discovery of retrolental fibroplasia and the role of oxygen: a historical review, 1942-1956. Neonatal Netw. 2004 Mar;23(2):31-8. 13. Huang H, Manton KG. The role of oxidative damage in mitochondria during aging: a review. Front Biosci. 2004 May 1;91100-17. 14. Inoue M, Sato EF, Nishikawa M, et al. Mitochondrial generation of reactive oxygen species and its role in aerobic life. Curr Med Chem. 2003 Dec;10(23):2495-505. 15. Ahsan H, Ali A, Ali R. Oxygen free radicals and systemic autoimmunity. Clin Exp Immunol. 2003 Mar;131(3):398-404. 16. Allen RG, Tresini M. Oxidative stress and gene regulation. Free Radic Biol Med. 2000 Feb 1;28(3):463-99. 17. Kashiwagi K, Shinkai T, Kajii E, Kashiwagi A. The effects of reactive oxygen species on amphibian aging. Comp Biochem Physiol C Toxicol Pharmacol. 2005 Feb;140(2):197-205. 18. Lishnevskaia VL. The role of free radicals oxidation in the deterioration of haemovascular homeostasis in aging. Adv Gerontol. 2004;13:52-7. 19. Karatas F, Ozates I, Canatan H, et al. Antioxidant status & lipid peroxidation in patients with rheumatoid arthritis. Indian J Med Res. 2003 Oct;118:178-81. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 447
20. Mazzetti I, Grigolo B, Pulsatelli L, et al. Differential roles of nitric oxide and oxygen radicals in chondrocytes affected by osteoarthritis and rheumatoid arthritis. Clin Sci (Lond). 2001 Dec;101(6):593-9. 21. Bagis S, Tamer L, Sahin G, et al. Free radicals and antioxidants in primary fibromyalgia: an oxidative stress disorder? Rheumatol Int. 2005 Apr;25(3):188-90. 22.Abou-Seif MA, Youssef AA. Evaluation of some biochemical changes in diabetic patients. Clin Chim Acta. 2004 Aug 16;346(2):161-70. 23. Cai Q, Shu XO, Wen W, et al. Genetic polymorphism in the manganese superoxide dismutase gene, antioxidant intake, and breast cancer risk: results from the Shanghai Breast Cancer Study. Breast Cancer Res. 2004;6(6):R647-R55. 24. Ough M, Lewis A, Zhang Y, et al. Inhibition of cell growth by overexpression of manganese superoxide dismutase (MnSOD) in human pancreatic carcinoma. Free Radic Res. 2004 Nov;38(11):1223-33. 25. Manju V, Balasubramanian V, Nalini N. Oxidative stress and tumor markers in cervical cancer patients. J Biochem Mol Biol Biophys. 2002 Dec;6(6):387-90. 26. Lund-Olesen K. Etiology of multiple sclerosis: role of superoxide dismutase. Med Hypotheses. 2000 Feb;54(2):321-2. 27. Choi J, Rees HD, Weintraub ST, et al. Oxidative modifications and aggregation of Cu,Zn-superoxide dismutase associated with Alzheimer and Parkinson diseases. J Biol Chem. 2005 Mar 25;280(12):11648-55. 28. Hattori N. Etiology and pathogenesis of Parkinsons disease: from mitochondrial dysfunctions to familial Parkinsons disease. Rinsho Shinkeigaku. 2004 Apr;44(4-5):24162. 29. Ueda K, Ogata M. Levels of erythrocyte superoxide dismutase activity in Japanese people. Acta Med Okayama. 1978 Dec;32(6):393-7. 30. Cutler RG. Antioxidants and longevity of mammalian species. Basic Life Sci. 1985;35:15-73. 31. Cutler RG. Antioxidants and aging. Am J Clin Nutr. 1991 Jan;53(1 Suppl):373S-9S. 32. Life Extension-sponsored study #1. Changes in serum levels of superoxide dismutase and catalase in humans after dietary SODzyme supplementation. 33. Bauerova K, Bezek A. Role of reactive oxygen and nitrogen species in etiopathologenesis of rheumatoid arthritis. Gen Physiol Biophys. 1999 Oct;18 Spec No:15-20. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 448
34. Hadjigogos K. The role of free radicals in the pathogenesis of rheumatoid arthritis. Panminerva Med. 2003 Mar;45(1):7-13. 35. Life Extension-sponsored study #2. Effects of oral SODzyme administration on pain scores in human subjects with arthritis. 36. Bijlsma JW, van de Putte LB. Non-steroidal anti-inflammatory agents (NSAIDs) with lesser side effects by selective inhibition of cyclo-oxygenase-2. Ned Tijdschr Geneeskd. 1998 Aug 1;142(31):1762-5. 37. Bjarnason I, Zanelli G, Smith T, et al. The pathogenesis and consequence of nonsteroidal anti-inflammatory drug induced small intestinal inflammation in man. Scand J Rheumatol Suppl. 1987;64:55-62. 38. Lazzaroni M, Bianchi PG. Gastrointestinal side effects of traditional non-steroidal anti-inflammatory drugs and new formulations. Aliment Pharmacol Ther. 2004 Jul;20 Suppl 248-58. 39. Beaugerie L, Thiefin G. Gastrointestinal complications related to NSAIDs. Gastroenterol Clin Biol. 2004 Apr;28 Spec No 3C62-C72. 40. Rudic RD, Brinster D, Cheng Y, et al. COX-2 derived prostacyclin modulates vascular remodeling. Circ Res. 2005 May 19. 41. Evensen S, Spigset O, Slordal L. COX-2 inhibitorsone step forward and two steps back. Tidsskr Nor Laegeforen. 2005 Apr 7;125(7):875-8. 42. Meier P, Meyer zu SA, Burnier M. Selective COX-2 inhibitors and cardiovascular risk. Rev Med Suisse. 2005 Feb 23;1(8):543-50. 43. Vouldoukis I, Conti M, Krauss P, et al. Supplementation with gliadin-combined plant superoxide dismutase extract promotes antioxidant defences and protects against oxidative stress. Phytother Res. 2004 Dec;18(12):957-62. 44. Vouldoukis I, Lacan D, Kamate C, et al. Antioxidant and anti-inflammatory properties of a Cucumis melo LC. extract rich in superoxide dismutase activity. J Ethnopharmacol. 2004 Sep;94(1):67-75. 45. Flohe L. Superoxide dismutase for therapeutic use: clinical experience, dead ends and hopes. Mol Cell Biochem. 1988 Dec;84(2):123-31. 46. Muth CM, Glenz Y, Klaus M, et al. Influence of an orally effective SOD on hyperbaric oxygen-related cell damage. Free Radic Res. 2004 Sep;38(9):927-32. 47. Dolegowska B, Chlubek D. Isoprostanesnew possibility of the oxidative stress estimation. Przegl Lek. 2004;61(12):1410-4. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 449
48.Caruso C, Lio D, Cavallone L, Francheschi C. Aging, longevity, inflammation, and cancer. Ann NY Acad Sci. 2004 Dec;1028:1-13. 49. Kortekangas P, Peltola O, Toivanen A, Aro HT. Synovial fliud L-lactic acid in acute arthritis of the adult knee joint. Scand J Rheumatol. 1995;24(2):98-101. 50. Kong Y, et al. korea Cancer Center Hospital. (2004) Influence of an orally effective superoxide dismutase (GliSODin) on strenuous exercise-induced changes of blood antioxidant enzymes and plasma lactate. Poster presentation at the AACC, July 2004. 51. Chenal H, Davit-Spraul A, Legrand J, et al. Restored antioxidant circulating capacities in west African AIDS patients receiving an antioxidant nutraceutical Cucumis melo extract rich in Superoxide dismutase activity (GliSODin). [Submitted for publication.]
Taurine - 20 STUDIES
Congestive Heart Failure
1. Arzneimittelforschung. 1993 Mar;43(3):308-12. (Animal Study) Effects on heart membranes after taurine treatment in rabbits with congestive heart failure. Elizarova EP, Orlova TR, Medvedeva NV. Russian Academy of Medical Science, Cardiology Research Center, Moscow. 2. Jpn Circ J. 1992 Jan;56(1):95-9. Usefulness of taurine in chronic congestive heart failure and its prospective application. Azuma J, Sawamura A, Awata N. Third Department of Internal Medicine, Osaka University Medical School, Japan. 3. Kardiologiia. 1991 Jun;31(6):77-80. (Animal Study) [Use of taurine in the treatment of experimental congestive heart failure] [Article in Russian] Orlova TsR, Elizarova EP, Ryff IM, Fetisova NI, Mit'kina LI. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 450
4. Am Heart J. 1986 Dec;112(6):1278-84. (Animal Study) Beneficial effect of taurine in rabbits with chronic congestive heart failure. Takihara K, Azuma J, Awata N, Ohta H, Hamaguchi T, Sawamura A, Tanaka Y, Kishimoto S, Sperelakis N. 5. Clin Cardiol. 1985 May;8(5):276-82. Therapeutic effect of taurine in congestive heart failure: a double-blind crossover trial. Azuma J, Sawamura A, Awata N, Ohta H, Hamaguchi T, Harada H, Takihara K, Hasegawa H, Yamagami T, Ishiyama T, et al. 6. Res Commun Chem Pathol Pharmacol. 1984 Aug;45(2):261-70. (Animal Study) Beneficial effect of taurine on congestive heart failure induced by chronic aortic regurgitation in rabbits. Azuma J, Takihara K, Awata N, Ohta H, Sawamura A, Harada H, Kishimoto S. 7. Clin Ther. 1983;5(4):398-408. Therapy of congestive heart failure with orally administered taurine. Azuma J, Hasegawa H, Sawamura A, Awata N, Ogura K, Harada H, Yamamura Y, Kishimoto S. 8. Physiol Chem Phys. 1977;9(3):259-63. (Animal Study) A relation between myocardial taurine contest and pulmonary wedge pressure in dogs with heart failure. Newman WH, Frangakis CJ, Grosso DS, Bressler R.
Hypertension
9. Amino Acids. 2002;23(4):381-93. Treatment of hypertension with oral taurine: experimental and clinical studies. Militante JD, Lombardini JB. Department of Pharmacology, Texas Tech University Health Sciences Center, Lubbock, Texas, USA.
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10. Poult Sci. 2001 Nov;80(11):1607-18. (Animal Study) Taurine, cardiopulmonary hemodynamics, and pulmonary hypertension syndrome in broilers. Ruiz-Feria CA, Wideman RF Jr. Department of Poultry Science, University of Arkansas, Fayetteville 72701, USA. cruizfe@hotmail.com 11. Amino Acids. 2000;19(3-4):643-65. (Animal Study) Effects of high salt diets and taurine on the development of hypertension in the strokeprone spontaneously hypertensive rat. Dawson R Jr, Liu S, Jung B, Messina S, Eppler B. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA. dawson@cop.health.ufl.edu 12. Amino Acids. 2000;19(3-4):643-65. (Animal Study) Effects of high salt diets and taurine on the development of hypertension in the strokeprone spontaneously hypertensive rat. Dawson R Jr, Liu S, Jung B, Messina S, Eppler B. Department of Pharmacodynamics, College of Pharmacy, University of Florida, Gainesville 32610, USA. dawson@cop.health.ufl.edu 13. Hypertens Res. 2000 May;23(3):277-84. Oral taurine supplementation prevents the development of ethanol-induced hypertension in rats. Harada H, Kitazaki K, Tsujino T, Watari Y, Iwata S, Nonaka H, Hayashi T, Takeshita T, Morimoto K, Yokoyama M. First Department of Internal Medicine, Kobe University School of Medicine, Japan. 14. Can J Physiol Pharmacol. 1999 Oct;77(10):749-54. (Animal Study) Taurine attenuates hypertension and improves insulin sensitivity in the fructose-fed rat, an animal model of insulin resistance. Anuradha CV, Balakrishnan SD. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 452
Department of Biochemistry, Annamalai University, Annamalai Nagar, Tamil Nadu, India. 15. Poult Sci. 1999 Nov;78(11):1627-33. (Animal Study) Plasma taurine levels in broilers with pulmonary hypertension syndrome induced by unilateral pulmonary artery occlusion. Ruiz-Feria CA, Beers KW, Kidd MT, Wideman RF Jr. Department of Poultry Science, University of Arkansas, Fayetteville 72701, USA. cruizfe@comp.uark.edu 16. J Hypertens. 1994 Jun;12(6):653-61. (Animal Study) Taurine amplifies renal kallikrein and prevents salt-induced hypertension in Dahl rats. Ideishi M, Miura S, Sakai T, Sasaguri M, Misumi Y, Arakawa K. Department of Internal Medicine, Fukuoka University School of Medicine, Japan. 17. Cardiovasc Res. 1988 May;22(5):351-8. (Animal Study) Retardation of the development of hypertension in DOCA salt rats by taurine supplement. Inoue A, Takahashi H, Lee LC, Sasaki S, Kohno Y, Takeda K, Yoshimura M, Nakagawa M. 2nd Department of Medicine, Kyoto Prefectural University of Medicine, Japan. 18. Hypertension. 1987 Oct;10(4):383-9. Inhibition of hypertension and salt intake by oral taurine treatment in hypertensive rats. Abe M, Shibata K, Matsuda T, Furukawa T. Department of Pharmacology, School of Medicine, Fukuoka University, Japan. 19. Jpn Heart J. 1983 Jan;24(1):91-102. Decrease of urinary taurine in essential hypertension. Kohashi N, Katori R.
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Glucose Metabolism
20. Amino Acids. 2002;22(1):27-38. Taurine modulates kallikrein activity and glucose metabolism in insulin resistant rats. Nandhini AT, Anuradha CV. Department of Biochemistry, Faculty of Science, Annamalai University, Tamil Nadu, India.
Pycnogenol 20 STUDIES
1. J Sex Marital Ther. 2003 May-Jun;29(3):207-13. Treatment of erectile dysfunction with pycnogenol and L-arginine. Stanislavov R, Nikolova V. Seminological Laboratory SBALAG, Maichin Dom, Sofia, Bulgaria. rstanik@abv.bg 2. Phytother Res. 2003 Jun;17(6):671-4. Pycnogenol prevents haemolytic injury in G6PD deficient human erythrocytes. Sharma SC, Sharma S, Gulati OP. Department of Pharmacology and Therapeutics, Trinity College, Dublin-2 Ireland. ssharma@tcd.ie 3. J Biochem Mol Toxicol. 2003;17(3):193-9. Effects of pycnogenol treatment on oxidative stress in streptozotocin-induced diabetic rats. Maritim A, Dene BA, Sanders RA, Watkins JB 3rd. Moi University Faculty of Health Sciences, Eldoret, Kenya. 4. J Med Food. 2001 Winter;4(4):201-209. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 454
Pycnogenol((R)) in the Management of Asthma. Hosseini S, Pishnamazi S, Sadrzadeh SM, Farid F, Farid R, Watson RR. College of Public Health and School of Medicine, The University of Arizona, 1501 N. Campbell Ave., Tucson, AZ 85724. 5. Phytother Res. 2003 Jan;17(1):66-9. Pycnogenol inhibits the release of histamine from mast cells. Sharma SC, Sharma S, Gulati OP. Department of Pharmacology and Therapeutics, Trinity College, Dublin-2, Ireland. ssharma@tcd.ie
6. J Am Diet Assoc. 2003 Jan;103(1):67-72. Pycnogenol does not impact the antioxidant or vitamin C status of healthy young adults. Silliman K, Parry J, Kirk LL, Prior RL. Department of Biological Sciences (Program in Nutrition and Food Science), California State University, Chico 95929, USA.
7. Int Ophthalmol. 2001;24(3):161-71. Pycnogenol for diabetic retinopathy. A review. Schonlau F, Rohdewald P. Institute of Pharmaceutical Chemistry, Westfalische Wilhelms Universitat Munster, Germany.
8. Phytother Res. 2002 Sep;16(6):567-71. Treatment of melasma with Pycnogenol.
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Ni Z, Mu Y, Gulati O. Beijing PHT Nutriment Science Technology Development Co. Ltd, Xiyuan Hospital of China Academy of Traditional Chinese Medicine, Institute of Food Safety Control and Inspection, Ministry of Public Health, Beijing, P R China. 9. Phytomedicine. 2002 Jul;9(5):414-8. Effect of PYCNOGENOL on the toxicity of heart, bone marrow and immune organs as induced by antitumor drugs. Feng WH, Wei HL, Liu GT. Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union of Medical College, Beijing, People's Republic of China. 10. Phytomedicine. 2002 Jul;9(5):410-3. PYCNOGENOL chewing gum minimizes gingival bleeding and plaque formation. Kimbrough C, Chun M, dela Roca G, Lau BH. School of Dentistry, Loma Linda University, California, USA. 11. J Atten Disord. 2002 Sep;6(2):49-60. An experimental comparison of Pycnogenol and methylphenidate in adults with Attention-Deficit/Hyperactivity Disorder (ADHD). Tenenbaum S, Paull JC, Sparrow EP, Dodd DK, Green L. The Attention Deficit Center in St. Louis 63141, MO. 12. Growth Horm IGF Res. 2002 Feb;12(1):34-40. Kyolic and Pycnogenol increase human growth hormone secretion in genetically-engineered keratinocytes. Buz'Zard AR, Peng Q, Lau BH. Department of Microbiology and Molecular Genetics, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA.
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13. Brain Res Mol Brain Res. 2002 Jul 15;104(1):55-65. Pycnogenol protects neurons from amyloid-beta peptide-induced apoptosis. Peng QL, Buz'Zard AR, Lau BH. Department of Microbiology and Molecular Genetics, School of Medicine, Loma Linda University, Loma Linda, CA 92350, USA. 14. Int J Clin Pharmacol Ther. 2002 Apr;40(4):158-68. A review of the French maritime pine bark extract (Pycnogenol), a herbal medication with a diverse clinical pharmacology. Rohdewald P. Institute Pharmaceutical Chemistry, Westfalische Wilhelms-Universitat Munster, Germany. rohdewa@uni-muenster.de 15. Phytother Res. 2002 Mar;16 Suppl 1:S1-5. Comparative study of Venostasin and Pycnogenol in chronic venous insufficiency. Koch R. Wolfsschlucht 6a, 34117 Kassel, Germany. 16. Phytother Res. 2001 Dec;15(8):698-704. Pycnogenol efficacy in the treatment of systemic lupus erythematosus patients. Stefanescu M, Matache C, Onu A, Tanaseanu S, Dragomir C, Constantinescu I, Schonlau F, Rohdewald P, Szegli G. Department of Immunology, Cantacuzino Institute, Splaiul Independentei 103, Bucharest, Romania. 17. Phytother Res. 2001 May;15(3):219-23. Treatment of vascular retinopathies with Pycnogenol. Spadea L, Balestrazzi E. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 457
Dipartimento di Discipline Chirurgiche, Cattedra di Clinica Oculistica, Facolta di Medicina e Chirurgia, Via Vetoio, Coppito 2, L'Aquila, Italy. 18. Free Radic Biol Med. 2000 Jan 15;28(2):219-27. Pine bark extract pycnogenol downregulates IFN-gamma-induced adhesion of T cells to human keratinocytes by inhibiting inducible ICAM-1 expression. Bito T, Roy S, Sen CK, Packer L. Department of Molecular and Cell Biology, University of California, Berkeley 947203200, USA. 19. J Agric Food Chem. 2000 Nov;48(11):5630-9. Enzyme inhibition and protein-binding action of the procyanidin-rich french maritime pine bark extract, pycnogenol: effect on xanthine oxidase. Moini H, Guo Q, Packer L. Department of Molecular and Cell Biology, 251 Life Sciences Addition, University of California at Berkeley, Berkeley, California 94720-3200, USA. 20. Phytomedicine. 2000 Oct;7(5):383-8. PYCNOGENOL in chronic venous insufficiency. Petrassi C, Mastromarino A, Spartera C. Cattedra e Scuola di Specializzazione in Chirurgia Vascolare, Dipartimento di Scienze Chirurgiche, Universita degli Studi di L'Aquila, Italy. chirvasc@cc.univaq.it
Licorice Root 21 STUDIES

1. Armanini D, Bonanni G, Palermo M. Reduction of serum testosterone in men by licorice. N Engl J Med 1999 Oct 7;341(15):1158 2. Bergner P. Adverse effects anecdotes. Medical Herbalism. 1998:10(4):15 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 458
3. Blumenthal, M [editor] The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, Texas: American Botanical Council, 1998 4. Budavari, S. [editor]. The Merck Index. Eleventh Edition. Rahway, New Jersey, 1989 5. De Klerk, G.J., Nieuwenhuis M.G., Beutler J.J. Hypokalemia and hypertension associated with use of liquorice flavoured chewing gum. BMJ 1997;314:731 (8 March) 6. Sakamoto K, Wakabayashi K Inhibitory effect of glycyrrhetinic acid on testosterone production in rat gonads. Endocrinol Jpn 1988 Apr;35(2):333-42 7. Takahashi K, Yoshino K, Shirai T, Nishigaki A, Araki Y, Kitao M. Effect of a traditional herbal medicine (shakuyaku-kanzo-to) on testosterone secretion in patients with polycystic ovary syndrome detected by ultrasound. Nippon Sanka Fujinka Gakkai Zasshi 1988 Jun;40(6):789-92 8. Takeuchi T, Nishii O, Okamura T, Yaginuma T. Effect of paeoniflorin, glycyrrhizin and glycyrrhetic acid on ovarian androgen production. Am J Chin Med 1991;19(1):73-8 9. Werbach M, and Murray M. Botanical Influences in Illness: A Sourcebook of Clinical Research. Tarzana, California: Third Line Press, 2000 10. Yaginuma T, Izumi R, Yasui H, Arai T, Kawabata M Effect of traditional herbal medicine on serum testosterone levels and its induction of regular ovulation in hyperandrogenic and oligomenorrheic women [Article in Japanese]. Nippon Sanka Fujinka Gakkai Zasshi 1982 Jul;34(7):939-44 11. Arase Y, Ikeda K, Murashima N, et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer. 1997;79(8):1494-1500. 12. Blumenthal M, ed. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin, Tx: American Botanical Council; 1998. 13. Davis EA, Morris DJ. Medicinal uses of licorice through the millennia: good and plenty of it. Mol Cell Endocrinol. 1991;78:1-6. 14. Edwards CR. Lessons from licorice. N Engl J Med. 1991;325:1242-1243. 15. Fu Y, Hsieh TC, Guo J, Kunicki J, Lee MY. Darzynkiewicz Z. Wu JM. Licochalcone-A, a novel flavonoid isolated from licorice root (Glycyrrhiza glabra), causes G2 and late-G1 arrests in androgen-independent PC-3 prostate cancer cells. Biochemical & Biophysical Research Communications. 322(1):263-70, 2004
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16. Guide to Medicinal and Aromatic Plants. Licorice Review. Purdue University. Available at: http://www.hort.purdue.edu/newcrop/med-aro/factsheets/LICORICE.html. Accessed August 24, 2005. 17. Memorial Sloan-Kettering Cancer Center. Licorice. Available at: http://www.mskcc.org/mskcc/html/11571.cfm?RecordID=416&tab=HC. Accessed August 25, 2005 18. Miyake K, Tango T, Ota Y, et al. Efficacy of stronger neo-minophagen C compared between two doses administered three times a week on patients with chronic viral hepatitis. J Gastroenterol Hepatol. 2002 Nov;17(11):1198-204. 19. Suzuki F, Schmitt DA, Utsunomiya T, et al. Stimulation of host resistance against tumors by glycyrrhizin, an active component of licorice roots. In Vivo. 1992;6:589-596. 20. Tamir S, Eizenberg M, Somjen D, et al. Estrogenic and antiproliferative properties of glabridin from licorice in human breast cancer cells.Cancer Research. 60(20):5704-9, 2000 21. Wang ZY, Nixon DW. Licorice and cancer. Nutrition & Cancer. 39(1):1-11, 2001.
BroccolI Stem - 26 STUDIES
1. Beecher C. Cancer preventive properties of varieties of Brassica oleracea: a review. Am J Clin Nutr 1994;59(Suppl):1166S-70S. 2. Ensminger AH, Esminger M. K. J. e. al. Food for Health: A Nutrition Encyclopedia. Clovis, California: Pegus Press; 1986. 3. Fahey JW, Haristoy X, Dolan PM et al. Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzopyrene-induced stomach tumors. Proc Natl Acad Sci USA 2002 May 28;99(11):7610-5. 4. Fahey JW, Zhang Y, Talalay P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci 1997;94:10367-72. 5. Gao X, Dinkova-Kostova AT, Talalay P. Powerful and prolonged protection of human retinal pigment epithelial cells, keratinocytes, and mouse leukemia cells against oxidative damage: the indirect antioxidant effects of sulforaphane. Proc Natl Acad Sci USA 2001 Dec 18;98(26):15221-6. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 460
6. Huxley RR, Neil HAW. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies,. European Journal of Clinical Nutrition (2003) 57, 904-908. 7. Jackson SJ, Singletary KW. Sulforaphane inhibits human mcf-7 mammary cancer cell mitotic progression and tubulin polymerization. J Nutr. 2004 Sep;134(9):2229-36. 8. Johnson IT. Vegetables yield anticancer chemical. Institute of Food Research, News Release, May 10, 2004. http://www.ifr.ac.uk . 9. Kawamori T, Tanaka T, Ohnishi M, et al. Chemoprevention of azoxymethane-induced colon carcinogenesis by dietary feeding of S-methyl methane thiosulfonate in male F344 rats. Cancer Res 1995 Sep 15;55(18):4053-8. 10. Kurilich AC, Tsau GJ, Brown A, et al. Carotene, tocopherol, and ascorbate contents in subspecies of Brassica oleracea. J Agric Food Chem 1999 Apr;47(4):1576-81. 11. Kushad MM, Brown AF, Kurilich AC, et al. Variation of glucosinolates in vegetable crops of Brassica oleracea. J Agric Food Chem 1999 Apr;47(4):1541-8. 12. McKillop DJ, Pentieva K, Daly D, McPartlin JM, Hughes J, Strain JJ, Scott JM, McNulty H. The effect of different cooking methods on folate retention in various foods that are amongst the major contributors to folate intake in the UK diet. Br J Nutr. 2002 Dec;88(6):681-8. 13. Meng Q, Goldberg ID, Rosen EM, Fan S. Inhibitory effects of Indole-3-carbinol on invasion and migration in human breast cancer cells. Breast Cancer Res Treat 2000 Sep;63(2):147-52. 14. Misiewicz I, Skupinska K, Kasprzycka-Guttman T. Sulforaphane and 2-oxohexyl isothiocyanate induce cell growth arrest and apoptosis in L-1210 leukemia and ME-18 melanoma cells. . Oncol Rep. 2003 Nov-Dec;10(6):2045-50. 15. Nestle M. Broccoli sprouts as inducers of carcinogen-detoxifying enzyme systems: clinical, dietary, and policy implications. Proc Natl Acad Sci USA 1997 Oct 14;94(21):11149-51. 16. Nutrition Action Healthletter. Nutrition Action Healthletter. Dec 1999. Volume 26, Number 10. 17. Pattison DJ, Silman AJ, Goodson NJ, Lunt M, Bunn D, Luben R, Welch A, Bingham S, Khaw KT, Day N, Symmons DP. Vitamin C and the risk of developing inflammatory polyarthritis: prospective nested case-control study. Ann Rheum Dis. 2004 Jul;63(7):8437.
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18. Stoewsand GS. Bioactive organosulfur phytochemicals in Brassica oleracea vegetables-- a review. Food Chem Toxicol 1995 Jun;33(6):537-43. 19. Thimmulappa RK, Mai KH, Srisuma S et al. Identification of Nrf2-regulated genes induced by the chemopreventive agent sulforaphane by oligonucleotide microarray. Cancer Res 2002 Sep 15;62(18):5196-5203. 20. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Calcium carbonate and the premenstrual syndrome: effects on premenstrual and menstrual symptoms. Premestrual syndrome study group. Am J Obstet Gynecol 1998;179(2): 444-52. 21. Vallejo F, Toms-Barbern F A, Garca-Viguera C. Phenolic compounds content in edible parts of broccoli inflorescences after domestic cooking. J Sci Food Agric, 2003 Volume 83(14). 22. Wood, Rebecca. The Whole Foods Encyclopedia. New York, NY: Prentice-Hall Press; 1988. 23. Wu L, Ashraf MH, Facci M, Wang R, Paterson PG, Ferrie A, Juurlink BH. Dietary approach to attenuate oxidative stress, hypertension, and inflammation in the cardiovascular system. Proc Natl Acad Sci U S A. 2004 May 4;101(18):7094-9. Epub 2004 Apr 21. 24. Yurtsever E, Yardimci KT. The in vivo effect of a Brassica oleracea var. capitata extract on Ehrlich ascites tumors of MUS musculus BALB/C mice. Drug Metabol Drug Interact 1999;15(2-3):215-22. 25. Zhang J, Hsu B A JC, Kinseth B A MA, Bjeldanes LF, Firestone GL. . Indole-3carbinol induces a G1 cell cycle arrest and inhibits prostate-specific antigen production in human LNCaP prostate carcinoma cells. Cancer. 2003 Dec 1;98(11):2511-20. 26. Zhang Y, Kensler TW, Cho CG, et al. Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proc Natl Acad Sci USA 1994 Apr 12;91(8):3147-50.
Lutein - 21 STUDIES
1. Bungard RA, Ruban AV, Hibberd JM, Press MC, Horton P, Scoles JD. Unusual carotenoid composition and a new type of xanthophylls cycle in plants. Proc Natl Acad Sci USA. 1999 Feb 2;96(3):1135-9.
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2. Bernstein PS, Zhao DY, Sharifzadeh M, Ermakov IV, Gellerman W. Resonance Raman measurement of macular carotenoids in the living human eye. Arch Biochem Biophys. 2004 Oct 15;430(2):163- 9. 3. Johnson EJ, Hammond BR, Yeum KJ, et al. Relation among serum and tissue concentrations of lutein and zeaxanthin and macular pigment density. Am J Clin Nutr. 2000 Jun;71(6):1555-62. 4. Alves-Rodrigues A, Shao A. The science behind lutein. Toxicol Lett. 2004 Apr 15;150(1):57-83. 5. Berendschot TT, Broekmans WM, Klopping-Ketelaars IA, Kardinaal AF, Van Poppel F, Van Norren D. Lens aging in relation to nutritional determinants and possible risk factors for age-related cataract. Arch Opthalmol. 2002 Dec;120(12):1732-7. 6. Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition. 2003 Jan;19(1):21-4. 7. Mitchell P, Smith W, Cumming RG, Flood V, Rochtchina E, Wang JJ. Nutritional factors in the development of age-related eye disease. Asia Pac J Clin Nutr. 2003;12 Suppl:S5. 8. Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplement Trial). Optometry. 2004 Apr;75(4):216-30. 9. Dagnelie G, Zorge IS, McDonald TM. Lutein improves visual function in some patients with retinal degeneration: a pilot study via the Internet. Optometry. 2000 Mar;71(3):147-64. 10. Nishino H, Murakosh M, Ii T, et al. Carotenoids in cancer chemoprevention. Cancer Metastasis Rev. 2002;21(3-4):257-64. 11. Yeum KJ, Ahn SH, Rupp de Paiva SA, Lee-Kim YC, Krinsky NI, Russell RM. Correlation between carotenoid concentrations in serum and normal breast adipose tissue of women with benign breast tumor or breast cancer. J Nutr. 1998 Nov;128(11):1920-6. 12. Tonioli P, Van Kappel AL, Akhmedkhanov A, et al. Serum carotenoids and breast cancer. Am J Epidemiol. 2001 Jun 15;153(12):1142-7. 13. Slattery ML, Benson J, Curtin K, Ma KN, Schaeffer D, Potter JD. Carotenoids and colon cancer. Am J Clin Nutr. 2000 Feb;71(2):575-82.
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14. Roodenburg AJ, Leenen R, van het Hof KH, Westrate JA, Tijburg LB. Amount of fat in the diet affects bioavailability of lutein esters but not of alpha-carotene, beta-carotene, and vitamin E in humans. Am J Clin Nutr. 2000 May;71(5):1187-93. 15. Pratt S. Dietary prevention of age-related macular degeneration. J Am Optom Assoc. 1999 Jan;70(1):39-47. 16. Brown L, Rimm EB, Seddon JM, et al. A prospective study of carotenoid intake and risk of cataract extraction in US men. Am J Clin Nutr. 1999 Oct;70(4):517-24. 17. Chung HY, Rasmussen HM, Johnson EJ. Lutein bioavailability is higher from luteinenriched eggs than from supplements or spinach in men. J Nutr. 2004 Aug;134(8):188793. 18. Le Marchand L, Hankin JH, Bach F, et al. An ecological study of diet and lung cancer in the South Pacific. Int J Cancer. 1995 Sep 27;63(1):18-23. 19. Kruger CL, Murphy M, DeFreitas Z, Pfannkuch F, Heimbach J. An innovative approach to the determination of safety for a dietary ingredient derived from a new source: case study using a crystalline lutein product. Food Chem Toxicol . 2002 Nov;40(11):1535-49. 20. Kostic D, White WS, Olson JA. Intestinal absorption, serum clearance, and interactions between lutein and beta-carotene when administered to human adults in separate or combined oral doses. Am J Clin Nutr. 1995 Sep;62(3):604-10. 21. Koonsvitsky BP, Berry DA, Jones MB, et al. Olestra affects serum concentrations of alpha-tocopherol and carotenoids but not vitamin D or vitamin K status in free-living subjects. J Nutr. 1997 Aug;127(8 Suppl):1636S-5S.
Cabbage Leaf 10 STUDIES

1. Tadi K, Chang Y, Ashok BT, Chen Y, Moscatello A, Schaefer SD, Schantz SP, Policastro AJ, Geliebter J, Tiwari RK. 3,3'-Diindolylmethane, a cruciferous vegetable derived synthetic anti-proliferative compound in thyroid disease. Biochem Biophys Res Commun. 2005 Nov 25;337(3):1019-25. Epub 2005 Oct 3. PMID: 16219298
2. Suzui M, Inamine M, Kaneshiro T, Morioka T, Yoshimi N, Suzuki R, Kohno H, Tanaka T. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 464
Indole-3-carbinol inhibits the growth of human colon carcinoma cells but enhances the tumor multiplicity and volume of azoxymethane-induced rat colon carcinogenesis. Int J Oncol. 2005 Nov;27(5):1391-9. PMID: 16211236 3. Tilton SC, Givan SA, Pereira CB, Bailey GS, Williams DE. Toxicogenomic Profiling of the Hepatic Tumor Promoters Indole-3-Carbinol, 17{beta}estradiol and {beta}-naphthoflavone in Rainbow Trout. Toxicol Sci. 2005 Sep 28; [Epub ahead of print] PMID: 16192472
4. Brew CT, Aronchik I, Hsu JC, Sheen JH, Dickson RB, Bjeldanes LF, Firestone GL. Indole-3-carbinol activates the ATM signaling pathway independent of DNA damage to stabilize p53 and induce G1 arrest of human mammary epithelial cells. Int J Cancer. 2005 Sep 8; [Epub ahead of print] PMID: 16152627
5. D'Agostini F, Izzotti A, Balansky RM, Bennicelli C, Flora SD. Modulation of apoptosis by cancer chemopreventive agents. Mutat Res. 2005 Dec 11;591(1-2):173-86. Epub 2005 Aug 30. PMID: 16137721 6. Manson MM. Inhibition of survival signalling by dietary polyphenols and indole-3-carbinol. Eur J Cancer. 2005 Sep;41(13):1842-53. PMID: 16087329 7. Izzotti A, Bagnasco M, Cartiglia C, Longobardi M, Camoirano A, Tampa E, Lubet RA, De Flora S. Modulation of multigene expression and proteome profiles by chemopreventive agents. Mutat Res. 2005 Dec 11;591(1-2):212-23. Epub 2005 Aug 3. PMID: 16083920
8. Aggarwal BB, Ichikawa H.
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Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle. 2005 Sep;4(9):1201-15. Epub 2005 Sep 6. PMID: 16082211
9. Crowell JA, Page JG, Levine BS, Tomlinson MJ, Hebert CD. Indole-3-carbinol, but not its major digestive product 3,3'-diindolylmethane, induces reversible hepatocyte hypertrophy and cytochromes P450. Toxicol Appl Pharmacol. 2005 Jul 22; [Epub ahead of print] PMID: 16043203
10. Wu HT, Lin SH, Chen YH. Inhibition of cell proliferation and in vitro markers of angiogenesis by indole-3-carbinol, a major indole metabolite present in cruciferous vegetables. J Agric Food Chem. 2005 Jun 29;53(13):5164-9. PMID: 15969492
Carrot Root - 11 STUDIES
1. Baybutt RC, Hu L, Molteni A. Vitamin A deficiency injures lung and liver parenchyma and impairs function of rat type II pneumocytes. J Nutr. 2000 May;130(5):1159-65. 2. Ensminger AH, Esminger M. K. J. e. al. Food for Health: A Nutrition Encyclopedia. Clovis, California: Pegus Press; 1986. 3. Gaziano JM, Manson JE, Branch LG, et al. A prospective study of consumption of carotenoids in fruits and vegetables and decreased cardiovascular mortality in the elderly. Ann. Epidemiol. 1995; 5:255-260. 4. Harris RA, Key TJ, Silcocks PB, et al. A case-controlled study of dietary carotene in men with lung cancer and in men with other epithelial cancers. Nutrition and Cancer(1991)15:63-68. 5. Kobaek-Larsen M, Christensen LP, Vach W, Ritskes-Hoitinga J, Brandt K. Inhibitory Effects of Feeding with Carrots or (-)-Falcarinol on Development of Azoxymethane-
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Induced Preneoplastic Lesions in the Rat Colon. J Agric Food Chem. 2005 Mar 9;53(5):1823-1827. 6. Kritchevsky SB. beta-Carotene, carotenoids and the prevention of coronary heart disease. J Nutr 1999 Jan;129(1):5-8. 7. Li T, Molteni A, Latkovich P, Castellani W, Baybutt RC. Vitamin A depletion induced by cigarette smoke is associated with the development of emphysema in rats. J Nutr. 2003 Aug;133(8):2629-34. 8. Michaud DS, Feskanich D, Rimm EB, et al. Intake of specific carotenoids and risk of lung cancer in 2 prospective US cohorts. Am J Clin Nutr(2000)Oct;72(4):990-7. 9. Suzuki K, Ito Y, Nakamura S et al. Relationship between serum carotenoids and hyperglycemia: a population- based cross-sectional study. J Epidemiol 2002 Sep;12(5):357-66. 10. Wald NJ, Thompson SG, Densem JW, et al. Serum beta-carotene and subsequent risk of cancer: results from the BUPA study. British Journal of Cancer(1988)57:428-33. 11. Ylonen K, Alfthan G, Groop, L et al. Dietary intakes and plasma concentrations of carotenoids and tocopherols in relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study. Am J Clin Nutr. 2003 Jun; 77(6):1434-41.
Milk Thistle Leaf - 27 STUDIES
1. Biosci Biotechnol Biochem. 2003;67(9):1857-1863. (Animal Study) Suppression of Ethanol and Lipopolysaccharide-induced Liver Injury by Extracts of Hydrangeae Dulcis Folium in Rats. Hashizume E, Nakagiri R, Shirai A, Kayahashi S, Yasushi S, Kamiya T. Kyowa Hakko Kogyo Co., LTD. 2. Toxicon. 2003 Sep;42(4):339-49. Cytotoxic fungi-an overview. Karlson-Stiber C, Persson H.
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Swedish Poisons Information Centre, Karolinska Sjukhuset, S-171 76, Stockholm, Sweden 3. J Chromatogr B Analyt Technol Biomed Life Sci. 2003 Sep 5;794(2):303-10. Application of liquid chromatography-electrospray ionization-ion trap mass spectrometry to investigate the metabolism of silibinin in human liver microsomes. Gunaratna C, Zhang T. Bioanalytical Systems, Inc., West Lafayette, IN 47906, USA. prema@bioanalytical.com 4. J Hepatol. 2003 Sep;39(3):333-40. (Animal Study) Silibinin protects mice from T cell-dependent liver injury( small star, filled ). Schumann J, Prockl J, Kiemer AK, Vollmar AM, Bang R, Tiegs G. Institute of Experimental and Clinical Pharmacology and Toxicology, University of Erlangen-Nuremberg, Fahrstrasse 17, DE-91054, Erlangen, Germany 5. Alcohol Alcohol. 2003 Sep-Oct;38(5):411-4. Primary human hepatocytes are protected against prolonged and repeated exposure to ethanol by silibinin-dihemisuccinate. van Pelt JF, Verslype C, Crabbe T, Zaman Z, Fevery J. Department of Liver and Pancreatic Diseases, University Hospital Gasthuisberg, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. Jos.vanPelt@med.kuleuven.ac.be 6. Arzneimittelforschung. 2003;53(6):420-7. Preparation and pharmacological evaluation of silibinin liposomes. Maheshwari H, Agarwal R, Patil C, Katare OP. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. 7. J Pharm Belg. 2003;58(1):28-31. [St. Mary's Thistle: an overview] [Article in French]
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Laekeman G, De Coster S, De Meyer K. K.U.Leuven. 8. Phytother Res. 2002 Nov;16(7):632-8. Effect of silybin and its congeners on human liver microsomal cytochrome P450 activities. Zuber R, Modriansky M, Dvorak Z, Rohovsky P, Ulrichova J, Simanek V, Anzenbacher P. Faculty of Chemical Technology, University of Pardubice, Nam. Cs. Legii 565, 532 10 Pardubice, Czech Republic. 9. Planta Med. 2002 Aug;68(8):676-9. (Animal Study) Physiological responses to a natural antioxidant flavonoid mixture, silymarin, in BALB/c mice: I induction of transforming growth factor beta1 and c-myc in liver with marginal effects on other genes. He Q, Osuchowski MF, Johnson VJ, Sharma RP. Department of Physiology and Pharmacology, College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7389, USA. 10. Tidsskr Nor Laegeforen. 2002 Mar 20;122(8):777-80. [Serious mushroom poisoning by Cortinarius and Amanita virosa] [Article in Norwegian] Svendsen BS, Gjellestad A, Eivindson G, Berentsen G, Jacobsen D. Giftinformasjonssentralen Postboks 8189 Dep 0034 Oslo. b.j.s.svendsen@giftinfo.no 11. Drugs. 2001;61(14):2035-63. The use of silymarin in the treatment of liver diseases. Saller R, Meier R, Brignoli R. Abteilung Naturheilkunde, University Hospital Zurich, Switzerland. 12. Am Fam Physician. 2001 Nov 1;64(9):1555-60.
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Erratum in: Am Fam Physician 2002 Jun 15;65(12):2438. Comment in: Am Fam Physician. 2001 Nov 1;64(9):1515-6. Preventive strategies in chronic liver disease: part I. Alcohol, vaccines, toxic medications and supplements, diet and exercise. Riley TR 3rd, Bhatti AM. Pennsylvania State University College of Medicine, Hershey, USA. triley@psu.edu 13. Am J Gastroenterol. 2001 Nov;96(11):3195-8. Comment in: Am J Gastroenterol. 2002 May;97(5):1272-3. Mushroom poisoning--from diarrhea to liver transplantation. Broussard CN, Aggarwal A, Lacey SR, Post AB, Gramlich T, Henderson JM, Younossi ZM. Department of Gastroenterology, The Cleveland Clinic Foundation, Ohio, USA. 14. Eksp Klin Farmakol. 2001 Jul-Aug;64(4):53-5. [Effect of Silybum marianum oil and legalon on lipid peroxidation and liver antioxidant systems in rats intoxicated with carbon tetrachloride] [Article in Russian] Batakov EA. Pharmacology Department, General Surgery Department, Samara State Medical University, Chapaevskaya ul. 89, Samara, 443099 Russia. 15. Effect of silibinin and vitamin E on restoration of cellular immune response after partial hepatectomy. Horvath ME, Gonzalez-Cabello R, Blazovics A, van der Looij M, Barta I, Muzes G, Gergely P, Feher J. Second Department of Medicine, Semmelweis University, Szentkiralyi str. 46, H-1088 Budapest, Hungary. 16. Hepatology. 2001 Aug;34(2):329-39. (Animal Study)
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Beneficial effects of silymarin on estrogen-induced cholestasis in the rat: a study in vivo and in isolated hepatocyte couplets. Crocenzi FA, Sanchez Pozzi EJ, Pellegrino JM, Favre CO, Rodriguez Garay EA, Mottino AD, Coleman R, Roma MG. Instituto de Fisiologia Experimental (IFISE)-Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET - U.N.R.), Rosario, Argentina. 17. Vopr Pitan. 2000;69(5):20-3. [Effects of bioflavonoids on the toxicity of T-toxin in rats. A biochemical study] [Article in Russian] Kravchenko LV, Avren'eva LI, Tutel'ian VA. The enrichment of a diet of rats by flavonoids of milk thistle, Silybum marianum, reduced toxicity of T-2 toxin and was accompanied by reduction of a degree of change of total and nonsedimentable activity of lysosomal enzymes and microsomal xenobiotic metabolizing enzymes. 18. Drug Metab Dispos. 2000 Nov;28(11):1270-3. Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures. Venkataramanan R, Ramachandran V, Komoroski BJ, Zhang S, Schiff PL, Strom SC. Department of Pharmaceutical Sciences School of Pharmacy, Pennsylvania, USA. rv+@pitt.edu 19. Ther Apher. 2000 Aug;4(4):303-7. Treatment of Amanita phalloides poisoning: I. Retrospective evaluation of plasmapheresis in 21 patients. Jander S, Bischoff J. Medizinische Klinik, Klinikum Ernst von Bergmann Potsdam, Germany. 20. Pharmacol Toxicol. 2000 Jun;86(6):250-6. Inhibitory effects of silibinin on cytochrome P-450 enzymes in human liver microsomes.
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Beckmann-Knopp S, Rietbrock S, Weyhenmeyer R, Bocker RH, Beckurts KT, Lang W, Hunz M, Fuhr U. Institute for Pharmacology, Clinical Pharmacology, University of Koln, Germany.
21. 27. Am J Gastroenterol. 1998 Feb;93(2):139-43.
Comment in: Am J Gastroenterol. 1999 Feb;94(2):545-6. Milk thistle (Silybum marianum) for the therapy of liver disease. Flora K, Hahn M, Rosen H, Benner K. Division of Gastroenterology, Oregon Health Sciences University, Portland 97201-3098, USA. 22. Arzneimittelforschung. 1997 Dec;47(12):1383-7. (Animal Study) Effects of silibinin and of a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts. Fuchs EC, Weyhenmeyer R, Weiner OH. Department of Clinical Chemistry, Philipps-Universitat, Koln, Germany. 23. Hepatology. 1997 Sep;26(3):643-9. (Animal Study) Comment in: Hepatology. 2001 Feb;33(2):483-4. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. Boigk G, Stroedter L, Herbst H, Waldschmidt J, Riecken EO, Schuppan D. 24. Am Fam Physician. 1997 Apr;55(5):1797-800, 1805-9, 1811-2. Mushroom poisoning. McPartland JM, Vilgalys RJ, Cubeta MA. Michigan State University College of Osteopathic Medicine, East Lansing, USA. 25. Minerva Anestesiol. 1996 May;62(5):187-93. [Silibinin and acute poisoning with Amanita phalloides]
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[Article in Italian] Carducci R, Armellino MF, Volpe C, Basile G, Caso N, Apicella A, Basile V. Cattedra di Tossicologia Ospedale A. Cardarelli, Universita degli Studi di Napoli Federico II. 26. Hepatology. 1996 Apr;23(4):749-54. (Animal Study) Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Dehmlow C, Erhard J, de Groot H. Institut fur Physiologische Chemie, Universitatsklinikum, Essen, Germany. 27. Life Sci. 1996;58(18):1591-600. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Dehmlow C, Murawski N, de Groot H. Institut fur Physiologische Chemie, Universitatsklinikum, Essen, Germany.
Bromelain 49 STUDIES
1. Rowan AD, Buttle DJ, Barrett AJ. The cysteine proteinases of the pineapple plant. Biochem J 1990;266:869-875. 2. Taussig SJ, Nieper HA. Bromelain: its use in prevention and treatment of cardiovascular disease, present status. J IAPM 1979;6:139-151. 3. Harrach T, Eckert K, Schulze-Forster K, et al. Isolation and partial characterization of basic proteinases from stem bromelain. J Protein Chem 1995;14:41-52. 4. Jeung A. Encyclopedeia of Common Natural Ingredients Used in Foods, Drugs, and Cosmetics. New York, NY: John Wiley & Sons;1980:74-76.
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5. White RR, Crawley FE, Vellini M, et al. Bioavailability of 125I bromelain after oral administration to rats. Biopharm Drug Dispos 1988;9:397-403. 6. Heinicke RM, Van der Wal M, Yokoyama MM. Effect of bromelain on human platelet aggrega tion. Experientia 1972;28:844-845. 7. Morita AH, Uchida DA, Taussig SJ. Chromato graphic fractionation and characterization of the active platelet aggregation inhibitory factor from bromelain. Arch Inter Phar Ther 1979;239:340-350. 8. Livio M, Bertoni MP, De Gaetano G, et al. Effect of bromelain on fibrinogen level, prothrombin complex factors and platelet aggregation in the rat - A preliminary report. Drugs Expt Clin Res 1978;4:49-53. 9. De-Giuli M, Pirotta F. Bromelain: interaction with some protease inhibitors and rabbit specific antiserum. Drugs Exp Clin Res 1978;4:21-23. 10. Inoue K, Motonaga A, Dainaka J, et al. Effect of etodolac on prostaglandin E2 biosynthesis, active oxygen generation and bradykinin formation. Prostaglandins Leukot Essent Fatty Acids 1994;51:457-462. 11. Uhlig G, Seifert J. The effect of proteolytic enzymes (traumanase) on posttraumatic edema. Fortschr Med 1981;99:554-556. 12. Vellini M, Desideri D, Milanese A, et al. Possible involvement of eicosanoids in the pharmacological action of bromelain. Arzneimittelforschung 1986;36:110-112. 13. Kumakura S, Yamashita M, Tsurufuji S. Effect of bromelain on kaolin-induced inflammation in rats. Eur J Pharmacol 1988;150:295-301. 14. Taussig SJ, Batkin S. Bromelain, the enzyme complex of pineapple (Ananas comosus) and its clinical application. An update. J Ethnopharmacol 1988;22:191-203. 15. Felton GE. Fibrinolytic and antithrombotic action of bromelain may eliminate thrombosis in heart patients. Med Hypotheses 1980;6:1123-1133. 16. Gerard G. Anti-cancer therapy with bromelain. Agress 1972;3:261-274. 17. Nieper HA. A program for the treatment of cancer. Krebs 1974;6:124-127. 18. Taussig SJ, Szekerczes J, Batkin S. Inhibition of tumor growth in vitro by bromelain, an extract of the pineapple plant (Ananas comosus). Planta Med 1985;6:538-539. 19. Batkin S, Taussig SJ, Szekerezes J. Antimetastatic effect of bromelain with or without its proteolytic and anticoagulant activity. J Cancer Res Clin Oncol 1988;114:507.
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20. Desser L, Rehberger A, Paukovits W. Proteolytic enzymes and amylase induce cytokine production in human peripheral blood mononuclear cells in vitro. Cancer Biother 1994;9:253-263. 21. Desser L, Rehberger A. Induction of tumor necrosis factor in human peripheral-blood mononuclear cells by proteolytic enzymes. Oncology 1990;47:475-477. 22. Desser L, Rehberger A, Kokron E, et al. Cytokine synthesis in human peripheral blood mononuclear cells after oral administration of polyenzyme preparations. Oncology 1993;50:403-407. 23. Munzig E, Eckert K, Harrach T, et al. Bromelain protease F9 reduces the CD44 mediated adhesion of human peripheral blood lymphocytes to human umbilical vein endothelial cells. FEBS Lett 1995;351:215-218. 24. Houck JC, Chang CM, Klein G. Isolation of an effective debriding agent from the stems of pineapple plants. Int J Tissue React 1983;5:125-134. 25. Klaue P, Dilbert G, Hinke G, et al. Tier-experimentelle untersuchungen zur enzymatischen lokalbehandlung subdermaler verbrennungen mit bromelain. Therapiewoche 1979;29:796-799. 26. Ahle NW, Hamlet MP. Enzymatic frostbite eschar debridement by bromelain. Ann Emerg Med 1987;16:1063-1065. 27. Moss JN, Frazier CV, Martin GJ. Bromelains, the pharmacology of the enzymes. Arch Int Pharmacodyn 1963;145:168. 28. Tinozzi S, Venegoni A. Effect of bromelain on serum and tissue levels of amoxycillin. Drugs Expt Clin Res 1978;4:39-44. 29. Luerti M, Vignali ML. Influence of bromelain on penetration of antibiotics in uterus, salpinx and ovary. Drugs Expt Clin Res 1978;4:45-48. 30. Renzinni G, Varengo M. The absorption of tetracyclin in conbination with bromelain by oral application. Arzneim-Forsch 1972;22:410-412. 31. Neubauer RA. A plant protease for potentiation of and possible replacement of antibiotics. Exp Med Surg 1961;19:143-160 32. Ryan RE. A double-blind clinical evaluation of bromelains in the treatment of acute sinusitis. Headache 1967;7:13-17. 33. Hunter RG, Henry GW, Heinicke RM. The action of papain and bromelain on the uterus. Am J Ob Gyn 1957;73:867-873.
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34. Suzuki K, Niho T, Yamada H, et al. [Experimental study of the effects of bromelain on the sputum consistency in rabbits]. Nippon Yakurigaku Zasshi 1983;81:211-216. 35. Knill-Jones RP, Pearce H, Batten J, et al. Comparative trial of Nutrizym in chronic pancreatic insufficiency. Brit Med J 1970;4:21. 36. Balakrishnan V, Hareendran A, Sukumaran Nair C. Double-blind cross-over trial of an enzyme preparation in pancreatic steatorrhea. J Asso Phys Ind 1981;29:207-209. 37. Seligman B. Bromelain-an anti-inflammatory agentthrombophlebitis. No toxicity. Angiology 1962;13:508-510. 38. Felton G. Does Kinin released by pineapple stem bromelain stimulate production of prostaglandin E1-like compound. Haw Med J 1976;2:39-47. 39. Tassman GC, Zafran JN, Zayon GM. Evaluation of a plant proteolytic enzyme for the control of inflammation and pain. J Dent Med 1964;19:73-77. 40. Tassman GC, Zafran JN, Zayon GM. A double-blind crossover study of a plant proteolytic enzyme in oral surgery. J Dent Med 1965;20:51-54. 41. Masson M. Bromelain in blunt injuries of the locomotor system. A study of observed applications in general practice. Fortschr Med 1995;113:303-306. 42. Giacca S. Clinical experiments with bromelain in peripheral venous diseases and chronic bronchitic states. Minerva Med 1965;56:Suppl.104. 43. Nieper HA. Effect of bromelain on coronary heart disease and angina pectoris. Acta Med Empirica 1978;5:274-278. 44. Nieper HA. Decrease of the incidence of coronary heart infarct by Mg- and K-orotate and bromelain. Acta Med Empirica 1977;12:614-618. 45. Seligman B. Oral bromelains as adjuncts in the treatment of acute thrombophlebitis. Angiology 1969;20:22-26. 46. Taussig SJ, Yokoyama MM, Chinen N, et al. Bromelain: A proteolytic enzyme and its clinical application. HirJ Med Sci 1975;24:185-193. 47. The influence of bromelain on platelet count and platelet activity in vitro. Platelets. 2006 Feb 1;17(1):37-41. PMID: 16308185 48. Metzig C, Grabowska E, Eckert K, Rehse K, Maurer HR.
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Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo. In Vivo. 1999 Jan-Feb;13(1):7-12. PMID: 10218125 49. Rashid F, Sharma S, Bano B. Detailed Biochemical Characterization of Human Placental Cystatin (HPC). Placenta. 2005 Nov 2; [Epub ahead of print] PMID: 16271758
Nutrients That Have Demonstrated The Ability To Slow Down the Rate at Which We Age Acetyl-L-Carnitine - 49 ABSTRACTS
ACETYL-L-CARNITINE: 50 RESEARCH ABSTRACTS 1_ Ophthalmologica. 2003 SepOct;217(5):3517. Mitotropic compounds for the treatment of agerelated macular degeneration. The metabolic approach and a pilot study. Feher J, Papale A, Mannino G, Gualdi L, Balacco Gabrieli C. Ophthalmic Neuroscience Program, Institute of Ophthalmology, University of Rome La Sapienza, Rome, Italy. Recent histopathologic studies have shown that mitochondria and peroxisomes of the retinal pigment epithelium may play a central role in the pathophysiology of agerelated macular degeneration (AMD). We supposed that compounds which improve mitochondrial functions (mitotropic compounds) may show beneficial effects in preventing AMD. Fourteen patients affected by early AMD were treated with a mixture containing acetylLcarnitine (ALC), polyunsaturated fatty acids (PUFAs), coenzyme Q10 (CoQ10) and vitamin E, while an equal number of age and sexmatched patients affected by early AMD were treated with vitamin E only. Recovery time after macular photostress, foveal sensitivity and mean defect in the visual field as well as blood lipid levels were recorded at the beginning and after 3, 6, 9, 12 and 24 months of followup. In the treated group, all the visual functions showed slight improvement which was evident after 3 months of treatment and remained nearly stationary by the end of 24 months. The same tests in the control group showed slow worsening. The divergence between treated and control groups became more marked with time, but the difference was not significant at any time of the followup. These findings suggest that the blend of ALC, PUFA, CoQ10 and vitamin E may improve retinal functions in early AMD. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 477
2_ Int J Tissue React. 2002;24(3):8996. Longterm ethanol administration enhances agedependent modulation of redox state in brain and peripheral organs of rat: protection by acetyl carnitine. Scapagnini G, Ravagna A, Bella R, Colombrita C, Pennisi G, Calvani M, Alkon D, Calabrese V. Blanchette Rockefeller Neurosciences Institute, West Virginia University, Rockville, USA. Evidence is accumulating that intermediates of oxygen reduction may be associated with the development of alcoholic disease. Free radicalinduced perturbation of the oxidant/antioxidant balance in the cell is widely recognized as the main causative factor of agerelated disorders. In the present study we investigated the effects of 20 months of ethanol consumption on the antioxidant defense system in different rat organs compared with normal aging in the absence and presence of treatment with Lacetyl carnitine. We demonstrate that aged rats underwent significant perturbation of the antioxidant defense system, as indicated by depletion of reduced glutathione (GSH) content, increased oxidized GSH, free radicalinduced luminescence associated with increased hydroxynonenal content and decreased GSH reductase activity. These modifications, observed particularly in brain and liver compared with other organs, were enhanced by longterm alcohol exposure and, interestingly, were significantly reduced with acetyl carnitine supplements. Our results indicate that decreased GSH reductase activity and thiol depletion are important factors in effecting a pathogenic role for oxidative stress in aging and in all situations in which agecorrelated and oxidantinduced changes occur, such as in alcoholism. Administration of acetyl carnitine greatly reduces these metabolic abnormalities. Our findings support its pharmacological potential in the management of alcoholic disturbances. 3_ Brain Res. 2002 Dec 13;957(2):22330. Reversal of biochemical and behavioral parameters of brain aging by melatonin and acetyl Lcarnitine. Sharman EH, Vaziri ND, Ni Z, Sharman KG, Bondy SC. Center for Occupational and Environmental Health, Department of Community and Environmental Medicine, University of California Irvine, Irvine, CA 926971825, USA. The potential utility of dietary supplementation in order to prevent some of the oxidative and inflammatory changes occurring in the brain with age, has been studied. The cerebral cortex of 27monthold male B6C3F1 mice had elevated levels of nitric oxide synthase 1 (EC 1.14.13.39) (nNOS) and peptide nitrotyrosine relative to cortices of younger (4monthold) animals. After 25monthold mice received basal diet together with 300 mg/l acetyl Lcarnitine in the drinking water for 8 weeks, these levels were fully restored to those found in younger animals. A partial restoration was found when old animals received basal diet supplemented with 200 ppm melatonin in the diet. Levels of mRNA (messenger RNA) for nNOS were unchanged following these treatments implying translational regulation of nNOS activity. Behavioral indices indicative of exploratory behavior were also depressed in aged animals. Dietary supplementation with melatonin or acetyl Lcarnitine partially reversed these Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 478
changes. These findings suggest that dietary supplementation cannot merely arrest but indeed reverse some agerelated increases in markers of oxidative and inflammatory events occurring with the cortex. 4_ Ann N Y Acad Sci. 2002 Apr;959:491507. Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetylLcarnitine and/or lipoic acid. Hagen TM, Moreau R, Suh JH, Visioli F. Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA. Mitochondrial decay has been postulated to be a significant underlying part of the aging process. Decline in mitochondrial function may lead to cellular energy deficits, especially in times of greater energy demand, and compromise vital ATPdependent cellular operations, including detoxification, repair systems, DNA replication, and osmotic balance. Mitochondrial decay may also lead to enhanced oxidant production and thus render the cell more prone to oxidative insult. In particular, the heart may be especially susceptible to mitochondrial dysfunction due to myocardial dependency on betaoxidation of fatty acids for energy and the postmitotic nature of cardiac myocytes, which would allow for greater accumulation of mitochondrial mutations and deletions. Thus, maintenance of mitochondrial function may be important to maintain overall myocardial function. Herein, we review the major agerelated changes that occur to mitochondria in the aging heart and the evidence that two such supplements, acetyllcarnitine (ALCAR) and (R)alphalipoic acid, may improve myocardial bioenergetics and lower the increased oxidative stress associated with aging. We and others have shown that feeding old rats ALCAR reverses the agerelated decline in carnitine levels and improves mitochondrial betaoxidation in a number of tissues studied. However, ALCAR supplementation does not appear to reverse the agerelated decline in cardiac antioxidant status and thus may not substantially alter indices of oxidative stress. Lipoic acid, a potent thiol antioxidant and mitochondrial metabolite, appears to increase low molecular weight antioxidant status and thereby decreases ageassociated oxidative insult. Thus, ALCAR along with lipoic acid may be effective supplemental regimens to maintain myocardial function. 5_ Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):187681. Ageassociated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substratebinding affinity and activity in brain by feeding old rats acetylL carnitine and/or Ralpha lipoic acid. Liu J, Killilea DW, Ames BN. Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA. We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased binding Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 479
affinity for substrate and whether this substrate, fed to old rats, restores CAT activity. The kinetics of CAT were analyzed by using the brains of young and old rats and of old rats supplemented for 7 weeks with the CAT substrate acetyllcarnitine (ALCAR) and/or the mitochondrial antioxidant precursor Ralphalipoic acid (LA). Old rats, compared with young rats, showed a decrease in CAT activity and in CATbinding affinity for both substrates, ALCAR and CoA. Feeding ALCAR or ALCAR plus LA to old rats significantly restored CATbinding affinity for ALCAR and CoA, and CAT activity. To explore the underlying mechanism, lipid peroxidation and total iron and copper levels were assayed; all increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of youngrat brain with Fe(II) caused loss of CAT activity and binding affinity. In vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not alter binding affinity. However, in vitro treatment of CAT with the lipid peroxidation products malondialdehyde or 4hydroxynonenal caused a decrease in CATbinding affinity and activity, thus mimicking agerelated change. Preincubation of CAT with ALCAR or CoA prevented malondialdehydeinduced dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substratebinding affinity, and mitochondrial dysfunction. 6_ Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):18705. Feeding acetylLcarnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress. Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN. Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. Mitochondrialsupported bioenergetics decline and oxidative stress increases during aging. To address whether the dietary addition of acetyllcarnitine [ALCAR, 1.5% (wt/vol) in the drinking water] and/or (R)alphalipoic acid [LA, 0.5% (wt/wt) in the chow] improved these endpoints, young (24 mo) and old (2428 mo) F344 rats were supplemented for up to 1 mo before death and hepatocyte isolation. ALCAR+LA partially reversed the agerelated decline in average mitochondrial membrane potential and significantly increased (P = 0.02) hepatocellular O(2) consumption, indicating that mitochondrialsupported cellular metabolism was markedly improved by this feeding regimen. ALCAR+LA also increased ambulatory activity in both young and old rats; moreover, the improvement was significantly greater (P = 0.03) in old versus young animals and also greater when compared with old rats fed ALCAR or LA alone. To determine whether ALCAR+LA also affected indices of oxidative stress, ascorbic acid and markers of lipid peroxidation (malondialdehyde) were monitored. The hepatocellular ascorbate level markedly declined with age (P = 0.003) but was restored to the level seen in young rats when ALCAR+LA was given. The level of malondialdehyde, which was significantly higher (P = 0.0001) in old versus young rats, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 480
also declined after ALCAR+LA supplementation and was not significantly different from that of young unsupplemented rats. Feeding ALCAR in combination with LA increased metabolism and lowered oxidative stress more than either compound alone. 7_ Neurochem Res. 2000 Mar;25(3):3959. Effect of longterm feeding with acetylLcarnitine on the agerelated changes in rat brain lipid composition: a study by 31P NMR spectroscopy. Aureli T, Di Cocco ME, Capuani G, Ricciolini R, Manetti C, Miccheli A, Conti F. Department of Biochemistry, SigmaTau Labs, Pomezia, Italy. Changes in brain lipid composition have been determined in 24 monthsold Fischer rats with respect to 6 monthsold ones. The cerebral levels of sphingomyelin and cholesterol were found to be significantly increased in aged rats, whereas the amount of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol, and phosphatidic acid appear to be unaffected by aging. Longterm feeding with acetylLcarnitine was able to reduce the agedependent increase of both sphingomyelin and cholesterol cerebral levels with no effect on the other measured phospholipids. These findings shown that changes in membrane lipid metabolism and/or composition represent one of the alterations occurring in rat brain with aging, and that longterm feeding with acetylLcarnitine can be useful in normalizing these agedependent disturbances. 8_ Am J Otol. 2000 Mar;21(2):1617. Biologic activity of mitochondrial metabolites on aging and agerelated hearing loss. Seidman MD, Khan MJ, Bai U, Shirwany N, Quirk WS. Department of Otolaryngology Head & Neck Surgery, Henry Ford Health System, Detroit, Michigan 48323, USA. HYPOTHESIS: Compounds that upregulate mitochondrial function in an aging model will improve hearing and reduce some of the effects of aging. BACKGROUND: Reactive oxygen metabolites (ROM) are known products of oxidative metabolism and are continuously generated in vivo. More than 100 human clinical conditions have been associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and cause extensive DNA, cellular, and tissue damage. Specific deletions within the mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. These deletions are the result of chronic exposure to ROM. When enough mtDNA damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the membrane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several agerelated processes. It is the purpose of this article to describe the effects of two mitochondrial metabolites, alphalipoic acid and acetyl Lcarnitine, on the preservation of agerelated hearing loss. METHODS:Twentyone Fischer rats, aged 24 months, were divided into three groups: acetyl1carnitine, alphalipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 481
and posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were obtained to assess for mtDNA mutations. RESULTS: The control group demonstrated an expected ageassociated threshold deterioration of 3 to 7 dB in the 6week study. The treated subjects experienced a delay in progression of hearing loss. Acetyl1carnitine improved auditory thresholds during the same time period (p<0.05). The mtDNA deletions associated with aging and presbyacusis were reduced in the treated groups in comparison with controls. CONCLUSIONS: These results indicate that in the proposed decline in mitochondrial function with age, senescence may be delayed by treatment with mitochondrial metabolites. Acetyl1carnitine and alphalipoic acid reduce ageassociated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair ageinduced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energyproducing capabilities. 9_ FEBS Lett. 1999 Jul 9;454(3):2079. The effect of aging and acetylLcarnitine on the pyruvate transport and oxidation in rat heart mitochondria. Paradies G, Petrosillo G, Gadaleta MN, Ruggiero FM. Department of Biochemistry and Molecular Biology, University of Bari, Italy. g.paradies@biologia.uniba.it The effect of aging and acute treatment with acetylLcarnitine on the pyruvate transport and oxidation in rat heart mitochondria was studied. The activity of the pyruvate carrier as well as the rates of pyruvatesupported respiration were both depressed (around 40%) in heart mitochondria from aged rats, the major decrease occurring during the second year of life. Administration of acetylLcarnitine to aged rats almost completely restored the rates of these metabolic functions to the level of young control rats. This effect of acetylLcarnitine was not due to changes in the content of pyruvate carrier molecules. The heart mitochondrial content of cardiolipin, a key phospholipid necessary for mitochondrial substrate transport, was markedly reduced (approximately 40%) in aged rats. Treatment of aged rats with acetylLcarnitine reversed the ageassociated decline in cardiolipin content. As the changes in cardiolipin content were correlated with changes in rates of pyruvate transport and oxidation, it is suggested that acetylLcarnitine reverses the agerelated decrement in the mitochondrial pyruvate metabolism by restoring the normal cardiolipin content. 10_ Altern Med Rev. 1999 Jun;4(3):14461. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Kidd PM. Dementias and other severe cognitive dysfunction states pose a daunting challenge to existing medical management strategies. An integrative, early intervention approach seems warranted. Whereas, allopathic treatment options are Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 482
highly limited, nutritional and botanical therapies are available which have proven degrees of efficacy and generally favorable benefittorisk profiles. This review covers five such therapies: phosphatidylserine (PS), acetyllcarnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and Bacopa monniera (Bacopa). PS is a phospholipid enriched in the brain, validated through doubleblind trials for improving memory, learning, concentration, word recall, and mood in middleaged and elderly subjects with dementia or agerelated cognitive decline. PS has an excellent benefittorisk profile. ALC is an energizer and metabolic cofactor which also benefits various cognitive functions in the middleaged and elderly, but with a slightly less favorable benefittorisk profile. Vinpocetine, found in the lesser periwinkle Vinca minor, is an excellent vasodilator and cerebral metabolic enhancer with proven benefits for vascularbased cognitive dysfunction. Two metaanalyses of GbE demonstrate the best preparations offer limited benefits for vascular insufficiencies and even more limited benefits for Alzheimer's, while "commodity" GbE products offer little benefit, if any at all. GbE (and probably also vinpocetine) is incompatible with bloodthinning drugs. Bacopa is an Ayurvedic botanical with apparent antianxiety, antifatigue, and memorystrengthening effects. These five substances offer interesting contributions to a personalized approach for restoring cognitive function, perhaps eventually in conjunction with the judicious application of growth factors. 11_ Mech Ageing Dev. 1995 Nov 3;85(1):3753. Age and traumadependent modifications of neuromuscular junction and skeletal muscle structure in the rat. Effects of longterm treatment with AcetylLCarnitine. De Angelis C, Scarfo C, Falcinelli M, Perna E, Ramacci MT, Angelucci L. Department of Morphometry and Histology, Institute for Research on Senescence, Rome, Italy. The influence of ageing and crushing of the sciatic nerve on the morphology of the neuromuscular junction (NMJ) and on the muscle fiber composition were studied in the rat soleus muscle using histochemical techniques associated with image analysis. The influence of a 6month treatment with AcetylLCarnitine (ALCAR, 150 mg/kg/day) on the age and crushingdependent changes of the NMJ and on agerelated modifications of the muscle fiber composition was assessed as well. In control old and injured young rats a loss of complexity of the NMJ was observed. Treatment with ALCAR resulted in an increased endplate complexity both in old rats and in young rats injured by crushing, in comparison with respective controls. The structure of the rat soleus muscle changes with increasing age. Modification mainly consists in a type II fiber atrophy, and in the alteration of the peculiar mosaic organization of the soleus muscle fibers. In ALCARtreated old rats, the morphology of the soleus muscle fibers was similar to that observed in adult animals. These findings suggest that treatment with ALCAR has a beneficial effect on NMJ and on muscle fiber structure in ageing or Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 483
after nerve crushing. The possible mechanism of action of this 'trophic' effect of ALCARtreatment is discussed. 12_ Mech Ageing Dev. 1995 Oct 13;84(2):10312. Carnitineacylcarnitine translocase activity in cardiac mitochondria from aged rats: the effect of acetylLcarnitine. Paradies G, Ruggiero FM, Petrosillo G, Gadaleta MN, Quagliariello E. Department of Biochemistry and Molecular Biology, University of Bari, Italy. Agerelated changes in mitochondrial fatty acids metabolism may underlie the progressive decline in cardiac function. The effect of aging and acute treatment with acetylLcarnitine on fatty acids oxidation and on carnitineacylcarnitine translocase activity in rat heart mitochondria was studied. Rates of palmitoylcarnitine supported respiration as well as carnitinecarnitine and carnitinepalmitoylcarnitine exchange reactions were all depressed (approx. 35%) in heart mitochondria from aged rats. These effects were almost completely reversed following treatment of aged rats with acetylLcarnitine. Heart mitochondrial cardiolipin content was significantly reduced (approx. 38%) in aged rats. Treatment of aged rats with acetylLcarnitine restored the level of cardiolipin to that of young rats. It is suggested that acetylLcarnitine is able to reverse agerelated decrement in mitochondrial carnitineacylcarnitine exchange activity by restoring the normal cardiolipin content. 13_ J Gerontol A Biol Sci Med Sci. 1995 Jul;50(4):B23236. AcetylLCarnitine: chronic treatment improves spatial acquisition in a new environment in aged rats. Caprioli A, Markowska AL, Olton DS. Institute for Research on Senescence, Sigma Tau, Rome, Italy. Chronic AcetylLCarnitine (ALCAR) treatment prevents some agerelated memory impairment. The present experiment examined the effects of aging and ALCAR in Fischer 344 rats on retention of spatial discrimination test in a familiar environment (FE), and on the acquisition of a spatial discrimination in a novel environment (NE). Rats 18 months or 3 months old were trained with a new procedure to assess spatial discrimination in the Morris water maze. Performance during acquisition in FE was used to assign each old rat to one of two classes: Good Performers (GP) and Poor Performers (PP) based on their swim time to reach the platform. The old rats displayed heterogeneous performance and a spatial discrimination deficit. Chronic ALCAR treatment enhanced spatial acquisition in the NE of rats with agerelated behavioral impairments and had a slight effect on retention of the spatial discrimination in the FE. 14_ Neurochem Res. 1994 Jul;19(7):7958. Agedependent loss of NMDA receptors in hippocampus, striatum, and frontal cortex of the rat: prevention by acetylLcarnitine. Castornia M, Ambrosini AM, Pacific L, Ramacci MT, Angelucci L. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 484
Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Italy. Acute i.p. administration of AcetylLCarnitine (ALCAR), a component of several biological systems, has been found to modify spontaneous and evoked electrocortical activity in young rats, and, in the old rats, to improve learning ability and to increase the number of NMDA receptors in the whole brain. The present study was aimed at ascertaining the effect of chronic treatment with ALCAR added to drinking water on agerelated changes in the different brain areas of rats. In twentyfourmonthold rats, ALCAR treatment for six months significantly impeded the decline in the number of NMDA receptors within the hippocampus, the frontal cortex and the striatum compared to the adult animal. This finding thus confirms the previously reported positive effect of ALCAR on the brain NMDA receptor system. 15_ Ann N Y Acad Sci. 1993 Sep 24;695:3246. AcetylLcarnitine and Alzheimer's disease: pharmacological considerations beyond the cholinergic sphere. Carta A, Calvani M, Bravi D, Bhuachalla SN. SigmaTau Pharmaceuticals, Department of Scientific Affairs, Gaithersburg, Maryland 20878. Since ALCAR and Lcarnitine are "shuttles" of long chain fatty acids between the cytosol and the mitochondria to undergo betaoxidation, they play an essential role in energy production and in clearing toxic accumulations of fatty acids in the mitochondria. ALCAR has been considered of potential use in senile dementia of the Alzheimer type (SDAT) because of its ability to serve as a precursor for acetylcholine. However, pharmacological studies with ALCAR in animals have demonstrated its facility to maximize energy production and promote cellular membrane stability, particularly its ability to restore membranal changes that are agerelated. Since recent investigations have implicated abnormal energy processing leading to cell death, and severitydependent membrane disruption in the pathology of Alzheimer's disease, we speculate that the beneficial effects associated with ALCAR administration in Alzheimer patients are due not only to its cholinergic properties, but also to its ability to support physiological cellular functioning at the mitochondrial level. This hypothetical mechanism of action is discussed with respect to compelling supportive animal studies and recent observations of significant decrease of carnitine acetyltransferase (the catalyst of Lcarnitine acylation to acetylLcarnitine) in autopsied Alzheimer brains. 16_ Physiol Behav. 1992 Jul;52(1):1857. Active avoidance learning in old rats chronically treated with levocarnitine acetyl. Ghirardi O, Caprioli A, Milano S, Giuliani A, Ramacci MT, Angelucci L. Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Rome, Italy.
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The aging laboratory animal is recognized as a suitable experimental model for the investigation on drugs potentially able to retard the agedependent decline in cognitive functions. There is robust evidence that levocarnitine acetyl (ALCAR), the acetyl derivative of carnitine, when administered chronically, prevents some agerelated deficits of the central nervous system, mainly at the hippocampal level. On the basis of this evidence and because learning of active avoidance was demonstrated to become impaired with age, we decided to investigate the effect of ALCAR in rats. For statistical evaluation of results, the Cluster Analysis technique was chosen. This procedure pointed out the great heterogeneity of the old population and allowed the classification of the animals into homogeneous groups according to their response pattern. The effect of ALCAR was evident in the higher number of treated old animals yielding escape responses, indicating that ALCAR can preserve, at least partially, learning and memory from the natural decay occurring with age. 17_ Int J Clin Pharmacol Res. 1992;12(56):25362. Morphological and electrophysiological changes of peripheral nervemuscle unit in the aged rat prevented by levocarnitine acetyl. Scarfo C, Falcinelli M, Pacifici L, Bellucci A, Reda E, De Angelis C, Ramacci MT, Angelucci L. Institute for Research on Senescence, Sigma Tau S.p.A. Pomezia, Rome, Italy. The effects of levocarnitine acetyl on structure and function of the sciatic nerve and neuromuscular junctions of the soleus and extensor digitorum longus muscles were studied in the aged rat. To that end, neuromuscular conduction velocity (NMCV) was measured in vivo and morphological and morphometric evaluations were performed. Treatment with levocarnitine acetyl, 150 mg/kg day for six months, restored NMCV values to the levels measured in the young rat; significantly reduced the number of degenerating elements; and increased the number of myelinated fibres having normal structural features. In the soleus and extensor digitorum longus muscles, levocarnitine acetyl increased the complexity of neuromuscular junctions. These experimental findings suggest a neurotrophic action of levocarnitine acetyl on the peripheral nervous system that might have therapeutical applications in agerelated peripheral nerve changes. 18_ J Neurosci Res. 1991 Nov;30(3):5559. Effect of acetylLcarnitine on the dopaminergic system in aging brain. Sershen H, Harsing LG Jr, BanaySchwartz M, Hashim A, Ramacci MT, Lajtha A. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York 10962. We studied the effect of acetylLcarnitine (ALCAR) on dopamine release and the effect of longterm acetylLcarnitine treatment on agerelated changes in striatal dopamine receptors and brain amino acid levels. In striatal tissue that had been incubated with [3H]dopamine, acetylLcarnitine increased the release of [3H]dopamine evoked by electrical stimulation. In striatal tissue from aged Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 486
mice administered acetylLcarnitine for 3 months, the release of [3H]dopamine evoked by electrical stimulation was higher than that of its aged control; the release after a second stimulation was similar in the two groups. There was a significant decline in the number of D1 striatal dopamine receptors with age. The Bmax was 51% lower in 1.5yearold mice than in 4monthold animals. Administration of acetylLcarnitine for 3 months diminished the reduction in the binding of [3H]SCH23390. [3H]Spiperone binding to D2 receptors was not decreased with age and was not affected by acetylLcarnitine treatment. Agerelated decreases in levels of several amino acids were observed in several brain regions. AcetylLcarnitine lessened the reduction in the level of taurine only in the striatum. The findings confirm the multiple effects of acetylLcarnitine in brain, and suggest that its administration can have a positive effect on agerelated changes in the dopaminergic system. 19_ Brain Res Dev Brain Res. 1991 Apr 24;59(2):22130. AcetylLcarnitine enhances the response of PC12 cells to nerve growth factor. Taglialatela G, Angelucci L, Ramacci MT, WerrbachPerez K, Jackson GR, PerezPolo JR. Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550. We have demonstrated that treatment of rat pheochromocytoma (PC12) cells with acetylLcarnitine (ALCAR) stimulates the synthesis of nerve growth factor receptors (NGFR). ALCAR has also been reported to prevent some agerelated impairments of the central nervous system (CNS). In particular, ALCAR reduces the loss of NGFR in the hippocampus and basal forebrain of aged rodents. On these bases, a study on the effect of NGF on the PC12 cells was carried out to ascertain whether ALCAR induction of NGFR resulted in an enhancement of NGF action. Treatment of PC12 cells for 6 days with ALCAR (10 mM) stimulated [125I]NGF PC12 cell uptake, consistent with increased NGFR levels. Also, neurite outgrowth elicited in PC12 cells by NGF (100 ng/ml) was greatly augmented by ALCAR pretreatment. When PC12 cells were treated with 10 mM ALCAR and then exposed to NGF (1 ng/ml), an NGF concentration that is insufficient to elicit neurite outgrowth under these conditions, there was an ALCAR effect on neurite outgrowth. The concentration of NGF necessary for survival of serumdeprived PC12 cells was 100fold lower for ALCARtreated cells as compared to controls. The minimal effective dose of ALCAR here was between 0.1 and 0.5 mM. This is similar to the reported minimal concentration of ALCAR that stimulates the synthesis of NGFR in these cells. The data here presented indicate that one mechanism by which ALCAR rescues aged neurons may be by increasing their responsiveness to neuronotrophic factors in the CNS. 20_ Neurobiol Aging. 1990 SepOct;11(5):4918. Acetyl1carnitine. 1: Effects on mortality, pathology and sensorymotor performance in aging rats. Markowska AL, Ingram DK, Barnes CA, Spangler EL, Lemken VJ, Kametani H, Yee W, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 487
Olton DS. Department of Psychology, University of Colorado, Boulder 80309. Three different test sites assessed the effects of acetyl1carnitine (AC) on agerelated changes in general health, sensorymotor skills, learning, and memory. Two groups of rats began the experiments at 16 months of age. One group (OLDAC) was given AC, 75 mg/kg/day, beginning at 16 months. The other group (OLDCON) was treated identically except it was not given the drug. Beginning at 22 months of age, these rats and a group of young (34 months old) rats (YGCON) were given a series of sensorymotor tasks. AC decreased mortality, and had no reliable effect on body weight, fluid intake, or the general health of the rats. These data indicate that a chronic dose of AC does not interfere with food and water intake, and may increase longevity. An agerelated decline of performance occurred in most of the sensorymotor tasks; locomotor activity was reduced in a novel environment and in a runwheel, and the ability to prevent falling was reduced in tests on a taut wire, rotorod, inclined screen, and several types of elevated bridges. An agerelated decline of performance did not occur in grooming, or in the latency to initiate several different behaviors. AC had no effect on performance in any sensorymotor task. These data indicate that the improvements produced by AC in some tests of spatial memory may be due to the effects of AC on cognitive abilities rather than on sensorymotor skills. 21_ Neurochem Res. 1990 Jun;15(6):597601. AcetylLcarnitine as a precursor of acetylcholine. White HL, Scates PW. Division of Pharmacology, Wellcome Research Laboratories, Research Triangle Park, North Carolina 27709. Synthesis of [3H]acetylcholine from [3H]acetylLcarnitine was demonstrated in vitro by coupling the enzyme systems choline acetyltransferase and carnitine acetyltransferase. Likewise, both [3H] and [14C] labeled acetylcholine were produced when [3H]acetylLcarnitine and D[U14C] glucose were incubated with synaptosomal membrane preparations from rat brain. Transfer of the acetyl moiety from acetylLcarnitine to acetylcholine was dependent on concentration of acetylLcarnitine and required the presence of coenzyme A, which is normally produced as an inhibitory product of choline acetyltransferase. These results provide further evidence for a role of mitochondrial carnitine acetyltransferase in facilitating transfer of acetyl groups across mitochondrial membranes, thus regulating the availability in the cytoplasm of acetylCoA, a substrate of choline acetyltransferase. They are also consistent with a possible utility of acetylLcarnitine in the treatment of agerelated cholinergic deficits. 22_ Int J Clin Pharmacol Res. 1990;10(12):658. Dietary acetylLcarnitine improves spatial behaviour of old rats. Markowska AL, Olton DS. Department of Psychology, Johns Hopkins University, Baltimore, Maryland. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 488
AcetylLcarnitine was given to aging rats to determine the extent to which it changed agerelated impairments in several different behaviours. One group of rats was given acetylLcarnitine, 80 mg/day, beginning at 16 months of age. A second group of rats was housed and treated identically, except that no drug was administered. At 22 months of age, both groups of rats began a series of behavioural tests, along with a group of young rats, four months of age. The tests included: place learning on a circular platform, probe reversal of place learning on a circular platform, two choice simultaneous spatial discrimination in the stem of a Tmaze spatial alternation in the arms of a Tmaze, and sensorymotor behaviour (initiation of walking, turning in an alley, walking on a square, round, and rectangular bridge, turning on an inclined grid, holding on to a wire, lightdark preference). The tasks varied in their sensitivity to agerelated impairments. These data indicate that longterm therapy with acetylLcarnitine attenuates certain agerelated cognitive deficits and may have a beneficial effect on longevity. 23_ Int J Clin Pharmacol Res. 1990;10(12):4951. Peroxidative stress and cerebral aging. Fariello RG. Department Neurological Sciences, RushPresbyterian St. Lukes Medical Center, Chicago, Illinois. In order to test the hypothesis that cerebral nuclei showing agerelated neuronal depletion would also show signs of vulnerability in their free radical scavenger systems and accumulation of the compounds resulting from peroxidation, the regional levels of a number of compounds were measured in mouse brains. With the exception of the tocopherols all the antioxidants had lower concentrations in the Substantia nigra which showed the most severe neuronal depletion with age. AcetylLcarnitine is being investigated as a determinant of neuronal longevity. 24_ J Neurosci Res. 1989 Aug;23(4):4626. AcetylLcarnitine reduces the agedependent loss of glucocorticoid receptors in the rat hippocampus: an autoradiographic study. Patacchioli FR, Amenta F, Ramacci MT, Taglialatela G, Maccari S, Angelucci L. Institute of Pharmacology II, Medical Faculty, University of Rome, La Sapienza, Italy. Brain autoradiography in adrenalectomized rats injected with 3Hcorticosterone 2 hr before sacrifice was used to study the effect of aging and longterm acetyllcarnitine treatment on the hippocampal glucocorticoid receptor. Densitometric analysis of silver grains in individual nerve cells of the hippocampus showed that pyramidal neurones of the CA1 field and granular cells of the dentate gyrus are richest in 3Hcorticosterone binding sites, whereas pyramidal neurons of the CA3 field have the lowest number of binding sites. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 489
There was a significant decline in the number of glucocorticoid receptors within the various hippocampal areas, both as the total number of 3Hcorticosterone binding sites and as the number per single pyramidal or granule neuron associated with aging and perhaps due to loss of adrenocorticoidcompetent neurons. The dentate gyrus and the CA1 region were mostly affected by the agedependent decrease in glucocorticoid receptors of the hippocampus. Twentyeightmonthold rats, treated with acetyllcarnitine for 7 months, showed a significantly higher number of 3Hcorticosterone binding sites within the various hippocampal regions examined than did agematched controls. The CA1 and the dentate gyrus were the regions most susceptible to amelioration by acetyllcarnitine treatment. These findings suggest a positive effect of acetyllcarnitine treatment on agerelated changes which occur in the hippocampus. 25_ Neurochem Res. 1988 Oct;13(10):90916. Action of Lacetylcarnitine on agedependent modifications of mitochondrial membrane proteins from rat cerebellum. Villa RF, Turpeenoja L, Benzi G, Giuffrida Stella AM. Institute of Pharmacology, Faculty of Science, University of Pavia, Italy. Protein patterns of mitochondrial outer membrane, inner membrane, and matrix from nonsynaptic (free) mitochondria from rat cerebellum at different ages (4, 8, 12, 16, 20, and 24 months) were analyzed by gel electrophoresis. Acute Lacetylcarnitine treatment was performed by a single i.p. injection (100 mg/kg body weight) of the substance 60 min before the sacrifice of the animals. Different agedependent changes were obtained for the proteins of the three fractions. The amount of some protein subunits increased and/or decreased after drug treatment. In particular, protein composition of the inner mitochondrial membrane showed significant agerelated modifications. This result probably indicates differences in protein synthesis and/or turnover rates in the various mitochondrial compartments during aging. Acute Lacetylcarnitine treatment caused: a high increase in the amount of one inner membrane protein with Mw 16 kDa, at all the ages studied; a decrease in the amount of many other inner membrane proteins; modifications of some matrix proteins. Our results show that in vivo administration of Lacetylcarnitine affects mainly the inner membrane protein composition of cerebellar mitochondria. 26_ J Neurosci Res. 1988 Aug;20(4):4916. Nerve growth factor binding in aged rat central nervous system: effect of acetylLcarnitine. Angelucci L, Ramacci MT, Taglialatela G, Hulsebosch C, Morgan B, WerrbachPerez K, PerezPolo R. Department of Pharmacology, University of Rome, Italy. The nerve growth factor protein (NGF) has been demonstrated to affect neuronal development and maintenance of the differentiated state in certain neurons of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 490
the peripheral and central nervous system (CNS) of mammals. In the CNS, NGF has sparing effects on cholinergic neurons of the rodent basal forebrain (BF) following lesions where it selectively induces choline acetyltransferase (ChAT). NGF also induces ChAT in the areas to which BF provides afferents. In aged rats, there is a reduction in the NGFbinding capacity of sympathetic ganglia. Here, we wish to report that there is a decrease in the NGFbinding capacity of the hippocampus and basal forebrain of aged (26monthold) rats as compared to 4monthold controls but no change in NGF binding in cerebellum. In all instances, equilibrium binding dissociation constants did not differ significantly. Treatment of rats with acetylLcarnitine, reported to improve cognitive performance of aged rats, ameliorates these agerelated deficits.
27_ Exp Brain Res. 2002 Jul;145(2):1829. Epub 2002 May 04. Systemic acetylLcarnitine eliminates sensory neuronal loss after peripheral axotomy: a new clinical approach in the management of peripheral nerve trauma. Hart AM, Wiberg M, Youle M, Terenghi G. University Department of Surgery, BlondMcIndoe Centre, Royal Free & University College Medical School, London, UK. Several hundred thousand peripheral nerve injuries occur each year in Europe alone. Largely due to the death of around 40% of primary sensory neurons, sensory outcome remains disappointingly poor despite considerable advances in surgical technique; yet no clinical therapies currently exist to prevent this neuronal death. Acetyl Lcarnitine (ALCAR) is a physiological peptide with roles in mitochondrial bioenergetic function, which may also increase binding of nerve growth factor by sensory neurons. Following unilateral sciatic nerve transection, adult rats received either one of two doses of ALCAR or sham, or no treatment. Either 2 weeks or 2 months later, L4 and L5 dorsal root ganglia were harvested bilaterally, in accordance with the Animal (Scientific Procedures) Act 1986. Neuronal death was quantified with a combination of TUNEL [TdT (terminal deoxyribonucleotidyl transferase) uptake nick end labelling] and neuron counts obtained using the optical disector technique. Sham treatment had no effect upon neuronal death. ALCAR treatment caused a large reduction in the number of TUNELpositive neurons 2 weeks after axotomy (sham treatment 33/group; lowdose ALCAR 6/group, P=0.132; highdose ALCAR 3/group, P<0.05), and almost eliminated neuron loss (sham treatment 21%; lowdose ALCAR 0%, P=0.007; highdose ALCAR 2%, P<0.013). Two months after axotomy the neuroprotective effect of highdose ALCAR treatment was preserved for both TUNEL counts (no treatment five/group; highdose ALCAR one/group) and neuron loss (no treatment 35%; highdose ALCAR 4%, P<0.001). These results provide further evidence for the role of mitochondrial bioenergetic dysfunction in posttraumatic sensory neuronal death, and also suggest that acetyl Lcarnitine may be the first agent suitable for clinical use in the prevention of neuronal death after peripheral nerve trauma.
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28_ Drug Saf. 1998 Dec;19(6):48194. Peripheral neuropathy with nucleoside antiretrovirals: risk factors, incidence and management. Moyle GJ, Sadler M. Kobler Clinic, Chelsea and Westminster Hospital, London, England. Distal symmetrical peripheral neuropathy is a common adverse experience in persons with HIV infection. This condition, which presents as a pain, numbness. burning and/or dysaethesia initially in the feet, is often multifactorial in its origin. Nucleoside analogue reverse transcriptase inhibitors represent an important contributor to peripheral neuropathy. Specifically, around 10% of patients receiving stavudine or zalcitabine and 1 to 2% of didanosine recipients may have to discontinue therapy with these agents due to neuropathy. Prompt withdrawal of these therapies enables gradual resolution of signs and symptoms in most patients, although a period of symptom intensification may occur shortly after withdrawal. Risk factors for developing peripheral neuropathy during nucleoside analogue therapy include low CD4+ cell count (<100 cells/mm3), a prior history of an AIDS defining illness or neoplasm, a history of peripheral neuropathy, use of other neurotoxic agents including high alcohol (ethanol) consumption and nutritional deficiencies such as low serum hydroxocobalamin levels. Thus, patients at increased risk of peripheral neuropathy should potentially avoid the use of the neurotoxic nucleoside analogues or be more carefully monitored during therapy. Management of this problem includes patient education. prompt withdrawal of the likely causative agent (giving consideration not to leave the patient on a suboptimal therapy regimen) and simple analgesia. with augmentation with tricyclic antidepressants or anticonvulsant agents when pain is severe. New agents that may assist in managing this condition include levacecarnine (acetylLcarnitine) and nerve growth factors such as recombinant human nerve growth factor. 29_ Exp Gerontol. 1996 SepOct;31(5):57787. Spatial memory and NGF levels in aged rats: natural variability and effects of acetylLcarnitine treatment. Taglialatela G, Caprioli A, Giuliani A, Ghirardi O. Institute for Research on Senescence, Sigma Tau S.p.A., Pomezia, Rome, Italy. The natural variability of behavioral performance of aged rats was used to evaluate the effect of acetylLcarnitine (ALCAR) on spatial learning and NGF levels in different brain areas. We used a cluster analysis procedure to subdivide the aged animals into three classes of performance (good, intermediate, and poor). These three classes were equally subdivided into controls and ALCARtreated animals in order to investigate its effect on spatial retention. The stratification of animals prior to treatment allowed us to highlight the state dependency of the action of ALCAR. The effect of the molecule in improving spatial retention was evident only in the intermediate performance group. Furthermore, the drug reduced the NGF levels in the basal Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 492
forebrain of treated animals, especially in the intermediate performance group. These results suggest a performancedependent effect of ALCAR and a nonlinear relationship between NGF levels and learning ability in aged rats. 30_ Neurochem Res. 1997 Mar;22(3):25765. AcetylLcarnitine arginine amide prevents beta 2535induced neurotoxicity in cerebellar granule cells. Scorziello A, Meucci O, Calvani M, Schettini G. Institute of Pharmacology, School of Medicine, University of Genova, Italia. Cerebellar granule cells (CGC) at different stages of maturation in vitro (1 or 6 DIV), were treated with beta 2535 and acetylLcarnitine arginine amide (ST857) in presence of 25 mM KCl in the culture medium, and neuronal viability was assessed. Three days of treatment slightly modified the survival of 1 DIVtreated cells, which degenerate and die five days later betaamyloid matching. Similarly, a significative neurotoxic effect was observed on 6 DIV treatedcells after 5 days of exposure to the peptide, while the death occurred within 8 days. ST857 coincubated with beta 2535 was able to rescue neurons from beta 2535induced neurotoxicity. We also studied the changes in Ca2+ homeostasis following glutamate stimulation, in control and betaamyloid treated single cells, either in presence or in absence of ST857. beta 2535 did not affect basal [Ca2+]i, while modified glutamateinduced [Ca2+]i increase, causing a sustained plateau phase of [Ca2+]i, that persisted after the removal of the agonist. ST857 pretreatment completely reverted this effect suggesting that, in CGC chronically treated with beta 2535, ST857 could protect the cells by neurotoxic insults of the peptide likely interfering with the cellular mechanisms involved in the control of Ca2+ homeostasis. 31_ Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11733. Effects of acetylLcarnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. Foreman PJ, PerezPolo JR, Angelucci L, Ramacci MT, Taglialatela G. Institute for Research on Senescence Sigma Tau, Pomezia, Italy. 1. There is growing evidence that the nerve growth factor protein (NGF), a neurotrophic factor for peripheral and central nervous system (CNS) neurons, may play a role in the modulation of the hypothalamopituitaryadrenocortical axis (HPAA). While NGF binding is decreased in rodent CNS after stress exposure, this reduction is prevented by treatment with AcetylLCarnitine (ALCAR), a chemical substance able to prevent some degenerative events associated with aging. 2. The authors studied the effect of cold stress on the lowaffinity NGF receptor (p75NGFR) mRNA levels in the basal forebrain and cerebellum of aged rats chronically treated with ALCAR. 3. The present results show that ALCAR abolished the Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 493
ageassociated reduction of p75NGFR mRNA levels in the basal forebrain of old animals, but did not affect the response to stress stimuli. 4. Also, treatment with ALCAR maintained p75NGFR mRNA levels in the cerebellum of old animals at levels almost identical to those observed in young control animals. 5. These results suggest a neuroprotective effect for ALCAR on central cholinergic neurons exerted at the level of transcription of p75NGFR. The restoration of p75NGFR levels could increase trophic support by NGF of these CNS cholinergic neurons which are implicated in degenerative events associated with aging. 32_ Neurochem Res. 1995 Jan;20(1):19. Neurite outgrowth in PC12 cells stimulated by acetylLcarnitine arginine amide. Taglialatela G, Navarra D, Olivi A, Ramacci MT, WerrbachPerez K, PerezPolo JR, Angelucci L. Institute for Research on Senescence SigmaTau, Pomezia, Italy. Senescence of the central nervous system is characterized by a progressive loss of neurons that can result in physiological and behavioral impairments. Reduction in the levels of central neurotrophic factors or of neurotrophin receptors may be one of the causes of the onset of these degenerative events. Thus, a proper therapeutic approach would be to increase support to degenerating neurons with trophic factors or to stimulate endogenous neurotrophic activity. Here we report that acetylLcarnitine arginine amide (ST857) is able to stimulate neurite outgrowth in rat pheochromocytoma PC12 cells in a manner similar to that elicited by nerve growth factor (NGF). Neurite induction by ST857 requires de novo mRNA synthesis and is independent of the action of several common trophic factors. The integrity of the molecular structure of ST857 is essential for its activity, as the single moieties of the molecule have no effect on PC12 cells, whether they are tested separately or together. Also, minor chemical modifications of ST857, such as the presence of the arginine moiety at a position other than the amino one, completely abolish its neuritogenic effect. Lastly, the presence of ST857 in the culture medium competes with the high affinity NGF binding in a dose dependent fashion. These results, although preliminary, are suggestive of a possible role for ST857 in the development of therapeutic strategies to counteract degenerative diseases of the CNS. 33_ Int J Dev Neurosci. 1995 Feb;13(1):139. AcetylLcarnitine restores choline acetyltransferase activity in the hippocampus of rats with partial unilateral fimbriafornix transection. Piovesan P, Quatrini G, Pacifici L, Taglialatela G, Angelucci L. Institute for Research on Senescence, SigmaTau, Pomezia, Italy. Transection of the fimbriafornix bundle in adult rats results in degeneration of the septohippocampal cholinergic pathway, reminiscent of that occurring in aging as well as Alzheimer disease. We report here a study of the effect of a treatment with acetylLcarnitine (ALCAR) in threemonthold Fischer 344 rats Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 494
bearing a partial unilateral fimbriafornix transection. ALCAR is known to ameliorate some morphological and functional disturbances in the aged central nervous system (CNS). We used choline acetyltransferase (ChAT) and acetyl cholinesterase (AChE) as markers of central cholinergic function, and nerve growth factor (NGF) levels as indicative of the trophic regulation of the medioseptal cholinergic system. ChAT and AChE activities were significantly reduced in the hippocampus (HIPP) ipsilateral to the lesion as compared to the contralateral one, while no changes were observed in the septum (SPT), nucleus basalis magnocellularis (NBM) or frontal cortex (FCX). ALCAR treatment restored ChAT activity in the ipsilateral HIPP, while AChE levels were not different from those of untreated animals, and did not affect NGF content in either SPT or HIPP. 34_ Neurol Res. 1995 Oct;17(5):3736. Effects of levoacetylcarnitine on second motoneuron survival after axotomy. Fernandez E, Pallini R, Tamburrini G, Lauretti L, Tancredi A, La Marca F. Department of Neurosurgery, Catholic University Medical School, Rome, Italy. Little is known about factors that regulate the survival of cranial motoneurons which project to peripheral targets. Various neurotrophic factors of central and peripheral origin have been isolated. In this study, we examined thirteen newborn Wistar rats to determine the effects of acetylLcarnitine treatment on the survival of motoneurons within the facial nucleus after transection of the facial nerve. AcetylLcarnitine was administered for 7 days in seven rats after nerve transection, while saline solution was injected in 6 rats used as controls. Both the motoneuron number and the motoneuron diameter were significantly higher in the facial nucleus of the rats treated with acetylLcarnitine than in the facial nucleus of the control rats. The results obtained suggest that acetylLcarnitine can rescue a substantial number of facial motoneurons from axotomyinduced cell death. Compared to neurotrophic factors, because of its simple molecular structure, acetylLcarnitine permits a safe oral and parenteral administration. It is suggested that acetylLcarnitine could be considered for use as a therapeutic agent in neurodegenerative disorders. 35_ J Pharmacol Exp Ther. 1995 Jul;274(1):43743. Developmental deficiency of the cholinergic system in congenitally hyperammonemic spf mice: effect of acetylLcarnitine. Ratnakumari L, Qureshi IA, Maysinger D, Butterworth RF. Division of Medical Genetics, SainteJustine Hospital, Montreal, Quebec, Canada. The sparsefur (spf) mutant mouse has an Xlinked deficiency of hepatic ornithine transcarbamylase (OTC) and develops hyperammonemia in the postnatal period similar to that seen in human patients. We studied the effect of congenital hyperammonemia on the development of cerebral cholinergic parameters such as choline acetyltransferase (ChAT), acetylcholinesterase (AChE) and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 495
highaffinity choline uptake (HACU) in spf mice. The serum ammonia levels of spf mutant mice were significantly elevated after weaning compared with control animals. ChAT activity levels started decreasing in mutant spf mice from the age of 30 days (i.e., immediately after weaning); it reached significantly lower levels in the adult animals. HACU was consistently lower (P < .01) in spf/Y mice compared with controls up to the adult stage. However, there were no marked changes in the activity of AChE between control and hyperammonemic spf mice. The levels of betaNGF, which is essential for cholinergic differentiation and function, were significantly lower in different brain regions of adult mutant mice compared with normal controls. A treatment of spf/spf breeding females with acetylLcarnitine, at a dose of 1.5 mM in drinking water, starting from day 1 of conception, resulted in a significant restoration of ChAT activity levels in some brain regions of the spf/Y offspring. The betaNGF levels were also significantly elevated after supplementation with ALCAR in mutant mice compared with untreated mutant mice. These data are suggestive of a neurotrophic property of ALCAR during cholinergic deficiency caused by congenital hyperammonemia. 36_ Int J Dev Neurosci. 1995 Feb;13(1):139. AcetylLcarnitine restores choline acetyltransferase activity in the hippocampus of rats with partial unilateral fimbriafornix transection. Piovesan P, Quatrini G, Pacifici L, Taglialatela G, Angelucci L. Institute for Research on Senescence, SigmaTau, Pomezia, Italy. Transection of the fimbriafornix bundle in adult rats results in degeneration of the septohippocampal cholinergic pathway, reminiscent of that occurring in aging as well as Alzheimer disease. We report here a study of the effect of a treatment with acetylLcarnitine (ALCAR) in threemonthold Fischer 344 rats bearing a partial unilateral fimbriafornix transection. ALCAR is known to ameliorate some morphological and functional disturbances in the aged central nervous system (CNS). We used choline acetyltransferase (ChAT) and acetyl cholinesterase (AChE) as markers of central cholinergic function, and nerve growth factor (NGF) levels as indicative of the trophic regulation of the medioseptal cholinergic system. ChAT and AChE activities were significantly reduced in the hippocampus (HIPP) ipsilateral to the lesion as compared to the contralateral one, while no changes were observed in the septum (SPT), nucleus basalis magnocellularis (NBM) or frontal cortex (FCX). ALCAR treatment restored ChAT activity in the ipsilateral HIPP, while AChE levels were not different from those of untreated animals, and did not affect NGF content in either SPT or HIPP. 37_ Neurochem Res. 1995 Jan;20(1):19. Neurite outgrowth in PC12 cells stimulated by acetylLcarnitine arginine amide. Taglialatela G, Navarra D, Olivi A, Ramacci MT, WerrbachPerez K, PerezPolo JR, Angelucci L. Institute for Research on Senescence SigmaTau, Pomezia, Italy.
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Senescence of the central nervous system is characterized by a progressive loss of neurons that can result in physiological and behavioral impairments. Reduction in the levels of central neurotrophic factors or of neurotrophin receptors may be one of the causes of the onset of these degenerative events. Thus, a proper therapeutic approach would be to increase support to degenerating neurons with trophic factors or to stimulate endogenous neurotrophic activity. Here we report that acetylLcarnitine arginine amide (ST857) is able to stimulate neurite outgrowth in rat pheochromocytoma PC12 cells in a manner similar to that elicited by nerve growth factor (NGF). Neurite induction by ST857 requires de novo mRNA synthesis and is independent of the action of several common trophic factors. The integrity of the molecular structure of ST857 is essential for its activity, as the single moieties of the molecule have no effect on PC12 cells, whether they are tested separately or together. Also, minor chemical modifications of ST857, such as the presence of the arginine moiety at a position other than the amino one, completely abolish its neuritogenic effect. Lastly, the presence of ST857 in the culture medium competes with the high affinity NGF binding in a dose dependent fashion. These results, although preliminary, are suggestive of a possible role for ST857 in the development of therapeutic strategies to counteract degenerative diseases of the CNS. 38_ Prog Neuropsychopharmacol Biol Psychiatry. 1995 Jan;19(1):11733. Effects of acetylLcarnitine treatment and stress exposure on the nerve growth factor receptor (p75NGFR) mRNA level in the central nervous system of aged rats. Foreman PJ, PerezPolo JR, Angelucci L, Ramacci MT, Taglialatela G. 005AInstitute for Research on Senescence Sigma Tau, Pomezia, Italy. 1. There is growing evidence that the nerve growth factor protein (NGF), a neurotrophic factor for peripheral and central nervous system (CNS) neurons, may play a role in the modulation of the hypothalamopituitaryadrenocortical axis (HPAA). While NGF binding is decreased in rodent CNS after stress exposure, this reduction is prevented by treatment with AcetylLCarnitine (ALCAR), a chemical substance able to prevent some degenerative events associated with aging. 2. The authors studied the effect of cold stress on the lowaffinity NGF receptor (p75NGFR) mRNA levels in the basal forebrain and cerebellum of aged rats chronically treated with ALCAR. 3. The present results show that ALCAR abolished the ageassociated reduction of p75NGFR mRNA levels in the basal forebrain of old animals, but did not affect the response to stress stimuli. 4. Also, treatment with ALCAR maintained p75NGFR mRNA levels in the cerebellum of old animals at levels almost identical to those observed in young control animals. 5. These results suggest a neuroprotective effect for ALCAR on central cholinergic neurons exerted at the level of transcription of p75NGFR. The restoration of p75NGFR levels could increase trophic support by NGF of these CNS cholinergic neurons which are implicated in degenerative events associated with aging.
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39_ Neurobiol Aging. 1995 JanFeb;16(1):14. Clinical and neurochemical effects of acetylLcarnitine in Alzheimer's disease. Pettegrew JW, Klunk WE, Panchalingam K, Kanfer JN, McClure RJ. Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh, School of Medicine, PA 15213, USA. In a doubleblind, placebo study, acetylLcarnitine was administered to 7 probable Alzheimer's disease patients who were then compared by clinical and 31P magnetic resonance spectroscopic measures to 5 placebotreated probable AD patients and 21 agematched healthy controls over the course of 1 year. Compared to AD patients on placebo, acetylLcarnitinetreated patients showed significantly less deterioration in their MiniMental Status and Alzheimer's Disease Assessment Scale test scores. Furthermore, the decrease in phosphomonoester levels observed in both the acetylLcarnitine and placebo AD groups at entry was normalized in the acetylLcarnitinetreated but not in the placebotreated patients. Similar normalization of highenergy phosphate levels was observed in the acetylLcarnitinetreated but not in the placebotreated patients. This is the first direct in vivo demonstration of a beneficial effect of a drug on both clinical and CNS neurochemical parameters in AD. 40_ Brain Res. 1995 Mar 13;674(1):1426. Spatial discrimination learning and choline acetyltransferase activity in streptozotocintreated rats: effects of chronic treatment with acetylLcarnitine. Prickaerts J, Blokland A, Honig W, Meng F, Jolles J. Department of Psychiatry and Neuropsychology, University of Limburg, Maastricht, The Netherlands. Treatment of rats with i.c.v. injected streptozotocin (STREP) may provide a relevant model of neurodegeneration that is induced by a decrease in the central metabolism of glucose. AcetylLcarnitine (ALCAR) enhances the utilization of alternative energy sources and by such a mechanism of action ALCAR could antagonize the effects of STREP treatment. In this study the effects of chronic treatment with ALCAR were evaluated on spatial discrimination learning in the Morris task and choline acetyltransferase (ChAT) activity of middleaged STREPtreated rats. Chronic treatment with ALCAR attenuated both the STREPinduced impairment in spatial bias and the decrease in hippocampal ChAT activity. These findings indicate that ALCAR treatment has a neuroprotective effect, although further studies are needed to characterize the mechanism of action of ALCAR in this model. 41_ Brain Res. 1994 Jan 7;633(12):7782. AcetylLcarnitine treatment increases choline acetyltransferase activity and NGF levels in the CNS of adult rats following total fimbriafornix transection. Piovesan P, Pacifici L, Taglialatela G, Ramacci MT, Angelucci L. Institute for Research on Senescence SigmaTau, Pomezia, Italy.
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Transection of the fimbriafornix in adult rats is a useful model for producing impairments of cholinergic activity in the hippocampus (HIPP) and atrophy of the medial septum cholinergic perikarya, similar to those observed during senescence, that are possibly due to the lack of nerve growth factor (NGF) retrogradely transported from the hippocampus. In our investigation we used choline acetyltransferase (ChAT) as an index of cholinergic activity in HIPP, frontal cortex (FCX), septum and nucleus basalis magnocellularis (NBM) along with measurements of NGF levels in the HIPP. Threemonthold rats with unilateral total fimbria transection received acetylLcarnitine (ALCAR) (150 mg/kg/day) in drinking water for 1 week before and 4 weeks after the lesion). ALCAR is a substance known to ameliorate some morphological and functional disturbances in the aging central nervous system (CNS). ChAT activity in septum and FCX, and NGF levels in HIPP were significantly increased in the treated group, compared with untreated control groups, while no changes were found in the NBM. On the other hand, a similar ALCAR treatment in unoperated animals induced an increase in ChAT activity in FCX but not in septum nor in NBM. These data are suggestive of a neurotrophic property of ALCAR exerted on those central cholinergic pathways typically damaged by aging. 42_ Exp Gerontol. 1994 JanFeb;29(1):5566. AcetylLcarnitine treatment increases nerve growth factor levels and choline acetyltransferase activity in the central nervous system of aged rats. Taglialatela G, Navarra D, Cruciani R, Ramacci MT, Alema GS, Angelucci L. Institute for Research on Senescence SigmaTau, Pomezia, Italy. The hypothesis that some neurodegenerative events associated with ageing of the central nervous system (CNS) may be due to a lack of neurotrophic support to neurons is suggestive of a possible reparative pharmacological strategy intended to enhance the activity of endogenous neurotrophic agents. Here we report that treatment with acetyllcarnitine (ALCAR), a substance which has been shown to prevent some impairments of the aged CNS in experimental animals as well as in patients, is able to increase the levels and utilization of nerve growth factor (NGF) in the CNS of old rats. The stimulation of NGF levels in the CNS can be attained when ALCAR is given either for long or short periods to senescent animals of various ages, thus indicating a direct effect of the substance on the NGF system which is independent of the actual degenerative stage of the neurons. Furthermore, longterm treatment with ALCAR completely prevents the loss of choline acetyltransferase (ChAT) activity in the CNS of aged rats, suggesting that ALCAR may rescue cholinergic pathways from ageassociated degeneration due to lack of retrogradely transported NGF. 43_ Life Sci. 1994;54(17):120514. AcetylLcarnitine affects aged brain receptorial system in rodents. Castorina M, Ferraris L. Institute for Research on Senescence, SigmaTau, Pomezia, Rome, Italy.
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AcetylLcarnitine (ALCAR), the acetyl ester of carnitine, is regarded as a compound of considerable interest because of its capacity to counteract several physiological and pathological modifications typical of brain ageing processes. In particular, it has been demonstrated that ALCAR can counteract the agedependent reduction of several receptors in the central nervous system of rodents, such as the NMDA receptorial system, the Nerve Growth Factor (NGF) receptors, those of glucocorticoids, neurotransmitters and others, thereby enhancing the efficiency of synaptic transmission, which is considerably slowed down by ageing. The present review thus postulates the importance of ALCAR administration in preserving and/or facilitating the functionality of carnitines, the concentrations of which are diminished in the brain of old animals. 44_ Biochem Pharmacol. 1992 Aug 4;44(3):57785. Stimulation of nerve growth factor receptors in PC12 by acetylLcarnitine. Taglialatela G, Angelucci L, Ramacci MT, WerrbachPerez K, Jackson GR, PerezPolo JR. Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550. AcetylLcarnitine (ALCAR) prevents some deficits associated with aging in the central nervous system (CNS), such as the agedrelated reduction of nerve growth factor (NGF) binding. The aim of this study was to ascertain whether ALCAR could affect the expression of an NGF receptor (p75NGFR). Treatment of PC12 cells with ALCAR increased equilibrium binding of 125INGF. ALCAR treatment also increased the amount of immunoprecipitable p75NGFR from PC12 cells. Lastly, the level of p75NGFR messenger RNA (mRNA) in PC12 was increased following ALCAR treatment. These results are in agreement with the hypothesis that there is a direct action of ALCAR on p75NGFR expression in aged rodent CNS. 45_ Int J Dev Neurosci. 1992 Aug;10(4):3219. Culture of dorsal root ganglion neurons from aged rats: effects of acetylLcarnitine and NGF. Manfridi A, Forloni GL, ArrigoniMartelli E, Mancia M. Institute of Human Physiology II, University of Milan, Italy. In vitro neuronal preparations are used to study the action mechanism of substances which are active in normal and pathological brain aging. One major concern with in vitro assays is that the use of embryonic or adult neurons may hamper an appreciation of the relevance of these substances on aged nervous tissue. In the present study for the first time cultures of aged dorsal root ganglia from 24monthsold rats were maintained in vitro up to 2 weeks. This model was used to investigate the neurotrophic/neuroprotective action of nerve growth factor and acetylLcarnitine. A large population of aged dorsal root ganglia neurons was responsive to nerve growth factor (100 ng/ml). Nerve growth factor induced an increase of initial rate of axonal regeneration and influenced Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 500
the survival time of these neurons. AcetylLcarnitine (250 microM) did not affect the axonal regeneration but substantially attenuated the rate of neuronal mortality. A significant difference was evident between the acetylLcarnitinetreated and the untreated neurons from the first cell counting (day 3 in culture). After 2 weeks the number of aged neurons treated with acetylLcarnitine was almost double that of the controls. The effects of acetylLcarnitine on aged DRG neurons potentially explain the positive effects in clinical and in vivo experimental studies. 46_ Brain Res Dev Brain Res. 1991 Apr 24;59(2):22130. AcetylLcarnitine enhances the response of PC12 cells to nerve growth factor. Taglialatela G, Angelucci L, Ramacci MT, WerrbachPerez K, Jackson GR, PerezPolo JR. Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 77550. We have demonstrated that treatment of rat pheochromocytoma (PC12) cells with acetylLcarnitine (ALCAR) stimulates the synthesis of nerve growth factor receptors (NGFR). ALCAR has also been reported to prevent some agerelated impairments of the central nervous system (CNS). In particular, ALCAR reduces the loss of NGFR in the hippocampus and basal forebrain of aged rodents. On these bases, a study on the effect of NGF on the PC12 cells was carried out to ascertain whether ALCAR induction of NGFR resulted in an enhancement of NGF action. Treatment of PC12 cells for 6 days with ALCAR (10 mM) stimulated [125I]NGF PC12 cell uptake, consistent with increased NGFR levels. Also, neurite outgrowth elicited in PC12 cells by NGF (100 ng/ml) was greatly augmented by ALCAR pretreatment. When PC12 cells were treated with 10 mM ALCAR and then exposed to NGF (1 ng/ml), an NGF concentration that is insufficient to elicit neurite outgrowth under these conditions, there was an ALCAR effect on neurite outgrowth. The concentration of NGF necessary for survival of serumdeprived PC12 cells was 100fold lower for ALCARtreated cells as compared to controls. The minimal effective dose of ALCAR here was between 0.1 and 0.5 mM. This is similar to the reported minimal concentration of ALCAR that stimulates the synthesis of NGFR in these cells. The data here presented indicate that one mechanism by which ALCAR rescues aged neurons may be by increasing their responsiveness to neuronotrophic factors in the CNS. 47_ Int J Dev Neurosci. 1991;9(1):3946. Effect of acetylLcarnitine on forebrain cholinergic neurons of developing rats. De Simone R, Ramacci MT, Aloe L. Institute of Neurobiology, C.N.R., Rome, Italy. It has been shown that the endogenous compound, acetylLcarnitine (ALCAR), acts in the brain as a metabolic cofactor in the synthesis of acetylcholine. In these studies, ALCAR was injected into the brain of developing rats every other day for the first three weeks after birth in order to assess its effect on forebrain Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 501
cholinergic neurons. The results showed that intracerebroventricular (icv) administration of ALCAR causes an increase of choline acetyltransferase (ChAT) activity and of nerve growth factor receptor expression in the striatum. Biological assays of brain tissues revealed that the level of nerve growth factor (NGF) in the hippocampus also increases. The ability of brain cholinergic tissues to respond to exogenous administration of ALCAR is discussed. 48_ J Neurosci Res. 1990 Mar;25(3):3315. 125Ibetanerve growth factor binding is reduced in rat brain after stress exposure. Taglialatela G, Angelucci L, Ramacci MT, Foreman PJ, PerezPolo JR. Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston 775502777. In the central nervous system (CNS), the presence of nerve growth factor (NGF) and its receptor, NGFR, in cholinergic neurons has been demonstrated. In this study we report that, after exposure to stress, there was a reduction in total binding of NGF in the hippocampus and basal forebrain of 3.5monthold rats without significant changes in the frontal cortex or cerebellum. Chronic treatment with acetyllcarnitine (ALCAR), that prevents some agerelated impairments of CNS, for 1.5 months, decreased NGF binding in hippocampus and basal forebrain but abolished the stressrelated reduction of NGF binding observed in the hippocampus of untreated rats. 49_ J Neurosci Res. 1988 Aug;20(4):4916. Nerve growth factor binding in aged rat central nervous system: effect of acetylLcarnitine. Angelucci L, Ramacci MT, Taglialatela G, Hulsebosch C, Morgan B, WerrbachPerez K, PerezPolo R. Department of Pharmacology, University of Rome, Italy. The nerve growth factor protein (NGF) has been demonstrated to affect neuronal development and maintenance of the differentiated state in certain neurons of the peripheral and central nervous system (CNS) of mammals. In the CNS, NGF has sparing effects on cholinergic neurons of the rodent basal forebrain (BF) following lesions where it selectively induces choline acetyltransferase (ChAT). NGF also induces ChAT in the areas to which BF provides afferents. In aged rats, there is a reduction in the NGFbinding capacity of sympathetic ganglia. Here, we wish to report that there is a decrease in the NGFbinding capacity of the hippocampus and basal forebrain of aged (26monthold) rats as compared to 4monthold controls but no change in NGF binding in cerebellum. In all instances, equilibrium binding dissociation constants did not differ significantly. Treatment of rats with acetylLcarnitine, reported to improve cognitive performance of aged rats, ameliorates these agerelated deficits.
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Alpha Lipoic Acid - 70 ABSTRACTS
ALPHA LIPOIC ACID: 70 RESEARCH ABSTRACTS
1. Endocr Rev. 2002 Oct;23(5):599-622. Oxidative stress and stress-activated signaling pathways: a unifying hypothesis of type 2 diabetes. Evans JL, Goldfine ID, Maddux BA, Grodsky GM. University of California at San Francisco, San Francisco, California 94143, USA. jevansphd@earthlink.net In both type 1 and type 2 diabetes, the late diabetic complications in nerve, vascular endothelium, and kidney arise from chronic elevations of glucose and possibly other metabolites including free fatty acids (FFA). Recent evidence suggests that common stress-activated signaling pathways such as nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases underlie the development of these late diabetic complications. In addition, in type 2 diabetes, there is evidence that the activation of these same stress pathways by glucose and possibly FFA leads to both insulin resistance and impaired insulin secretion. Thus, we propose a unifying hypothesis whereby hyperglycemia and FFA-induced activation of the nuclear factor-kappaB, p38 MAPK, and NH2-terminal Jun kinases/stress-activated protein kinases stress pathways, along with the activation of the advanced glycosy ation endproducts/receptor for advanced glycosylation end-products, protein kinase C, and sorbitol stress pathways, plays a key role in causing late complications in type 1 and type 2 diabetes, along with insulin resistance and impaired insulin secretion in type 2 diabetes. Studies with antioxidants such as vitamin E, alpha-lipoic acid, and N-acetylcysteine suggest that new strategies may become available to treat these conditions. 2. Exp Gerontol. 2002 Jan-Mar;37(2-3):401-10. Alpha-lipoic acid modulates NF-kappaB activity in human monocytic cells by direct interaction with DNA. Lee HA, Hughes DA. Immunology Group, Nutrition and Consumer Science Division, Institute of Food Research, Norwich Research Park, Colney, Norwich, Norfolk NR4 7UA, UK. The constitutive activity of the redox-sensitive transcription factor, NF-kappaB, which regulates the production of many inflammatory cytokines and adhesion molecules, appears to be up-regulated in an age-associated manner and it is thought this might contribute to the increased incidence of chronic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 503
inflammatory conditions observed with increasing age. As some antioxidants have demonstrated protective effects against rheumatoid arthritis, we are investigating the effects of vitamin E, vitamin C and alpha-lipoic acid (ALA) on NF-kappaB activity and on the expression of intracellular adhesion molecule (ICAM)-1. MonoMac6 cells (a human monocytic cell line) stimulated with tumour necrosis factor-alpha (TNF-alpha) were treated with antioxidants at physiological achievable levels and ICAM-1 mRNA levels investigated. Both vitamin E and vitamin C had no effect on ICAM-1 expression at the doses used, but ALA reduced the TNF-alpha-stimulated ICAM-1 expression in a dose-dependent manner, to levels observed in unstimulated cells. Alpha-lipoic acid also reduced NFkappaB activity in these cells in a dose-dependent manner. Addition of ALA to the binding reaction of nuclear extract with DNA prior to gel-shift analysis showed that it caused inhibition at this level. These initial results suggest that antioxidant modulation of monocyte activity might have potential benefits in inhibiting the dysregulated activity of redox-sensitive transcription factors that occurs with increasing age. 3. FASEB J. 2001 Nov;15(13):2423-32. Alpha-lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells. Zhang WJ, Frei B. Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA. Endothelial activation and monocyte adhesion are initiating steps in atherogenesis thought to be caused in part by oxidative stress. The metabolic thiol antioxidant alpha-lipoic acid has been suggested to be of therapeutic value in pathologies associated with redox imbalances. We investigated the role of (R)-alpha-lipoic acid (LA) vs. glutathione and ascorbic acid in tumor necrosis factor alpha (TNF-alpha) -induced adhesion molecule expression and nuclear factor kappaB (NF-kappaB) signaling in human aortic endothelial cells (HAEC). Preincubation of HAEC for 48 h with LA (0.05-1 mmol/l) dose-dependently inhibited TNF-alpha (10 U/ml) -induced adhesion of human monocytic THP-1 cells, as well as mRNA and protein expression of E-selectin, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. LA also strongly inhibited TNF-alpha-induced mRNA expression of monocyte chemoattractant protein-1 but did not affect expression of TNF-alpha receptor 1. Furthermore, LA dose-dependently inhibited TNF-alphainduced IkappaB kinase activation, subsequent degradation of IkappaB, the cytoplasmic NF-kappaB inhibitor, and nuclear translocation of NF-kappaB. In contrast, TNF-alpha-induced NF-kappaB activation and adhesion molecule expression were not affected by ascorbic acid or by manipulating cellular glutathione status with l-2oxo-4-thiazolidinecarboxylic acid, N-acetyl-l-cysteine, or d,l-buthionine-S,Rsulfoximine. Our data show that clinically relevant concentrations of LA, but neither vitamin C nor glutathione, inhibit adhesion molecule expression in HAEC and monocyte adhesion by inhibiting the IkappaB/NF-kappaB signaling pathway at the level, or upstream, of IkappaB kinase. 4. Drug Metab Rev. 1998 May;30(2):245-75. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 504
alpha-Lipoic acid: a metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury. Packer L. Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA. Although the metabolic role of alpha-lipoic acid has been known for over 40 years, it is only recently that its effects when supplied exogenously have become known. Exogenous alpha-lipoic acid is reduced intracellularly by at least two and possibly three enzymes, and through the actions of its reduced form, it influences a number of cell process. These include direct radical scavenging, recycling of other antioxidants, accelerating GSH synthesis, and modulating transcription factor activity, especially that of NF-kappa B (Fig. 12). These mechanisms may account for the sometimes dramatic effects of alpha-lipoic acid in oxidative stress conditions (e.g., brain ischemia-reperfusion), and point the way toward its therapeutic use. 5. Biochem Biophys Res Commun. 1992 Dec 30;189(3):1709-15. Alpha-lipoic acid is a potent inhibitor of NF-kappa B activation in human T cells. Suzuki YJ, Aggarwal BB, Packer L. Department of Molecular & Cell Biology, University of California, Berkeley 94720. Acquired immunodeficiency syndrome (AIDS) results from infection with a human immunodeficiency virus (HIV). The long terminal repeat (LTR) region of HIV proviral DNA contains binding sites for nuclear factor kappa B (NF-kappa B), and this transcriptional activator appears to regulate HIV activation. Recent findings suggest an involvement of reactive oxygen species (ROS) in signal transduction pathways leading to NF-kappa B activation. The present study was based on reports that antioxidants which eliminate ROS should block the activation of NF-kappa B and subsequently HIV transcription, and thus antioxidants can be used as therapeutic agents for AIDS. Incubation of Jurkat T cells (1 x 10(6) cells/ml) with a natural thiol antioxidant, alpha-lipoic acid, prior to the stimulation of cells was found to inhibit NF-kappa B activation induced by tumor necrosis factor-alpha (25 ng/ml) or by phorbol 12-myristate 13-acetate (50 ng/ml). The inhibitory action of alpha-lipoic acid was found to be very potent as only 4 mM was needed for a complete inhibition, whereas 20 mM was required for N-acetylcysteine. These results indicate that alpha-lipoic acid may be effective in AIDS therapeutics. AGING 6. J Alzheimers Dis. 2003 Jun;5(3):229-39. Protection against amyloid beta peptide and iron/hydrogen peroxide toxicity by alpha lipoic acid. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 505
Lovell MA, Xie C, Xiong S, Markesbery WR. Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY, USA. Current evidence supports the role of oxidative stress in the pathogenesis of neuron degeneration in Alzheimer's disease (AD). alpha-Lipoic acid (LA), an essential cofactor in mitochondrial dehydrogenase reactions, functions as an antioxidant and reduces oxidative stress in aged animals. Here, we describe the effects of LA and its reduced form, dihydrolipoic acid (DHLA), in neuron cultures treated with amyloid betapeptide (Abeta 25-35) and iron/hydrogen peroxide (Fe/H_2O_2). Pretreatment of dissociated primary hippocampal cultures with LA significantly protected against Abeta and Fe/H_2O_2toxicity. In contrast, concomitant treatment of cultures with LA and Fe/H_2O_2 significantly potentiated the toxicity. Decreased cell survival in cultures treated concomitantly with LA and Fe/H_2O_2 correlated with increased free radical production measured by dichlorofluorescein fluorescence. Treatment of cortical neurons with DHLA significantly protected glucose-transport against Fe/H_2O_2 or betamediated decreases although treatment with LA did not provide protection. These data suggest that DHLA, the reduced form of LA, significantly protects against both Abetaand Fe/H_2O_2 mediated toxicity. The data also suggest that concomitant exposure to LA and Fe/H_2O_2 significantly potentiates the oxidative stress. Overall, these data suggest that the oxidation state of LA is critical to its function and that in the absence of studies of LA/DHLA equilibria in human brain the use of LA as an antioxidant in disorders where there is increased Fe such as AD is of questionable efficacy. 7. Neurosci Lett. 2002 Aug 9;328(2):93-6. Alpha-lipoic acid prevents ethanol-induced protein oxidation in mouse hippocampal HT22 cells. Pirlich M, Kiok K, Sandig G, Lochs H, Grune T. Department of Gastroenterology and Hepatology, University Hospital Charite, Humboldt-University Berlin, Schumannstr. 20/21, 10098, Berlin, Germany. Oxidative stress is involved in a number of neurological disorders, including the neurotoxic effects of ethanol. Recent studies have described a neuroprotective potential of alpha-lipoic acid (LC) in several models of neuronal cell death related to oxidative stress. We tested the hypothesis that LC could be effective in preventing ethanol-induced neurotoxicity employing the clonal hippocampa cell line HT22. A 24 h incubation with ethanol 100-600 mM caused a dose-dependent loss of cell viability and a significant increase of the overall intracellular protein oxidation. Coincubation with LC 0.1 mM resulted in a significant decrease of ethanol-related neurotoxicity and a complete prevention of the ethanol-induced intracellular protein oxidation. These results indicate that the radical scavenging properties of LC are effective to ameliorate ethanol-induced neurotoxicity. 8. Neurosci Lett. 2002 Mar 15;321(1-2):100-4. Beneficial effects of alpha-lipoic acid plus vitamin E on neurological deficit, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 506
reactive gliosis and neuronal remodeling in the penumbra of the ischemic rat brain. Gonzalez-Perez O, Gonzalez-Castaneda RE, Huerta M, Luquin S, Gomez-Pinedo U, Sanchez-Almaraz E, Navarro-Ruiz A, Garcia-Estrada J. Division de Neurociencias, Centro de Investigacion Biomedica de Occidente (CIBO) del Instituto Mexicano del Seguro Social (IMSS), Sierra Mojada 800, Guadalajara Jalisco 44340, Mexico. During cerebral ischemia-reperfusion, the enhanced production of oxygen-derived free radicals contributes to neuronal death. The antioxidants alpha-lipoic acid and vitamin E have shown synergistic effects against lipid peroxidation by oxidant radicals in several pathological conditions. A thromboembolic stroke model in rats was used to analyze the effects of this mixture under two oral treatments: intensive and prophylactic. Neurological functions, glial reactivity and neuronal remodeling were assessed after experimental infarction. Neurological recovery was only found in the prophylactic group, and both antioxidant schemes produced down-regulation of astrocytic and microglial reactivity, as well as higher neuronal remodeling in the penumbra area, as compared with controls. The beneficial effects of this antioxidant mixture suggest that it may be valuable for the treatment of cerebral ischemia in humans. 9. Free Radic Biol Med. 1997;22(1-2):359-78. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Packer L, Tritschler HJ, Wessel K. Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA. Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological intervention strategies are currently available for the treatment of stroke and numerous other brain Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 507
disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders. CATARACT 10. Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):44-50. Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gamma-linolenic acid conjugate. Borenshtein D, Ofri R, Werman M, Stark A, Tritschler HJ, Moeller W, Madar Z. Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel. BACKGROUND: Diabetes commonly leads to long-term complications such as cataract. This study investigated the effects of alpha-lipoic acid (LPA) and its gamma-linolenic acid (GLA) conjugate on cataract development in diabetic sand rats. METHODS: Two separate experiments were conducted. In Experiment 1, sand rats were fed a "high-energy" diet (70% starch), an acute model of Type 2 diabetes, and injected with LPA. In Experiment 2, the animals received a "medium-energy" diet (59% starch), a chronic diabetic model, and were intubated with LPA or its GLA conjugate. Throughout the experiments, blood glucose levels and cataract development were measured. At the termination of the experiments, lens aldose reductase (AR) activity and lenticular reduced glutathione (GSH) levels were analyzed. RESULTS: LPA injection significantly inhibited cataract development and reduced blood glucose levels in rats fed the "high-energy" diet. Lens AR activity tended to be lower, while lenticular GSH levels increased. In sand rats fed a "medium-energy" diet (59% starch), LPA intubation had no effect on blood glucose levels and cataract development but GSH levels were increased. In contrast, sand rats intubated with GLA conjugate showed the highest blood glucose levels and accelerated cataract development. The conjugate treatment also decreased lenticular GSH content. CONCLUSIONS: The hypoglycemic effects of LPA are beneficial in the prevention of acute symptoms of Type 2 diabetes. It remains to be shown that the antioxidant activity of LPA is responsible for prevention or inhibition of cataract progression in sand rats. Copyright 2000 John Wiley & Sons, Ltd. 11. Biochem Mol Biol Int. 1998 Oct;46(3):585-95. Modelling cortical cataractogenesis XX. In vitro effect of alpha-lipoic acid on glutathione concentrations in lens in model diabetic cataractogenesis. Kilic F, Handelman GJ, Traber K, Tsang K, Packer L, Trevithick JR. Department of Biochemistry, University of Western Ontario, London, Canada.
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In previous studies stereospecific protection against lens opacity was consistent with specific reduction of R-alpha-lipoic acid(R-alpha-LA) in mitochondria of the vulnerable cells at the lens equator where the first globular degeneration is seen in glucose cataract. In this study two further possible explanations of this effect were investigated: (1) increased glucose uptake by the lens, leading to increased glycolysis and release of lactate into the incubation medium and/or (2) maintenance of glutathione levels by the R-alpha-LA. The data did not support 1, but was consistent with 2, after 24 hr incubation. The concentrations of glutathione in normal lenses or lenses incubated with R- or racemic alpha-LA were not significantly different, but the concentration of glutathione in lenses incubated with S-alpha-LA was significantly lower than the R-alpha-LA-incubated lenses. 12. Biochem Biophys Res Commun. 1996 Apr 16;221(2):422-9. Stereospecific effects of R-lipoic acid on buthionine sulfoximine-induced cataract formation in newborn rats. Maitra I, Serbinova E, Tritschler HJ, Packer L. Department of Molecular and Cell Biology, University of California, Berkeley, 94720-3200, USA. This study revealed a marked stereospecificity in the prevention of buthionine sulfoximine-induced cataract, and in the protection of lens antioxidants, in newborn rats by alpha-lipoate, R- and racemic alpha-lipoate decreased cataract formation from 100% (buthionine sulfoximine only) to 55% (buthionine sulfoximine + R-alpha-lipoic acid) and 40% (buthionine sulfoximine + rac-alpha-lipoic acid) (p<0.05 compared to buthionine sulfoximine only). S-alpha-lipoic acid had no effect on cataract formation induced by buthionine sulfoximine. The lens antioxidants glutathione, ascorbate, and vitamin E were depleted to 45, 62, and 23% of control levels, respectively, by buthionine sulfoximine treatment, but were maintained at 84-97% of control levels when R-alpha-lipoic acid or rac-alpha-lipoic acid were administered with buthionine sulfoximine; S-alpha-lipoic acid administration had no protective effect on lens antioxidants. When enantiomers of alpha-lipoic acid were administered to animals, R-alpha-lipoic acid was taken up by lens and reached concentrations 2to 7-fold greater than those of S-alpha-lipoic acid, with rac-alpha-lipoic acid reaching levels midway between the R-isomer and racemic form. Reduced lipoic acid, dihydrolipoic acid, reached the highest levels in lens of the rac-alpha-lipoic acid-treated animals and the lowest levels in S-alpha-lipoic acid-treated animals. These results indicate that the protective effects of alpha-lipoic acid against buthionine sulfoximine-induced cataract are probably due to its protective effects on lens antioxidants, and that the stereospecificity exhibited is due to selective uptake and reduction of R-alpha-lipoic acid by lens cells. 13. Biochem Mol Biol Int. 1995 Oct;37(2):361-70. Modelling cortical cataractogenesis 17: in vitro effect of a-lipoic acid on Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 509
glucose-induced lens membrane damage, a model of diabetic cataractogenesis. Kilic F, Handelman GJ, Serbinova E, Packer L, Trevithick JR. Dept. of Biochemistry, University of Western Ontario, London, Canada. The effect of R, S, and racemic forms of a-lipoic acid was tested on the formation of opacity in normal rat lenses incubated with 55.6 mM glucose, as a model for in vivo diabetic cataractogenesis. Control lenses, incubated 8 days with 5.56 mM glucose, did not develop opacities. Formation of lens opacities in vitro was correlated with lactate dehydrogenase (LDH) leakage into the incubation medium. Opacity formation and LDH leakage, resulting from incubation in medium containing 55.6 mM glucose to model diabetes, were both suppressed by the addition of 1 mM R-lipoic acid. Addition of 1 mM racemic lipoic acid reduces these damaging effects to the lens by one-half, while S-lipoic acid potentiated LDH leakage, consistent with the hypothesis that R-lipoic acid is the active form. Although HPLC analysis demonstrated that both stereoisomers of lipoic acid were reduced to dihydrolipoate at comparable rates by the intact lens, the mitochondrial lipoamide dehydrogenase system is highly specific for reduction of exogenous R-lipoic to dihydrolipoic acid. Therefore, stereospecific protection against this opacity is consistent with specific reduction of R-lipoic acid in mitochondria of the vulnerable cells at the lens equator where the first globular degeneration is seen in glucose cataract. ____________________________________________________________ DIABETES 14. Vnitr Lek. 2002 Jun;48(6):534-41. [Autonomic neuropathy in diabetics, treatment possibilities] [Article in Czech] Lacigova S, Rusavy Z, Cechurova D, Jankovec Z, Zourek M. I. interni klinika Fakultni nemocnice, Plzen. Diabetic neuropathy is a chronic complication of diabetes. It involves non-inflammatory damage of the function and structure of peripheral nerves by metabolic vascular pathogenic processes. In case of affection of vegetative nerves (small non-myelinated C fibres) autonomic neuropathy develops. It is a relatively frequent form of neuropathy which remains for a long time without clinical symptoms and therefore is rarely diagnosed and treated. Manifestations of the affection are encountered in all organs which are supplied by vegetative nerves. The presence of this complication of diabetes is signalized by tachycardia at rest, deterioration of gastric evacuation, diabetic diarrhoea or constipation, erectile dysfunction, impaired function of the sweat glans or impaired pupillary reaction. The advanced form involves the danger of latent myocardial ischaemia, serious postural hypotension and sudden death. It increases significantly the mortality of the affected patients. Similarly as the treatment of other complication of diabetes, treatment of autonomic neuropathy is difficult. The objective of the present paper is to review contemporary Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 510
therapeutic possibilities. An essential prerequisite remain efforts to achieve optimal compensation. The authors draw attention to the effect of alpha-lipoic acid which exerts a positive effect not only on subjective symptoms but also on the objective finding. The other mentioned drugs are used either only experimentally or for purely symptomatic treatment. 15. Diabetes Metab Res Rev. 2002 May-Jun;18(3):176-84. Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives. van Dam PS. Department of Internal Medicine and Endocrinology, University Medical Center, Utrecht, The Netherlands. P.S.vanDam@digd.azu.nl Increased oxidative stress is a mechanism that probably plays a major role in the development of diabetic complications, including peripheral neuropathy. This review summarises recent data from in vitro and in vivo studies that have been performed both to understand this aspect of the pathophysiology of diabetic neuropathy and to develop therapeutic modalities for its prevention or treatment. Extensive animal studies have demonstrated that oxidative stress may be a final common pathway in the development of diabetic neuropathy, and that antioxidants can prevent or reverse hyperglycaemia-induced nerve dysfunction. Most probably, the effects of antioxidants are mediated by correction of nutritive blood flow, although direct effects on endoneurial oxidative state are not excluded. In a limited number of clinical studies, antioxidant drugs including alpha-lipoic acid and vitamin E were found to reduce neuropathic symptoms or to correct nerve conduction velocity. These data are promising, and additional larger studies with alpha-lipoic acid are currently being performed. Copyright 2002 John Wiley & Sons, Ltd. Endocr Pract. 2002 Jan-Feb;8(1):29-35. Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlled-release formulation of alpha-lipoic acid. Evans JL, Heymann CJ, Goldfine ID, Gavin LA. Northern California Diabetes Institute, Seton Medical Center, Dale City, CA 94015, USA. OBJECTIVE: To determine the pharmacokinetics, safety, and tolerability of a novel, controlled-release oral formulation of alpha-lipoic acid (LA) and to investigate whether sustaining the concentration of LA in plasma would have a beneficial effect on glycemic control in patients with type 2 diabetes. METHODS: For the pharmacokinetic study, a single, 600-mg dose of either controlled-release LA (CRLA) or quick-release LA (QRLA) was administered orally to 12 normal human subjects. The plasma profile of LA was determined for 24 hours after administration of the dose,and pharmacokinetic analyses were performed. For the safety and tolerability study, 21 patients with type 2 diabetes were given 900 mg of CRLA daily for 6 weeks, followed by 1,200 mg of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 511
CRLA daily for an additional 6 weeks. Active treatment was followed by a 3-week washout period. Throughout the study, patients continued to take their prestudy antidiabetic medications, which included metformin (Glucophage), sulfonylureas (Amaryl, glyburide, and Glucotrol), acarbose (Precose), troglitazone (Rezulin), and insulin (either as monotherapy or in combination). CRLA was evaluated for safety and tolerability as well as for effects on glycemic control. RESULTS: The Tmax (time to maximal plasma concentration) of LA administered as CRLA was 1.25 hours and was approximately 2.5-fold longer in comparison with the Tmax for QRLA (Tn,5X = 0.5 hour; P<0.02). No severe side effects or changes in either liver or kidney function or hematologic profiles were noted after the administration of CRLA. In 15 patients, the mean plasma fructosamine concentration was reduced from 313 to 283 micromol/L(P<0.05) after 12 weeks of treatment with CRLA. CONCLUSION: CRLA increased the plasma concentration of LA over time in healthy subjects, and CRLA was safe, well tolerated, and effective in reducing plasma fructosamine in patients with type 2 diabetes. 16. Nutrition. 2001 Oct;17(10):888-95. Molecular aspects of lipoic acid in the prevention of diabetes complications. Packer L, Kraemer K, Rimbach G. Department of Molecular Pharmacology and Toxicology, School of Pharmacy, University of Southern California, 1985 Zonal Avenue, Los Angeles, CA 90098-9121, USA. packerresearch@aol.com Alpha-lipoic acid (LA) and its reduced form, dihydrolipoic acid, are powerful antioxidants. LA scavenges hydroxyl radicals, hypochlorous acid, peroxynitrite, and singlet oxygen. Dihydrolipoic acid also scavenges superoxide and peroxyl radicals and can regenerate thioredoxin, vitamin C, and glutathione, which in turn can recycle vitamin E. There are several possible sources of oxidative stress in diabetes including glycation reactions, decompartmentalization of transition metals, and a shift in the reduced-oxygen status of the diabetic cells. Diabetics have increased levels of lipid hydroperoxides, DNA adducts, and protein carbonyls. Available data strongly suggest that LA, because of its antioxidant properties, is particularly suited to the prevention and/or treatment of diabetic complications that arise from an overproduction of reactive oxygen and nitrogen species. In addition to its antioxidant properties, LA increases glucose uptake through recruitment of the glucose transporter-4 to plasma membranes, a mechanism that is shared with insulin-stimulated glucose uptake. Further, recent trials have demonstrated that LA improves glucose disposal in patients with type II diabetes. In experimental and clinical studies, LA markedly reduced the symptoms of diabetic pathologies, including cataract formation, vascular damage, and polyneuropathy. To develop a better understanding of the preventative and therapeutic potentials of LA, much of the current interest is focused on elucidating its molecular mechanisms in redox dependent gene expression. 17. J Am Coll Nutr. 2001 Oct;20(5 Suppl):363S-369S; discussion 381S-383S. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 512
Use of antioxidant nutrients in the prevention and treatment of type 2 diabetes. Ruhe RC, McDonald RB. Department of Nutrition, University of California, Davis 95616-8669, USA. Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), is increasingly common throughout the world. The World Health Organization has predicted that between 1997 and 2025, the number of diabetics will double from 143 million to about 300 million. The incidence of NIDDM is highest in economically developed nations, particularly the U.S., where approximately 6.5% of the population (17 million people) have either diagnosed or undiagnosed diabetes. The two most important factors contributing to the development of NIDDM are obesity and physical inactivity. The leading cause of mortality and morbidity in people with NIDDM is cardiovascular disease caused by macro- and microvascular degeneration. Current therapies for NIDDM focus primarily on weight reduction. Indeed, several investigations indicate that 65% to 75% of cases of diabetes in Caucasians could be avoided if individuals in this subgroup did not exceed their ideal weight. The success of this approach has been, at best, modest. An alternate approach to the control of Type 2 diabetes is to arrest the progress of the pathology until a cure has been found. To this end, some investigators suggest that dietary antioxidants may be of value. Several studies in humans and laboratory animals with NIDDM indicate that vitamin E and lipoic acid supplements lessen the impact of oxidative damage caused by dysregulation of glucose metabolism. In this brief review, we discuss the incidence, etiology, and current therapies for NIDDM and further explore the usefulness of dietary antioxidants in treating this disorder. 18. Metabolism. 2001 Aug;50(8):868-75. The effects of treatment with alpha-lipoic acid or evening primrose oil on vascular hemostatic and lipid risk factors, blood flow, and peripheral nerve conduction in the streptozotocin-diabetic rat. Ford I, Cotter MA, Cameron NE, Greaves M. Departments of Medicine & Therapeutics, University of Aberdeen, Aberdeen, Scotland. Oxidative stress and defective fatty acid metabolism in diabetes may lead to impaired nerve perfusion and contribute to the development of peripheral neuropathy. We studied the effects of 2-week treatments with evening primrose oil (EPO; n = 16) or the antioxidant alpha-lipoic acid (ALA; n = 16) on endoneurial blood flow, nerve conduction parameters, lipids, coagulation, and endothelial factors, in rats with streptozotocin-induced diabetes. Compared with their nondiabetic littermates, untreated diabetic rats had impaired sciatic motor and saphenous sensory nerve-conduction velocity (NCV; P <.001), reduced endoneurial blood flow (P <.001), and increased serum triglycerides (P <.01), cholesterol (P < 0.01), plasma factor VII (P <.0001), and von Willebrand factor (vWF; P <.0001). Plasma fibrinogen and serum high-density lipoprotein concentrations were not significantly different. Treatment with either ALA or Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 513
EPO effectively corrected the deficits in NCV and endoneurial blood flow. ALA was associated with marked and statistically significant decreases in fibrinogen, factor VII, vWF, and triglycerides (P <.01, paired t tests before v after treatment). In contrast, EPO was associated with significant (P <.05) increases in fibrinogen, factor VII, vWF, triglycerides, and cholesterol and a significant decrease in high-density lipoprotein. Changes in levels of coagulation factors and lipids, qualitatively similar to those found with EPO, were obtained with a diet containing sunflower oil (to control for calorific and lipid content) or with a normal diet alone. Blood glucose and hematocrit levels were not significantly altered by treatments. These data suggest that although both ALA and EPO improve blood flow and nerve function, their actions on vascular factors differ. The marked effects of ALA in lowering lipid and hemostatic risk factors for cardiovascular disease indicate potential antithrombotic and antiatherosclerotic actions that could be of benefit in human diabetes and merit further study. Copyright 2001 by W.B. Saunders Company 19. Diabetes Technol Ther. 2000 Autumn;2(3):401-13. Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes. Evans JL, Goldfine ID. Medical Research Institute, San Bruno, California 94066, USA. jevans@lipoic.com Alpha-Lipoic acid (LA) is a disulfide compound that is produced in small quantities in cells, and functions naturally as a co-enzyme in the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase mitochondrial enzyme complexes. In pharmacological doses, LA is a multifunctional antioxidant. LA has been used in Germany for over 30 years for the treatment of diabetes-induced neuropathy. In patients with type 2 diabetes, recent studies have reported that intravenous (i.v.) infusion of LA increases insulin-mediated glucose disposal, whereas oral administration of LA has only marginal effects. If the limitations of oral therapy can be overcome, LA could emerge as a safe and effective adjunctive antidiabetic agent with insulin sensitizing activity. 20. Free Radic Biol Med. 2001 Jul 1;31(1):53-61. Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress. Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T. Universitatsklinikum Hamburg-Eppendorf Klinik und Poliklinik fur Innere Medizin, Abteilung Kardiologie, Hamburg, Germany. heitzer@uke.uni-hamburg.de The impairment of nitric oxide (NO)-mediated vasodilation in diabetes has been attributed to increased vascular oxidative stress. Lipoic acid has been shown to have substantial antioxidative properties. The aim of this study was to assess the effect of lipoic acid on NO-mediated vasodilation in diabetic patients in comparison with the well-recognized effect of ascorbic acid. Using venous Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 514
occlusion plethysmography, we examined the effects of lipoic acid (0.2 mM) and ascorbic acid (1 and 10 mM) on forearm blood flow responses to acetylcholine, sodium nitroprusside and concomitant infusion of the NO-inhibitor, N(G)-monomethyl-L-arginine, in 39 diabetic patients and 11 control subjects. Plasma levels of antioxidants and parameters of lipid peroxidation were measured and correlated to endothelial function tests. Lipoic acid improved NO-mediated vasodilation in diabetic patients, but not in controls. NO-mediated vasodilation was improved by ascorbic acid at 10 mM, but not 1 mM. Improvements of endothelial function by ascorbic acid and lipoic acid were closely related. The beneficial effects of lipoic acid were positively related to plasma levels of malondialdehyde and inversely related to levels of ubiquinol-10. These findings support the concept that oxidative stress contributes to endothelial dysfunction and suggest a therapeutic potential of lipoic acid particularly in patients with imbalance between increased oxidative stress and depleted antioxidant defense. 21. Diabetes Res Clin Pract. 2001 Jun;52(3):175-83. Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study. Morcos M, Borcea V, Isermann B, Gehrke S, Ehret T, Henkels M, Schiekofer S, Hofmann M, Amiral J, Tritschler H, Ziegler R, Wahl P, Nawroth PP. Department of Internal Medicine I, University of Heidelberg, Bergheimerstr. 58, 69115 Heidelberg, Germany. michael_morcos@med.uni-heidelberg.de Oxidative stress plays a central role in the pathogenesis and progression of late microangiopathic complications (diabetic nephropathy) in diabetes mellitus. Previous studies suggested that treatment of diabetic patients with the antioxidant alpha-lipoic acid reduce oxidative stress and urinary albumin excretion. In this prospective, open and non-randomized study, the effect of alpha-lipoic acid on the progression of endothelial cell damage and the course of diabetic nephropathy, as assessed by measurement of plasma thrombomodulin and urinary albumin concentration (UAC), was evaluated in 84 patients with diabetes mellitus over 18 months. Forty-nine patients (34 with Type 1 diabetes, 15 with Type 2 diabetes) had no antioxidant treatment and served as a control group. Thirty-five patients (20 with Type 1 diabetes, 15 with Type 2 diabetes) were treated with 600 mg alpha-lipoic acid per day. Only patients with an urinary albumin concentration <200 mg/l were included into the study. After 18 months of follow up, the plasma thrombomodulin level increased from 35.9+/-9.5 to 39.7+/-9.9 ng/ml (P<0.05) in the control group. In the alpha-lipoic acid treated group the plasma thrombomodulin level decreased from 37.5+/-16.2 to 30.9+/-14.5 ng/ml (P<0.01). The UAC increased in patients without alpha-lipoic acid treatment from 21.2+/-29.5 to 36.9+/-60.6 ng/l (P<0.05), but was unchanged with alpha-lipoic acid. It is postulated that the significant decrease in plasma thrombomodulin and failure of UAC to increase observed in the alpha-lipoic acid treated group is due to antioxidative effects of alpha-lipoic acid, and if so that oxidative stress plays a central role in the pathogenesis of diabetic nephropathy. Furthermore, progression of the disease might be inhibited by Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 515
antioxidant drugs. A placebo-controlled study is needed. 22. Bull Exp Biol Med. 2000 Oct;130(10):986-90. The function of endogenous protective systems in patients with insulin-dependent diabetes mellitus and polyneuropathy: effect of antioxidant therapy. Strokov IA, Manukhina EB, Bakhtina LY, Malyshev IY, Zoloev GK, Kazikhanova SI, Ametov AS. Department of Endocrinology and Diabetology, Russian Medical Academy of Postgraduate Education, Moscow. alpha-Lipoic acid is a very efficient antioxidants for the treatment and prevention of diabetic neuropathy. The aim of the present study was to evaluate the function of nitric oxide (NO) and stress proteins (HSP72) in insulin-dependent diabetes complicated by polyneuropathy and possible contribution of these systems to the therapeutic effects of alpha-lipoic acid. Plasma content of nitrites and nitrates in diabetic patients was almost 2-fold below the normal. The treatment with alpha-lipoic acid completely normalized the plasma content of these stable NO metabolites. The majority of patients had also low level of HSP72. Positive clinical effects of alpha-lipoic acid were accompanied by normalization of HSP72 synthesis. Thus, activation of the NO and HSP protective systems is involved in the therapeutic effect of alpha-lipoic acid in diabetic patients (type 1 diabetes mellitus) with polyneuropathy. 23. Free Radic Biol Med. 2000 Dec;29(11):1122-8. Lipoic acid decreases lipid peroxidation and protein glycosylation and increases (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-treated human erythrocytes. Jain SK, Lim G. Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. sjain@lsuhsc.edu Lipoic acid supplementation has been found to be beneficial in preventing neurovascular abnormalities in diabetic neuropathy. Insufficient (Na(+) + K(+))-ATPase activity has been suggested as a contributing factor in the development of diabetic neuropathy. This study was undertaken to test the hypothesis that lipoic acid reduces lipid peroxidation and glycosylation and can increase the (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM lipoic acid (mixture of S and R sterioisomers) in a shaking water bath at 37 degrees C for 24 h. There was a significant stimulation of glucose consumption by RBC in the presence of lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC exposed to high glucose concentrations. High glucose treatment significantly lowered the activities of (Na(+) + K(+))- and Ca(++)-ATPases of RBC membranes. Lipoic acid addition significantly blocked the reduction in activities of (Na(+) + K(+))- and Ca(++)Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 516
ATPases in high glucose-treated RBC. There were no differences in lipid peroxidation, GHb and (Na(+) + K(+))- and Ca(++)-ATPase activity levels in normal glucose-treated RBC with and without lipoic acid. Thus, lipoic acid can lower lipid peroxidation and protein glycosylation, and increase (Na(+) + K(+))- and Ca(++)-ATPase activities in high-glucose exposed RBC, which provides a potential mechanism by which lipoic acid may delay or inhibit the development of neuropathy in diabetes. 24. Med Hypotheses. 2000 Dec;55(6):510-2. Alpha lipoic acid: a novel treatment for depression. Salazar MR. Amherst College, Amherst, Massachusetts, USA. Insulin resistance has been associated with people diagnosed with depression. Conversely, it has also been documented that diabetics have an increased risk of depression. Evidence suggests that insulin activity plays a role in serotonergic activity by increasing the influx of tryptophan into the brain. This increased influx of tryptophan has been shown to result in an increase in serotonin synthesis. In accordance with the serotonin theory of depression, it may be possible to treat depression by increasing insulin activity. The antioxidant alpha lipoic acid has been shown to increase insulin sensitivity and is used to treat people with diabetes. Therefore, the nutrient alpha lipoic acid should be clinically tested as an adjunct treatment for depression. Copyright 2000 Harcourt Publishers Ltd. 25. Wien Klin Wochenschr. 2000 Jul 28;112(14):610-6. Therapeutic potential of glutathione. Exner R, Wessner B, Manhart N, Roth E. Department of Surgery, University of Vienna, Austria. Reactive oxygen species, formed in various biochemical reactions, are normally scavenged by antioxidants. Glutathione in its reduced form (GSH) is the most powerful intracellular antioxidant, and the ratio of reduced to oxidised glutathione (GSH:GSSG) serves as a representative marker of the antioxidative capacity of the cell. Several clinical conditions are associated with reduced GSH levels which as a consequence can result in a lowered cellular redox potential. GSH and the redox potential of the cell are components of the cell signaling system influencing the translocation of the transcription factor NF kappa B which regulates the synthesis of cytokines and adhesion molecules. Therefore, one possibility to protect cells from damage caused by reactive oxygen species is to restore the intracellular glutathione levels. Cellular GSH concentration can be influenced by exogenous administration of GSH (as intravenous infusion or as aerosol), of glutathione esters or of GSH precursors such as glutamine or cysteine (in form of N-acetyl-L-cysteine, alpha-lipoic acid). The modulation of GSH metabolism might present a useful adjuvant therapy in many
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pathologies such as intoxication, diabetes, uremia, sepsis, inflammatory lung processes, coronary disease, cancer and immunodeficiency states. 26. Exp Clin Endocrinol Diabetes. 2000;108(3):168-74. Effects of alpha-lipoic acid on microcirculation in patients with peripheral diabetic neuropathy. Haak E, Usadel KH, Kusterer K, Amini P, Frommeyer R, Tritschler HJ, Haak T. Medical Department I, Center of Internal Medicine, University Hospital, Frankfurt, Germany. E.Haak@em.uni-frankfurt.de Diabetic polyneuropathy is a serious complication in patients with diabetes mellitus. In addition to the maintenance of a sufficient metabolic control, alpha-lipoic acid (ALA) (Thioctacid, Asta Medica) is known to have beneficial effects on diabetic polyneuropathy although the exact mechanism by which ALA exerts its effect is unknown. In order to study the effect of ALA on microcirculation in patients with diabetes mellitus and peripheral neuropathy one group of patients (4 female, 4 male, age 60+/-3 years, diabetes duration 19+/-4 years, BMI 24.8+/-1.3 kg/m2) received 1200 mg ALA orally per day over 6 weeks (trial 1). A second group of patients (5 female, 4 male, age 65+/-3 years, diabetes duration 14+/-4 years, BMI 23.6+/-0.7 kg/m2) was studied before and after they had received 600 mg ALA or placebo intravenously over 15 minutes in order to investigate whether ALA has an acute effect on microcirculation (trial 2). Patients were investigated by nailfold video-capillaroscopy. Capillary blood cell velocity was examined at rest and during postreactive hyperemia (occlusion of the wrist for 2 minutes, 200 mmHg) which is a parameter of the perfusion reserve on demand. The oral therapy with ALA resulted in a significant decrease in the time to peak capillary blood cell velocity (tpCBV) during postocclusive hyperemia (trial 1: 12.6+/-3.1 vs 35.4+/-10.9 s, p<0.05). The infusion of ALA also decreased the tpCBV in patients with diabetic neuropathy (trial 2: before: 20.8+/-4,5, ALA: 11.74+/-4.4, placebo: 21.9-5.0 s, p<0.05 ALA vs both placebo and before infusions) indicating that ALA has an acute effect on microcirculation. Capillary blood cell velocity at rest (rCBV), hemodynamic parameters, hemoglobinA1c and local skin temperature remained unchanged in both studies. These results demonstrate that in patients with diabetic polyneuropathy ALA improves microcirculation as indicated by an increased perfusion reserve on demand. The observed effects are apparently acute effects. With the restriction of the pilot character of this investigation the findings support the assumption that ALA might exert its beneficial effects at least partially by improving microcirculation which is likely to occur also at the level of the vasa nervorum. 27. In Vivo. 2000 Mar-Apr;14(2):327-30. In vivo effect of lipoic acid on lipid peroxidation in patients with diabetic neuropathy. Androne L, Gavan NA, Veresiu IA, Orasan R. Diabetes Center & Clinic, Cluj Napoca. BACKGROUND: The diabetic state, in both humans and experimental animals, is Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 518
associated with oxidative stress. Lipid peroxidation of nerve membranes has been suggested as a mechanism by which peripheral nerve ischemia and hypoxia could cause neuropathy. Lipoic acid (LA) is a powerful inhibitor of iron-dependent lipid peroxidation and reactive oxygen species. The treatment of diabetic peripheral and cardiac autonomic neuropathy with LA is based on good clinical and experimental evidence. MATERIALS AND METHODS: To investigate the magnitude of the oxidative stress, serum ceruloplasmin (Cp) and lipid peroxide (Lp) levels were measured in 10 patients with diabetic neuropathy, before and 70 days after treatment with single dose of 600 mg LA/day. For other 12 healthy age- and sex-matched control subjects the serum Cp and Lp levels were evaluated. RESULTS: Our results show that hyperglycemia is a factor for an increase in serum ceruloplasmin in patients with diabetic neuropathy compared to healthy subjects (p < 0.0001). High serum ceruloplasmin (Cp) level in patients with diabetes may be related to antioxidant defense. The treatment of diabetic neuropathy with LA does not affect significantly the serum Cp activity. The serum Lp levels after LA administration were significantly lower (p < 0.005) than those before treatment. CONCLUSIONS: The antioxidant therapy with LA improves and may prevent diabetic neuropathy. This improvement is associated with a reduction in the indexes of lipid peroxidation. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia autooxidation. 28. Diabet Med. 1999 Dec;16(12):1040-3. Effects of 3-week oral treatment with the antioxidant thioctic acid (alpha-lipoic acid) in symptomatic diabetic polyneuropathy. Ruhnau KJ, Meissner HP, Finn JR, Reljanovic M, Lobisch M, Schutte K, Nehrdich D, Tritschler HJ, Mehnert H, Ziegler D. Deutsches Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf, Germany. AIMS: To evaluate the efficacy and safety of short-term oral treatment with the antioxidant thioctic acid (TA) on neuropathic symptoms and deficits in patients with Type 2 diabetes mellitus with symptomatic polyneuropathy. METHODS: Patients were randomly assigned to oral treatment with 600 mg of TA t.i.d. (n = 12) or placebo (n = 12) for 3 weeks. Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) in the feet were scored at weekly intervals and summarized as a Total Symptom Score (TSS). The Hamburg Pain Adjective List (HPAL) and the Neuropathy Disability Score (NDS) were assessed at baseline and day 19. RESULTS: At baseline the TSS, HPAL, and NDS were not significantly different between the groups. The TSS in the foot decreased from baseline to day 19 by -3.75 +/1.88 points (-47%) in the TA group and by -1.94 +/- 1.50 points (-24%) in the placebo group (P= 0.021 for TA vs. placebo). The total HPAL score decreased from baseline to day 19 by -2.20 +/- 1.65 points (-60%) in the TA group and by -0.96 +/- 1.32 points (29%) in the placebo group (P = 0.072 for TA vs. placebo). The NDS decreased by -0.27 +/- 0.47 points in the TA group, whereas it slightly increased by +0.18 +/- 0.4 points in the placebo group (P = 0.025 for TA vs. placebo). No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS: These preliminary findings indicate that oral treatment with 600 mg of TA t.i.d. for 3 weeks may improve Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 519
symptoms and deficits resulting from polyneuropathy in Type 2 diabetic patients, without causing significant adverse reactions. 29. Biofactors. 1999;10(2-3):157-67. The role of oxidative stress and NF-kappaB activation in late diabetic complications. Mohamed AK, Bierhaus A, Schiekofer S, Tritschler H, Ziegler R, Nawroth PP. Medizinische Klinik I der Universitat Heidelberg, Germany. A common endpoint of hyperglycemia dependent cellular changes is the generation of reactive oxygen intermediates (ROIs) and the presence of elevated oxidative stress. Therefore, oxidative stress is supposed to play an important role in the development of late diabetic complications. Formation of advanced glycation end products (AGE's) due to elevated nonenzymatic glycation of proteins, lipids and nucleic acids is accompanied by oxidative, radical-generating reactions and thus represents a major source for oxygen free radicals under hyperglycemic conditions. Once formed, AGE's can influence cellular function by binding to several binding sites including the receptor for AGE's, RAGE. Binding of AGE's (and other ligands) to RAGE results in generation of intracellular oxidative stress and subsequent activation of the redox-sensitive transcription factor NFkappaB in vitro and in vivo. Consistently, activation of NF-kappaB in diabetic patients correlates with the quality of glycemic control and can be reduced by treatment with the antioxidant alpha-lipoic acid. The development of techniques allowing for a tissue culture independent measurement of NF-kappaB activation in patients with diabetes mellitus gives insights into the molecular mechanisms linking diabetes mellitus and hyperglycemia with formation of advanced glycated endproducts and generation of oxidative stress finally resulting in oxidative stress mediated cellular activation. 30. Exp Clin Endocrinol Diabetes. 1999;107(7):421-30. Alpha-lipoic acid in the treatment of diabetic polyneuropathy in Germany: current evidence from clinical trials. Ziegler D, Reljanovic M, Mehnert H, Gries FA. Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf, Germany. dan.ziegler@dfi.uni-duesseldorf.de Diabetic neuropathy represents a major health problem, as it is responsible for substantial morbidity, increased mortality, and impaired quality of life. Near-normoglycaemia is now generally accepted as the primary approach to prevention of diabetic neuropathy, but is not achievable in a considerable number of patients. In the past two decades several medical treatments that exert their effects despite hyperglycaemia have been derived from the experimental pathogenetic concepts of diabetic neuropathy. Such compounds have been designed to improve or slow the progression of the neuropathic process and are being evaluated in clinical trials, but with the exception of alpha-lipoic acid (thioctic acid) which is available in Germany, none of these drugs is currently available in clinical practice. Here we review the current evidence Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 520
from the clinical trials that assessed the therapeutic efficacy and safety of thioctic acid in diabetic polyneuropathy. Thus far, 15 clinical trials have been completed using different study designs, durations of treatment, doses, sample sizes, and patient populations. Within this variety of clinical trials, those with beneficial effects of thioctic acid on either neuropathic symptoms and deficits due to polyneuropathy or reduced heart rate variability resulting from cardiac autonomic neuropathy used doses of at least 600 mg per day. The following conclusions can be drawn from the recent controlled clinical trials. 1.) Short-term treatment for 3 weeks using 600 mg of thioctic acid i.v. per day appears to reduce the chief symptoms of diabetic polyneuropathy. A 3-week pilot study of 1800 mg per day given orally indicates that the therapeutic effect may be independent of the route of administration, but this needs to be confirmed in a larger sample size. 2.) The effect on symptoms is accompanied by an improvement of neuropathic deficits. 3.) Oral treatment for 4-7 months tends to reduce neuropathic deficits and improves cardiac autonomic neuropathy. 4.) Preliminary data over 2 years indicate possible long-term improvement in motor and sensory nerve conduction in the lower limbs. 5.) Clinical and postmarketing surveillance studies have revealed a highly favourable safety profile of the drug. Based on these findings, a pivotal long-term multicenter trial of oral treatment with thioctic acid (NATHAN I Study) is being conducted in North America and Europe aimed at slowing the progression of diabetic polyneuropathy using a clinically meaningful and reliable primary outcome measure that combines clinical and neurophysiological assessment. 31. Free Radic Biol Med. 1999 Aug;27(3-4):309-14. Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl and City Hospital, Baden-Baden, Germany. snjacob@med.uni-tuebingen.de Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 521
and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different alpha-lipoic acid groups, all subjects receiving ALA were combined in the "active" group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations. 32. Free Radic Biol Med. 1999 Jun;26(11-12):1495-500. alpha-Lipoic acid decreases oxidative stress even in diabetic patients with poor glycemic control and albuminuria. Borcea V, Nourooz-Zadeh J, Wolff SP, Klevesath M, Hofmann M, Urich H, Wahl P, Ziegler R, Tritschler H, Halliwell B, Nawroth PP. Department of Internal Medicine I, University of Heidelberg, Germany. In the present cross-sectional study, the influence of alpha-lipoic acid on markers of oxidative stress, assessed by measurement of plasma lipid hydroperoxides (ROOHs), and on the balance between oxidative stress and antioxidant defence, determined by the ratio ROOH/(alpha-tocopherol/cholesterol), was examined in 107 patients with diabetes mellitus. Patients receiving alpha-lipoic acid (600 mg/day for > 3 months) had significant lower ROOHs and a lower ROOH/(alpha-tocopherol/cholesterol) ratio than those without alpha-lipoic acid treatment [ROOH: 4.76 +/- 2.49 vs. 7.16 +/3.22 mumol/l; p < .0001] and [ROOH/(alpha-tocopherol/cholesterol): 1.37 +/- 0.72 vs. 2.16 +/- 1.17; p < 0.0001]. In addition, the influence of glycemic control and albuminuria on ROOHs and on the ratio of ROOH/(alpha-tocopherol/cholesterol) was examined in the presence and absence of alpha-lipoic acid treatment. Patients were subdivided into three groups based on (1) their HbA1 levels (< 7.5, 7.5-9.5, and > 9.5%) and (2) their urinary albumin concentrations (< 20, 20-200, and > 200 mg/l). Neither poor glycemic control, nor the presence of micro- or macroalbuminuria prevented the antioxidant effect of alpha-lipoic acid. Using stepwise multiple regression analysis, alpha-lipoic acid was found to be the only factor significantly predicting low ROOHs and a low ratio of ROOH/(alpha-tocopherol/cholesterol). These data provide evidence that treatment with alpha-lipoic acid improves significantly the imbalance between increased oxidative stress and depleted antioxidant defence even in patients with poor glycemic control and albuminuria. 33. Microvasc Res. 1999 Jul;58(1):28-34. The effect of alpha-lipoic acid on the neurovascular reflex arc in patients with diabetic neuropathy assessed by capillary microscopy. Haak ES, Usadel KH, Kohleisen M, Yilmaz A, Kusterer K, Haak T. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 522
Center of Internal Medicine, Johann Wolfgang Goethe-University, Frankfurt, D-60590, Germany. Patients with diabetic polyneuropathy are known to have an impaired neurovascular reflex arc compared to healthy controls. This is seen in a delayed decrease in microcirculation of the ipsilateral hand after cooling of the contralateral hand. The aim of this pilot study was to investigate whether intravenous alpha-lipoic acid (ALA) (Thioctacid, Asta Medica) therapy might be able to improve this impaired neurovascular reflex arc in patients with diabetic neuropathy. In addition, clinical effects were evaluated with the aid of the neuropathy symptom score (NSS) and the neuropathy disability score (NDS). Ten patients with diabetes mellitus and polyneuropathy (5 females, 5 males, 2 smokers, 5 IDDM, 5 NIDDM, body mass index 26.1 +/- 1.0 kg/m2, age 58.3 +/- 9.5 years, diabetes duration 15.7 +/- 11.2 years, Hb A1c 6.8 +/- 0.3%) were investigated by nail-fold capillaroscopy after contralateral cooling before and after intravenous therapy with 600 mg alpha-lipoic acid per day over 3 weeks. Cardiac autonomic neuropathy was excluded by beat-to-beat variation analysis. Symptoms of diabetic neuropathy were evaluated before and after therapy with the aid of the NSS and NDS. Capillary blood cell velocity (CBV) of the hand was determined before, during, and for the following 30 min after cooling (3 min at 15 degrees C) of the contralateral hand. Blood pressure, heart rate, and local skin temperature were monitored at 2-min intervals. ALA therapy resulted in a significant improvement of the microcirculatory response to cooling, as seen by an immediate decrease in CBV of 12. 3% (P < 0.02 vs before treatment), which was absent before therapy. Blood pressure, heart rate, and local skin temperature were not different between investigations. There was a significant improvement of the NSS after therapy (5.4 +/- 1.1 vs 8.6 +/- 1.1 points, P < 0.01). These results demonstrate that intravenous therapy with ALA has a positive influence on the impaired neurovascular reflex arc in patients with diabetic neuropathy. Copyright 1999 Academic Press. 34. Diabetes Care. 1999 Feb;22(2):280-7. alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, Tritschler HJ, Cobelli C, Usadel KH. Department of Internal Medicine, J.W. Goethe-University, Frankfurt, Germany. OBJECTIVE: We examined the effect of lipoic acid (LA), a cofactor of the pyruvate dehydrogenase complex (PDH), on insulin sensitivity (SI) and glucose effectiveness (SG) and on serum lactate and pyruvate levels after oral glucose tolerance tests (OGTTs) and modified frequently sampled intravenous glucose tolerance tests (FSIGTTs) in lean (n = 10) and obese (n = 10) patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: FSIGTT data were analyzed by minimal modeling technique to determine SI and SG before and after oral treatment (600 mg, twice a day, for 4 weeks). Serum lactate and pyruvate levels of diabetic patients after Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 523
glucose loading were compared with those of lean (n = 10) and obese (n = 10) healthy control subjects in which SI and SG were also determined from FSIGTT data. RESULTS: Fasting lactate and pyruvate levels were significantly increased in patients with type 2 diabetes. These metabolites did not exceed elevated fasting concentrations after glucose loading in lean patients with type 2 diabetes. However, a twofold increase of lactate and pyruvate levels was measured in obese diabetic patients. LA treatment was associated with increased SG in both diabetic groups (lean 1.28 +/- 0.14 to 1.93 +/- 0.13; obese 1.07 +/- 0.11 to 1.53 +/- 0.08 x 10(-2) min-1, P < 0.05). Higher SI and lower fasting glucose were measured in lean diabetic patients only (P < 0.05). Lactate and pyruvate before and after glucose loading were approximately 45% lower in lean and obese diabetic patients after LA treatment. CONCLUSIONS: Treatment of lean and obese diabetic patients with LA prevents hyperglycemia-induced increments of serum lactate and pyruvate levels and increases SG. 35. Diabetologia. 1999 Feb;42(2):222-32. Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kappaB. Hofmann MA, Schiekofer S, Isermann B, Kanitz M, Henkels M, Joswig M, Treusch A, Morcos M, Weiss T, Borcea V, Abdel Khalek AK, Amiral J, Tritschler H, Ritz E, Wahl P, Ziegler R, Bierhaus A, Nawroth PP. Department of Medicine, University of Heidelberg, Germany. Increased oxidative stress and subsequent activation of the transcription factor NF-kappaB has been linked to the development of late diabetic complications. To determine whether oxidative stress dependent NF-kappaB activation is evident in patients with diabetic nephropathy we used an Electrophoretic Mobility Shift Assay based semiquantitative detection system which enabled us to determine NF-kappaB activation in ex vivo isolated peripheral blood mononuclear cells. We examined 33 patients with diabetes mellitus (Type I and Type II). Patients with diabetic nephropathy showed higher NF-kappaB binding activity in Electrophoretic Mobility Shift Assays and stronger immunohistological staining for activated NFkappaBp65 than patients without renal complications. NF-kappaB binding activity correlated with the degree of albuminuria (r = 0.316) and with thrombomodulin plasma concentrations (r = 0.33), indicative for albuminuria associated endothelial dysfunction. In a 3 day intervention study in which 600 mg of the antioxidant thioctic acid (alpha-lipoic acid) per day were given to nine patients with diabetic nephropathy oxidative stress in plasma samples was decreased by 48% and NF-kappaB binding activity in ex vivo isolated peripheral blood mononuclear cells by 38%. In conclusion, activation of the transcription factor NF-kappaB in ex vivo isolated peripheral blood mononuclear cells of patients with diabetes mellitus correlates with the degree of diabetic nephropathy. NF-kappaB activation is at least in part dependent on oxidative stress since thioctic acid (alpha-lipoic acid) reduced NF-kappaB binding Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 524
activity. 36. Diabetes Metab. 1998 Nov;24 Suppl 3:79-83. Future prevention and treatment of diabetic neuropathy. Tomlinson DR. Department of Pharmacology, Queen Mary and Westfield College, London, UK. d.tomlinson@qmw.ac.uk This review orders the likely components of the pathogenesis of diabetic neuropathy into vertical (temporal) and horizontal dimensions. It is argued that the effects of hyperglycaemia are transduced to neuronal dysfunction via at least three secondary biochemical disturbances--the sorbitol (polyol) pathway, non-enzymatic glycation of proteins and oxidative stress--and that there are clear interactions between them. Because of these interactions, interference with one of these biochemical transducers could either worsen or attenuate the effects of the others. Examples of these alternatives are given. It is suggested that the prime goal for pharmacological intervention should be a combined attack on all three sources of disturbance. Interventions further on in the sequence of pathogenesis are also considered, and the arguments for the use of neurotrophic factors are persuasive because of their selectivity for different neuronal phenotypes, even though side-effects may be inevitable. Finally, a novel conjugate of gamma-linolenic acid and alpha-lipoic acid is considered as an agent with the potential to correct effects arising from more than one pathway of disorder in experimental diabetic neuropathy. The preliminary results with this agent have been encouraging. 37. Diabetes Care. 1998 Aug;21(8):1310-6. Insufficient glycemic control increases nuclear factor-kappa B binding activity in peripheral blood mononuclear cells isolated from patients with type 1 diabetes. Hofmann MA, Schiekofer S, Kanitz M, Klevesath MS, Joswig M, Lee V, Morcos M, Tritschler H, Ziegler R, Wahl P, Bierhaus A, Nawroth PP. Department of Medicine, University of Heidelberg, Germany. OBJECTIVE: The redox-sensitive transcription factor nuclear factor-kappa B (NF-kappa B) is believed to contribute to late diabetic complications. It is unknown whether NF-kappa B is influenced by glycemic control. RESEARCH DESIGN AND METHODS: To determine whether NF-kappa B is activated in patients with insufficient glycemic control (HbA1c > 10%), we developed a tissue culture-independent electrophoretic mobility shift assay (EMSA)-based semiquantitative detection system that allowed us to determine NF-kappa B activation in ex vivo-isolated peripheral blood mononuclear cells (PBMCs). We included 43 patients with type 1 diabetes in this cross-sectional study. 10 of those received the antioxidant thioctic acid (600 mg/day p.o.) for 2 weeks. RESULTS: Monocytes of patients with HbA1c levels > 10% demonstrated significantly higher NF-kappa B binding activity in an EMSA and a stronger Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 525
NF-kappa B staining in immunohistochemistry than monocytes of patients with HbA1c levels of 6-8%. The increase in NF-kappa B activation correlated with an increase in plasmatic markers of lipid peroxidation. Treatment with the antioxidant thioctic acid decreased NF-kappa B binding activity. CONCLUSIONS: Hyperglycemia induces activation of the transcription factor NF-kappa B in ex vivo-isolated PBMCs of patients with type 1 diabetes. NF-kappa B activation is at least partially dependent on oxidative stress, since the antioxidant thioctic acid significantly lowered the extent of NF-kappa B binding activity. 38. Diabetes. 1997 Sep;46(9):1481-90. Advanced glycation end product-induced activation of NF-kappaB is suppressed by alpha-lipoic acid in cultured endothelial cells. Bierhaus A, Chevion S, Chevion M, Hofmann M, Quehenberger P, Illmer T, Luther T, Berentshtein E, Tritschler H, Muller M, Wahl P, Ziegler R, Nawroth PP. Department of Internal Medicine, University of Heidelberg, Germany. Depletion of cellular antioxidant defense mechanisms and the generation of oxygen free radicals by advanced glycation end products (AGEs) have been proposed to play a major role in the pathogenesis of diabetic vascular complications. Here we demonstrate that incubation of cultured bovine aortic endothelial cells (BAECs) with AGE albumin (500 nmol/l) resulted in the impairment of reduced glutathione (GSH) and ascorbic acid levels. As a consequence, increased cellular oxidative stress led to the activation of the transcription factor NF-kappaB and thus promoted the upregulation of various NF-kappaB-controlled genes, including endothelial tissue factor. Supplementation of the cellular antioxidative defense with the natural occurring antioxidant alphalipoic acid before AGE albumin induction completely prevented the AGE albumindependent depletion of reduced glutathione and ascorbic acid. Electrophoretic mobility shift assays (EMSAs) revealed that AGE albumin-mediated NF-kappaB activation was also reduced in a time- and dose-dependent manner as long as alpha-lipoic acid was added at least 30 min before AGE albumin stimulation. Inhibition was not due to physical interactions with protein DNA binding, since alpha-lipoic acid, directly included into the binding reaction, did not prevent binding activity of recombinant NFkappaB. Western blots further demonstrated that alpha-lipoic acid inhibited the release and translocation of NF-kappaB from the cytoplasm into the nucleus. As a consequence, alpha-lipoic acid reduced AGE albumin-induced NF-kappaB mediated transcription and expression of endothelial genes relevant in diabetes, such as tissue factor and endothelin1. Thus, supplementation of cellular antioxidative defense mechanisms by extracellularly administered alpha-lipoic acid reduces AGE albumin-induced endothelial dysfunction in vitro. 39. Diabetes. 1997 Sep;46 Suppl 2:S62-6. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Ziegler D, Gries FA. Diabetes Research Institute at the Heinrich Heine University, Dusseldorf, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 526
Germany. Antioxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes, providing a rationale for a potential therapeutic value in diabetic patients. The effects of the antioxidant alpha-lipoic acid (thioctic acid) were studied in two multicenter, randomized, double-blind placebo-controlled trials. In the Alpha-Lipoic Acid in Diabetic Neuropathy Study, 328 patients with NIDDM and symptomatic peripheral neuropathy were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (ALA 1,200 mg; 600 mg; 100 mg) or placebo (PLAC) over 3 weeks. The total symptom score (TSS) (pain, burning, paresthesia, and numbness) in the feet decreased significantly from baseline to day 19 in ALA 1,200 and ALA 600 vs. PLAC. Each of the four individual symptom scores was significantly lower in ALA 600 than in PLAC after 19 days (all P < 0.05). The total scale of the Hamburg Pain Adjective List (HPAL) was significantly reduced in ALA 1,200 and ALA 600 compared with PLAC after 19 days (both P < 0.05). In the Deutsche Kardiale Autonome Neuropathie Studie, patients with NIDDM and cardiac autonomic neuropathy diagnosed by reduced heart rate variability were randomly assigned to treatment with a daily oral dose of 800 mg alphalipoic acid (ALA) (n = 39) or placebo (n = 34) for 4 months. Two out of four parameters of heart rate variability at rest were significantly improved in ALA compared with placebo. A trend toward a favorable effect of ALA was noted for the remaining two indexes. In both studies, no significant adverse events were observed. In conclusion, intravenous treatment with alpha-lipoic acid (600 mg/day) over 3 weeks is safe and effective in reducing symptoms of diabetic peripheral neuropathy, and oral treatment with 800 mg/day for 4 months may improve cardiac autonomic dysfunction in NIDDM. 40. Diabetes. 1997 Sep;46 Suppl 2:S38-42. The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy. Low PA, Nickander KK, Tritschler HJ. Department of Neurology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA. Oxidative stress is present in the diabetic state. Our work has focused on its presence in peripheral nerves. Antioxidant enzymes are reduced in peripheral nerves and are further reduced in diabetic nerves. That lipid peroxidation will cause neuropathy is supported by evidence of the development of neuropathy de novo when normal nerves are rendered alpha-tocopherol deficient and by the augmentation of the conduction deficit in diabetic nerves subjected to this insult. Oxidative stress appears to be primarily due to the processes of nerve ischemia and hyperglycemia auto-oxidation. The indexes of oxidative stress include an increase in nerve, dorsal root, and sympathetic ganglia lipid hydroperoxides and conjugated dienes. The most reliable and sensitive index, however, is a reduction in reduced glutathione. Experimental diabetic neuropathy Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 527
results in myelinopathy of dorsal roots and a vacuolar neuropathy of dorsal root ganglion. The vacuoles are mitochondrial; we posit that lipid peroxidation causes mitochondrial DNA mutations that increase reduced oxygen species, causing further damage to mitochondrial respiratory chain and function and resulting in a sensory neuropathy. Alpha-lipoic acid is a potent antioxidant that prevents lipid peroxidation in vitro and in vivo. We evaluated the efficacy of the drug in doses of 20, 50, and 100 mg/kg administered intraperitoneally in preventing the biochemical, electrophysiological, and nerve blood flow deficits in the peripheral nerves of experimental diabetic neuropathy. Alpha-lipoic acid dose- and time-dependently prevented the deficits in nerve conduction and nerve blood flow and biochemical abnormalities (reductions in reduced glutathione and lipid peroxidation). The nerve blood flow deficit was 50% (P < 0.001). Supplementation dose-dependently prevented the deficit; at the highest concentration, nerve blood flow was not different from that of control nerves. Digital nerve conduction underwent a dose-dependent improvement at 1 month (P < 0.05). By 3 months, all treated groups had lost their deficit. The antioxidant drug is potentially efficacious for human diabetic sensory neuropathy. 41. Metabolism. 1997 Jul;46(7):763-8. Lipoic acid reduces glycemia and increases muscle GLUT4 content in streptozotocin-diabetic rats. Khamaisi M, Potashnik R, Tirosh A, Demshchak E, Rudich A, Tritschler H, Wessel K, Bashan N. Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel. Alpha lipoic acid (lipoate [LA]), a cofactor of alpha-ketodehydrogenase, exhibits unique antioxidant properties. Recent studies suggest a direct effect of LA on glucose metabolism in both human and experimental diabetes. This study examines the possibility that LA positively affects glucose homeostasis in streptozotocin (STZ)-induced diabetic rats by altering skeletal muscle glucose utilization. Blood glucose concentration in STZ-diabetic rats following 10 days of intraperitoneal (i.p.) injection of LA 30 mg/kg was reduced compared with that in vehicle-treated diabetic rats (495 +/- 131 v 641 +/- 125 mg/dL in fed state, P = .003, and 189 +/- 48 v 341 +/- 36 mg/dL after 12-hour fast, P = .001). No effect of LA on plasma insulin was observed. Gastrocnemius muscle crude membrane GLUT4 protein was elevated both in control and in diabetic rats treated with LA by 1.5- and 2.8-fold, respectively, without significant changes in GLUT4 mRNA levels. Gastrocnemius lactic acid was increased in diabetic rats (19.9 +/- 5.5 v 10.4 +/- 2.8 mumol/g muscle, P < .05 v nondiabetic rats), and was normal in LA-treated diabetic rats (9.1 +/- 5.0 mumol/g muscle). Insulin-stimulated 2-deoxyglucose (2 DG) uptake into isolated soleus muscle was reduced in diabetic rats compared with the control group (474 +/- 15 v 568 +/52 pmol/mg muscle 30 min, respectively, P = .05). LA treatment prevented this reduction, resulting in insulin-stimulated glucose uptake comparable to that of nondiabetic animals. These results suggest that daily LA treatment may reduce blood glucose concentrations in STZ-diabetic rats by enhancing muscle GLUT4 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 528
protein content and by increasing muscle glucose utilization. 42. Diabetes Care. 1997 Mar;20(3):369-73. Comment in: Diabetes Care. 1997 Dec;20(12):1918-20. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Deutsche Kardiale Autonome Neuropathie. Ziegler D, Schatz H, Conrad F, Gries FA, Ulrich H, Reichel G. Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf, Germany. OBJECTIVE: To evaluate the efficacy and safety of oral treatment with the antioxidant alpha-lipoic acid (ALA) in NIDDM patients with cardiac autonomic neuropathy (CAN), assessed by heart rate variability (HRV). RESEARCH DESIGN AND METHODS: In a randomized, double-blind placebo-controlled multicenter trial (Deutsche Kardiale Autonome Neuropathie [DEKAN] Study), NIDDM patients with reduced HRV were randomly assigned to treatment with daily oral dose of 800 mgALA (n = 39) or placebo (n = 34) for 4 months. Parameters of HRV at rest included the coefficient of variation (CV), root mean square successive difference (RMSSD), and spectral power in the low-frequency (LF; 0.05-0.15 Hz) and high-frequency (HF; 0.150.5 Hz) bands. In addition, cardiovascular autonomic symptoms were assessed. RESULTS: Seventeen patients dropped out of the study (ALA n = 10; placebo n = 7). Mean blood pressure and HbA1 levels did not differ between the groups at baseline and during the study, but heart rate at baseline was higher in the group treated with ALA (P < 0.05). RMSSD increased from baseline to 4 months by 1.5 ms (-37.6 to 77.1) [median (minimum-maximum)] in the group given ALA and decreased by -0.1 ms (-19.2 to 32.8) in the placebo group (P < 0.05 for ALA vs. placebo). Power spectrum in the LF band increased by 0.06 bpm2 (-0. 09 to 0.62) in ALA, whereas it declined by -0.01 bpm2 (0.48 to 1.86) in placebo (P < 0.05 for ALA vs. placebo). Furthermore, there was a trend toward a favorable effect of ALA versus placebo for the CV and HF band power spectrum (P = 0.097 and P = 0.094 for ALA vs. placebo). The changes in cardiovascular autonomic symptoms did not differ significantly between the groups during the period studied. No differences between the groups were noted regarding the rates of adverse events. CONCLUSIONS: These findings suggest that treatment with ALA using a welltolerated oral dose of 800 mg/day for 4 months may slightly improve CAN in NIDDM patients. 43. Biochem Pharmacol. 1997 Feb 7;53(3):393-9. Modulation of cellular reducing equivalent homeostasis by alpha-lipoic acid. Mechanisms and implications for diabetes and ischemic injury. Roy S, Sen CK, Tritschler HJ, Packer L. Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, U.S.A. sashwati@violet.berkeley.edu The therapeutic potential of alpha-lipoic acid (thioctic acid) was evaluated Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 529
with respect to its influence on cellular reducing equivalent homeostasis. The requirement of NADH and NADPH as cofactors in the cellular reduction of alpha-lipoic acid to dihydrolipoate has been reported in various cells and tissues. However, there is no direct evidence describing the influence of such reduction of alpha-lipoate on the levels of cellular reducing equivalents and homeostasis of the NAD(P)H/NAD(P) ratio. Treatment of the human Wurzburg T-cell line with 0.5 mM alpha-lipoate for 24 hr resulted in a 30% decrease in cellular NADH levels. alpha-Lipoate treatment also decreased cellular NADPH, but this effect was relatively less and slower compared with that of NADH. A concentration-dependent increase in glucose uptake was observed in Wurzburg cells treated with alpha-lipoate. Parallel decreases (30%) in cellular NADH/NAD+ and in lactate/pyruvate ratios were observed in alpha-lipoate-treated cells. Such a decrease in the NADH/NAD+ ratio following treatment with alpha-lipoate may have direct implications in diabetes, ischemia-reperfusion injury, and other pathologies where reductive (high NADH/NAD+ ratio) and oxidant (excess reactive oxygen species) imbalances are considered as major factors contributing to metabolic disorders. Under conditions of reductive stress, alpha-lipoate decreases high NADH levels in the cell by utilizing it as a co-factor for its own reduction process, whereas in oxidative stress both alpha-lipoate and its reduced form, dihydrolipoate, may protect by direct scavenging of free radicals and recycling other antioxidants from their oxidized forms. 44, Free Radic Biol Med. 1997;22(1-2):359-78. Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Packer L, Tritschler HJ, Wessel K. Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA. Reactive oxygen species are thought to be involved in a number of types of acute and chronic pathologic conditions in the brain and neural tissue. The metabolic antioxidant alpha-lipoate (thioctic acid, 1, 2-dithiolane-3-pentanoic acid; 1, 2-dithiolane-3 valeric acid; and 6, 8-dithiooctanoic acid) is a low molecular weight substance that is absorbed from the diet and crosses the blood-brain barrier. alpha-Lipoate is taken up and reduced in cells and tissues to dihydrolipoate, which is also exported to the extracellular medium; hence, protection is afforded to both intracellular and extracellular environments. Both alpha-lipoate and especially dihydrolipoate have been shown to be potent antioxidants, to regenerate through redox cycling other antioxidants like vitamin C and vitamin E, and to raise intracellular glutathione levels. Thus, it would seem an ideal substance in the treatment of oxidative brain and neural disorders involving free radical processes. Examination of current research reveals protective effects of these compounds in cerebral ischemia-reperfusion, excitotoxic amino acid brain injury, mitochondrial dysfunction, diabetes and diabetic neuropathy, inborn errors of metabolism, and other causes of acute or chronic damage to brain or neural tissue. Very few neuropharmacological Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 530
intervention strategies are currently available for the treatment of stroke and numerous other brain disorders involving free radical injury. We propose that the various metabolic antioxidant properties of alpha-lipoate relate to its possible therapeutic roles in a variety of brain and neuronal tissue pathologies: thiols are central to antioxidant defense in brain and other tissues. The most important thiol antioxidant, glutathione, cannot be directly administered, whereas alpha-lipoic acid can. In vitro, animal, and preliminary human studies indicate that alpha-lipoate may be effective in numerous neurodegenerative disorders. 45. Exp Clin Endocrinol Diabetes. 1996;104(3):284-8. Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl, Germany. Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore, pharmacological intervention should aim to improve insulin sensitivity. Thioctic acid (TA), a naturally occurring compound, was shown to enhance glucose utilization in various experimental models after acute and chronic administration. It also increased insulin-stimulated glucose disposal in patients with NIDDM after acute administration. This pilot study was initiated to see whether this compound also augments glucose disposal in humans after repeated treatment. Twenty patients with NIDDM received TA (500 mg/ 500 ml NaCl, 0.9%) as daily infusions over a period of ten days. A hyperinsulinaemic, isoglycaemic glucose-clamp was done on day 0 and day 11. Parenteral administration of TA resulted in a significant increase of insulin-stimulated glucose-disposal by about 30% (metabolic clearance rate for glucose, 2.5 +/- 0.3 vs. 3.2 +/- 0.4 ml/kg/min and insulin-sensitivityindex: 3.5 +/- 0.5 vs. 4.7 +/- 0.4 mg/kg/microU/ml; p < 0.05, Wilcoxon-Rank-Sum-Test). There were no changes in fasting plasma levels for glucose or insulin; this can be explained, however, by the short period of treatment and observation. This is the first clinical study to show that a ten day administration of TA is able to improve resistance of insulin-stimulated glucose disposal in NIDDM. Experimental data suggest several mechanisms in the mode of action. As the present investigation was an uncontrolled pilot trial, the encouraging results call for controlled studies to further elucidate the clinical relevance of the findings and the mode of action of this compound. 46. Diabetologia. 1995 Dec;38(12):1425-33. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schutte K, Gries FA. Diabetes-Forschungsinstitut an der Heinrich-Heine-Universitat, Dusseldorf, Germany.
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Anti-oxidant treatment has been shown to prevent nerve dysfunction in experimental diabetes mellitus, thus providing a rationale of potential therapeutic value for diabetic patients. The effects of the anti-oxidant alpha-lipoic acid (thioctic acid) were studied in a 3-week multicentre, randomized, double-blind placebo-controlled trial (Alpha-Lipoic Acid in Diabetic Neuropathy; ALADIN) in 328 non-insulin-dependent diabetic patients with symptomatic peripheral neuropathy who were randomly assigned to treatment with intravenous infusion of alpha-lipoic acid using three doses (1200, 600, or 100 mg ALA) or placebo (PLAC). Neuropathic symptoms (pain, burning, paraesthesiae, and numbness) were scored at baseline and at each visit (days 2-5, 8-12, and 15-19) prior to infusion. In addition, the Hamburg Pain Adjective List, a multidimensional specific pain questionnaire, and the Neuropathy Symptom and Disability Scores were assessed at baseline and day 19. According to the protocol 260 (65/63/66/66) patients completed the study. The total symptom score in the feet decreased from baseline to day 19 by -4.5 +/- 3.7 (-58.6%) points (mean +/- SD) in ALA 1200, -5.0 +/- 4.1 (-63.5%) points in ALA 600, -3.3 +/- 2.8 (-43.2%) points in ALA 100, and -2.6 +/- 3.2 (-38.4%) points in PLAC (ALA 1200 vs PLAC: p = 0.003; ALA 600 vs PLAC: p < 0.001). The response rates after 19 days, defined as an improvement in the total symptom score of at least 30%, were 70.8% in ALA 1200, 82.5% in ALA 600, 65.2% in ALA 100, and 57.6% in PLAC (ALA 600 vs PLAC; p = 0.002). The total scale of the Pain Adjective List was significantly reduced in ALA 1200 and ALA 600 as compared with PLAC after 19 days (both p < 0.01). The rates of adverse events were 32.6% in ALA 1200, 18.2% in ALA 600, 13.6% in ALA 100, and 20.7% in PLAC. These findings substantiate that intravenous treatment with alpha-lipoic acid using a dose of 600 mg/day over 3 weeks is superior to placebo in reducing symptoms of diabetic peripheral neuropathy, without causing significant adverse reactions. 47. Arzneimittelforschung. 1995 Aug;45(8):872-4. Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ, Dietze GJ. Department of Internal Medicine, City Hospital, Baden-Baden, Germany. Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore pharmacological interventions should aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural occurring compound frequently used for treatment of diabetic polyneuropathy, enhances glucose utilization in various experimental models. To see whether this compound also augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 mg/Thioctacid/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were comparable in age, body-mass index and duration of diabetes and had a similar degree of insulin resistance at baseline. Acute parenteral administration of ALA resulted in a significant increase of insulin-stimulated glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 532
(3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p < 0.05), whereas the control group did not show any significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This is the first clinical study to show that alpha-lipoic acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of ALA and its potential use as an antihyperglycemic agent require further investigation. ________________________________________________________________ AGE-RELATED 48. Eur Neuropsychopharmacol. 2003 Aug;13(4):241-7. Effect of alpha lipoic acid on intracerebroventricular streptozotocin model of cognitive impairment in rats. Sharma M, Gupta YK. Neuropharmacology Laboratory, Department of Pharmacology, All India Institute of Medical Sciences, New Delhi 110029, India. In the present study, the effect of alpha lipoic acid, a potent free radical scavenger, was investigated against the intracerebroventricular streptozotocin model of cognitive impairment in rats, which is characterized by a progressive deterioration of memory, cerebral glucose and energy metabolism, and oxidative stress. Wistar rats were injected with intracerebroventricular streptozotocin bilaterally. The rats were treated chronically with alpha lipoic acid (50, 100 and 200 mg/kg) orally for 21 days starting from day 1 of streptozotocin injection in separate groups. The learning and memory behavior was evaluated and the rats were sacrificed for estimation of oxidative stress. The intracerebroventricular streptozotocin rats treated with alpha lipoic acid (200 mg/kg, p.o.) showed significantly less cognitive impairment as compared to the vehicle treated rats. There was also an insignificant increase in oxidative stress in the alpha lipoic acid treated groups. The study demonstrated the effectiveness of alpha lipoic acid in preventing cognitive impairment and oxidative stress induced by intracerebroventricular streptozotocin and its potential in dementia associated with age and age related neurodegenerative disorders where oxidative stress is involved such as Alzheimer's disease. 49. J Neurochem. 2003 Mar;84(5):1173-83. The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice. Farr SA, Poon HF, Dogrukol-Ak D, Drake J, Banks WA, Eyerman E, Butterfield DA, Morley JE. Geriatric Research Education and Clinical Center (GRECC), VA Medical Center (151/JC), 915 N. Grand Boulevard, St. Louis, MO 63109, USA. farrsa52@aol.com Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 533
SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants. 50. Exp Gerontol. 2002 Dec;37(12):1489-94. Neurochemical changes related to ageing in the rat brain and the effect of DL-alpha-lipoic acid. Arivazhagan P, Panneerselvam C. Department of Medical Biochemistry, Dr AL Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, India. Age-related impairments of cognitive and motor function have been linked to a number of deleterious morphological and functional changes involving different areas of the brain. Loss of neurotransmitters, their receptors and responsiveness to neurotransmitters are key manifestations of neurological ageing and age-related disorders. In the present investigation we have evaluated the effect of DL-alpha-lipoic acid on neurotransmitters in discrete brain regions of young and aged rats. The levels of neurotransmitters were found to be lowered in aged rats. Moreover, DL-alpha-lipoic acid treated aged rats showed a increase in the status of dopamine, serotonin and norepinephrine. The results of this study provide evidence that DL-alpha-lipoic acid (a potent antioxidant) treatment can improve neurotransmitters during ageing. Hence, it can be concluded that DL-alpha-lipoic acid act as a potent neuromodulator in the brain of aged rats. 51. Ann N Y Acad Sci. 2002 Apr;959:508-16. Can antioxidant diet supplementation protect against age-related mitochondrial damage? Miquel J. Department of Biotechnology, University of Alicante, E-03080 Alicante, Spain. Harman's free radical theory of aging and our electron-microscopic finding of an Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 534
age-related mitochondrial degeneration in the somatic tissues of the insect Drosophila melanogaster as well as in the fixed postmitotic Leydig and Sertoli cells of the mouse testis led us to propose a mitochondrial theory of aging, according to which metazoan senescence may be linked to oxygen stress-injury to the genome and membranes of the mitochondria of somatic differentiated cells. These concepts attract a great deal of attention, since, according to recent work, the mitochondrial damage caused by reactive oxygen species (ROS) and concomitant decline in ATP synthesis seem to play a key role not only in aging, but also in the fundamental cellular process of apoptosis. Although diet supplementation with antioxidants has not been able to increase consistently the species-characteristic maximum life span, it results in significant extension of the mean life span of laboratory animals. Moreover, diets containing high levels of antioxidants such as vitamins C and E seem able to reduce the risk of suffering age-related immune dysfunctions and arteriosclerosis. Presently, the focus of age-related antioxidant research is on compounds, such as deprenyl, coenzyme Q10, alpha-lipoic acid, and the glutathione-precursors thioproline and N-acetylcysteine, which may be able to neutralize the ROS at their sites of production in the mitochondria. Diet supplementation with these antioxidants may protect the mitochondria against respiration-linked oxygen stress, with preservation of the genomic and structural integrity of these energy-producing organelles and concomitant increase in functional life span. 52. Ann N Y Acad Sci. 2002 Apr;959:491-507. Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid. Hagen TM, Moreau R, Suh JH, Visioli F. Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, Oregon 97331, USA. tory.hagen@orst.edu Mitochondrial decay has been postulated to be a significant underlying part of the aging process. Decline in mitochondrial function may lead to cellular energy deficits, especially in times of greater energy demand, and compromise vital ATP-dependent cellular operations, including detoxification, repair systems, DNA replication, and osmotic balance. Mitochondrial decay may also lead to enhanced oxidant production and thus render the cell more prone to oxidative insult. In particular, the heart may be especially susceptible to mitochondrial dysfunction due to myocardial dependency on beta-oxidation of fatty acids for energy and the postmitotic nature of cardiac myocytes, which would allow for greater accumulation of mitochondrial mutations and deletions. Thus, maintenance of mitochondrial function may be important to maintain overall myocardial function. Herein, we review the major age-related changes that occur to mitochondria in the aging heart and the evidence that two such supplements, acetyl-l-carnitine (ALCAR) and (R)-alpha-lipoic acid, may improve myocardial bioenergetics and lower the increased oxidative stress associated with aging. We and others have shown that feeding old rats ALCAR reverses the age-related decline in carnitine levels and improves mitochondrial beta-oxidation in a number of tissues studied. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 535
However, ALCAR supplementation does not appear to reverse the age-related decline in cardiac antioxidant status and thus may not substantially alter indices of oxidative stress. Lipoic acid, a potent thiol antioxidant and mitochondrial metabolite, appears to increase low molecular weight antioxidant status and thereby decreases age-associated oxidative insult. Thus, ALCAR along with lipoic acid may be effective supplemental regimens to maintain myocardial function. 53. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1876-81. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184. Age-associated mitochondrial oxidative decay: improvement of carnitine acetyltransferase substrate-binding affinity and activity in brain by feeding old rats acetyl-L- carnitine and/or R-alpha -lipoic acid. Liu J, Killilea DW, Ames BN. Division of Biochemistry and Molecular Biology, University of California, Berkeley, CA 94720, USA. We test whether the dysfunction with age of carnitine acetyltransferase (CAT), a key mitochondrial enzyme for fuel utilization, is due to decreased binding affinity for substrate and whether this substrate, fed to old rats, restores CAT activity. The kinetics of CAT were analyzed by using the brains of young and old rats and of old rats supplemented for 7 weeks with the CAT substrate acetyl-l-carnitine (ALCAR) and/or the mitochondrial antioxidant precursor R-alpha-lipoic acid (LA). Old rats, compared with young rats, showed a decrease in CAT activity and in CAT-binding affinity for both substrates, ALCAR and CoA. Feeding ALCAR or ALCAR plus LA to old rats significantly restored CAT-binding affinity for ALCAR and CoA, and CAT activity. To explore the underlying mechanism, lipid peroxidation and total iron and copper levels were assayed; all increased in old rats. Feeding old rats LA or LA plus ALCAR inhibited lipid peroxidation but did not decrease iron and copper levels. Ex vivo oxidation of young-rat brain with Fe(II) caused loss of CAT activity and binding affinity. In vitro oxidation of purified CAT with Fe(II) inactivated the enzyme but did not alter binding affinity. However, in vitro treatment of CAT with the lipid peroxidation products malondialdehyde or 4-hydroxy-nonenal caused a decrease in CATbinding affinity and activity, thus mimicking age-related change. Preincubation of CAT with ALCAR or CoA prevented malondialdehyde-induced dysfunction. Thus, feeding old rats high levels of key mitochondrial metabolites can ameliorate oxidative damage, enzyme activity, substrate-binding affinity, and mitochondrial dysfunction. 54. Proc Natl Acad Sci U S A. 2002 Feb 19;99(4):1870-5. Erratum in: Proc Natl Acad Sci U S A 2002 May 14;99(10):7184. Feeding acetyl-L-carnitine and lipoic acid to old rats significantly improves metabolic function while decreasing oxidative stress.
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Hagen TM, Liu J, Lykkesfeldt J, Wehr CM, Ingersoll RT, Vinarsky V, Bartholomew JC, Ames BN. Department of Biochemistry and Biophysics, Linus Pauling Institute, Oregon State University, Corvallis, OR 97331, USA. Mitochondrial-supported bioenergetics decline and oxidative stress increases during aging. To address whether the dietary addition of acetyl-l-carnitine [ALCAR, 1.5% (wt/vol) in the drinking water] and/or (R)-alpha-lipoic acid [LA, 0.5% (wt/wt) in the chow] improved these endpoints, young (2-4 mo) and old (24-28 mo) F344 rats were supplemented for up to 1 mo before death and hepatocyte isolation. ALCAR+LA partially reversed the age-related decline in average mitochondrial membrane potential and significantly increased (P = 0.02) hepatocellular O(2) consumption, indicating that mitochondrial-supported cellular metabolism was markedly improved by this feeding regimen. ALCAR+LA also increased ambulatory activity in both young and old rats; moreover, the improvement was significantly greater (P = 0.03) in old versus young animals and also greater when compared with old rats fed ALCAR or LA alone. To determine whether ALCAR+LA also affected indices of oxidative stress, ascorbic acid and markers of lipid peroxidation (malondialdehyde) were monitored. The hepatocellular ascorbate level markedly declined with age (P = 0.003) but was restored to the level seen in young rats when ALCAR+LA was given. The level of malondialdehyde, which was significantly higher (P = 0.0001) in old versus young rats, also declined after ALCAR+LA supplementation and was not significantly different from that of young unsupplemented rats. Feeding ALCAR in combination with LA increased metabolism and lowered oxidative stress more than either compound alone. 55. Exp Gerontol. 2001 Dec;37(1):81-7. Effect of DL-alpha-lipoic acid on glutathione metabolic enzymes in aged rats. Arivazhagan P, Ramanathan K, Panneerselvam C. Department of Medical Biochemistry, Dr AL Mudaliar Post Graduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, 600 113, Chennai, India. palaniarivu@yahoo.com Ageing is characterized by a failure to maintain homeostasis under conditions of physiological stress, with an increasing susceptibility to disease and death. The accumulation of errors committed by faulty biochemical reactions over a vast period generates the cumulative effect observed during ageing. The most notable among the effects of ageing are the age-related disorders where free radicals are the major cause. When the level of free radicals increases because of diet, lifestyle, environment or other influences, it results in subsequent reduction of antioxidants. Reduced glutathione is one of the most fascinating molecules virtually present in all animal cells in often quite higher concentrations. An essential mechanism that accounts for most of the metabolic and cell regulatory properties of glutathione is the thiol disulfide exchange equilibria. We evaluated the age-associated alterations in glutathione dependent enzymes, glutathione and hydroxyl radicals in young and aged rats with respect to lipoate Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 537
supplementation. In aged rats, activities of glutathione peroxidase, glutathione reductase, glutathione-S-transferase and glucose-6-phosphate dehydrogenase and the level of glutathione were low, whereas the level of hydroxyl radical was higher than in the young ones. Administration of DL-alpha-lipoic acid, a thiol antioxidant intraperitoneally to the aged rats, led to a time-dependent reduction in hydroxyl radicals and elevation in the activities/level of glutathione systems. Hence it can be suggested that lipoate, a dithiol prevents the oxidation of reduced glutathione and protects its related enzymes from peroxidative damage. 56. FASEB J. 2001 Mar;15(3):700-6. Oxidative stress in the aging rat heart is reversed by dietary supplementation with (R)-(alpha)-lipoic acid. Suh JH, Shigeno ET, Morrow JD, Cox B, Rocha AE, Frei B, Hagen TM. Linus Pauling Institute, Department of Biochemistry, Oregon State University, Corvallis, Oregon 97331, USA. Oxidative stress has been implicated as a causal factor in the aging process of the heart and other tissues. To determine the extent of age-related myocardial oxidative stress, oxidant production, antioxidant status, and oxidative DNA damage were measured in hearts of young (2 months) and old (28 months) male Fischer 344 rats. Cardiac myocytes isolated from old rats showed a nearly threefold increase in the rate of oxidant production compared to young rats, as measured by the rates of 2,7-dichlorofluorescin diacetate oxidation. Determination of myocardial antioxidant status revealed a significant twofold decline in the levels of ascorbic acid (P = 0.03), but not alpha-tocopherol. A significant age-related increase (P = 0.05) in steady-state levels of oxidative DNA damage was observed, as monitored by 8-oxo-2'-deoxyguanosine levels. To investigate whether dietary supplementation with (R)-alpha-lipoic acid (LA) was effective at reducing oxidative stress, young and old rats were fed an AIN-93M diet with or without 0.2% (w/w) LA for 2 wk before death. Cardiac myocytes from old, LAsupplemented rats exhibited a markedly lower rate of oxidant production that was no longer significantly different from that in cells from unsupplemented, young rats. Lipoic acid supplementation also restored myocardial ascorbic acid levels and reduced oxidative DNA damage. Our data indicate that the aging rat heart is under increased mitochondrial-induced oxidative stress, which is significantly attenuated by lipoic acid supplementation. 57. Antioxid Redox Signal. 2000 Fall;2(3):473-83. (R)-alpha-lipoic acid reverses the age-associated increase in susceptibility of hepatocytes to tert-butylhydroperoxide both in vitro and in vivo. Hagen TM, Vinarsky V, Wehr CM, Ames BN. Department of Molecular and Cell Biology, University of California at Berkeley 94720, USA. Hepatocytes were isolated from young (3-5 months) and old (24-28 months) rats Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 538
and incubated with various concentrations of tert-butylhydroperoxide (t-BuOOH). The t-BuOOH concentration that killed 50% of cells (LC50) in 2 hr declined nearly two-fold from 721 +/- 32 microM in cells from young rats to 391 +/- 31 microM in cells from old rats. This increased sensitivity of hepatocytes from old rats may be due, in part, to changes in glutathione (GSH) levels, because total cellular and mitochondrial GSH were 37.7% and 58.3% lower, respectively, compared to cells from young rats. Cells from old animals were incubated with either (R)- or (S)-lipoic acid (100 microM) for 30 min prior to the addition of 300 microM t-BuOOH. The physiologically relevant (R)-form, a coenzyme in mitochondria, as opposed to the (S)-form significantly protected hepatocytes against t-BuOOH toxicity. Dietary supplementation of (R)-lipoic acid [0.5% (wt/wt)] for 2 weeks also completely reversed the age-related decline in hepatocellular GSH levels and the increased vulnerability to t-BuOOH as well. An identical supplemental diet fed to young rats did not enhance the resistance to t-BuOOH, indicating that antioxidant protection was already optimal in young rats. Thus, this study shows that cells from old animals are more susceptible to oxidant insult and (R)-lipoic acid, after reduction to an antioxidant in the mitochondria, effectively reverses this age-related increase in oxidant vulnerability. 58. Am J Otol. 2000 Mar;21(2):161-7. Biologic activity of mitochondrial metabolites on aging and age-related hearing loss. Seidman MD, Khan MJ, Bai U, Shirwany N, Quirk WS. Department of Otolaryngology Head & Neck Surgery, Henry Ford Health System, Detroit, Michigan 48323, USA. HYPOTHESIS: Compounds that upregulate mitochondrial function in an aging model will improve hearing and reduce some of the effects of aging. BACKGROUND: Reactive oxygen metabolites (ROM) are known products of oxidative metabolism and are continuously generated in vivo. More than 100 human clinical conditions have been associated with ROM, including atherosclerosis, arthritis, autoimmune diseases, cancers, heart disease, cerebrovascular accidents, and aging. The ROM are extremely reactive and cause extensive DNA, cellular, and tissue damage. Specific deletions within the mitochondrial DNA (mtDNA) occur with increasing frequency in age and presbyacusis. These deletions are the result of chronic exposure to ROM. When enough mtDNA damage accrues, the cell becomes bioenergetically deficient. This mechanism is the basis of the mitochondrial clock theory of aging, also known as the membrane hypothesis of aging. Nutritional compounds have been identified that enhance mitochondrial function and reverse several age-related processes. It is the purpose of this article to describe the effects of two mitochondrial metabolites, alpha-lipoic acid and acetyl L-carnitine, on the preservation of age-related hearing loss. METHODS: Twenty-one Fischer rats, aged 24 months, were divided into three groups: acetyl-1-carnitine, alpha-lipoic acid, and control. The subjects were orally supplemented with either a placebo or one of the two nutritional compounds for 6 weeks. Auditory brainstem response testing was used to obtain baseline and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 539
posttreatment hearing thresholds. Cochlear, brain, and skeletal muscle tissues were obtained to assess for mtDNA mutations. RESULTS: The control group demonstrated an expected age-associated threshold deterioration of 3 to 7 dB in the 6-week study. The treated subjects experienced a delay in progression of hearing loss. Acetyl-1-carnitine improved auditory thresholds during the same time period (p<0.05). The mtDNA deletions associated with aging and presbyacusis were reduced in the treated groups in comparison with controls. CONCLUSIONS:These results indicate that in the proposed decline in mitochondrial function with age, senescence may be delayed by treatment with mitochondrial metabolites. Acetyl-1carnitine and alpha-lipoic acid reduce age-associated deterioration in auditory sensitivity and improve cochlear function. This effect appears to be related to the mitochondrial metabolite ability to protect and repair age-induced cochlear mtDNA damage, thereby upregulating mitochondrial function and improving energy-producing capabilities. 59. Neurobiol Aging. 1999 Nov-Dec;20(6):655-64. Age-related changes in LTP and antioxidant defenses are reversed by an alpha-lipoic acid-enriched diet. McGahon BM, Martin DS, Horrobin DF, Lynch MA. Department of Physiology, Trinity College, Dublin, Ireland. Among the age-related changes identified in rat hippocampus are impairments in LTP and glutamate release. These deficits have been coupled with decreased arachidonic acid concentration. In this study we compared LTP and glutamate release in groups of aged and young rats fed for 8 weeks on a control diet or on a diet enriched in alpha-lipoic acid. Dietary supplementation in aged rats restored hippocampal arachidonic acid concentration to levels observed in tissue prepared from young rats. We observed that aged rats that received the experimental diet sustained LTP in perforant path-granule cell synapses in a manner indistinguishable from young rats whereas the age-related impairment in glutamate release was reversed in synaptosomes prepared from dentate gyrus obtained from these rats. The evidence presented supports the hypothesis that the alpha-lipoic acid-enriched diet has antioxidant properties, because the age-related increase in superoxide dismutase activity and decrease in alpha-tocopherol concentration were reversed. The finding that the age-related increase in interleukin-1 (IL-1)beta concentration was also reversed suggests a possible role for this cytokine in ageing. 60. FASEB J. 1999 Feb;13(2):411-8. (R)-alpha-lipoic acid-supplemented old rats have improved mitochondrial function, decreased oxidative damage, and increased metabolic rate. Hagen TM, Ingersoll RT, Lykkesfeldt J, Liu J, Wehr CM, Vinarsky V, Bartholomew JC, Ames AB. Department of Molecular and Cell Biology, University of California at Berkeley, Berkeley, California 94720, USA. A diet supplemented with (R)-lipoic acid, a mitochondrial coenzyme, was fed to Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 540
old rats to determine its efficacy in reversing the decline in metabolism seen with age. Young (3 to 5 months) and old (24 to 26 months) rats were fed an AIN-93M diet with or without (R)-lipoic acid (0.5% w/w) for 2 wk, killed, and their liver parenchymal cells were isolated. Hepatocytes from untreated old rats vs. young controls had significantly lower oxygen consumption (P<0. 03) and mitochondrial membrane potential. (R)-Lipoic acid supplementation reversed the age-related decline in O2 consumption and increased (P<0.03) mitochondrial membrane potential. Ambulatory activity, a measure of general metabolic activity, was almost threefold lower in untreated old rats vs. controls, but this decline was reversed (P<0.005) in old rats fed (R)-lipoic acid. The increase of oxidants with age, as measured by the fluorescence produced on oxidizing 2',7'-dichlorofluorescin, was significantly lowered in (R)-lipoic acid supplemented old rats (P<0.01). Malondialdehyde (MDA) levels, an indicator of lipid peroxidation, were increased fivefold with age in cells from unsupplemented rats. Feeding rats the (R)-lipoic acid diet reduced MDA levels markedly (P<0.01). Both glutathione and ascorbic acid levels declined in hepatocytes with age, but their loss was completely reversed with (R)-lipoic acid supplementation. Thus, (R)-lipoic acid supplementation improves indices of metabolic activity as well as lowers oxidative stress and damage evident in aging. 61. Pharmacol Biochem Behav. 1993 Dec;46(4):799-805. The potent free radical scavenger alpha-lipoic acid improves memory in aged mice: putative relationship to NMDA receptor deficits. Stoll S, Hartmann H, Cohen SA, Muller WE. Central Institute for Mental Health, Department of Psychopharmacology, Mannheim, Germany. alpha-Lipoic acid (alpha-LA) improved longer-term memory of aged female NMRI mice in the habituation in the open field test at a dose of 100 mg/kg body weight for 15 days. In a separate experiment, no such effect could be found for young mice. alpha-LA alleviated age-related NMDA receptor deficits (Bmax) without changing muscarinic, benzodiazepine, and alpha 2-adrenergic receptor deficits in aged mice. The carbachol-stimulated accumulation of inositol monophosphates was not changed by the treatment with alpha-LA. These results give tentative support to the hypothesis that alpha-LA improves memory in aged mice, probably by a partial compensation of NMDA receptor deficits. Possible modes of action of alpha-LA based on its free radical scavenger properties are discussed in relation to the membrane hypothesis of aging. ___________________________________________________________ 62. Arzneimittelforschung 1995 Aug;45(8):872-4 Enhancement of glucose disposal in patients with type 2 diabetes by alpha-lipoic acid. Jacob S, Henriksen EJ, Schiemann AL, Simon I, Clancy DE, Tritschler HJ, Jung WI, Augustin HJ, Dietze GJ. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 541
Department of Internal Medicine, City Hospital, Baden-Baden, Germany. Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Type II diabetes (NIDDM); therefore pharmacological interventions should aim to improve insulin sensitivity. Alpha-lipoic acid (CAS 62-46-4, thioctic acid, ALA), a natural occurring compound frequently used for treatment of diabetic polyneuropathy, enhances glucose utilization in various experimental models. To see whether this compound also augments insulin mediated glucose disposal in NIDDM, 13 patients received either ALA (1000 mg/Thioctacid/500 ml NaCl, n = 7) or vehicle only (500 ml NaCl, n = 6) during a glucose-clamp study. Both groups were comparable in age, body-mass index and duration of diabetes and had a similar degree of insulin resistance at baseline. Acute parenteral administration of ALA resulted in a significant increase of insulin-stimulated glucose disposal; metabolic clearance rate (MCR) for glucose rose by about 50% (3.76 ml/kg/min = pre vs. 5.82 ml/kg/min = post, p < 0.05), whereas the control group did not show any significant change (3.57 ml/kg/min = pre vs. 3.91 ml/kg/min = post). This is the first clinical study to show that alpha-lipoic acid increases insulin stimulated glucose disposal in NIDDM. The mode of action of ALA and its potential use as an antihyperglycemic agent require further investigation. 63. Diabetes 1996 Aug;45(8):1024-9 The antioxidant alpha-lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle. Jacob S, Streeper RS, Fogt DL, Hokama JY, Tritschler HJ, Dietze GJ, Henriksen EJ. Department of Physiology, University of Arizona College of Medicine, Tucson, USA. Insulin resistance of muscle glucose metabolism is a hallmark of NIDDM. The obese Zucker (fa/fa) rat--an animal model of muscle insulin resistance--was used to test whether acute (100 mg/kg body wt for 1 h) and chronic (5-100 mg/kg for 10 days) parenteral treatments with a racemic mixture of the antioxidant alpha-lipoic acid (ALA) could improve glucose metabolism in insulin-resistant skeletal muscle. Glucose transport activity (assessed by net 2-deoxyglucose [2-DG] uptake), net glycogen synthesis, and glucose oxidation were determined in the isolated epitrochlearis muscles in the absence or presence of insulin (13.3 nmol/l). Severe insulin resistance of 2-DG uptake, glycogen synthesis, and glucose oxidation was observed in muscle from the vehicle-treated obese rats compared with muscle from vehicle-treated lean (Fa/-) rats. Acute and chronic treatments (30 mg.kg-1.day-1, a maximally effective dose) with ALA significantly (P < 0.05) improved insulin-mediated 2-DG uptake in epitrochlearis muscles from the obese rats by 62 and 64%, respectively. Chronic ALA treatment increased both insulin-stimulated glucose oxidation (33%) and glycogen synthesis (38%) and was associated with a significantly greater (21%) in vivo muscle glycogen concentration. These adaptive responses after chronic ALA administration were also associated with significantly lower (15-17%) plasma levels of insulin and free fatty acids. No significant effects on glucose transporter (GLUT4) protein level or on the activities of hexokinase and citrate synthase were observed. Collectively, these findings indicate that parenteral administration of the antioxidant ALA significantly enhances the capacity of the insulinCopyright Gary Null & Associates, Inc., 2005 All Rights Reserved 542
stimulatable glucose transport system and of both oxidative and nonoxidative pathways of glucose metabolism in insulin-resistant rat skeletal muscle. 64. Am J Physiol 1997 Jul;273(1 Pt 1):E185-91 Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. Streeper RS, Henriksen EJ, Jacob S, Hokama JY, Fogt DL, Tritschler HJ. Department of Physiology, University of Arizona, Tucson 85721-0093, USA. The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulinstimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer. 65. Free Radic Biol Med 2000 Dec;29(11):1122-8 Lipoic acid decreases lipid peroxidation and protein glycosylation and increases (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-treated human erythrocytes. Jain SK, Lim G. Department of Pediatrics, Louisiana State University Health Sciences Center, Shreveport, LA 71130, USA. sjain@lsuhsc.edu Lipoic acid supplementation has been found to be beneficial in preventing neurovascular abnormalities in diabetic neuropathy. Insufficient (Na(+) + K(+))-ATPase activity has been suggested as a contributing factor in the development of diabetic neuropathy. This study was undertaken to test the hypothesis that lipoic acid reduces lipid peroxidation and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 543
glycosylation and can increase the (Na(+) + K(+))- and Ca(++)-ATPase activities in high glucose-exposed red blood cells (RBC). Washed normal human RBC were treated with normal (6 mM) and high glucose concentrations (45 mM) with 0-0.2 mM lipoic acid (mixture of S and R sterioisomers) in a shaking water bath at 37 degrees C for 24 h. There was a significant stimulation of glucose consumption by RBC in the presence of lipoic acid both in normal and high glucose-treated RBC. Lipoic acid significantly lowered the level of glycated hemoglobin (GHb) and lipid peroxidation in RBC exposed to high glucose concentrations. High glucose treatment significantly lowered the activities of (Na(+) + K(+))- and Ca(++)-ATPases of RBC membranes. Lipoic acid addition significantly blocked the reduction in activities of (Na(+) + K(+))and Ca(++)-ATPases in high glucose- treated RBC. There were no differences in lipid peroxidation, GHb and (Na(+) + K(+))- and Ca(++)-ATPase activity levels in normal glucose-treated RBC with and without lipoic acid. Thus, lipoic acid can lower lipid peroxidation and protein glycosylation, and increase (Na(+) + K(+))- and Ca(++)-ATPase activities in high-glucose exposed RBC, which provides a potential mechanism by which lipoic acid may delay or inhibit the development of neuropathy in diabetes. 66. Free Radic Biol Med 1999 Aug;27(3-4):309-14 Oral administration of RAC-alpha-lipoic acid modulates insulin sensitivity in patients with type-2 diabetes mellitus: a placebo-controlled pilot trial. Jacob S, Ruus P, Hermann R, Tritschler HJ, Maerker E, Renn W, Augustin HJ, Dietze GJ, Rett K. Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl and City Hospital, Baden-Baden, Germany. snjacob@med.uni-tuebingen.de Alpha-lipoic acid (ALA), a naturally occuring compound and a radical scavenger was shown to enhance glucose transport and utilization in different experimental and animal models. Clinical studies described an increase of insulin sensitivity after acute and short-term (10 d) parenteral administration of ALA. The effects of a 4-week oral treatment with alpha-lipoic acid were evaluated in a placebo-controlled, multicenter pilot study to determine see whether oral treatment also improves insulin sensitivity. Seventy-four patients with type-2 diabetes were randomized to either placebo (n = 19); or active treatment in various doses of 600 mg once daily (n = 19), twice daily (1200 mg; n = 18), or thrice daily (1800 mg; n = 18) alpha-lipoic acid. An isoglycemic glucose-clamp was done on days 0 (pre) and 29 (post). In this explorative study, analysis was done according to the number of subjects showing an improvement of insulin sensitivity after treatment. Furthermore, the effects of active vs. placebo treatment on insulin sensitivity was compared. All four groups were comparable and had a similar degree of hyperglycemia and insulin sensitivity at baseline. When compared to placebo, significantly more subjects had an increase in insulin-stimulated glucose disposal (MCR) after ALA treatment in each group. As there was no dose effect seen in the three different alpha-lipoic acid groups, all subjects receiving ALA were combined in the "active" group and then compared to placebo. This revealed significantly different changes in MCR after treatment (+27% vs. placebo; p < .01). This placebo-controlled explorative study confirms Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 544
previous observations of an increase of insulin sensitivity in type-2 diabetes after acute and chronic intravenous administration of ALA. The results suggest that oral administration of alpha-lipoic acid can improve insulin sensitivity in patients with type-2 diabetes. The encouraging findings of this pilot trial need to be substantiated by further investigations. 67. Diabetes Care 1999 Feb;22(2):280-7 alpha-Lipoic acid treatment decreases serum lactate and pyruvate concentrations and improves glucose effectiveness in lean and obese patients with type 2 diabetes. Konrad T, Vicini P, Kusterer K, Hoflich A, Assadkhani A, Bohles HJ, Sewell A, Tritschler HJ, Cobelli C, Usadel KH. Department of Internal Medicine, J.W. Goethe-University, Frankfurt, Germany. OBJECTIVE: We examined the effect of lipoic acid (LA), a cofactor of the pyruvate dehydrogenase complex (PDH), on insulin sensitivity (SI) and glucose effectiveness (SG) and on serum lactate and pyruvate levels after oral glucose tolerance tests (OGTTs) and modified frequently sampled intravenous glucose tolerance tests (FSIGTTs) in lean (n = 10) and obese (n = 10) patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: FSIGTT data were analyzed by minimal modeling technique to determine SI and SG before and after oral treatment (600 mg, twice a day, for 4 weeks). Serum lactate and pyruvate levels of diabetic patients after glucose loading were compared with those of lean (n = 10) and obese (n = 10) healthy control subjects in which SI and SG were also determined from FSIGTT data. RESULTS: Fasting lactate and pyruvate levels were significantly increased in patients with type 2 diabetes. These metabolites did not exceed elevated fasting concentrations after glucose loading in lean patients with type 2 diabetes. However, a twofold increase of lactate and pyruvate levels was measured in obese diabetic patients. LA treatment was associated with increased SG in both diabetic groups (lean 1.28 +/- 0.14 to 1.93 +/- 0.13; obese 1.07 +/- 0.11 to 1.53 +/- 0.08 x 10(-2) min-1, P < 0.05). Higher SI and lower fasting glucose were measured in lean diabetic patients only (P < 0.05). Lactate and pyruvate before and after glucose loading were approximately 45% lower in lean and obese diabetic patients after LA treatment. CONCLUSIONS: Treatment of lean and obese diabetic patients with LA prevents hyperglycemia-induced increments of serum lactate and pyruvate levels and increases SG. 68. Exp Clin Endocrinol Diabetes 1996;104(3):284-8 Improvement of insulin-stimulated glucose-disposal in type 2 diabetes after repeated parenteral administration of thioctic acid. Jacob S, Henriksen EJ, Tritschler HJ, Augustin HJ, Dietze GJ. Hypertension and Diabetes Research Unit, Max Grundig Clinic, Buhl, Germany. Insulin resistance of skeletal muscle glucose uptake is a prominent feature of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 545
Type II diabetes (NIDDM); therefore, pharmacological intervention should aim to improve insulin sensitivity. Thioctic acid (TA), a naturally occurring compound, was shown to enhance glucose utilization in various experimental models after acute and chronic administration. It also increased insulin-stimulated glucose disposal in patients with NIDDM after acute administration. This pilot study was initiated to see whether this compound also augments glucose disposal in humans after repeated treatment. Twenty patients with NIDDM received TA (500 mg/ 500 ml NaCl, 0.9%) as daily infusions over a period of ten days. A hyperinsulinaemic, isoglycaemic glucose-clamp was done on day 0 and day 11. Parenteral administration of TA resulted in a significant increase of insulin-stimulated glucose-disposal by about 30% (metabolic clearance rate for glucose, 2.5 +/- 0.3 vs. 3.2 +/- 0.4 ml/kg/min and insulin-sensitivity-index: 3.5 +/- 0.5 vs. 4.7 +/0.4 mg/kg/microU/ml; p < 0.05, Wilcoxon-Rank-Sum-Test). There were no changes in fasting plasma levels for glucose or insulin; this can be explained, however, by the short period of treatment and observation. This is the first clinical study to show that a ten day administration of TA is able to improve resistance of insulin-stimulated glucose disposal in NIDDM. Experimental data suggest several mechanisms in the mode of action. As the present investigation was an uncontrolled pilot trial, the encouraging results call for controlled studies to further elucidate the clinical relevance of the findings and the mode of action of this compound.
69. Protection against oxidative stress-induced insulin resistance in rat L6 muscle cells by mircomolar concentrations of alpha-lipoic acid. Maddux BA, See W, Lawrence JC Jr, Goldfine AL, Goldfine ID, Evans JL. Diabetes Research Laboratory, Mount Zion Hospital, San Francisco, California 94143-1616, USA. bmaddux@itsa.ucsf.edu Diabetes. 2001 Feb;50(2):404-10. Free Full Text Article Here http://diabetes.diabetesjournals.org/cgi/content/full/50/2/404 In diabetic patients, alpha-lipoic acid (LA) improves skeletal muscle glucose transport, resulting in increased glucose disposal; however, the molecular mechanism of action of LA is presently unknown. We studied the effects of LA on basal and insulin-stimulated glucose transport in cultured rat L6 muscle cells that overexpress GLUT4. When 2-deoxy-D-glucose uptake was measured in these cells, they were more sensitive and responsive to insulin than wild-type L6 cells. LA, at concentrations < or = 1 mmol/l, had only small effects on glucose transport in cells not exposed to oxidative stress. When cells were exposed to glucose oxidase and glucose to generate H2O2 and cause oxidative stress, there was a marked decrease in insulinstimulated glucose transport. Pretreatment with LA over the concentration range of 10-1,000 pmol/l protected the insulin effect from inhibition by H2O2. Both the R and S isomers of LA were equally effective. In addition, oxidative stress caused a significant decrease (approximately 50%) in reduced glutathione concentration, along with the rapid activation of the stress-sensitive p38 mitogen-activated protein kinase. Pretreatment with LA prevented both of these events, coincident with protecting insulin action. These studies indicate that in muscle, the major site of insulin-stimulated glucose disposal, one important effect of LA on the insulin-signaling cascade is to protect cells from oxidative stress-induced insulin resistance. 70. Cataract development in diabetic sand rats treated with alpha-lipoic acid and its gamma-linolenic acid conjugate. Borenshtein D, Ofri R, Werman M, Stark A, Tritschler HJ, Moeller W, Madar Z.
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Faculty of Agricultural, Food and Environmental Quality Sciences, The Hebrew University of Jerusalem, Rehovot 76100, Israel. Diabetes Metab Res Rev. 2001 Jan-Feb;17(1):44-50. BACKGROUND: Diabetes commonly leads to long-term complications such as cataract. This study investigated the effects of alpha-lipoic acid (LPA) and its gamma-linolenic acid (GLA) conjugate on cataract development in diabetic sand rats. METHODS: Two separate experiments were conducted. In Experiment 1, sand rats were fed a "highenergy" diet (70% starch), an acute model of Type 2 diabetes, and injected with LPA. In Experiment 2, the animals received a "medium-energy" diet (59% starch), a chronic diabetic model, and were intubated with LPA or its GLA conjugate. Throughout the experiments, blood glucose levels and cataract development were measured. At the termination of the experiments, lens aldose reductase (AR) activity and lenticular reduced glutathione (GSH) levels were analyzed. RESULTS: LPA injection significantly inhibited cataract development and reduced blood glucose levels in rats fed the "high-energy" diet. Lens AR activity tended to be lower, while lenticular GSH levels increased. In sand rats fed a "medium-energy" diet (59% starch), LPA intubation had no effect on blood glucose levels and cataract development but GSH levels were increased. In contrast, sand rats intubated with GLA conjugate showed the highest blood glucose levels and accelerated cataract development. The conjugate treatment also decreased lenticular GSH content. CONCLUSIONS: The hypoglycemic effects of LPA are beneficial in the prevention of acute symptoms of Type 2 diabetes. It remains to be shown that the antioxidant activity of LPA is responsible for prevention or inhibition of cataract progression in sand rats. Copyright 2000 John Wiley & Sons, Ltd.
Mixed Tocopherols - 398 Studies

1. Am J Clin Nutr. 2005 Feb;81(2):508-14. Relation of the tocopherol forms to incident Alzheimer disease and to cognitive change. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS, Aggarwal NT, Scherr PA. Rush Institute for Healthy Aging, Rush University Medical Center, Chicago, IL 60612, USA. martha_c_morris@rush.edu BACKGROUND: High intake of vitamin E from food (tocopherol), but not from supplements (which usually contain alpha-tocopherol), is inversely associated with Alzheimer disease. OBJECTIVE: We examined whether food intakes of vitamin E, alpha-tocopherol equivalents (a measure of the relative biologic activity of tocopherols and tocotrienols), or individual tocopherols would protect against incident Alzheimer disease and cognitive decline over 6 y in participants of the Chicago Health and Aging Project. DESIGN: The 1993-2002 study of community residents aged >or=65 y included the administration of 4 cognitive tests and clinical evaluations for Alzheimer disease. Dietary assessment was by food-frequency questionnaire. RESULTS: Tocopherol intake from food was related to the 4-y incidence of Alzheimer disease determined by logistic regression in 1041 participants who were clinically evaluated (n=162 incident cases) and to change in a global cognitive score determined by mixed models in 3718 participants. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 547
Higher intakes of vitamin E (relative risk: 0.74 per 5 mg/d increase; 95% CI: 0.62, 0.88) and alpha-tocopherol equivalents (relative risk: 0.56 per 5 mg/d increase; 95% CI: 0.32, 0.98) were associated with a reduced incidence of Alzheimer disease in separate multiple-adjusted models that included intakes of saturated and trans fats and docosahexaenoic acid. alpha- and gamma-Tocopherol had independent associations. In separate mixed models, a slower rate of cognitive decline was associated with intakes of vitamin E, alpha-tocopherol equivalents, and alpha- and gamma-tocopherols. CONCLUSION: The results suggest that various tocopherol forms rather than alphatocopherol alone may be important in the vitamin E protective association with Alzheimer disease. PMID: 15699242 [PubMed - indexed for MEDLINE] 2. Am J Clin Nutr. 2003 Apr;77(4):975-84. High-dose antioxidant supplements and cognitive function in community-dwelling elderly women. Grodstein F, Chen J, Willett WC. Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. fran.grodstein@channing.harvard.edu BACKGROUND: telephone tests of cognitive function [Telephone Interview of Cognitive Status (TICS), delayed recall of the TICS 10-word list, immediate and delayed recall of a short paragraph, a test of verbal fluency, and a digit span backwards test] were administered to the women, who were 70-79 y of age at that time. We used linear and logistic regression models to calculate multivariate-adjusted mean differences in test scores and relative risks of a low score for specific supplement users compared with nonusers. RESULTS: Long-term, current users of vitamin E with vitamin C had significantly better mean performance, as judged by a global score that combined individual test scores, than did women who had never used vitamin E or C (P = 0.03); there was a trend for increasingly higher mean scores with increasing durations of use (P = 0.04). These associations were strongest among women with low dietary intakes of alpha-tocopherol. Benefits were less consistent for women taking vitamin E alone, with no evidence of higher scores with longer durations of use. Use of specific vitamin C supplements alone had little relation to performance on our cognitive tests. CONCLUSION: The use of specific vitamin E supplements, but not specific vitamin C supplements, may be related to modest cognitive benefits in older women. PMID: 12663300 [PubMed - indexed for MEDLINE] 3. JAMA. 2002 Jun 26;287(24):3223-9. Dietary intake of antioxidants and risk of Alzheimer disease. Engelhart MJ, Geerlings MI, Ruitenberg A, van Swieten JC, Hofman A, Witteman JC, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 548
Breteler MM. Department of Epidemiology and Biostatistics, Erasmus Medical Center, 3000 DR Rotterdam, The Netherlands. CONTEXT: Laboratory findings have suggested that oxidative stress may contribute to the pathogenesis of Alzheimer disease. Therefore, the risk of Alzheimer disease might be reduced by intake of antioxidants that counteract the detrimental effects of oxidative stress. OBJECTIVE: To determine whether dietary intake of antioxidants is related to risk of Alzheimer disease. DESIGN AND SETTING: The Rotterdam Study, a population-based, prospective cohort study conducted in the Netherlands. PARTICIPANTS: A total of 5395 participants who, at baseline (1990-1993), were aged at least 55 years, free of dementia, and noninstitutionalized and had reliable dietary assessment. Participants were reexamined in 1993-1994 and 1997-1999 and were continuously monitored for incident dementia. MAIN OUTCOME MEASURES: Incidence of Alzheimer disease, based on Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition (DSM-III-R) criteria and National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) criteria, associated with dietary intake of beta carotene, flavonoids, vitamin C, and vitamin E. RESULTS: After a mean follow-up of 6 years, 197 participants developed dementia, of whom 146 had Alzheimer disease. When adjustments were made for age, sex, baseline Mini-Mental State Examination score, alcohol intake, education, smoking habits, pack-years of smoking, body mass index, total energy intake, presence of carotid plaques, and use of antioxidative supplements, high intake of vitamin C and vitamin E was associated with lower risk of Alzheimer disease (rate ratios [RRs] per 1-SD increase in intake were 0.82 [95% confidence interval [CI], 0.68-0.99] and 0.82 [95% CI, 0.66-1.00], respectively). Among current smokers, this relationship was most pronounced (RRs, 0.65 [95% CI, 0.37-1.14] and 0.58 [95% CI, 0.30-1.12], respectively) and also was present for intake of beta carotene (RR, 0.49 [95% CI, 0.27-0.92]) and flavonoids (RR, 0.54 [95% CI, 0.310.96]). The associations did not vary by education or apolipoprotein E genotype. CONCLUSION: High dietary intake of vitamin C and vitamin E may lower the risk of Alzheimer disease. 4. Arch Neurol. 2002 Jul;59(7):1125-32. Vitamin E and cognitive decline in older persons. Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Department of Preventive medicine, Rush Institute for Healthy Aging, RushPresbyterian-St Luke's Medical Center, 1645 W Jackson, Suite 675, Chicago, IL 60612, USA. mmorris@rush.edu BACKGROUND: Previous studies raise the possibility that antioxidants protect against neurodegenerative diseases. OBJECTIVE: To examine whether intake of antioxidant nutrients, including vitamin E, vitamin C, and carotene, is associated with reduced Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 549
cognitive decline with age. DESIGN: Longitudinal population-based study conducted from September 17, 1993, to November 20, 2000, with an average follow-up of 3.2 years. PATIENTS: The patients were 2889 community residents, aged 65 to 102 years, who completed a food frequency questionnaire, on average 18 months after baseline. MAIN OUTCOME MEASURE: Cognitive change as measured by 4 tests (the East Boston Memory Test, which tests immediate and delayed recall; the Mini-Mental State Examination; and the Symbol Digit Modalities Test) at baseline and 3 years for all participants, and at 6 months for 288 randomly selected participants. RESULTS: We used random-effects models to estimate nutrient effects on individual change in the average score of the 4 cognitive tests. The cognitive score declined on average by 5.0 x 10(-2) standardized units per year. There was a 36% reduction in the rate of decline among persons in the highest quintile of total vitamin E intake (-4.3 x 10(-2) standardized units per year) compared with those in the lowest quintile (-6.7 x 10(-2) standardized units per year) (P =.05), in a model adjusted for age, race, sex, educational level, current smoking, alcohol consumption, total calorie (energy) intake, and total intakes of vitamin C, carotene, and vitamin A. We also observed a reduced decline with higher vitamin E intake from foods (P =.03 for trend). There was little evidence of association with vitamin C or carotene intake. CONCLUSION: Vitamin E intake, from foods or supplements, is associated with less cognitive decline with age. 5. Mixed Tocopherols (Vitamin E)
1: Taylor PR, Qiao YL, Abnet CC, Dawsey SM, Yang CS, Gunter EW, Wang W, Blot WJ, Dong ZW, Mark SD. Prospective study of serum vitamin E levels and esophageal and gastric cancers. J Natl Cancer Inst. 2003 Sep 17;95(18):1414-6. PMID: 13130117 2: Engler MM, Engler MB, Malloy MJ, Chiu EY, Schloetter MC, Paul SM, Stuehlinger M, Lin KY, Cooke JP, Morrow JD, Ridker PM, Rifai N, Miller E, Witztum JL, Mietus-Snyder M. Antioxidant vitamins C and E improve endothelial function in children with hyperlipidemia: Endothelial Assessment of Risk from Lipids in Youth (EARLY) Trial. Circulation. 2003 Sep 2;108(9):1059-63. Epub 2003 Aug 11. PMID: 12912807 3: Kugelmas M, Hill DB, Vivian B, Marsano L, McClain CJ. Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Hepatology. 2003 Aug;38(2):413-9. PMID: 12883485 4: Miller RR Jr, Olson BM, Rorick N, Wittingen AL, Bullock M. Embryonic exposure to exogenous alpha- and gamma-tocopherol partially attenuates ethanol-induced changes in brain morphology and brain membrane fatty acid composition. Nutr Neurosci. 2003 Aug;6(4):201-12. PMID: 12887137 5: Virtamo J, Pietinen P, Huttunen JK, Korhonen P, Malila N, Virtanen MJ, Albanes D, Taylor PR, Albert P; ATBC Study Group.
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Incidence of cancer and mortality following alpha-tocopherol and beta-carotene supplementation: a postintervention follow-up. JAMA. 2003 Jul 23;290(4):476-85. PMID: 12876090 6: Fariss MW, Zhang JG. Vitamin E therapy in Parkinson's disease. Toxicology. 2003 Jul 15;189(1-2):129-46. Review. PMID: 12821288 7: Ruffini I, Belcaro G, Cesarone MR, Geroulakos G, Di Renzo A, Milani M, Coen L, Ricci A, Brandolini R, Dugall M, Pomante P, Cornelli U, Acerbi G, Corsi M, Griffin M, Ippolito E, Bavera P. Evaluation of the local effects of vitamin E (E-Mousse) on free radicals in diabetic microangiopathy: a randomized, controlled trial. Angiology. 2003 Jul-Aug;54(4):415-21. PMID: 12934761 8: Pathak A, Roth P, Piscitelli J, Johnson L. Effects of vitamin E supplementation during erythropoietin treatment of the anaemia of prematurity. Arch Dis Child Fetal Neonatal Ed. 2003 Jul;88(4):F324-8. PMID: 12819167 9: Jessup JV, Horne C, Yarandi H, Quindry J. The effects of endurance exercise and vitamin E on oxidative stress in the elderly. Biol Res Nurs. 2003 Jul;5(1):47-55. PMID: 12886670 10: Peluzio MC, Miguel E Jr, Drumond TC, Cesar GC, Santiago HC, Teixeira MM, Vieira EC, Arantes RM, Alvarez-Leite JI. Monocyte chemoattractant protein-1 involvement in the alpha-tocopherol-induced reduction of atherosclerotic lesions in apolipoprotein E knockout mice. Br J Nutr. 2003 Jul;90(1):3-11. PMID: 12844369 11: Ahmed J, Zaman MM, Ali K. Antioxidant vitamins improves hemoglobin level in children with group a beta hemolytic streptococcal infection. Mymensingh Med J. 2003 Jul;12(2):120-3. PMID: 12894046 12: Joachims HZ, Segal J, Golz A, Netzer A, Goldenberg D. Antioxidants in treatment of idiopathic sudden hearing loss. Otol Neurotol. 2003 Jul;24(4):572-5. PMID: 12851547 13: Hirnerova E, Krahulec B, Strbova L, Stecova A, Dekret J, Hajovska A. [Effect of vitamin E therapy on progression of diabetic nephropathy] Vnitr Lek. 2003 Jul;49(7):529-34. Slovak. PMID: 12931434 14: Ylonen K, Alfthan G, Groop L, Saloranta C, Aro A, Virtanen SM. Dietary intakes and plasma concentrations of carotenoids and tocopherols in
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relation to glucose metabolism in subjects at high risk of type 2 diabetes: the Botnia Dietary Study. Am J Clin Nutr. 2003 Jun;77(6):1434-41. PMID: 12791620 15: Mathew JP, Thomas VC, Thomas I. Selenite cataract and its attenuation by vitamin E in Wistar rats. Indian J Ophthalmol. 2003 Jun;51(2):161-70. PMID: 12831147 16: Lin JY, Selim MA, Shea CR, Grichnik JM, Omar MM, Monteiro-Riviere NA, Pinnell SR. UV photoprotection by combination topical antioxidants vitamin C and vitamin E. J Am Acad Dermatol. 2003 Jun;48(6):866-74. PMID: 12789176 17: Botsoglou NA, Govaris A, Botsoglou EN, Grigoropoulou SH, Papageorgiou G. Antioxidant activity of dietary oregano essential oil and alpha-tocopheryl acetate supplementation in long-term frozen stored turkey meat. J Agric Food Chem. 2003 May 7;51(10):2930-6. PMID: 12720373 18: Bilgihan A, Bilgihan K, Yis O, Sezer C, Akyol G, Hasanreisoglu B. Effects of topical vitamin E on corneal superoxide dismutase, glutathione peroxidase activities and polymorphonuclear leucocyte infiltration after photorefractive keratectomy. Acta Ophthalmol Scand. 2003 Apr;81(2):177-80. PMID: 12752058 19: Stone WL, LeClair I, Ponder T, Baggs G, Reis BB. Infants discriminate between natural and synthetic vitamin E. Am J Clin Nutr. 2003 Apr;77(4):899-906. PMID: 12663289 20: Prieto Castro RM, Leva Vallejo ME, Regueiro Lopez JC, Anglada Curado FJ, Alvarez Kindelan J, Requena Tapia MJ. Combined treatment with vitamin E and colchicine in the early stages of Peyronie's disease. BJU Int. 2003 Apr;91(6):522-4. PMID: 12656907 21: Fujikawa A, Gong H, Amemiya T. Vitamin E prevents changes in the cornea and conjunctiva due to vitamin A deficiency. Graefes Arch Clin Exp Ophthalmol. 2003 Apr;241(4):287-97. Epub 2003 Mar 15. PMID: 12719990 22: Bruunsgaard H, Poulsen HE, Pedersen BK, Nyyssonen K, Kaikkonen J, Salonen JT. Long-term combined supplementations with alpha-tocopherol and vitamin C have no detectable anti-inflammatory effects in healthy men. J Nutr. 2003 Apr;133(4):1170-3. PMID: 12672938
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23: Canbaz S, Duran E, Ege T, Sunar H, Cikirikcioglu M, Acipayam M. The effects of intracoronary administration of vitamin E on myocardial ischemia-reperfusion injury during coronary artery surgery. Thorac Cardiovasc Surg. 2003 Apr;51(2):57-61. PMID: 12730811 24: Yousef MI, Abdallah GA, Kamel KI. Effect of ascorbic acid and Vitamin E supplementation on semen quality and biochemical parameters of male rabbits. Anim Reprod Sci. 2003 Mar 20;76(1-2):99-111. PMID: 12559724 25: Kogure K, Manabe S, Hama S, Tokumura A, Fukuzawa K. Potentiation of anti-cancer effect by intravenous administration of vesiculated alpha-tocopheryl hemisuccinate on mouse melanoma in vivo. Cancer Lett. 2003 Mar 20;192(1):19-24. PMID: 12637149 26: Keskes-Ammar L, Feki-Chakroun N, Rebai T, Sahnoun Z, Ghozzi H, Hammami S, Zghal K, Fki H, Damak J, Bahloul A. Sperm oxidative stress and the effect of an oral vitamin E and selenium supplement on semen quality in infertile men. Arch Androl. 2003 Mar-Apr;49(2):83-94. PMID: 12623744 27: Morinobu T, Yoshikawa S, Hamamura K, Tamai H. Measurement of vitamin E metabolites by high-performance liquid chromatography during high-dose administration of alpha-tocopherol. Eur J Clin Nutr. 2003 Mar;57(3):410-4. PMID: 12627176 28: Shang F, Lu M, Dudek E, Reddan J, Taylor A. Vitamin C and vitamin E restore the resistance of GSH-depleted lens cells to H2O2. Free Radic Biol Med. 2003 Mar 1;34(5):521-30. PMID: 12614841 29: Di Leo MA, Ghirlanda G, Gentiloni Silveri N, Giardina B, Franconi F, Santini SA. Potential therapeutic effect of antioxidants in experimental diabetic retina: a comparison between chronic taurine and vitamin E plus selenium supplementations. Free Radic Res. 2003 Mar;37(3):323-30. PMID: 12688428 30: Pace A, Savarese A, Picardo M, Maresca V, Pacetti U, Del Monte G, Biroccio A, Leonetti C, Jandolo B, Cognetti F, Bove L. Neuroprotective effect of vitamin E supplementation in patients treated with cisplatin chemotherapy. J Clin Oncol. 2003 Mar 1;21(5):927-31. PMID: 12610195 31: Rangarajan M, Zatz JL. Effect of formulation on the topical delivery of alpha-tocopherol.
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J Cosmet Sci. 2003 Mar-Apr;54(2):161-74. PMID: 12715093 32: Manson JE, Bassuk SS, Stampfer MJ. Does vitamin E supplementation prevent cardiovascular events? J Womens Health (Larchmt). 2003 Mar;12(2):123-36. Review. PMID: 12741415 33: Salonen RM, Nyyssonen K, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Rissanen TH, Tuomainen TP, Valkonen VP, Ristonmaa U, Lakka HM, Vanharanta M, Salonen JT, Poulsen HE; Antioxidant Supplementation in Atherosclerosis Prevention Study. Six-year effect of combined vitamin C and E supplementation on atherosclerotic progression: the Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) Study. Circulation. 2003 Feb 25;107(7):947-53. PMID: 12600905 34: Cyrus T, Yao Y, Rokach J, Tang LX, Pratico D. Vitamin E reduces progression of atherosclerosis in low-density lipoprotein receptor-deficient mice with established vascular lesions. Circulation. 2003 Feb 4;107(4):521-3. PMID: 12566360 35: Aghdassi E, Wendland BE, Steinhart AH, Wolman SL, Jeejeebhoy K, Allard JP. Antioxidant vitamin supplementation in Crohn's disease decreases oxidative stress. a randomized controlled trial. Am J Gastroenterol. 2003 Feb;98(2):348-53. PMID: 12591053 36: Chang CW, Chu G, Hinz BJ, Greve MD. Current use of dietary supplementation in patients with age-related macular degeneration. Can J Ophthalmol. 2003 Feb;38(1):27-32. PMID: 12608514 37: Letur-Konirsch H, Delanian S. Successful pregnancies after combined pentoxifylline-tocopherol treatment in women with premature ovarian failure who are resistant to hormone replacement therapy. Fertil Steril. 2003 Feb;79(2):439-41. PMID: 12568863 38: Ortuno J, Esteban MA, Meseguer J. The effect of dietary intake of vitamins C and E on the stress response of gilthead seabream (Sparus aurata L.). Fish Shellfish Immunol. 2003 Feb;14(2):145-56. PMID: 12526878 39: Bae JH, Schwemmer M, Lee IK, Lee HJ, Park KR, Kim KY, Bassenge E. Postprandial hypertriglyceridemia-induced endothelial dysfunction in healthy subjects is independent of lipid oxidation. Int J Cardiol. 2003 Feb;87(2-3):259-67. PMID: 12559548
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40: Abubakar MG, Taylor A, Ferns GA. Aluminium administration is associated with enhanced hepatic oxidant stress that may be offset by dietary vitamin E in the rat. Int J Exp Pathol. 2003 Feb;84(1):49-54. PMID: 12694486 41: Olanow CW. Dietary vitamin E and Parkinson's disease: something to chew on. Lancet Neurol. 2003 Feb;2(2):74. PMID: 12849259 42: Martin A. Antioxidant vitamins E and C and risk of Alzheimer's disease. Nutr Rev. 2003 Feb;61(2):69-73. Review. PMID: 12674439 43: Bulger EM, Maier RV. An argument for Vitamin E supplementation in the management of systemic inflammatory response syndrome. Shock. 2003 Feb;19(2):99-103. Review. PMID: 12578114 44: Mishima K, Tanaka T, Pu F, Egashira N, Iwasaki K, Hidaka R, Matsunaga K, Takata J, Karube Y, Fujiwara M. Vitamin E isoforms alpha-tocotrienol and gamma-tocopherol prevent cerebral infarction in mice. Neurosci Lett. 2003 Jan 30;337(1):56-60. PMID: 12524170 45: Rehim WM, Sharaf IA, Hishmat M, el-Toukhy MA, Rawash NA, Fouad HN. Antioxidant capacity in Fasciola hepatica patients before and after treatment with triclabendazole alone or in combination with ascorbic acid (vitamin C) and tocofersolan (vitamin E). Arzneimittelforschung. 2003;53(3):214-20. PMID: 12705178 46: Brockes C, Buchli C, Locher R, Koch J, Vetter W. Vitamin E prevents extensive lipid peroxidation in patients with hypertension. Br J Biomed Sci. 2003;60(1):5-8. PMID: 12680623 47: Lohr JB, Kuczenski R, Niculescu AB. Oxidative mechanisms and tardive dyskinesia. CNS Drugs. 2003;17(1):47-62. Review. PMID: 12467492 48: Yap SP, Yuen KH, Lim AB. Influence of route of administration on the absorption and disposition of alpha-, gamma- and delta-tocotrienols in rats. J Pharm Pharmacol. 2003 Jan;55(1):53-8. PMID: 12625867 49: Olmedilla B, Granado F, Blanco I, Vaquero M. Lutein, but not alpha-tocopherol, supplementation improves visual function in
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patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition. 2003 Jan;19(1):21-4. PMID: 12507634 50: Falsini B, Piccardi M, Iarossi G, Fadda A, Merendino E, Valentini P. Influence of short-term antioxidant supplementation on macular function in age-related maculopathy: a pilot study including electrophysiologic assessment. Ophthalmology. 2003 Jan;110(1):51-60; discussion 61. PMID: 12511345 51: Lin Y, Huang R, Santanam N, Liu YG, Parthasarathy S, Huang RP. Profiling of human cytokines in healthy individuals with vitamin E supplementation by antibody array. Cancer Lett. 2002 Dec 10;187(1-2):17-24. PMID: 12359346 52: Kogure K, Hama S, Manabe S, Tokumura A, Fukuzawa K. High cytotoxicity of alpha-tocopheryl hemisuccinate to cancer cells is due to failure of their antioxidative defense systems. Cancer Lett. 2002 Dec 5;186(2):151-6. PMID: 12213284 53: Jacobs EJ, Henion AK, Briggs PJ, Connell CJ, McCullough ML, Jonas CR, Rodriguez C, Calle EE, Thun MJ. Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Am J Epidemiol. 2002 Dec 1;156(11):1002-10. PMID: 12446256 54: Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella F, Garcia I, Maier RV. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002 Dec;236(6):814-22. PMID: 12454520 55: Malafa MP, Fokum FD, Smith L, Louis A. Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate. Ann Surg Oncol. 2002 Dec;9(10):1023-32. PMID: 12464597 56: Peponis V, Papathanasiou M, Kapranou A, Magkou C, Tyligada A, Melidonis A, Drosos T, Sitaras NM. Protective role of oral antioxidant supplementation in ocular surface of diabetic patients. Br J Ophthalmol. 2002 Dec;86(12):1369-73. PMID: 12446368 57: Scorolli L, Scalinci SZ, Limoli PG, Morara M, Vismara S, Scorolli L, Corazza D, Meduri R. [Photodynamic therapy for age related macular degeneration with and without antioxidants]
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Can J Ophthalmol. 2002 Dec;37(7):399-404. French. PMID: 12518724 58: Mayer-Davis EJ, Costacou T, King I, Zaccaro DJ, Bell RA; The Insulin Resistance and Atherosclerosis Study (IRAS). Plasma and dietary vitamin E in relation to incidence of type 2 diabetes: The Insulin Resistance and Atherosclerosis Study (IRAS). Diabetes Care. 2002 Dec;25(12):2172-7. PMID: 12453956 59: Jialal I, Devaraj S, Venugopal SK. Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res. 2002 Dec;36(12):1331-6. Review. PMID: 12607825 60: Jaarin K, Gapor MT, Nafeeza MI, Fauzee AM. Effect of various doses of palm vitamin E and tocopherol on aspirin-induced gastric lesions in rats. Int J Exp Pathol. 2002 Dec;83(6):295-302. PMID: 12657138 61: Ringseis R, Eder K. Insufficient dietary vitamin e increases the concentration of 7beta-hydroxycholesterol in tissues of rats fed salmon oil. J Nutr. 2002 Dec;132(12):3732-5. PMID: 12468614 62: Wan Nazaimoon WM, Khalid BA. Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats. Malays J Pathol. 2002 Dec;24(2):77-82. PMID: 12887164 63: Vasdev S, Gill V, Parai S, Longerich L, Gadag V. Dietary vitamin E and C supplementation prevents fructose induced hypertension in rats. Mol Cell Biochem. 2002 Dec;241(1-2):107-14. PMID: 12482032 64: Sahin K, Sahin N, Onderci M. Vitamin E supplementation can alleviate negative effects of heat stress on egg production, egg quality, digestibility of nutrients and egg yolk mineral concentrations of Japanese quails. Res Vet Sci. 2002 Dec;73(3):307-12. PMID: 12443690 65: Chow CK, Hong CB. Dietary vitamin E and selenium and toxicity of nitrite and nitrate. Toxicology. 2002 Nov 15;180(2):195-207. Review. PMID: 12324194
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66: Kolb E, Seehawer J. [Significance and application of vitamin E in broilers and laying hens, especially during supplementation with fish oil] Berl Munch Tierarztl Wochenschr. 2002 Nov-Dec;115(11-12):458-64. Review. German. PMID: 12481654 67: Jacobs EJ, Henion AK, Briggs PJ, Connell CJ, McCullough ML, Jonas CR, Rodriguez C, Calle EE, Thun MJ. Vitamin C and vitamin E supplement use and bladder cancer mortality in a large cohort of US men and women. Am J Epidemiol. 2002 Dec 1;156(11):1002-10. PMID: 12446256 68: Nathens AB, Neff MJ, Jurkovich GJ, Klotz P, Farver K, Ruzinski JT, Radella F, Garcia I, Maier RV. Randomized, prospective trial of antioxidant supplementation in critically ill surgical patients. Ann Surg. 2002 Dec;236(6):814-22. PMID: 12454520 69: Malafa MP, Fokum FD, Smith L, Louis A. Inhibition of angiogenesis and promotion of melanoma dormancy by vitamin E succinate. Ann Surg Oncol. 2002 Dec;9(10):1023-32. PMID: 12464597 70: Peponis V, Papathanasiou M, Kapranou A, Magkou C, Tyligada A, Melidonis A, Drosos T, Sitaras NM. Protective role of oral antioxidant supplementation in ocular surface of diabetic patients. Br J Ophthalmol. 2002 Dec;86(12):1369-73. PMID: 12446368 71: Scorolli L, Scalinci SZ, Limoli PG, Morara M, Vismara S, Scorolli L, Corazza D, Meduri R. [Photodynamic therapy for age related macular degeneration with and without antioxidants] Can J Ophthalmol. 2002 Dec;37(7):399-404. French. PMID: 12518724 72: Jialal I, Devaraj S, Venugopal SK. Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res. 2002 Dec;36(12):1331-6. Review. PMID: 12607825 73: Jaarin K, Gapor MT, Nafeeza MI, Fauzee AM. Effect of various doses of palm vitamin E and tocopherol on aspirin-induced gastric lesions in rats. Int J Exp Pathol. 2002 Dec;83(6):295-302. PMID: 12657138 74: Ringseis R, Eder K. Insufficient dietary vitamin e increases the concentration of
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7beta-hydroxycholesterol in tissues of rats fed salmon oil. J Nutr. 2002 Dec;132(12):3732-5. PMID: 12468614 75: Wan Nazaimoon WM, Khalid BA. Tocotrienols-rich diet decreases advanced glycosylation end-products in non-diabetic rats and improves glycemic control in streptozotocin-induced diabetic rats. Malays J Pathol. 2002 Dec;24(2):77-82. PMID: 12887164 76: Vasdev S, Gill V, Parai S, Longerich L, Gadag V. Dietary vitamin E and C supplementation prevents fructose induced hypertension in rats. Mol Cell Biochem. 2002 Dec;241(1-2):107-14. PMID: 12482032 77: Sahin K, Sahin N, Onderci M. Vitamin E supplementation can alleviate negative effects of heat stress on egg production, egg quality, digestibility of nutrients and egg yolk mineral concentrations of Japanese quails. Res Vet Sci. 2002 Dec;73(3):307-12. PMID: 12443690 78: Castellini C, Lattaioli P, Bosco AD, Beghelli D. Effect of supranutritional level of dietary alpha-tocopheryl acetate and selenium on rabbit semen. Theriogenology. 2002 Dec;58(9):1723-32. PMID: 12472142 79: Wu K, Li Y, Zhao Y, Shan YJ, Xia W, Yu WP, Zhao L. Roles of Fas signaling pathway in vitamin E succinate-induced apoptosis in human gastric cancer SGC-7901 cells. World J Gastroenterol. 2002 Dec;8(6):982-6. PMID: 12439910 80: Chow CK, Hong CB. Dietary vitamin E and selenium and toxicity of nitrite and nitrate. Toxicology. 2002 Nov 15;180(2):195-207. Review. PMID: 12324194 81: Kolb E, Seehawer J. [Significance and application of vitamin E in broilers and laying hens, especially during supplementation with fish oil] Berl Munch Tierarztl Wochenschr. 2002 Nov-Dec;115(11-12):458-64. Review. German. PMID: 12481654 82: Wu K, Willett WC, Chan JM, Fuchs CS, Colditz GA, Rimm EB, Giovannucci EL. A prospective study on supplemental vitamin e intake and risk of colon cancer in women and men. Cancer Epidemiol Biomarkers Prev. 2002 Nov;11(11):1298-304. PMID: 12433706
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83: Ghosh D, Das UB, Misro M. Protective role of alpha-tocopherol-succinate (provitamin-E) in cyclophosphamide induced testicular gametogenic and steroidogenic disorders: a correlative approach to oxidative stress. Free Radic Res. 2002 Nov;36(11):1209-18. PMID: 12592673 84: Roongpraiwan R, Suthutvoravut U, Feungpean B, Phuapradit P. Effect of oral vitamin E supplementation in children with cholestasis. J Med Assoc Thai. 2002 Nov;85 Suppl 4:S1199-205. PMID: 12549795 85: Liu L, Meydani M. Combined vitamin C and E supplementation retards early progression of arteriosclerosis in heart transplant patients. Nutr Rev. 2002 Nov;60(11):368-71. Review. PMID: 12462519 86: Stohs SJ, Ohia S, Bagchi D. Naphthalene toxicity and antioxidant nutrients. Toxicology. 2002 Oct 30;180(1):97-105. Review. PMID: 12324202 87: Kuriyama K, Shimizu T, Horiguchi T, Watabe M, Abe Y. Vitamin E ointment at high dose levels suppresses contact dermatitis in rats by stabilizing keratinocytes. Inflamm Res. 2002 Oct;51(10):483-9. PMID: 12477076 88: Boshtam M, Rafiei M, Sadeghi K, Sarraf-Zadegan N. Vitamin E can reduce blood pressure in mild hypertensives. Int J Vitam Nutr Res. 2002 Oct;72(5):309-14. PMID: 12463106 89: Bozkurt AK. Alpha-tocopherol (Vitamin E) and iloprost attenuate reperfusion injury in skeletal muscle ischemia/reperfusion injury. J Cardiovasc Surg (Torino). 2002 Oct;43(5):693-6. PMID: 12386586 90: Chao JT, Gapor A, Theriault A. Inhibitory effect of delta-tocotrienol, a HMG CoA reductase inhibitor, on monocyte-endothelial cell adhesion. J Nutr Sci Vitaminol (Tokyo). 2002 Oct;48(5):332-7. PMID: 12656204 91: Soybir N, Soybir G, Lice H, Dolay K, Ozseker A, Koksoy F. The effects of desferrioxamin and vitamin E as supplements to antibiotics in the treatment of peritonitis in rats. J R Coll Surg Edinb. 2002 Oct;47(5):700-4. PMID: 12463711 92: Frenoux JM, Noirot B, Prost ED, Madani S, Blond JP, Belleville JL, Prost JL.
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Very high alpha-tocopherol diet diminishes oxidative stress and hypercoagulation in hypertensive rats but not in normotensive rats. Med Sci Monit. 2002 Oct;8(10):BR401-7. PMID: 12388913 93: Senatore M, Nicoletti A, Rizzuto G. Is the bioreactivity of vitamin-E-modified dialyzer an expression of increased plasmatic vitamin E concentration? Nephron. 2002 Oct;92(2):487-9. PMID: 12218339 94: Martin A, Youdim K, Szprengiel A, Shukitt-Hale B, Joseph J. Roles of vitamins E and C on neurodegenerative diseases and cognitive performance. Nutr Rev. 2002 Oct;60(10 Pt 1):308-26. Review. PMID: 12392148 95: Zhao Y, Wu K, Xia W, Shan YJ, Wu LJ, Yu WP. The effects of vitamin E succinate on the expression of c-jun gene and protein in human gastric cancer SGC-7901 cells. World J Gastroenterol. 2002 Oct;8(5):782-6. PMID: 12378615 96: Hodis HN, Mack WJ, LaBree L, Mahrer PR, Sevanian A, Liu CR, Liu CH, Hwang J, Selzer RH, Azen SP; VEAPS Research Group. Alpha-tocopherol supplementation in healthy individuals reduces low-density lipoprotein oxidation but not atherosclerosis: the Vitamin E Atherosclerosis Prevention Study (VEAPS). Circulation. 2002 Sep 17;106(12):1453-9. PMID: 12234947 97: Huang HY, Appel LJ, Croft KD, Miller ER 3rd, Mori TA, Puddey IB. Effects of vitamin C and vitamin E on in vivo lipid peroxidation: results of a randomized controlled trial. Am J Clin Nutr. 2002 Sep;76(3):549-55. PMID: 12197998 98: Chappell LC, Seed PT, Kelly FJ, Briley A, Hunt BJ, Charnock-Jones DS, Mallet A, Poston L. Vitamin C and E supplementation in women at risk of preeclampsia is associated with changes in indices of oxidative stress and placental function. Am J Obstet Gynecol. 2002 Sep;187(3):777-84. PMID: 12237663 99: Romieu I, Sienra-Monge JJ, Ramirez-Aguilar M, Tellez-Rojo MM, Moreno-Macias H, Reyes-Ruiz NI, del Rio-Navarro BE, Ruiz-Navarro MX, Hatch G, Slade R, Hernandez-Avila M. Antioxidant supplementation and lung functions among children with asthma exposed to high levels of air pollutants. Am J Respir Crit Care Med. 2002 Sep 1;166(5):703-9. PMID: 12204869 100: Harris A, Devaraj S, Jialal I. Oxidative stress, alpha-tocopherol therapy, and atherosclerosis.
561
Curr Atheroscler Rep. 2002 Sep;4(5):373-80. Review. PMID: 12162937 101: Velasquez-Pereira J, Arechiga CF, McDowell LR, Hansen PJ, Chenoweth PJ, Calhoun MC, Risco CA, Batra TR, Williams SN, Wilkinson NS. Effects of gossypol from cottonseed meal and dietary vitamin E on the reproductive characteristics of superovulated beef heifers. J Anim Sci. 2002 Sep;80(9):2485-92. PMID: 12350026 102: Kessler M, Ubeaud G, Walter T, Sturm F, Jung L. Free radical scavenging and skin penetration of troxerutin and vitamin derivatives. J Dermatolog Treat. 2002 Sep;13(3):133-41. PMID: 12227877 103: Pasantes-Morales H, Quiroz H, Quesada O. Treatment with taurine, diltiazem, and vitamin E retards the progressive visual field reduction in retinitis pigmentosa: a 3-year follow-up study. Metab Brain Dis. 2002 Sep;17(3):183-97. PMID: 12322788 104: Reis EA, Zugno AI, Franzon R, Tagliari B, Matte C, Lammers ML, Netto CA, Wyse AT. Pretreatment with vitamins E and C prevent the impairment of memory caused by homocysteine administration in rats. Metab Brain Dis. 2002 Sep;17(3):211-7. PMID: 12322790 105: Barnett KT, Fokum FD, Malafa MP. Vitamin E succinate inhibits colon cancer liver metastases. J Surg Res. 2002 Aug;106(2):292-8. PMID: 12175981 106: Akazawa A, Nishikawa K, Suzuki K, Asano R, Kumadaki I, Satoh H, Hagiwara K, Shin SJ, Yano T. Induction of apoptosis in a human breast cancer cell overexpressing ErbB-2 receptor by alpha-tocopheryloxybutyric acid. Jpn J Pharmacol. 2002 Aug;89(4):417-21. PMID: 12233821 107: Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Vitamin E and cognitive decline in older persons. Arch Neurol. 2002 Jul;59(7):1125-32. PMID: 12117360 108: Morton LW, Ward NC, Croft KD, Puddey IB. Evidence for the nitration of gamma-tocopherol in vivo: 5-nitro-gamma-tocopherol is elevated in the plasma of subjects with coronary heart disease. Biochem J. 2002 Jun 15;364(Pt 3):625-8. PMID: 11960550
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109: Malmberg KJ, Lenkei R, Petersson M, Ohlum T, Ichihara F, Glimelius B, Frodin JE, Masucci G, Kiessling R. A short-term dietary supplementation of high doses of vitamin E increases T helper 1 cytokine production in patients with advanced colorectal cancer. Clin Cancer Res. 2002 Jun;8(6):1772-8. PMID: 12060616 110: Desideri G, Croce G, Marinucci MC, Masci PG, Stati M, Valeri L, Santucci A, Ferri C. Prolonged, low dose alpha-tocopherol therapy counteracts intercellular cell adhesion molecule-1 activation. Clin Chim Acta. 2002 Jun;320(1-2):5-9. PMID: 11983194 111: Radosavac D, Graf P, Polidori MC, Sies H, Stahl W. Tocopherol metabolites 2, 5, 7, 8-tetramethyl-2-(2'-carboxyethyl)-6-hydroxychroman (alpha-CEHC) and 2, 7, 8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) in human serum after a single dose of natural vitamin E. Eur J Nutr. 2002 Jun;41(3):119-24. PMID: 12111049 112: Masaki H, Okano Y, Ochiai Y, Obayashi K, Akamatsu H, Sakurai H. alpha-tocopherol increases the intracellular glutathione level in HaCaT keratinocytes. Free Radic Res. 2002 Jun;36(6):705-9. PMID: 12180196 113: Desideri G, Marinucci MC, Tomassoni G, Masci PG, Santucci A, Ferri C. Vitamin E supplementation reduces plasma vascular cell adhesion molecule-1 and von Willebrand factor levels and increases nitric oxide concentrations in hypercholesterolemic patients. J Clin Endocrinol Metab. 2002 Jun;87(6):2940-5. PMID: 12050277 114: LeBlanc SJ, Duffield TF, Leslie KE, Bateman KG, TenHag J, Walton JS, Johnson WH. The effect of prepartum injection of vitamin E on health in transition dairy cows. J Dairy Sci. 2002 Jun;85(6):1416-26. PMID: 12146472 115: Rajagopalan R, Wani K, Huilgol NG, Kagiya TV, Nair CK. Inhibition of gamma-radiation induced DNA damage in plasmid pBR322 by TMG, a water-soluble derivative of vitamin E. J Radiat Res (Tokyo). 2002 Jun;43(2):153-9. PMID: 12238329 116: Sagach VF, Scrosati M, Fielding J, Rossoni G, Galli C, Visioli F. The water-soluble vitamin E analogue Trolox protects against ischaemia/reperfusion damage in vitro and ex vivo. A comparison with vitamin E. Pharmacol Res. 2002 Jun;45(6):435-9. PMID: 12162942
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117: Neuzil J. Alpha-tocopheryl succinate epitomizes a compound with a shift in biological activity due to pro-vitamin-to-vitamin conversion. Biochem Biophys Res Commun. 2002 May 24;293(5):1309-13. Review. PMID: 12054655 118: Ledee-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Reprod. 2002 May;17(5):1249-53. PMID: 11980747 119: Mydlik M, Derzsiova K, Racz O, Sipulova A, Boldizsar J, Lovasova E, Hribikova M. Vitamin E as an antioxidant agent in CAPD patients. Int J Artif Organs. 2002 May;25(5):373-8. PMID: 12074333 120: Cuppini R, Ciaroni S, Cecchini T, Ambrogini P, Ferri P, Cuppini C, Ninfali P, Del Grande P. Tocopherols enhance neurogenesis in dentate gyrus of adult rats. Int J Vitam Nutr Res. 2002 May;72(3):170-6. PMID: 12098885 121: Hatfield PG, Robinson BL, Minikhiem DL, Kott RW, Roth NI, Daniels JT, Swenson CK. Serum alpha-tocopherol and immune function in yearling ewes supplemented with zinc and vitamin E. J Anim Sci. 2002 May;80(5):1329-34. PMID: 12019622 122: Ikeda S, Tohyama T, Yamashita K. Dietary sesame seed and its lignans inhibit 2,7,8-trimethyl2(2'-carboxyethyl)-6-hydroxychroman excretion into urine of rats fed gamma-tocopherol. J Nutr. 2002 May;132(5):961-6. PMID: 11983822 123: Mune M, Otani H, Yukawa S. Effects of antioxidants on kidney disease. Mech Ageing Dev. 2002 Apr 30;123(8):1041-6. PMID: 12044953 124: Mu L, Feng SS. Vitamin E TPGS used as emulsifier in the solvent evaporation/extraction technique for fabrication of polymeric nanospheres for controlled release of paclitaxel (Taxol). J Control Release. 2002 Apr 23;80(1-3):129-44. PMID: 11943393 125: Park S, Choi SB. Effects of alpha-tocopherol supplementation and continuous subcutaneous insulin infusion on oxidative stress in Korean patients with type 2 diabetes.
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Am J Clin Nutr. 2002 Apr;75(4):728-33. PMID: 11916760 126: Neuzil J, Kagedal K, Andera L, Weber C, Brunk UT. Vitamin E analogs: a new class of multiple action agents with anti-neoplastic and anti-atherogenic activity. Apoptosis. 2002 Apr;7(2):179-87. Review. PMID: 11865203 127: Smith KJ, Norwood C, Skelton H. Treatment of disseminated granuloma annulare with a 5-lipoxygenase inhibitor and vitamin E. Br J Dermatol. 2002 Apr;146(4):667-70. PMID: 11966702 128: Bolisetty S, Naidoo D, Lui K, Koh TH, Watson D, Whitehall J. Antenatal supplementation of antioxidant vitamins to reduce the oxidative stress at delivery--a pilot study. Early Hum Dev. 2002 Apr;67(1-2):47-53. PMID: 11893435 129: Rivera JD, Duff GC, Galyean ML, Walker DA, Nunnery GA. Effects of supplemental vitamin E on performance, health, and humoral immune response of beef cattle. J Anim Sci. 2002 Apr;80(4):933-41. PMID: 12002330 130: Kamiyama S, Howlader ZH, Ito M, Komai M, Furukawa Y. Effect of deficiency of vitamins C and/or E on lipoprotein metabolism in osteogenic disorder Shionogi rat, a strain unable to synthesize ascorbic acid. J Nutr Sci Vitaminol (Tokyo). 2002 Apr;48(2):95-101. PMID: 12171442 131: Pinelli A, Trivulzio S, Tomasoni L, Bertolini B, Pinelli G. High-dose vitamin E lowers urine porphyrin levels in patients affected by porphyria cutanea tarda. Pharmacol Res. 2002 Apr;45(4):355-9. PMID: 12030801 132: Ciocoiu M, Badescu M, Paduraru I, Colev-Luca V. [Platelet adhesion and antioxidant therapy in experimental stress] Rev Med Chir Soc Med Nat Iasi. 2002 Apr-Jun;107(2):331-3. Romanian. PMID: 12638285 133: Fang JC, Kinlay S, Beltrame J, Hikiti H, Wainstein M, Behrendt D, Suh J, Frei B, Mudge GH, Selwyn AP, Ganz P. Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet. 2002 Mar 30;359(9312):1108-13. PMID: 11943259 134: Neuzil J, Zhao M, Ostermann G, Sticha M, Gellert N, Weber C, Eaton JW, Brunk UT. Alpha-tocopheryl succinate, an agent with in vivo anti-tumour activity, induces
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apoptosis by causing lysosomal instability. Biochem J. 2002 Mar 15;362(Pt 3):709-15. PMID: 11879199 135: Weber T, Lu M, Andera L, Lahm H, Gellert N, Fariss MW, Korinek V, Sattler W, Ucker DS, Terman A, Schroder A, Erl W, Brunk UT, Coffey RJ, Weber C, Neuzil J. Vitamin E succinate is a potent novel antineoplastic agent with high selectivity and cooperativity with tumor necrosis factor-related apoptosis-inducing ligand (Apo2 ligand) in vivo. Clin Cancer Res. 2002 Mar;8(3):863-9. PMID: 11895920 136: Devaraj S, Chan AV Jr, Jialal I. alpha-Tocopherol supplementation decreases plasminogen activator inhibitor-1 and P-selectin levels in type 2 diabetic patients. Diabetes Care. 2002 Mar;25(3):524-9. PMID: 11874941 137: Tsoureli-Nikita E, Hercogova J, Lotti T, Menchini G. Evaluation of dietary intake of vitamin E in the treatment of atopic dermatitis: a study of the clinical course and evaluation of the immunoglobulin E serum levels. Int J Dermatol. 2002 Mar;41(3):146-50. PMID: 12010339 138: Sahin K, Kucuk O, Sahin N, Sari M. Effects of vitamin C and vitamin E on lipid peroxidation status, serum hormone, metabolite, and mineral concentrations of Japanese quails reared under heat stress (34 degrees C). Int J Vitam Nutr Res. 2002 Mar;72(2):91-100. PMID: 11944200 139: Tabet N, Mantle D, Walker Z, Orrell M. Endogenous antioxidant activities in relation to concurrent vitamins A, C, and E intake in dementia. Int Psychogeriatr. 2002 Mar;14(1):7-15. PMID: 12094909 140: Moreira I, Mahan DC. Effect of dietary levels of vitamin E (all-rac-tocopheryl acetate) with or without added fat on weanling pig performance and tissue alpha-tocopherol concentration. J Anim Sci. 2002 Mar;80(3):663-9. PMID: 11890402 141: Brancato R, Fiore T, Papucci L, Schiavone N, Formigli L, Orlandini SZ, Gobbi PG, Carones F, Donnini M, Lapucci A, Capaccioli S. Concomitant effect of topical ubiquinone Q10 and vitamin E to prevent keratocyte apoptosis after excimer laser photoablation in rabbits. J Refract Surg. 2002 Mar-Apr;18(2):135-9. PMID: 11934201
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142: Tauler P, Aguilo A, Fuentespina E, Tur JA, Pons A. Diet supplementation with vitamin E, vitamin C and beta-carotene cocktail enhances basal neutrophil antioxidant enzymes in athletes. Pflugers Arch. 2002 Mar;443(5-6):791-7. Epub 2002 Jan 31. PMID: 11889577 143: Harper L, Nuttall SL, Martin U, Savage CO. Adjuvant treatment of patients with antineutrophil cytoplasmic antibody-associated vasculitis with vitamins E and C reduces superoxide production by neutrophils. Rheumatology (Oxford). 2002 Mar;41(3):274-8. PMID: 11934963 144: Terentis AC, Thomas SR, Burr JA, Liebler DC, Stocker R. Vitamin E oxidation in human atherosclerotic lesions. Circ Res. 2002 Feb 22;90(3):333-9. PMID: 11861423 145: Isler M, Delibas N, Guclu M, Gultekin F, Sutcu R, Bahceci M, Kosar A. Superoxide dismutase and glutathione peroxidase in erythrocytes of patients with iron deficiency anemia: effects of different treatment modalities. Croat Med J. 2002 Feb;43(1):16-9. PMID: 11828552 146: Dimakakos PB, Kotsis T, Kondi-Pafiti A, Katsenis K, Doufas A, Chondros K, Kouskouni E. Oxygen free radicals in abdominal aortic surgery. An experimental study. J Cardiovasc Surg (Torino). 2002 Feb;43(1):77-82. PMID: 11803334 147: Morinobu T, Ban R, Yoshikawa S, Murata T, Tamai H. The safety of high-dose vitamin E supplementation in healthy Japanese male adults. J Nutr Sci Vitaminol (Tokyo). 2002 Feb;48(1):6-9. PMID: 12026191 148: Jones KH, Liu JJ, Roehm JS, Eckel JJ, Eckel TT, Stickrath CR, Triola CA, Jiang Z, Bartoli GM, Cornwell DG. Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells. Lipids. 2002 Feb;37(2):173-84. PMID: 11908909 149: Chylack LT Jr, Brown NP, Bron A, Hurst M, Kopcke W, Thien U, Schalch W. The Roche European American Cataract Trial (REACT): a randomized clinical trial to investigate the efficacy of an oral antioxidant micronutrient mixture to slow progression of age-related cataract. Ophthalmic Epidemiol. 2002 Feb;9(1):49-80. PMID: 11815895 150: van Winden SC, Kuiper R. [Congenital white muscle disease in a Belgian blue calf] Tijdschr Diergeneeskd. 2002 Feb 1;127(3):74-7. Dutch. PMID: 11858038
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151: Fleshner NE. Vitamin E and prostate cancer. Urol Clin North Am. 2002 Feb;29(1):107-13, ix. Review. PMID: 12109337 152: Wu K, Zhao Y, Liu BH, Li Y, Liu F, Guo J, Yu WP. RRR-alpha-tocopheryl succinate inhibits human gastric cancer SGC-7901 cell growth by inducing apoptosis and DNA synthesis arrest. World J Gastroenterol. 2002 Feb;8(1):26-30. PMID: 11833065 153: Mireles-Rocha H, Galindo I, Huerta M, Trujillo-Hernandez B, Elizalde A, Cortes-Franco R. UVB photoprotection with antioxidants: effects of oral therapy with d-alpha-tocopherol and ascorbic acid on the minimal erythema dose. Acta Derm Venereol. 2002;82(1):21-4. PMID: 12013192 154: Sarlos P, Molnar A, Kokai M, Gabor G, Ratky J. Comparative evaluation of the effect of antioxidants in the conservation of ram semen. Acta Vet Hung. 2002;50(2):235-45. PMID: 12113179 155: Raederstorff D, Elste V, Aebischer C, Weber P. Effect of either gamma-tocotrienol or a tocotrienol mixture on the plasma lipid profile in hamsters. Ann Nutr Metab. 2002;46(1):17-23. PMID: 11914511 156: Woodson K, Triantos S, Hartman T, Taylor PR, Virtamo J, Albanes D. Long-term alpha-tocopherol supplementation is associated with lower serum vascular endothelial growth factor levels. Anticancer Res. 2002 Jan-Feb;22(1A):375-8. PMID: 12017317 157: Nafeeza MI, Fauzee AM, Kamsiah J, Gapor MT. Comparative effects of a tocotrienol-rich fraction and tocopherol in aspirin-induced gastric lesions in rats. Asia Pac J Clin Nutr. 2002;11(4):309-13. PMID: 12495264 158: Theriault A, Chao JT, Gapor A, Chao JT, Gapor A. Tocotrienol is the most effective vitamin E for reducing endothelial expression of adhesion molecules and adhesion to monocytes. Atherosclerosis. 2002 Jan;160(1):21-30. Erratum in: Atherosclerosis. 2002;164(2):389.. PMID: 11755919 159: Stone WL, Papas AM, LeClair IO, Qui M, Ponder T. The influence of dietary iron and tocopherols on oxidative stress and ras-p21 levels in the colon. Cancer Detect Prev. 2002;26(1):78-84. PMID: 12088207
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160: Vaney N, Chouhan S, Bhatia MS, Tandon OP. Event related evoked potentials in dementia: role of vitamin E. Indian J Physiol Pharmacol. 2002 Jan;46(1):61-8. PMID: 12024959 161: Avdeeva MG, Moisova DL, Gorodin VN, Kostomarov AM, Zotov SV, Cherniavskaia OV. [The role glucose-6-phosphate dehydrogenase in pathogenesis of anemia in leptospirosis] Klin Med (Mosk). 2002;80(6):42-4. Russian. PMID: 12138802 162: Cornwell DG, Williams MV, Wani AA, Wani G, Shen E, Jones KH. Mutagenicity of tocopheryl quinones: evolutionary advantage of selective accumulation of dietary alpha-tocopherol. Nutr Cancer. 2002;43(1):111-8. PMID: 12467142 163: Slamenova D, Chalupa I, Robichova S, Gabelova A, Farkasova T, Hrusovska L, Bacova G, Sebova L, Eckl P, Bresgen N, Zeitheim P, Schneider P, Wsolova L, Barancokova M, Kazimirova A, Navarova J, Bezek S. Effect of dietary intake of vitamin A or E on the level of DNA damage, chromosomal aberrations, and micronuclei induced in freshly isolated rat hepatocytes by different carcinogens. Nutr Cancer. 2002;42(1):117-24. PMID: 12235643 164: Haqqani AS, Sandhu JK, Birnboim HC. Dietary vitamin E affects neutrophil distribution and genetic instability in murine Mutatect tumors. Nutr Cancer. 2002;42(1):105-11. PMID: 12235641 165: Nagyova A, Mongiellova V, Krivosikova Z, Blazicek P, Spustova V, Gajdos M, Dzurik R. Serum ex vivo lipoprotein oxidizability in patients with ischemic heart disease supplemented with vitamin E. Physiol Res. 2002;51(5):457-64. PMID: 12470198 166: Saral Y, Uyar B, Ayar A, Naziroglu M. Protective effects of topical alpha-tocopherol acetate on UVB irradiation in guinea pigs: importance of free radicals. Physiol Res. 2002;51(3):285-90. PMID: 12234121 167: Jachec W, Tomasik A, Tarnawski R, Chwalinska E. Evidence of oxidative stress in the renal cortex of diabetic rats: favourable effect of vitamin E. Scand J Clin Lab Invest. 2002;62(1):81-8. PMID: 12002418 168: Malafa MP, Fokum FD, Mowlavi A, Abusief M, King M. Vitamin E inhibits melanoma growth in mice.
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Surgery. 2002 Jan;131(1):85-91. PMID: 11812968 169: Zhang JG, Nicholls-Grzemski FA, Tirmenstein MA, Fariss MW. Vitamin E succinate protects hepatocytes against the toxic effect of reactive oxygen species generated at mitochondrial complexes I and III by alkylating agents. Chem Biol Interact. 2001 Dec 21;138(3):267-84. PMID: 11714483 170: Schnell JW, Anderson RA, Stegner JE, Schindler SP, Weinberg RB. Effects of a high polyunsaturated fat diet and vitamin E supplementation on high-density lipoprotein oxidation in humans. Atherosclerosis. 2001 Dec;159(2):459-66. PMID: 11730827 171: Peluzio MC, Homem AP, Cesar GC, Azevedo GS, Amorim R, Cara DC, Saliba H, Vieira EC, Arantes RE, Alvarez-Leite J. Influences of alpha-tocopherol on cholesterol metabolism and fatty streak development in apolipoprotein E-deficient mice fed an atherogenic diet. Braz J Med Biol Res. 2001 Dec;34(12):1539-45. PMID: 11717706 172: Sylvester PW, McIntyre BS, Gapor A, Briski KP. Vitamin E inhibition of normal mammary epithelial cell growth is associated with a reduction in protein kinase C(alpha) activation. Cell Prolif. 2001 Dec;34(6):347-57. PMID: 11736999 173: Kumar B, Cole WC, Prasad KN. Alpha tocopheryl succinate, retinoic acid and polar carotenoids enhanced the growth-inhibitory effect of a cholesterol-lowering drug on immortalized and transformed nerve cells in culture. J Am Coll Nutr. 2001 Dec;20(6):628-36. PMID: 11771679 174: Cornelli U, Terranova R, Luca S, Cornelli M, Alberti A. Bioavailability and antioxidant activity of some food supplements in men and women using the D-Roms test as a marker of oxidative stress. J Nutr. 2001 Dec;131(12):3208-11. PMID: 11739867 175: Shimizu K, Kondo R, Sakai K, Takeda N, Nagahata T, Oniki T. Novel vitamin E derivative with 4-substituted resorcinol moiety has both antioxidant and tyrosinase inhibitory properties. Lipids. 2001 Dec;36(12):1321-6. PMID: 11834083 176: [No authors listed] Dietary supplements reduce risk of vision loss from age-related macular degeneration. Optom Vis Sci. 2001 Dec;78(12):856. PMID: 11780662
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177: Bang OS, Park JH, Kang SS. Activation of PKC but not of ERK is required for vitamin E-succinate-induced apoptosis of HL-60 cells. Biochem Biophys Res Commun. 2001 Nov 9;288(4):789-97. PMID: 11688977 178: Bidoli E, La Vecchia C, Talamini R, Negri E, Parpinel M, Conti E, Montella M, Carbone MA, Franceschi S. Micronutrients and ovarian cancer: a case-control study in Italy. Ann Oncol. 2001 Nov;12(11):1589-93. PMID: 11822759 179: Bidoli E, La Vecchia C, Talamini R, Negri E, Parpinel M, Conti E, Montella M, Carbone MA, Franceschi S. Micronutrients and ovarian cancer: a case-control study in Italy. Ann Oncol. 2001 Nov;12(11):1589-93. PMID: 11822759 180: Zaluska WT, Ksiazek A, Roliski J. Effect of vitamin E modified cellulose membrane on human lymphocyte, monocyte, and granulocyte CD11b/CD18 adhesion molecule expression during hemodialysis. ASAIO J. 2001 Nov-Dec;47(6):619-22. PMID: 11730199 181: Ziaei S, Faghihzadeh S, Sohrabvand F, Lamyian M, Emamgholy T. A randomised placebo-controlled trial to determine the effect of vitamin E in treatment of primary dysmenorrhoea. BJOG. 2001 Nov;108(11):1181-3. PMID: 11762659 182: Hirvonen T, Virtamo J, Korhonen P, Albanes D, Pietinen P. Flavonol and flavone intake and the risk of cancer in male smokers (Finland). Cancer Causes Control. 2001 Nov;12(9):789-96. PMID: 11714106 183: Ikeda S, Toyoshima K, Yamashita K. Dietary sesame seeds elevate alpha- and gamma-tocotrienol concentrations in skin and adipose tissue of rats fed the tocotrienol-rich fraction extracted from palm oil. J Nutr. 2001 Nov;131(11):2892-7. PMID: 11694614 184: Pehrson B, Holmgren N, Trafikowska U. The influence of parenterally administered alpha-tocopheryl acetate to sows on the vitamin E status of the sows and suckling piglets and piglets after weaning. J Vet Med A Physiol Pathol Clin Med. 2001 Nov;48(9):569-75. PMID: 11765814 185: Bayes B, Pastor MC, Bonal J, Junca J, Romero R. Homocysteine and lipid peroxidation in haemodialysis: role of folinic acid and vitamin E. Nephrol Dial Transplant. 2001 Nov;16(11):2172-5. PMID: 11682663
571
186: Grau A, Guardiola F, Grimpa S, Barroeta AC, Codony R. Oxidative stability of dark chicken meat through frozen storage: influence of dietary fat and alpha-tocopherol and ascorbic acid supplementation. Poult Sci. 2001 Nov;80(11):1630-42. PMID: 11732681 187: Leshchinsky TV, Klasing KC. Relationship between the level of dietary vitamin E and the immune response of broiler chickens. Poult Sci. 2001 Nov;80(11):1590-9. PMID: 11732676 188: Rao MV, Sharma PS. Protective effect of vitamin E against mercuric chloride reproductive toxicity in male mice. Reprod Toxicol. 2001 Nov-Dec;15(6):705-12. PMID: 11738524 189: Soltani-Frisk S, Gronowitz E, Andersson H, Strandvik B. Water-miscible tocopherol is not superior to fat-soluble preparation for vitamin E absorption in cystic fibrosis. Acta Paediatr. 2001 Oct;90(10):1112-5. PMID: 11697419 190: Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001 Oct;119(10):1417-36. PMID: 11594942 191: Iuliano L, Micheletta F, Maranghi M, Frati G, Diczfalusy U, Violi F. Bioavailability of vitamin E as function of food intake in healthy subjects: effects on plasma peroxide-scavenging activity and cholesterol-oxidation products. Arterioscler Thromb Vasc Biol. 2001 Oct;21(10):E34-7. PMID: 11597949 192: Limaye LS, Kale VP. Cryopreservation of human hematopoietic cells with membrane stabilizers and bioantioxidants as additives in the conventional freezing medium. J Hematother Stem Cell Res. 2001 Oct;10(5):709-18. PMID: 11672518 193: Qureshi AA, Salser WA, Parmar R, Emeson EE. Novel tocotrienols of rice bran inhibit atherosclerotic lesions in C57BL/6 ApoE-deficient mice. J Nutr. 2001 Oct;131(10):2606-18. PMID: 11584079 194: Lee L, Kang SA, Lee HO, Lee BH, Jung IK, Lee JE, Hoe YS. Effect of supplementation of vitamin E and vitamin C on brain acetylcholinesterase activity and neurotransmitter levels in rats treated with scopolamine, an inducer of dementia.
572
J Nutr Sci Vitaminol (Tokyo). 2001 Oct;47(5):323-8. PMID: 11814146 195: Tidow-Kebritchi S, Mobarhan S. Effects of diets containing fish oil and vitamin E on rheumatoid arthritis. Nutr Rev. 2001 Oct;59(10):335-8. Review. PMID: 11669239 196: Muscari A, Bastagi L, Poggiopollini G, Tomassetti V, Massarelli G, Boni P, Puddu P. Short term effect of atorvastatin and vitamin E on serum levels of C3, a sensitive marker of the risk of myocardial infarction in men. Cardiovasc Drugs Ther. 2001 Sep;15(5):453-8. PMID: 11855664 197: Gaede P, Poulsen HE, Parving HH, Pedersen O. Double-blind, randomised study of the effect of combined treatment with vitamin C and E on albuminuria in Type 2 diabetic patients. Diabet Med. 2001 Sep;18(9):756-60. PMID: 11606175 198: Gabsi S, Gouider-Khouja N, Belal S, Fki M, Kefi M, Turki I, Ben Hamida M, Kayden H, Mebazaa R, Hentati F. Effect of vitamin E supplementation in patients with ataxia with vitamin E deficiency. Eur J Neurol. 2001 Sep;8(5):477-81. PMID: 11554913 199: Lyons NM, Woods JA, O'Brien NM. alpha-Tocopherol, but not gamma-tocopherol inhibits 7 beta-hydroxycholesterol-induced apoptosis in human U937 cells. Free Radic Res. 2001 Sep;35(3):329-39. PMID: 11697131 200: Toyokuni S, Masumizu T, Ozeki M, Kondo S, Hiroyasu M, Kohno M, Hiai H. An electron spin resonance study on alkylperoxyl radical in thin-sliced renal tissues from ferric nitrilotriacetate-treated rats: the effect of alpha-tocopherol feeding. Free Radic Res. 2001 Sep;35(3):245-55. PMID: 11697123 201: Kakizaki S, Takagi H, Fukusato T, Toyoda M, Horiguchi N, Sato K, Takayama H, Nagamine T, Mori M. Effect of alpha-tocopherol on hepatocarcinogenesis in transforming growth factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine. Int J Vitam Nutr Res. 2001 Sep;71(5):261-7. PMID: 11725690 202: Stulak JM, Lerman A, Porcel MR, Caccitolo JA, Romero JC, Schaff HV, Napoli C, Lerman LO. Renal vascular function in hypercholesterolemia is preserved by chronic antioxidant supplementation. J Am Soc Nephrol. 2001 Sep;12(9):1882-91. PMID: 11518781
573
203: Zhang WR, Hayashi T, Sasaki C, Sato K, Nagano I, Manabe Y, Abe K. Attenuation of oxidative DNA damage with a novel antioxidant EPC-K1 in rat brain neuronal cells after transient middle cerebral artery occlusion. Neurol Res. 2001 Sep;23(6):676-80. PMID: 11547942 204: Shen CT, Wang NK. Antioxidants may mitigate the deterioration of coronary arteritis in patients with Kawasaki disease unresponsive to high-dose intravenous gamma-globulin. Pediatr Cardiol. 2001 Sep-Oct;22(5):419-22. PMID: 11526424 205: Zhao BQ, Suzuki Y, Kondo K, Ikeda Y, Umemura K. Combination of a free radical scavenger and heparin reduces cerebral hemorrhage after heparin treatment in a rabbit middle cerebral artery occlusion model. Stroke. 2001 Sep;32(9):2157-63. PMID: 11546911 206: Fariss MW, Nicholls-Grzemski FA, Tirmenstein MA, Zhang JG. Enhanced antioxidant and cytoprotective abilities of vitamin E succinate is associated with a rapid uptake advantage in rat hepatocytes and mitochondria. Free Radic Biol Med. 2001 Aug 15;31(4):530-41. PMID: 11498286 207: Alleva R, Tomasetti M, Andera L, Gellert N, Borghi B, Weber C, Murphy MP, Neuzil J. Coenzyme Q blocks biochemical but not receptor-mediated apoptosis by increasing mitochondrial antioxidant protection. FEBS Lett. 2001 Aug 10;503(1):46-50. PMID: 11513852 208: Hayes K, Pronczuk A, Perlman D. Vitamin E in fortified cow milk uniquely enriches human plasma lipoproteins. Am J Clin Nutr. 2001 Aug;74(2):211-8. PMID: 11470723 209: Gupta RC, Milatovic D, Dettbarn WD. Nitric oxide modulates high-energy phosphates in brain regions of rats intoxicated with diisopropylphosphorofluoridate or carbofuran: prevention by N-tert-butyl-alpha-phenylnitrone or vitamin E. Arch Toxicol. 2001 Aug;75(6):346-56. PMID: 11570692 210: Bauersachs J, Fleming I, Fraccarollo D, Busse R, Ertl G. Prevention of endothelial dysfunction in heart failure by vitamin E: attenuation of vascular superoxide anion formation and increase in soluble guanylyl cyclase expression. Cardiovasc Res. 2001 Aug 1;51(2):344-50. PMID: 11470474 211: Gokkusu C, Palanduz S, Ademoglu E, Tamer S. Oxidant and antioxidant systems in niddm patients: influence of vitamin E supplementation.
574
Endocr Res. 2001 Aug;27(3):377-86. PMID: 11678585 212: Montero D, Tort L, Robaina L, Vergara JM, Izquierdo MS. Low vitamin E in diet reduces stress resistance of gilthead seabream (Sparus aurata) juveniles. Fish Shellfish Immunol. 2001 Aug;11(6):473-90. PMID: 11556478 213: Kontush A, Mann U, Arlt S, Ujeyl A, Luhrs C, Muller-Thomsen T, Beisiegel U. Influence of vitamin E and C supplementation on lipoprotein oxidation in patients with Alzheimer's disease. Free Radic Biol Med. 2001 Aug 1;31(3):345-54. PMID: 11461772 214: Klipstein-Grobusch K, den Breeijen JH, Grobbee DE, Boeing H, Hofman A, Witteman JC. Dietary antioxidants and peripheral arterial disease : the Rotterdam Study. Am J Epidemiol. 2001 Jul 15;154(2):145-9. PMID: 11447047 215: Scott KC, Hill RC, Lewis DD, Boning AJ Jr, Sundstrom DA. Effect of alpha-tocopheryl acetate supplementation on vitamin E concentrations in Greyhounds before and after a race. Am J Vet Res. 2001 Jul;62(7):1118-20. PMID: 11453489 216: Soltys K, Dikdan G, Koneru B. Oxidative stress in fatty livers of obese Zucker rats: rapid amelioration and improved tolerance to warm ischemia with tocopherol. Hepatology. 2001 Jul;34(1):13-8. PMID: 11431728 217: Gonzalez R, Sanchez de Medina F, Galvez J, Rodriguez-Cabezas ME, Duarte J, Zarzuelo A. Dietary vitamin E supplementation protects the rat large intestine from experimental inflammation. Int J Vitam Nutr Res. 2001 Jul;71(4):243-50. PMID: 11582860 218: Roeber DL, Belk KE, Tatum JD, Wilson JW, Smith GC. Effects of three levels of alpha-tocopheryl acetate supplementation to feedlot cattle on performance of beef cuts during retail display. J Anim Sci. 2001 Jul;79(7):1814-20. PMID: 11465368 219: Khajehdehi P, Mojerlou M, Behzadi S, Rais-Jalali GA. A randomized, double-blind, placebo-controlled trial of supplementary vitamins E, C and their combination for treatment of haemodialysis cramps. Nephrol Dial Transplant. 2001 Jul;16(7):1448-51. PMID: 11427639
575
220: Ruiz JA, Guerrero L, Arnau J, Guardia MD, Esteve-Garcia E. Descriptive sensory analysis of meat from broilers fed diets containing vitamin E or beta-carotene as antioxidants and different supplemental fats. Poult Sci. 2001 Jul;80(7):976-82. PMID: 11469665 221: Manzella D, Barbieri M, Ragno E, Paolisso G. Chronic administration of pharmacologic doses of vitamin E improves the cardiac autonomic nervous system in patients with type 2 diabetes. Am J Clin Nutr. 2001 Jun;73(6):1052-7. PMID: 11382659 222: Bass RT 2nd, Swecker WS Jr, Eversole DE. Effects of oral vitamin E supplementation during late gestation in beef cattle that calved in late winter and late summer. Am J Vet Res. 2001 Jun;62(6):921-7. PMID: 11400851 223: Cederberg J, Siman CM, Eriksson UJ. Combined treatment with vitamin E and vitamin C decreases oxidative stress and improves fetal outcome in experimental diabetic pregnancy. Pediatr Res. 2001 Jun;49(6):755-62. PMID: 11385134 224: Yano T, Yano Y, Yajima S, Kumadaki I, Ichikawa T, Otani S, Hagiwara K. The suppression of ornithine decarboxylase expression and cell proliferation at the promotion stage of lung tumorigenesis in mice by alpha-tocopheryloxybutyric acid. Biochem Pharmacol. 2001 May 1;61(9):1177-81. PMID: 11301052 225: Vetrugno M, Maino A, Cardia G, Quaranta GM, Cardia L. A randomised, double masked, clinical trial of high dose vitamin A and vitamin E supplementation after photorefractive keratectomy. Br J Ophthalmol. 2001 May;85(5):537-9. PMID: 11316710 226: Tesoriere L, D'Arpa D, Butera D, Allegra M, Renda D, Maggio A, Bongiorno A, Livrea MA. Oral supplements of vitamin E improve measures of oxidative stress in plasma and reduce oxidative damage to LDL and erythrocytes in beta-thalassemia intermedia patients. Free Radic Res. 2001 May;34(5):529-40. PMID: 11378535 227: Musaev MU, Mavlianov IR. [Effect of tocopherol acetate, indomethacin and dexamethasone on some indices of local lung defense in rheumatoid arthritis] Lik Sprava. 2001 May-Jun;(3):110-3. Russian. PMID: 11559995 228: Gille L, Staniek K, Nohl H. Effects of tocopheryl quinone on the heart: model experiments with xanthine oxidase, heart mitochondria, and isolated perfused rat hearts.
576
Free Radic Biol Med. 2001 Apr 15;30(8):865-76. PMID: 11295529 229: Stolzenberg-Solomon RZ, Pietinen P, Barrett MJ, Taylor PR, Virtamo J, Albanes D. Dietary and other methyl-group availability factors and pancreatic cancer risk in a cohort of male smokers. Am J Epidemiol. 2001 Apr 1;153(7):680-7. PMID: 11282796 230: Kennedy M, Bruninga K, Mutlu EA, Losurdo J, Choudhary S, Keshavarzian A. Successful and sustained treatment of chronic radiation proctitis with antioxidant vitamins E and C. Am J Gastroenterol. 2001 Apr;96(4):1080-4. PMID: 11316150 231: Thomas SR, Leichtweis SB, Pettersson K, Croft KD, Mori TA, Brown AJ, Stocker R. Dietary cosupplementation with vitamin E and coenzyme Q(10) inhibits atherosclerosis in apolipoprotein E gene knockout mice. Arterioscler Thromb Vasc Biol. 2001 Apr;21(4):585-93. PMID: 11304477 232: Cataldi A, Gasbarro V, Viaggi R, Soverini R, Gresta E, Mascoli F. [Effectiveness of the combination of alpha tocopherol, rutin, melilotus, and centella asiatica in the treatment of patients with chronic venous insufficiency] Minerva Cardioangiol. 2001 Apr;49(2):159-63. Italian. PMID: 11292962 233: Morelli S, Sgreccia A, Bernardo ML, Gurgo Di Castelmenardo A, Petrilli AC, De Leva R, Nuccio F, Calvieri S. Systemic sclerosis (scleroderma). A case of recovery of cardiomyopathy after vitamin E treatment. Minerva Cardioangiol. 2001 Apr;49(2):127-30. English, Italian. PMID: 11292956 234: Galobart J, Barroeta AC, Baucells MD, Codony R, Ternes W. Effect of dietary supplementation with rosemary extract and alpha-tocopheryl acetate on lipid oxidation in eggs enriched with omega3-fatty acids. Poult Sci. 2001 Apr;80(4):460-7. PMID: 11297285 235: Altavilla D, Saitta A, Cucinotta D, Galeano M, Deodato B, Colonna M, Torre V, Russo G, Sardella A, Urna G, Campo GM, Cavallari V, Squadrito G, Squadrito F. Inhibition of lipid peroxidation restores impaired vascular endothelial growth factor expression and stimulates wound healing and angiogenesis in the genetically diabetic mouse. Diabetes. 2001 Mar;50(3):667-74. PMID: 11246889 236: Horton JW, White DJ, Maass DL, Hybki DP, Haudek S, Giroir B. Antioxidant vitamin therapy alters burn trauma-mediated cardiac NF-kappaB
577
activation and cardiomyocyte cytokine secretion. J Trauma. 2001 Mar;50(3):397-406; discussion 407-8. PMID: 11265018 237: Roghani M, Behzadi G. Neuroprotective effect of vitamin E on the early model of Parkinson's disease in rat: behavioral and histochemical evidence. Brain Res. 2001 Feb 16;892(1):211-7. PMID: 11172767 238: Ishige K, Schubert D, Sagara Y. Flavonoids protect neuronal cells from oxidative stress by three distinct mechanisms. Free Radic Biol Med. 2001 Feb 15;30(4):433-46. PMID: 11182299 239: Andreone P, Fiorino S, Cursaro C, Gramenzi A, Margotti M, Di Giammarino L, Biselli M, Miniero R, Gasbarrini G, Bernardi M. Vitamin E as treatment for chronic hepatitis B: results of a randomized controlled pilot trial. Antiviral Res. 2001 Feb;49(2):75-81. PMID: 11248360 240: Naziroglu M, Cay M. Protective role of intraperitoneally administered vitamin E and selenium on the antioxidative defense mechanisms in rats with diabetes induced by streptozotocin. Biol Trace Elem Res. 2001 Feb;79(2):149-59. PMID: 11330521 241: Orbe J, Rodriguez JA, Calvo A, Grau A, Belzunce MS, Martinez-Caro D, Paramo JA. Vitamins C and E attenuate plasminogen activator inhibitor-1 (PAI-1) expression in a hypercholesterolemic porcine model of angioplasty. Cardiovasc Res. 2001 Feb 1;49(2):484-92. PMID: 11164859 242: Jialal I, Traber M, Devaraj S. Is there a vitamin E paradox? Curr Opin Lipidol. 2001 Feb;12(1):49-53. Review. PMID: 11176203 243: Neuzil J, Weber T, Schroder A, Lu M, Ostermann G, Gellert N, Mayne GC, Olejnicka B, Negre-Salvayre A, Sticha M, Coffey RJ, Weber C. Induction of cancer cell apoptosis by alpha-tocopheryl succinate: molecular pathways and structural requirements. FASEB J. 2001 Feb;15(2):403-15. PMID: 11156956 244: Lopez Bote CJ, Isabel B, Flores JM. Effect of dietary linoleic acid concentration and vitamin E supplementation on cell desquamation and susceptibility to oxidative damage of pig jejunal mucosa. J Anim Physiol Anim Nutr (Berl). 2001 Feb;85(1-2):22-8. PMID: 11686769
578
245: Gupta R, Singhal S, Goyle A, Sharma VN. Antioxidant and hypocholesterolaemic effects of Terminalia arjuna tree-bark powder: a randomised placebo-controlled trial. J Assoc Physicians India. 2001 Feb;49:231-5. PMID: 11225136 246: Meydani M. Vitamin E and atherosclerosis: beyond prevention of LDL oxidation. J Nutr. 2001 Feb;131(2):366S-8S. Review. PMID: 11160562 247: Packer L, Weber SU, Rimbach G. Molecular aspects of alpha-tocotrienol antioxidant action and cell signalling. J Nutr. 2001 Feb;131(2):369S-73S. Review. PMID: 11160563 248: Freedman JE, Keaney JF Jr. Vitamin E inhibition of platelet aggregation is independent of antioxidant activity. J Nutr. 2001 Feb;131(2):374S-7S. Review. PMID: 11160564 249: Qureshi AA, Peterson DM, Hasler-Rapacz JO, Rapacz J. Novel tocotrienols of rice bran suppress cholesterogenesis in hereditary hypercholesterolemic swine. J Nutr. 2001 Feb;131(2):223-30. PMID: 11160537 250: Galli F, Varga Z, Balla J, Ferraro B, Canestrari F, Floridi A, Kakuk G, Buoncristiani U. Vitamin E, lipid profile, and peroxidation in hemodialysis patients. Kidney Int Suppl. 2001 Feb;78:S148-54. PMID: 11169001 251: Mydlik M, Derzsiova K, Racz O, Sipulova A, Lovasova E, Petrovicova J. A modified dialyzer with vitamin E and antioxidant defense parameters. Kidney Int Suppl. 2001 Feb;78:S144-7. PMID: 11169000 252: Wu K, Shan YJ, Zhao Y, Yu JW, Liu BH. Inhibitory effects of RRR-alpha-tocopheryl succinate on benzo(a)pyrene (B(a)P)-induced forestomach carcinogenesis in female mice. World J Gastroenterol. 2001 Feb;7(1):60-5. PMID: 11819734 253: Chen R, Tunstall-Pedoe H, Bolton-Smith C, Hannah MK, Morrison C. Association of dietary antioxidants and waist circumference with pulmonary function and airway obstruction. Am J Epidemiol. 2001 Jan 15;153(2):157-63. PMID: 11159161 254: Neuzil J, Weber T, Gellert N, Weber C. Selective cancer cell killing by alpha-tocopheryl succinate.
579
Br J Cancer. 2001 Jan 5;84(1):87-9. PMID: 11139318 255: Helmy M, Shohayeb M, Helmy MH, el-Bassiouni EA. Antioxidants as adjuvant therapy in rheumatoid disease. A preliminary study. Arzneimittelforschung. 2001;51(4):293-8. PMID: 11367869 256: Yam D, Peled A, Shinitzky M. Suppression of tumor growth and metastasis by dietary fish oil combined with vitamins E and C and cisplatin. Cancer Chemother Pharmacol. 2001;47(1):34-40. PMID: 11221959 257: Hirvonen T, Pietinen P, Virtanen M, Ovaskainen ML, Hakkinen S, Albanes D, Virtamo J. Intake of flavonols and flavones and risk of coronary heart disease in male smokers. Epidemiology. 2001 Jan;12(1):62-7. PMID: 11138821 258: Fischer M, Wohlrab J, Marsch W. Crux medicorum ulcerated radiation-induced fibrosis - successful therapy with pentoxifylline and vitamin E. Eur J Dermatol. 2001 Jan-Feb;11(1):38-40. PMID: 11174136 259: Kaul N, Devaraj S, Jialal I. Alpha-tocopherol and atherosclerosis. Exp Biol Med (Maywood). 2001 Jan;226(1):5-12. Review. PMID: 11368238 260: Bron D, Asmis R. Vitamin E and the prevention of atherosclerosis. Int J Vitam Nutr Res. 2001 Jan;71(1):18-24. Review. PMID: 11276917 261: Preuss HG, Marcusen C, Regan J, Klimberg IW, Welebir TA, Jones WA. Randomized trial of a combination of natural products (cernitin, saw palmetto, B-sitosterol, vitamin E) on symptoms of benign prostatic hyperplasia (BPH). Int Urol Nephrol. 2001;33(2):217-25. PMID: 12092634 262: Rose AT, McFadden DW. Alpha-tocopherol succinate inhibits growth of gastric cancer cells in vitro. J Surg Res. 2001 Jan;95(1):19-22. PMID: 11120630 263: Cooney RV, Custer LJ, Okinaka L, Franke AA. Effects of dietary sesame seeds on plasma tocopherol levels. Nutr Cancer. 2001;39(1):66-71. PMID: 11588904
580
264: Cinar MG, Ulker S, Alper G, Evinc A. Effect of dietary vitamin E supplementation on vascular reactivity of thoracic aorta in streptozotocin-diabetic rats. Pharmacology. 2001 Jan;62(1):56-64. PMID: 11150923 265: Hartman TJ, Dorgan JF, Woodson K, Virtamo J, Tangrea JA, Heinonen OP, Taylor PR, Barrett MJ, Albanes D. Effects of long-term alpha-tocopherol supplementation on serum hormones in older men. Prostate. 2001 Jan 1;46(1):33-8. PMID: 11170129 266: Neuzil J, Weber T, Terman A, Weber C, Brunk UT. Vitamin E analogues as inducers of apoptosis: implications for their potential antineoplastic role. Redox Rep. 2001;6(3):143-51. Review. PMID: 11523588 267: Parkhomets' VP, Silonov SB, Donchenko HV. [Effect of alpha-tocopherol, tocopheryl quinone and other complexes with tocopherol-binding proteins on the activity of enzymes metabolizing arachidonic acid] Ukr Biokhim Zh. 2001 Jan-Feb;73(1):43-7. Ukrainian. PMID: 11599425 268: Helzlsouer KJ, Huang HY, Alberg AJ, Hoffman S, Burke A, Norkus EP, Morris JS, Comstock GW. Association between alpha-tocopherol, gamma-tocopherol, selenium, and subsequent prostate cancer. J Natl Cancer Inst. 2000 Dec 20;92(24):2018-23. PMID: 11121464 269: Preiser JC, Van Gossum A, Berre J, Vincent JL, Carpentier Y. Enteral feeding with a solution enriched with antioxidant vitamins A, C, and E enhances the resistance to oxidative stress. Crit Care Med. 2000 Dec;28(12):3828-32. PMID: 11153621 270: Title LM, Cummings PM, Giddens K, Nassar BA. Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E. J Am Coll Cardiol. 2000 Dec;36(7):2185-91. PMID: 11127459 272: Baldi A, Savoini G, Pinotti L, Monfardini E, Cheli F, Dell'Orto V. Effects of vitamin E and different energy sources on vitamin E status, milk quality and reproduction in transition cows. J Vet Med A Physiol Pathol Clin Med. 2000 Dec;47(10):599-608. PMID: 11199208 272: Schuelke M, Finckh B, Sistermans EA, Ausems MG, Hubner C, von Moers A. Ataxia with vitamin E deficiency: biochemical effects of malcompliance with vitamin E therapy.
581
Neurology. 2000 Nov 28;55(10):1584-6. PMID: 11094124 273: Fogarty A, Lewis S, Weiss S, Britton J. Dietary vitamin E, IgE concentrations, and atopy. Lancet. 2000 Nov 4;356(9241):1573-4. PMID: 11075775 274: Engelen W, Keenoy BM, Vertommen J, De Leeuw I. Effects of long-term supplementation with moderate pharmacologic doses of vitamin E are saturable and reversible in patients with type 1 diabetes. Am J Clin Nutr. 2000 Nov;72(5):1142-9. PMID: 11063441 275: Mares-Perlman JA, Lyle BJ, Klein R, Fisher AI, Brady WE, VandenLangenberg GM, Trabulsi JN, Palta M. Vitamin supplement use and incident cataracts in a population-based study. Arch Ophthalmol. 2000 Nov;118(11):1556-63. PMID: 11074813 276: Yano T, Yajima S, Hagiwara K, Kumadaki I, Yano Y, Otani S, Uchida M, Ichikawa T. Vitamin E inhibits cell proliferation and the activation of extracellular signal-regulated kinase during the promotion phase of lung tumorigenesis irrespective of antioxidative effect. Carcinogenesis. 2000 Nov;21(11):2129-33. PMID: 11062179 277: Vlasov AP, Tarasova TV, Sudakova GIu, Ashirov RS, Kil'diushov AN, Dubovskaia TN, Rubtsov OIu, Lazareva OA. [Effect of antioxidants on endotoxicosis in experimental peritonitis] Eksp Klin Farmakol. 2000 Nov-Dec;63(6):58-61. Russian. PMID: 11202515 278: Salonen JT, Nyyssonen K, Salonen R, Lakka HM, Kaikkonen J, Porkkala-Sarataho E, Voutilainen S, Lakka TA, Rissanen T, Leskinen L, Tuomainen TP, Valkonen VP, Ristonmaa U, Poulsen HE. Antioxidant Supplementation in Atherosclerosis Prevention (ASAP) study: a randomized trial of the effect of vitamins E and C on 3-year progression of carotid atherosclerosis. J Intern Med. 2000 Nov;248(5):377-86. PMID: 11123502 279: Delvin EE, Salle BL, Reygrobellet B, Mellier G, Claris O. Vitamin A and E supplementation in breast-fed newborns. J Pediatr Gastroenterol Nutr. 2000 Nov;31(5):562-5. PMID: 11144444 280: Devaraj S, Jialal I. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients. Free Radic Biol Med. 2000 Oct 15;29(8):790-2. PMID: 11053781
582
281: Al Deeb S, Al Moutaery K, Arshaduddin M, Tariq M. Vitamin E decreases valproic acid induced neural tube defects in mice. Neurosci Lett. 2000 Oct 13;292(3):179-82. PMID: 11018306 282: Boaz M, Smetana S, Weinstein T, Matas Z, Gafter U, Iaina A, Knecht A, Weissgarten Y, Brunner D, Fainaru M, Green MS. Secondary prevention with antioxidants of cardiovascular disease in endstage renal disease (SPACE): randomised placebo-controlled trial. Lancet. 2000 Oct 7;356(9237):1213-8. PMID: 11072938 283: Yamamoto S, Tamai H, Ishisaka R, Kanno T, Arita K, Kobuchi H, Utsumi K. Mechanism of alpha-tocopheryl succinate-induced apoptosis of promyelocytic leukemia cells. Free Radic Res. 2000 Oct;33(4):407-18. PMID: 11022849 284: Andres D, Alvarez AM, Diez-Fernandez C, Zaragoza A, Cascales M. HSP70 induction by cyclosporine A in cultured rat hepatocytes: effect of vitamin E succinate. J Hepatol. 2000 Oct;33(4):570-9. PMID: 11059862 285: Pearce KA, Boosalis MG, Yeager B. Update on vitamin supplements for the prevention of coronary disease and stroke. Am Fam Physician. 2000 Sep 15;62(6):1359-66. Review. PMID: 11011864 286: Huraib S, Tanimu D, Shaheen F, Hejaili F, Giles C, Pagayon V. Effect of vitamin-E-modified dialysers on dialyser clotting, erythropoietin and heparin dosage: a comparative crossover study. Am J Nephrol. 2000 Sep-Oct;20(5):364-8. PMID: 11092992 287: Jain SK, McVie R, Smith T. Vitamin E supplementation restores glutathione and malondialdehyde to normal concentrations in erythrocytes of type 1 diabetic children. Diabetes Care. 2000 Sep;23(9):1389-94. PMID: 10977039
288: Woodson K, Stewart C, Barrett M, Bhat NK, Virtamo J, Taylor PR, Albanes D. Effect of vitamin intervention on the relationship between GSTM1, smoking, and lung cancer risk among male smokers. Cancer Epidemiol Biomarkers Prev. 1999 Nov;8(11):965-70. PMID: 10566550 289: Pignatelli P, Pulcinelli FM, Lenti L, Gazzaniga PP, Violi F. Vitamin E inhibits collagen-induced platelet activation by blunting hydrogen peroxide. Arterioscler Thromb Vasc Biol. 1999 Oct;19(10):2542-7. PMID: 10521385
583
290: Barbagallo M, Dominguez LJ, Tagliamonte MR, Resnick LM, Paolisso G. Effects of vitamin E and glutathione on glucose metabolism: role of magnesium. Hypertension. 1999 Oct;34(4 Pt 2):1002-6. PMID: 10523398 291: Steiner M. Vitamin E, a modifier of platelet function: rationale and use in cardiovascular and cerebrovascular disease. Nutr Rev. 1999 Oct;57(10):306-9. PMID: 10575906 292: Chappell LC, Seed PT, Briley AL, Kelly FJ, Lee R, Hunt BJ, Parmar K, Bewley SJ, Shennan AH, Steer PJ, Poston L. Effect of antioxidants on the occurrence of pre-eclampsia in women at increased risk: a randomised trial. Lancet. 1999 Sep 4;354(9181):810-6. PMID: 10485722 293: Bursell SE, King GL. Can protein kinase C inhibition and vitamin E prevent the development of diabetic vascular complications? Diabetes Res Clin Pract. 1999 Sep;45(2-3):169-82. Review. PMID: 10588370 294: Inal M, Kanbak G, Sen S, Akyuz F, Sunal E. Antioxidant status and lipid peroxidation in hemodialysis patients undergoing erythropoietin and erythropoietin-vitamin E combined therapy. Free Radic Res. 1999 Sep;31(3):211-6. PMID: 10499778 295: Bursell SE, Clermont AC, Aiello LP, Aiello LM, Schlossman DK, Feener EP, Laffel L, King GL. High-dose vitamin E supplementation normalizes retinal blood flow and creatinine clearance in patients with type 1 diabetes. Diabetes Care. 1999 Aug;22(8):1245-51. PMID: 10480765 296: Salasche SJ, Lebwohl M. Clinical pearl: vitamin E (alpha-tocopherol), 800 IU daily, may reduce retinoid toxicity. J Am Acad Dermatol. 1999 Aug;41(2 Pt 1):260. PMID: 10426898 297: Farrag EK. Interaction between supplemented selenium and/or vitamin E and Mn, Zn, Fe, and Cu in Schistosoma infected mice. J Egypt Soc Parasitol. 1999 Aug;29(2):517-29. PMID: 10605502 298: Hoffman RM, Garewal HS. Alpha-tocopherol supplementation for men with existing coronary artery disease: a feasibility study. Prev Med. 1999 Aug;29(2):112-8. Erratum in: Prev Med 2000 Jan;30(1):80. PMID: 10446037
584
299: Fighera MR, Queiroz CM, Stracke MP, Brauer MC, Gonzalez-Rodriguez LL, Frussa-Filho R, Wajner M, de Mello CF. Ascorbic acid and alpha-tocopherol attenuate methylmalonic acid-induced convulsions. Neuroreport. 1999 Jul 13;10(10):2039-43. PMID: 10424671 300: van Dam PS, Bravenboer B, van Asbeck BS, Marx JJ, Gispen WH. High rat food vitamin E content improves nerve function in streptozotocin-diabetic rats. Eur J Pharmacol. 1999 Jul 9;376(3):217-22. PMID: 10448879 301: Zheng K, Adjei AA, Shinjo M, Shinjo S, Todoriki H, Ariizumi M. Effect of dietary vitamin E supplementation on murine nasal allergy. Am J Med Sci. 1999 Jul;318(1):49-54. PMID: 10408761 302: Carrasquedo F, Glanc M, Fraga CG. Tissue damage in acute myocardial infarction: selective protection by vitamin E. Free Radic Biol Med. 1999 Jun;26(11-12):1587-90. PMID: 10401625 303: Velasquez-Pereira J, Risco CA, McDowell LR, Staples CR, Prichard D, Chenoweth PJ, Martin FG, Williams SN, Rojas LX, Calhoun MC, Wilkinson NS. Long-term effects of feeding gossypol and vitamin E to dairy calves. J Dairy Sci. 1999 Jun;82(6):1240-51. PMID: 10386310 304: Gorgun M, Erdogan D, Abban G, Turkozkan N, Elbeg S. Effect of vitamin E on adriamycin- induced nephrotoxicity at the ultrastructural level in guinea pigs. Nephron. 1999 Jun;82(2):155-63. PMID: 10364708 305: Ferro D, Basili S, Pratico D, Iuliano L, FitzGerald GA, Violi F. Vitamin E reduces monocyte tissue factor expression in cirrhotic patients. Blood. 1999 May 1;93(9):2945-50. PMID: 10216089 306: Behl C. Vitamin E and other antioxidants in neuroprotection. Int J Vitam Nutr Res. 1999 May;69(3):213-9. PMID: 10389030 307: Kugiyama K, Motoyama T, Doi H, Kawano H, Hirai N, Soejima H, Miyao Y, Takazoe K, Moriyama Y, Mizuno Y, Tsunoda R, Ogawa H, Sakamoto T, Sugiyama S, Yasue H. Improvement of endothelial vasomotor dysfunction by treatment with alpha-tocopherol in patients with high remnant lipoproteins levels. J Am Coll Cardiol. 1999 May;33(6):1512-8. PMID: 10334416
585
308: Bennett RT, Mazzaccaro RJ, Chopra N, Melman A, Franco I. Suppression of renal inflammation with vitamins A and E in ascending pyelonephritis in rats. J Urol. 1999 May;161(5):1681-4. PMID: 10210439 309: Naito Y, Yoshikawa T, Matsuyama K, Yagi N, Kasai K, Sugimoto N, Masui Y, Yoshida N, Kondo M. Effect of vitamin E in gastric mucosal injury induced by ischaemia-reperfusion in nitric oxide-depleted rats. Aliment Pharmacol Ther. 1999 Apr;13(4):553-9. PMID: 10215742 310: Vogel R. Antioxidants are useful in preventing cardiovascular disease: a debate. Pro antioxidants. Can J Cardiol. 1999 Apr;15 Suppl B:23B-25B. PMID: 10350680 311: Canturk Z, Canturk NZ, Ozbilim G, Yenisey C. Experimental cirrhosis of the liver and cytoprotective effects of alpha tocopherol. East Afr Med J. 1999 Apr;76(4):223-7. PMID: 10442105 312: Chugh SN, Kakkar R, Kalra S, Sharma A. An evaluation of oxidative stress in diabetes mellitus during uncontrolled and controlled state and after vitamin E supplementation. J Assoc Physicians India. 1999 Apr;47(4):380-3. PMID: 10778519 313: Zhang S, Hunter DJ, Forman MR, Rosner BA, Speizer FE, Colditz GA, Manson JE, Hankinson SE, Willett WC. Dietary carotenoids and vitamins A, C, and E and risk of breast cancer. J Natl Cancer Inst. 1999 Mar 17;91(6):547-56. PMID: 10088626 314: Yasuda S, Watanabe S, Kobayashi T, Hata N, Misawa Y, Utsumi H, Okuyama H. Dietary docosahexaenoic acid enhances ferric nitrilotriacetate-induced oxidative damage in mice but not when additional alpha-tocopherol is supplemented. Free Radic Res. 1999 Mar;30(3):199-205. PMID: 10711790 315: Lefaix JL, Delanian S, Vozenin MC, Leplat JJ, Tricaud Y, Martin M. Striking regression of subcutaneous fibrosis induced by high doses of gamma rays using a combination of pentoxifylline and alpha-tocopherol: an experimental study. Int J Radiat Oncol Biol Phys. 1999 Mar 1;43(4):839-47. PMID: 10098440 316: Morgante M, Beghelli D, Pauselli M, Dall'Ara P, Capuccella M, Ranucci S. Effect of administration of vitamin E and selenium during the dry period on mammary health and milk cell counts in dairy ewes.
586
J Dairy Sci. 1999 Mar;82(3):623-31. PMID: 10194683 317: Venditti P, Masullo P, Di Meo S, Agnisola C. Protection against ischemia-reperfusion induced oxidative stress by vitamin E treatment. Arch Physiol Biochem. 1999 Feb;107(1):27-34. PMID: 10455556 318: Avunduk AM, Yardimci S, Avunduk MC, Kurnaz L, Aydin A, Kockar MC, Delibasi T, Dayanir V. Prevention of lens damage associated with cigarette smoke exposure in rats by alpha-tocopherol (vitamin E) treatment. Invest Ophthalmol Vis Sci. 1999 Feb;40(2):537-41. PMID: 9950617 319: Palace VP, Hill MF, Farahmand F, Singal PK. Mobilization of antioxidant vitamin pools and hemodynamic function after myocardial infarction. Circulation. 1999 Jan 5-12;99(1):121-6. PMID: 9884388 320: Seth RK, Kharb S. Protective function of alpha-tocopherol against the process of cataractogenesis in humans. Ann Nutr Metab. 1999;43(5):286-9. PMID: 10749028 321: Sharma N, Desigan B, Ghosh S, Sanyal SN, Ganguly NK, Majumdar S. Effect of antioxidant vitamin E as a protective factor in experimental atherosclerosis in rhesus monkeys. Ann Nutr Metab. 1999;43(3):181-90. PMID: 10545674 322: Melhus H, Michaelsson K, Holmberg L, Wolk A, Ljunghall S. Smoking, antioxidant vitamins, and the risk of hip fracture. J Bone Miner Res. 1999 Jan;14(1):129-35. PMID: 9893075 323: Daneyemez M, Kurt E, Cosar A, Yuce E, Ide T. Methylprednisolone and vitamin E therapy in perinatal hypoxic-ischemic brain damage in rats. Neuroscience. 1999;92(2):693-7. PMID: 10408617 324: Landmark K. [Vitamin E is beneficial for the immune system in the elderly] Tidsskr Nor Laegeforen. 1998 Nov 20;118(28):4403-4. Review. Norwegian. PMID: 9889616 325: Motoyama T, Kawano H, Kugiyama K, Hirashima O, Ohgushi M, Tsunoda R, Moriyama Y, Miyao Y, Yoshimura M, Ogawa H, Yasue H. Vitamin E administration improves impairment of endothelium-dependent vasodilation in patients with coronary spastic angina.
587
J Am Coll Cardiol. 1998 Nov 15;32(6):1672-9. PMID: 9822095 326: Tutuncu NB, Bayraktar M, Varli K. Reversal of defective nerve conduction with vitamin E supplementation in type 2 diabetes: a preliminary study. Diabetes Care. 1998 Nov;21(11):1915-8. PMID: 9802743 327: Hahn S, Kuemmerle NB, Chan W, Hisano S, Saborio P, Krieg RJ Jr, Chan JC. Glomerulosclerosis in the remnant kidney rat is modulated by dietary alpha-tocopherol. J Am Soc Nephrol. 1998 Nov;9(11):2089-95. PMID: 9808095 328: Nugent D, Newton H, Gallivan L, Gosden RG. Protective effect of vitamin E on ischaemia-reperfusion injury in ovarian grafts. J Reprod Fertil. 1998 Nov;114(2):341-6. PMID: 10070363 329: Rosen P, Du X, Tschope D. Role of oxygen derived radicals for vascular dysfunction in the diabetic heart: prevention by alpha-tocopherol? Mol Cell Biochem. 1998 Nov;188(1-2):103-11. Review. PMID: 9823016 330: Ribeiro Jorge PA, Neyra LC, Ozaki RM, de Almeida E. Improvement in the endothelium-dependent relaxation in hypercholesterolemic rabbits treated with vitamin E. Atherosclerosis. 1998 Oct;140(2):333-9. PMID: 9862276 331: Campbell MH, Miller JK. Effect of supplemental dietary vitamin E and zinc on reproductive performance of dairy cows and heifers fed excess iron. J Dairy Sci. 1998 Oct;81(10):2693-9. PMID: 9812274 332: Webel DM, Mahan DC, Johnson RW, Baker DH. Pretreatment of young pigs with vitamin E attenuates the elevation in plasma interleukin-6 and cortisol caused by a challenge dose of lipopolysaccharide. J Nutr. 1998 Oct;128(10):1657-60. PMID: 9772132 333: Chan AC. Vitamin E and atherosclerosis. J Nutr. 1998 Oct;128(10):1593-6. Review. PMID: 9772122 334: Fedoruk AS, Gozhenko AI, Rogovyi IuE. [The protective action of alpha-tocopherol on kidney function and lipid peroxidation in acute hemic hypoxia]
588
Patol Fiziol Eksp Ter. 1998 Oct-Dec;(4):35-8. Russian. PMID: 9951303 335: Pizarro M, Lissi E, Reyes J, Holmgren J. [Duchenne muscular dystrophy. Effects of vitamin E administration on urinary luminescence] Rev Med Chil. 1998 Oct;126(10):1165-72. Spanish. PMID: 10030087 336: Konopacka M, Widel M, Rzeszowska-Wolny J. Modifying effect of vitamins C, E and beta-carotene against gamma-ray-induced DNA damage in mouse cells. Mutat Res. 1998 Sep 11;417(2-3):85-94. PMID: 9733928 337: Allard JP, Aghdassi E, Chau J, Tam C, Kovacs CM, Salit IE, Walmsley SL. Effects of vitamin E and C supplementation on oxidative stress and viral load in HIV-infected subjects. AIDS. 1998 Sep 10;12(13):1653-9. PMID: 9764785 338: Morris MC, Beckett LA, Scherr PA, Hebert LE, Bennett DA, Field TS, Evans DA. Vitamin E and vitamin C supplement use and risk of incident Alzheimer disease. Alzheimer Dis Assoc Disord. 1998 Sep;12(3):121-6. PMID: 9772012 339: Barak Y, Swartz M, Shamir E, Stein D, Weizman A. Vitamin E (alpha-tocopherol) in the treatment of tardive dyskinesia: a statistical meta-analysis. Ann Clin Psychiatry. 1998 Sep;10(3):101-5. PMID: 9781472 340: Green D, O'Driscoll G, Rankin JM, Maiorana AJ, Taylor RR. Beneficial effect of vitamin E administration on nitric oxide function in subjects with hypercholesterolaemia. Clin Sci (Lond). 1998 Sep;95(3):361-7. PMID: 9730857 341: Jain SK, Krueger KS, McVie R, Jaramillo JJ, Palmer M, Smith T. Relationship of blood thromboxane-B2 (TxB2) with lipid peroxides and effect of vitamin E and placebo supplementation on TxB2 and lipid peroxide levels in type 1 diabetic patients. Diabetes Care. 1998 Sep;21(9):1511-6. PMID: 9727900 342: Neunteufl T, Kostner K, Katzenschlager R, Zehetgruber M, Maurer G, Weidinger F. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol. 1998 Sep;32(3):711-6. PMID: 9741516
589
343: Weiss WP. Requirements of fat-soluble vitamins for dairy cows: a review. J Dairy Sci. 1998 Sep;81(9):2493-501. Review. PMID: 9785241 344: Davey PJ, Schulz M, Gliksman M, Dobson M, Aristides M, Stephens NG. Cost-effectiveness of vitamin E therapy in the treatment of patients with angiographically proven coronary narrowing (CHAOS trial). Cambridge Heart Antioxidant Study. Am J Cardiol. 1998 Aug 15;82(4):414-7. PMID: 9723625 345: Meydani SN, Meydani M, Blumberg JB, Leka LS, Pedrosa M, Diamond R, Schaefer EJ. Assessment of the safety of supplementation with different amounts of vitamin E in healthy older adults. Am J Clin Nutr. 1998 Aug;68(2):311-8. PMID: 9701188 346: Steinberg FM, Chait A. Antioxidant vitamin supplementation and lipid peroxidation in smokers. Am J Clin Nutr. 1998 Aug;68(2):319-27. Erratum in: Am J Clin Nutr 1999 Jun;69(6):1293. PMID: 9701189 347: Delanian S. Striking regression of radiation-induced fibrosis by a combination of pentoxifylline and tocopherol. Br J Radiol. 1998 Aug;71(848):892-4. PMID: 9828807 348: Inan C, Kilinc K, Kotiloglu E, Akman HO, Kilic I, Michl J. Antioxidant therapy of cobalt and vitamin E in hemosiderosis. J Lab Clin Med. 1998 Aug;132(2):157-65. PMID: 9708577 349: Wittenborg A, Petersen G, Lorkowski G, Brabant T. [Effectiveness of vitamin E in comparison with diclofenac sodium in treatment of patients with chronic polyarthritis] Z Rheumatol. 1998 Aug;57(4):215-21. German. PMID: 9782602 350: Sangha O, Stucki G. [Vitamin E in therapy of rheumatic diseases] Z Rheumatol. 1998 Aug;57(4):207-14. Review. German. PMID: 9782601 351: Bartfay WJ, Hou D, Brittenham GM, Bartfay E, Sole MJ, Lehotay D, Liu PP. The synergistic effects of vitamin E and selenium in iron-overloaded mouse hearts. Can J Cardiol. 1998 Jul;14(7):937-41. Review. PMID: 9706279
590
352: Cinar MG, Can C, Ulker S, Gok S, Coker C, Soykan N, Kosay S, Evinc A. Effect of vitamin E on vascular responses of thoracic aorta in rat experimental arthritis. Gen Pharmacol. 1998 Jul;31(1):149-53. PMID: 9595294 353: Sajjad SH. Vitamin E in the treatment of tardive dyskinesia: a preliminary study over 7 months at different doses. Int Clin Psychopharmacol. 1998 Jul;13(4):147-55. PMID: 9727725 354: Feldmann M, Jachens G, Holtershinken M, Scholz H. [Effects of a selenium/vitamin E substitution on the development of newborn calves on selenium-deficient farms] Tierarztl Prax Ausg G Grosstiere Nutztiere. 1998 Jul;26(4):200-4. German. PMID: 9710921 355: Vatassery GT, Fahn S, Kuskowski MA. Alpha tocopherol in CSF of subjects taking high-dose vitamin E in the DATATOP study. Parkinson Study Group. Neurology. 1998 Jun;50(6):1900-2. PMID: 9633757 356: Halliday GM, Yuen KS, Bestak R, Barnetson RS. Sunscreens and vitamin E provide some protection to the skin immune system from solar-simulated UV radiation. Australas J Dermatol. 1998 May;39(2):71-5. Review. PMID: 9611373 357: Berrocal MC, Bujan J, Jurado F, Abeger A. Vitamin E improves the uptake of unsaturated soya lecithin liposomes by human fibroblasts in vitro. J Microencapsul. 1998 May-Jun;15(3):347-59. PMID: 9608397 358: Adhirai M, Selvam R. Effect of cyclosporin on liver antioxidants and the protective role of vitamin E in hyperoxaluria in rats. J Pharm Pharmacol. 1998 May;50(5):501-5. PMID: 9643443 359: de la Fuente M, Ferrandez MD, Burgos MS, Soler A, Prieto A, Miquel J. Immune function in aged women is improved by ingestion of vitamins C and E. Can J Physiol Pharmacol. 1998 Apr;76(4):373-80. PMID: 9795745 360: Yoshida WB, Alasio T, Mazziotta R, Qin F, Kashani M, Lee S, Dardik H, Becker R. Effect of alpha-tocopherol, taurine and selenium on the attenuation of ischemia/reperfusion injury of splanchnic organs. Cardiovasc Surg. 1998 Apr;6(2):178-87. Erratum in: Cardiovasc Surg 1998 Dec;6(6):682. PMID: 9610832
591
361: Suntres ZE, Shek PN. Prophylaxis against lipopolysaccharide-induced acute lung injury by alpha-tocopherol liposomes. Crit Care Med. 1998 Apr;26(4):723-9. PMID: 9559611 362: Kott RW, Thomas VM, Hatfield PG, Evans T, Davis KC. Effects of dietary vitamin E supplementation during late pregnancy on lamb mortality and ewe productivity. J Am Vet Med Assoc. 1998 Apr 1;212(7):997-1000. PMID: 9540871 363: Ikarashi Y, Tsuchiya T, Nakamura A, Beppu M, Kikugawa K. Effect of vitamin E on contact sensitization responses induced by 2,4-dinitrochlorobenzene in mice. J Nutr Sci Vitaminol (Tokyo). 1998 Apr;44(2):225-36. PMID: 9675703 364: Tong WM, Wang F. Alterations in rat pancreatic islet beta cells induced by Keshan disease pathogenic factors: protective action of selenium and vitamin E. Metabolism. 1998 Apr;47(4):415-9. PMID: 9550538 365: Bonn D. Vitamin E may reduce prostate-cancer incidence. Lancet. 1998 Mar 28;351(9107):961. PMID: 9734953 366: Kolaja KL, Xu Y, Walborg EF Jr, Stevenson DE, Klaunig JE. Vitamin E modulation of dieldrin-induced hepatic focal lesion growth in mice. J Toxicol Environ Health A. 1998 Mar 27;53(6):479-92. PMID: 9537283 367: Smigel K. Vitamin E reduces prostate cancer rates in Finnish trial: U.S. considers follow-up. J Natl Cancer Inst. 1998 Mar 18;90(6):416-7. PMID: 9521161 368: Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, Hartman AM, Haapakoski J, Malila N, Rautalahti M, Ripatti S, Maenpaa H, Teerenhovi L, Koss L, Virolainen M, Edwards BK. Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. J Natl Cancer Inst. 1998 Mar 18;90(6):440-6. PMID: 9521168 369: Watanabe H, Kakihana M, Ohtsuka S, Sugishita Y. [Randomized, double-blind, placebo-controlled study of supplemental vitamin E on attenuation of the development of nitrate tolerance] J Cardiol. 1998 Mar;31(3):173-81. Japanese. PMID: 9557281
592
370: Mutaku JF, Many MC, Colin I, Denef JF, van den Hove MF. Antigoitrogenic effect of combined supplementation with dl-alpha-tocopherol, ascorbic acid and beta-carotene and of dl-alpha-tocopherol alone in the rat. J Endocrinol. 1998 Mar;156(3):551-61. PMID: 9582512 371: Wolf R, Wolf D, Ruocco V. Vitamin E: the radical protector. J Eur Acad Dermatol Venereol. 1998 Mar;10(2):103-17. Review. PMID: 9553906 372: Chan W, Krieg RJ Jr, Norkus EP, Chan JC. alpha-Tocopherol reduces proteinuria, oxidative stress, and expression of transforming growth factor beta 1 in IgA nephropathy in the rat. Mol Genet Metab. 1998 Mar;63(3):224-9. PMID: 9608545 373: Lopez-Torres M, Thiele JJ, Shindo Y, Han D, Packer L. Topical application of alpha-tocopherol modulates the antioxidant network and diminishes ultraviolet-induced oxidative damage in murine skin. Br J Dermatol. 1998 Feb;138(2):207-15. PMID: 9602862 374: Canturk NZ, Canturk Z, Utkan NZ, Yenisey C, Ozbilim G, Yildirir C, Yalman Y. Cytoprotective effects of alpha tocopherol against liver injury induced by extrahepatic biliary obstruction. East Afr Med J. 1998 Feb;75(2):77-80. PMID: 9640827 375: Brown KM, Morrice PC, Duthie GG. Erythrocyte membrane fatty acid composition of smokers and non-smokers: effects of vitamin E supplementation. Eur J Clin Nutr. 1998 Feb;52(2):145-50. PMID: 9505161 376: Barton DL, Loprinzi CL, Quella SK, Sloan JA, Veeder MH, Egner JR, Fidler P, Stella PJ, Swan DK, Vaught NL, Novotny P. Prospective evaluation of vitamin E for hot flashes in breast cancer survivors. J Clin Oncol. 1998 Feb;16(2):495-500. PMID: 9469333 377: Mitchinson M. Long-term alpha tocopherol may yet prolong life. BMJ. 1998 Jan 24;316(7127):308. PMID: 9472536 378: Fuller CJ, Huet BA, Jialal I. Effects of increasing doses of alpha-tocopherol in providing protection of low-density lipoprotein from oxidation. Am J Cardiol. 1998 Jan 15;81(2):231-3. PMID: 9591910
593
379: Gogos CA, Ginopoulos P, Salsa B, Apostolidou E, Zoumbos NC, Kalfarentzos F. Dietary omega-3 polyunsaturated fatty acids plus vitamin E restore immunodeficiency and prolong survival for severely ill patients with generalized malignancy: a randomized control trial. Cancer. 1998 Jan 15;82(2):395-402. PMID: 9445198 380: Bekyarova G, Yankova T, Kozarev I. Combined application of alpha-tocopherol and FC-43 perfluorocarbon emulsion suppresses early postburn lipid peroxidation and improves deformability of erythrocytes. Acta Chir Plast. 1998;40(1):17-21. PMID: 9640804 381: Bekyarova G, Yankova T. alpha-Tocopherol and reduced glutathione deficiency and decreased deformability of erythrocytes after thermal skin injury. Acta Physiol Pharmacol Bulg. 1998;23(2):55-9. PMID: 10347621 382: Personelle J, Bolivar de Souza Pinto E, Ruiz RO. Injection of vitamin A acid, vitamin E, and vitamin C for treatment of tissue necrosis. Aesthetic Plast Surg. 1998 Jan-Feb;22(1):58-64. PMID: 9456357 383: Cartier R, Bouchard D. [The beneficial effect of natural antioxidants on the endothelial function of regenerated endothelium] Ann Chir. 1998;52(8):827-33. French. PMID: 9846436 384: Thurich T, Bereiter-Hahn J, Schneider M, Zimmer G. Cardioprotective effects of dihydrolipoic acid and tocopherol in right heart hypertrophy during oxidative stress. Arzneimittelforschung. 1998 Jan;48(1):13-21. PMID: 9522025 385: Gey KF. Vitamins E plus C and interacting conutrients required for optimal health. A critical and constructive review of epidemiology and supplementation data regarding cardiovascular disease and cancer. Biofactors. 1998;7(1-2):113-74. Review. PMID: 9523035 386: Koya D, Haneda M, Kikkawa R, King GL. d-alpha-tocopherol treatment prevents glomerular dysfunctions in diabetic rats through inhibition of protein kinase C-diacylglycerol pathway. Biofactors. 1998;7(1-2):69-76. PMID: 9523030 387: Kunisaki M, Bursell SE, Umeda F, Nawata H, King GL. Prevention of diabetes-induced abnormal retinal blood flow by treatment with d-alpha-tocopherol.
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Biofactors. 1998;7(1-2):55-67. PMID: 9523029 388: Suzukawa M, Ayaori M, Shige H, Hisada T, Ishikawa T, Nakamura H. Effect of supplementation with vitamin E on LDL oxidizability and prevention of atherosclerosis. Biofactors. 1998;7(1-2):51-4. Review. PMID: 9523028 389: Surai P, Kostjuk I, Wishart G, Macpherson A, Speake B, Noble R, Ionov I, Kutz E. Effect of vitamin E and selenium supplementation of cockerel diets on glutathione peroxidase activity and lipid peroxidation susceptibility in sperm, testes, and liver. Biol Trace Elem Res. 1998 Summer;64(1-3):119-32. PMID: 9845467 390: Brown DJ, Goodman J. A review of vitamins A, C, and E and their relationship to cardiovascular disease. Clin Excell Nurse Pract. 1998 Jan;2(1):10-22. Review. PMID: 12675072 391: Walker MK, Vergely C, Lecour S, Abadie C, Maupoil V, Rochette L. Vitamin E analogues reduce the incidence of ventricular fibrillations and scavenge free radicals. Fundam Clin Pharmacol. 1998;12(2):164-72. PMID: 9565770 392: Haklar G, Sirikci O, Ozer NK, Yalcin AS. Measurement of reactive oxygen species by chemiluminescence in diet-induced atherosclerosis: protective roles of vitamin E and probucol on different radical species. Int J Clin Lab Res. 1998;28(2):122-6. PMID: 9689555 393: Eberlein-Konig B, Placzek M, Przybilla B. Protective effect against sunburn of combined systemic ascorbic acid (vitamin C) and d-alpha-tocopherol (vitamin E). J Am Acad Dermatol. 1998 Jan;38(1):45-8. PMID: 9448204 394: Sobajic SS, Mihailovic MB, Miric MO. The effects of selenium deficiency, dietary selenium, and vitamin E supplementation on the oxidative status of pig liver. J Environ Pathol Toxicol Oncol. 1998;17(3-4):265-70. PMID: 9726800 395: Dursun SM, Oluboka OJ, Devarajan S, Kutcher SP. High-dose vitamin E plus vitamin B6 treatment of risperidone-related neuroleptic malignant syndrome. J Psychopharmacol. 1998;12(2):220-1. PMID: 9694035
595
396: Lee KT, Tsai LY, Sheen PC. Effect of vitamin E, topical hypothermia and steroid on ischemic liver in rats. Kaohsiung J Med Sci. 1998 Jan;14(1):6-12. PMID: 9519683 397: Sieradzki E, Olejarz E, Strauss K, Marzec A, Mieszkowska M, Kaluzny J. [The effect of selenium and vitamin E on the healing process of experimental corneal lesions in the eye of the rabbit] Klin Oczna. 1998;100(2):85-8. Polish. PMID: 9695542 398: McBride JM, Kraemer WJ, Triplett-McBride T, Sebastianelli W. Effect of resistance exercise on free radical production. Med Sci Sports Exerc. 1998 Jan;30(1):67-72. PMID: 9475646
Glycerylphosphorylcholine 4 Studies
1. Mech Ageing Dev 2001 Nov;122(16):2025-40 Multicentre study of l-alpha-glyceryl-phosphorylcholine vs ST200 among patients with probable senile dementia of Alzheimers type.
A multicentre, randomized, controlled study compared the efficacy of l-alpha-glyceryl-phosphorylcholine (alpha GPC) and ST200 (acetyl-l-carnitine) among 126 patients with probable senile dementia of Alzheimers type (SDAT) of mild to moderate degree. Efficacy was evaluated by means of behavioural scales and psychometric tests. The results showed significant improvements in most neuropsychological parameters in the alpha GPC recipients. Improvements also occurred in the ST200 recipients but to a lesser extent. Tolerability was good in both groups. These positive findings require replication in larger, doubleblind, longitudinal studies coupling clinical and biological determinations.
2. Drugs Aging 1993 Mar-Apr;3(2):159-64 Alpha-glycerophosphocholine in the mental recovery of cerebral ischemic attacks. An Italian multicenter clinical trial.
The clinical efficacy and the tolerability of alpha-glycerophosphocholine (alpha-GPC), a drug able to provide high levels of choline for the nervous cells of the brain and to protect their cell walls, have been tested in a clinical open multicenter trial on 2,044 patients suffering from recent stroke or transient ischemic attacks. alpha-GPC was administered after the attack at the daily dose of 1000 mg im for 28 days and orally at the dose of 400 mg tid during the following five months after the first phase. The evaluation of the efficacy on the psychic recovery was done by the Mathew Scale (MS) during the period of im drug administration, and using the Mini Mental State Test (MMST), the Crichton Rating Scale (CRS) and the
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Global Deterioration Scale (GDS) during the following period of oral administration. The MS mean increased 15.9 points in 28 days in a statistically significant way (p < 0.001) from 58.7 to 74.6. At the end of the five month oral administration, the CRS mean significantly decreased 4.3 points, from 20.2 to 15.9 (p < 0.001); the MMST mean significantly increased (p < 0.001) from 21 to 24.3 at the end of the trial, reaching the normality score at the 3rd month assessment. The GDS score at the end of the trial corresponded to no cognitive decline or forgetfulness in 71% of the patients. Adverse events were complained of by 44 patients (2.14%); in 14 (0.7%) the investigator preferred to discontinue therapy. The most frequent complaints were heartburn (0.7%), nausea-vomit (0.5%), insomnia-excitation (0.4%), and headache (0.2%). The trial confirms the therapeutic role of alpha-GPC on the cognitive recovery of patients with acute stroke or TIA, and the low percentage of adverse events confirms its excellent tolerability.
Ann N Y Acad Sci 1994 Jun 30;717:253-69 3. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data.
This paper has reviewed the documentation on the clinical efficacy of choline alphoscerate, a cholinergic precursor, considered as a centrally acting parasympathomimetic drug in dementia disorders and in acute cerebrovascular disease. Thirteen published clinical trials, examining in total 4,054 patients, have evaluated the use of choline alphoscerate in various forms of dementia disorders of degenerative, vascular or combined origin, such as senile dementia of the Alzheimers type (SDAT) or vascular dementia (VaD) and in acute cerebrovascular diseases, such as transitory ischemic attack (TIA) and stroke. Analysis has assessed the design of each study, in particular with respect to experimental design, number of cases, duration of treatment and tests used to evaluate drug clinical efficacy. Most of the 10 studies performed in dementia disorders were controlled trials versus a reference drug or placebo. Overall, 1,570 patients were assessed in these studies, 854 of which in controlled trials. As detected by validated and appropriate tests, such as Mini Mental State Evaluation (MMSE) in SDAT and Sandoz Clinical Assessment Geriatric (SCAG) in VaD, administration of choline alphoscerate significantly improved patient clinical condition. Clinical results obtained with choline alphoscerate were superior or equivalent to those observed in control groups under active treatment and superior to the results observed in placebo groups. Analysis stresses the clear internal consistency of clinical data gathered by different experimental situations on the drug effect, especially with regard to the cognitive symptoms (memory, attention) characterizing the clinical picture of adult-onset dementia disorders. The therapeutic usefulness of choline alphoscerate in relieving cognitive symptoms of chronic cerebral deterioration differentiates this drug from cholinergic precursors used in the past, such as choline and lecithin. Three uncontrolled trials were performed with choline alphoscerate in acute cerebrovascular stroke and TIA, totaling 2,484 patients. The results of these trials suggest that this drug might favor functional recovery of patients with cerebral stroke and should be confirmed in future investigations aimed at establishing the efficacy of the drug in achieving functional recovery of patients with acute cerebrovascular disease.
Mech Ageing Dev 2001 Nov;122(16):2041-55 4. Behavioral effects of L-alpha-glycerylphosphorylcholine: influence on cognitive mechanisms in the rat.
The phosphorylcholine precursor, L-alpha-glycerylphosphorylcholine (alpha-GPC), was injected at the dose of 100 mg/kg/day for 20 days to aged male rats of the Sprague-Dawley strain, 24 months old, showing a deficit of learning and memory capacity. The drug was also administered to rats with amnesia induced pharmacologically with bilateral injections of kainic acid into the nucleus basalis magnocellularis (NBM). Learning and memory capacity of the animals, studied with tests of active and passive avoidance behavior, was improved after treatment with alpha-GPC in all experimental groups. These results indicate that this drug affects cognitive mechanisms in the rat through an involvement of central neurotransmission.
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Pharmacol Biochem Behav 1992 Feb;41(2):445-8
Carnosine - 47 ABSTRACTS
CARNOSINE: 47 RESEARCH ABSTRACTS
1. Bull Exp Biol Med. 2003 Feb;135(2):130-2. Protective effect of carnosine on Cu,Zn-superoxide dismutase during impaired oxidative metabolism in the brain in vivo. Stvolinskii SL, Fedorova TN, Yuneva MO, Boldyrev AA. Institute of Neurology, Russian Academy of Medical Sciences, Moscow. sls@bio.inevro.msk.ru Natural hydrophilic antioxidant carnosine protects cerebral cytosolic Cu,Zn-superoxide dismutase (SOD) under conditions of oxidative stress in various in vivo models: short-term hypobaric hypoxia in rats and accumulation of age-related changes in senescence-accelerated mice (SAMP). Administration of carnosine preventing Cu,Zn-SOD inactivation reduced mortality in rats and prolonged average life span in SAMP-mice. 2. Bull Exp Biol Med. 2002 Jun;133(6):559-61. Effect of carnosine on Drosophila melanogaster lifespan. Yuneva AO, Kramarenko GG, Vetreshchak TV, Gallant S, Boldyrev AA. M. V. Lomonosov Moscow State University, Moscow. A positive dose-dependent effect of carnosine (beta-alanyl-L-histidine) on the lifespan of male Drosophila melanogaster flies was shown. The mean lifespan of male flies receiving 200 mg/liter carnosine approached that of females. At the same time carnosine had no effect on the lifespan of female flies. This positive effect of carnosine probably reflects its protective action against age-related accumulation of free radicals and did not depend on carnosine metabolism in the body. Addition of 200 mg/liter histidine and beta-alanine (separately or in combination) had no effect on the mean lifespan of flies. 3. Biogerontology. 2001;2(1):19-34. AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs? Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G. Physiological Chemistry I, Biocenter, University of Wurzburg, Germany. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 598
In Alzheimer's disease, age-related cellular changes such as compromised energy production and increased radical formation are worsened by the presence of AGEs as additional, AD specific stress factors. Intracellular AGEs (most likely derived from methylglyoxal) crosslink cytoskeletal proteins and render them insoluble. These aggregates inhibit cellular functions including transport processes and contribute to neuronal dysfunction and death. Extracellular AGEs, which accumulate in ageing tissue (but most prominently on long-lived protein deposits like the senile plaques) exert chronic oxidative stress on neurons. In addition, they activate glial cells to produce free radicals (superoxide and NO) and neurotoxic cytokines such as TNF-alpha. Drugs, which inhibit the formation of AGEs by specific chemical mechanisms (AGE-inhibitors), including aminoguanidine, carnosine, tenilsetam, OPB-9195 and pyridoxamine, attenuate the development of (AGE-mediated) diabetic complications. Assuming that 'carbonyl stress' contributes significantly to the progression of Alzheimer's disease, AGE-inhibitors might also become interesting novel therapeutic drugs for treatment of AD. 4. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4765-9. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS. Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, 76107, USA. The hypothesis that age-associated impairment of cognitive and motor functions is due to oxidative molecular damage was tested in the mouse. In a blind study, senescent mice (aged 22 months) were subjected to a battery of behavioral tests for motor and cognitive functions and subsequently assayed for oxidative molecular damage as assessed by protein carbonyl concentration in different regions of the brain. The degree of age-related impairment in each mouse was determined by comparison to a reference group of young mice (aged 4 months) tested concurrently on the behavioral battery. The age-related loss of ability to perform a spatial swim maze task was found to be positively correlated with oxidative molecular damage in the cerebral cortex, whereas age-related loss of motor coordination was correlated with oxidative molecular damage within the cerebellum. These results support the view that oxidative stress is a causal factor in brain senescence. Furthermore, the findings suggest that age-related declines of cognitive and motor performance progress independently, and involve oxidative molecular damage within different regions of the brain. 5. J Histochem Cytochem. 1998 Jun;46(6):731-5. Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4-dinitrophenylhydrazine. Smith MA, Sayre LM, Anderson VE, Harris PL, Beal MF, Kowall N, Perry G. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 599
Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. Formation of carbonyls derived from lipids, proteins, carbohydrates, and nucleic acids is common during oxidative stress. For example, metal-catalyzed, "site-specific" oxidation of several amino acid side-chains produces aldehydes or ketones, and peroxidation of lipids generates reactive aldehydes such as malondialdehyde and hydroxynonenal. Here, using in situ 2,4-dinitrophenylhydrazine labeling linked to an antibody system, we describe a highly sensitive and specific cytochemical technique to specifically localize biomacromolecule-bound carbonyl reactivity. When this technique was applied to tissues from cases of Alzheimer disease, in which oxidative events including lipoperoxidative, glycoxidative, and other oxidative protein modifications have been reported, we detected free carbonyls not only in the disease-related intraneuronal lesions but also in other neurons. In marked contrast, free carbonyls were not found in neurons or glia in age-matched control cases. Importantly, this assay was highly specific for detecting disease-related oxidative damage because the site of oxidative damage can be assessed in the midst of concurrent age-related increases in free carbonyls in vascular basement membrane that would contaminate biochemical samples subjected to bulk analysis. These findings demonstrate that oxidative imbalance and stress are key elements in the pathogenesis of Alzheimer disease.
6. Carnosine prevents activation of free-radical lipid oxidation during stress. Gulyaeva NV, Dupin AM, Levshina IP. Bull Exp Biol Med. 1989; 107(2):148-152.
No abstract available. Neurosci Lett. 1998 Feb 13;242(2):105-8. Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN. Institute of Gerontology, King's College London, UK. j.preston@kcl.ac.uk The effect of a truncated form of the neurotoxin beta-amyloid peptide (A beta25-35) on rat brain vascular endothelial cells (RBE4 cells) was studied in cell culture. Toxic effects of the peptide were seen at 200 microg/ml A beta using a mitochondrial dehydrogenase activity (MTT) reduction assay, lactate dehydrogenase release and glucose consumption. Cell damage could be prevented completely at 200 microg/ml A beta and partially at 300 microg/ml A beta, by the dipeptide carnosine. Carnosine is a naturally occurring dipeptide found at high levels in brain tissue and innervated muscle of mammals including humans. Agents which share properties similar to carnosine, such as beta-alanine, homocarnosine, the anti-glycating agent aminoguanidine, and the antioxidant superoxide dismutase (SOD), also partially rescued cells, although not as effectively as carnosine. We postulate that the mechanism of carnosine protection lies in its anti-glycating and antioxidant activities, both of which are implicated in neuronal and endothelial cell damage during Alzheimer's Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 600
disease. Carnosine may therefore be a useful therapeutic agent. 7. FEBS Lett. 1995 Aug 28;371(1):81-5. Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent. Hipkiss AR, Michaelis J, Syrris P. Division of Biomolecular Engineering, CSIRO, North Ryde, NSW, Australia. The dipeptide carnosine (beta-alanyl-L-histidine) was readily glycosylated non-enzymatically upon incubation with the sugars glucose, galactose, deoxyribose and the triose dihydroxyacetone. Carnosine inhibited glycation of actyl-Lys-His-amide by dihydroxyacetone and it protected alpha-crystallin, superoxide dismutase and catalise against glycation and cross-linking mediated by ribose, deoxyribose, dihydroxyacetone, dihydroxyacetone phosphate and fructose. Unlike certain glycated amino acids, glycated carnosine was non-mutagenic. The potential biological and therapeutic significance of these observations are discussed. 8. Biochim Biophys Acta. 1997 Feb 27;1360(1):17-29. Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham AM. Theodor-Boveri-Institute (Biocenter), Wurzburg, Germany. muench@biozentrum.uni-wuerzburg.de Nucleation-dependent polymerization of beta-amyloid peptide, the major component of plaques in patients with Alzheimer's disease, is significantly accelerated by crosslinking through Advanced Glycation End-products (AGEs) in vitro. During the polymerization process, both nucleus formation and aggregate growth are accelerated by AGE-mediated crosslinking. Formation of the AGE-crosslinked amyloid peptide aggregates could be attenuated by the AGE-inhibitors Tenilsetam, aminoguanidine and carnosine. These experimental data, and clinical studies, reporting a marked improvement in cognition and memory in Alzheimer's disease patients after Tenilsetam treatment, suggest that AGEs might play an important role in the etiology or progression of the disease. Thus AGE-inhibitors may generally 9. Biochem Biophys Res Commun. 1998 Jul 9;248(1):28-32. Carnosine protects proteins against methylglyoxal-mediated modifications. Hipkiss AR, Chana H. Molecular Biology and Biophysics Group, King's College London, United Kingdom. alan.hipkiss@kcl.ac.uk Methylglyoxal (MG) (pyruvaldehyde) is an endogenous metabolite which is present in increased concentrations in diabetics and implicated in formation of advanced Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 601
glycosylation end-products (AGEs) and secondary diabetic complications. Carnosine (beta-alanyl-L-histidine) is normally present in long-lived tissues at concentrations up to 20 mM in humans. Previous studies showed that carnosine can protect proteins against aldehyde-containing cross-linking agents such as aldose and ketose hexose and triose sugars, and malon-dialdehyde, the lipid peroxidation product. Here we examine whether carnosine can protect protein exposed to MG. Our results show that carnosine readily reacts with MG thereby inhibiting MG-mediated protein modification as revealed electrophoretically. We also investigated whether carnosine could intervene when proteins were exposed to an MG-induced AGE (i.e. lysine incubated with MG). Our results show that carnosine can inhibit protein modification induced by a lysine-MG-AGE; this suggests a second intervention site for carnosine and emphasizes its potential as a possible non-toxic modulator of diabetic complications. 10. Free Radic Biol Med. 2000 May 15;28(10):1564-70. Carnosine reacts with a glycated protein. Brownson C, Hipkiss AR. Division of Biomolecular Science, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London, UK. Oxidation and glycation induce formation of carbonyl (CO) groups in proteins, a characteristic of cellular aging. The dipeptide carnosine (beta-alanyl-L-histidine) is often found in long-lived mammalian tissues at relatively high concentrations (up to 20 mM). Previous studies show that carnosine reacts with low-molecular-weight aldehydes and ketones. We examine here the ability of carnosine to react with ovalbumin CO groups generated by treatment of the protein with methylglyoxal (MG). Incubation of MG-treated protein with carnosine accelerated a slow decline in CO groups as measured by dinitrophenylhydrazine reactivity. Incubation of [(14)C]-carnosine with MG-treated ovalbumin resulted in a radiolabeled precipitate on addition of trichloroacetic acid (TCA); this was not observed with control, untreated protein. The presence of lysine or N-(alpha)-acetylglycyl-lysine methyl ester caused a decrease in the TCA-precipitable radiolabel. Carnosine also inhibited cross-linking of the MG-treated ovalbumin to lysine and normal, untreated alpha-crystallin. We conclude that carnosine can react with protein CO groups (termed "carnosinylation") and thereby modulate their deleterious interaction with other polypeptides. It is proposed that, should similar reactions occur intracellularly, then carnosine's known "anti-aging" actions might, at least partially, be explained by the dipeptide facilitating the inactivation/removal of deleterious proteins bearing carbonyl groups. 11.Neurosci Lett. 1997 Dec 5;238(3):135-8. Protective effects of carnosine against malondialdehyde-induced toxicity towards cultured rat brain endothelial cells. Hipkiss AR, Preston JE, Himswoth DT, Worthington VC, Abbot NJ. Molecular Biology and Biophysics Group, King's College London, Strand, UK. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 602
Malondialdehyde (MDA) is a deleterious end-product of lipid peroxidation. The naturally-occurring dipeptide carnosine (beta-alanyl-L-histidine) is found in brain and innervated tissues at concentrations up to 20 mM. Recent studies have shown that carnosine can protect proteins against cross-linking mediated by aldehyde-containing sugars and glycolytic intermediates. Here we have investigated whether carnosine is protective against malondialdehyde-induced protein damage and cellular toxicity. The results show that carnosine can (1) protect cultured rat brain endothelial cells against MDA-induced toxicity and (2) inhibit MDA-induced protein modification (formation of cross-links and carbonyl groups). 12. Cell Mol Neurobiol. 1997 Apr;17(2):259-71. Biochemical and physiological evidence that carnosine is an endogenous neuroprotector against free radicals. Boldyrev AA, Stvolinsky SL, Tyulina OV, Koshelev VB, Hori N, Carpenter DO. M. V. Lomonosov Moscow State University, Moscow, Russia. 1. Carnosine, anserine, and homocarnosine are endogenous dipeptides concentrated in brain and muscle whose biological functions remain in doubt. 2. We have tested the hypothesis that these compounds function as endogenous protective substances against molecular and cellular damage from free radicals, using two isolated enzyme systems and two models of ischemic brain injury. Carnosine and homocarnosine are both effective in activating brain Na, K-ATPase measured under optimal conditions and in reducing the loss of its activity caused by incubation with hydrogen peroxide. 3. In contrast, all three endogenous dipeptides cause a reduction in the activity of brain tyrosine hydroxylase, an enzyme activated by free radicals. In hippocampal brain slices subjected to ischemia, carnosine increased the time to loss of excitability. 4. In in vivo experiments on rats under experimental hypobaric hypoxia, carnosine increased the time to loss of ability to stand and breath and decreased the time to recovery. 5. These actions are explicable by effects of carnosine and related compounds which neutralize free radicals, particularly hydroxyl radicals. In all experiments the effective concentration of carnosine was comparable to or lower than those found in brain. These observations provide further support for the conclusion that protection against free radical damage is a major role of carnosine, anserine, and homocarnosine. 13. Ann N Y Acad Sci. 1998 Nov 20;854:37-53. Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M, Michaelis J, Lawrence J, Mateen A, Allende L, Eagles PA, Abbott NJ. Molecular Biology and Biophysics Group, King's College London, Strand, United Kingdom. alan.hipkiss@kcl.ac.uk Carnosine is a naturally occurring dipeptide (beta-alanyl-L-histidine) found in Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 603
brain, innervated tissues, and the lens at concentrations up to 20 mM in humans. In 1994 it was shown that carnosine could delay senescence of cultured human fibroblasts. Evidence will be presented to suggest that carnosine, in addition to antioxidant and oxygen free-radical scavenging activities, also reacts with deleterious aldehydes to protect susceptible macromolecules. Our studies show that, in vitro, carnosine inhibits nonenzymic glycosylation and cross-linking of proteins induced by reactive aldehydes (aldose and ketose sugars, certain triose glycolytic intermediates and malondialdehyde (MDA), a lipid peroxidation product). Additionally we show that carnosine inhibits formation of MDA-induced protein-associated advanced glycosylation end products (AGEs) and formation of DNA-protein cross-links induced by acetaldehyde and formaldehyde. At the cellular level 20 mM carnosine protected cultured human fibroblasts and lymphocytes, CHO cells, and cultured rat brain endothelial cells against the toxic effects of formaldehyde, acetaldehyde and MDA, and AGEs formed by a lysine/deoxyribose mixture. Interestingly, carnosine protected cultured rat brain endothelial cells against amyloid peptide toxicity. We propose that carnosine (which is remarkably nontoxic) or related structures should be explored for possible intervention in pathologies that involve deleterious aldehydes, for example, secondary diabetic complications, inflammatory phenomena, alcoholic liver disease, and possibly Alzheimer's disease. 14. Exp Cell Res. 1994 Jun;212(2):167-75. Retardation of the senescence of cultured human diploid fibroblasts by carnosine. McFarland GA, Holliday R. CSIRO Division of Biomolecular Engineering, Sydney Laboratory, NSW, Australia. We have examined the effects of the naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) on the growth, morphology, and lifespan of cultured human diploid fibroblasts. With human foreskin cells, HFF-1, and fetal lung cells, MRC-5, we have shown that carnosine at high concentrations (20-50 mM) in standard medium retards senescence and rejuvenates senescent cultures. These late-passage cultures preserve a nonsenescent morphology in the presence of carnosine, in comparison to the senescent morphology first described by Hayflick and Moorhead. Transfer of these late-passage cells in medium containing carnosine to unsupplemented normal medium results in the appearance of the senescent phenotype. The serial subculture of cells in the presence of carnosine does not prevent the Hayflick limit to growth, although the lifespan in population doublings as well as chronological age is often increased. This effect is obscured by the normal variability of human fibroblast lifespans, which we have confirmed. Transfer of cells approaching senescence in normal medium to medium supplemented with carnosine rejuvenates the cells but the extension in lifespan is variable. Neither D-carnosine, (beta-alanyl-D-histidine), homocarnosine, anserine, nor beta-alanine had the same effects as carnosine on human fibroblasts. Carnosine is an antioxidant, but Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 604
it is more likely that it preserves cellular integrity by its effects on protein metabolism. 15. Exp Gerontol. 1999 Jan;34(1):35-45. Further evidence for the rejuvenating effects of the dipeptide L-carnosine on cultured human diploid fibroblasts. McFarland GA, Holliday R. CSIRO Division of Molecular Science, Sydney Laboratory, North Ryde, Australia. We have confirmed and extended previous results on the beneficial effects of L-carnosine on growth, morphology, and longevity of cultured human fibroblasts, strains MRC-5 and HFF-1. We have shown that late-passage HFF-1 cells retain a juvenile appearance in medium containing 50 mM carnosine, and revert to a senescent phenotype when carnosine is removed. Switching cells between medium with and without carnosine also switches their phenotype from senescent to juvenile, and the reverse. The exact calculation of fibroblast lifespans in population doublings (PDs) depends on the proportion of inoculated cells that attach to their substrate and the final yield of cells in each subculture. We have shown that carnosine does not affect cell attachment, but does increase longevity in PDs. However, the plating efficiency of MRC-5 cells seeded at low density is strongly increased in young and senescent cells by carnosine, as shown by the growth of individual colonies. We have also demonstrated that very late-passage MRC-5 cells (with weekly change of medium without subculture) remain attached to their substrate much longer in medium containing carnosine in comparison to control cultures, and also retain a much more normal phenotype. Carnosine is a naturally occurring dipeptide present at high concentration in a range of human tissues. We suggest it has an important role in cellular homeostasis and maintenance. Biosci Rep. 1999 Dec;19(6):581-7. 16. Carnosine, the protective, anti-aging peptide. Boldyrev AA, Gallant SC, Sukhich GT. Center for Molecular Medicine, Department of Biochemistry, Biological Faculty, MV Lomonosov, Moscow State University, Vorobjovy Gory, Russia. aab@1.biocenter.bio.msu.ru Carnosine attenuates the development of senile features when used as a supplement to a standard diet of senescence accelerated mice (SAM). Its effect is apparent on physical and behavioral parameters and on average life span. Carnosine has a similar effect on mice of the control strain, but this is less pronounced due to the non-accelerated character of their senescence processes. 17. Effect of carnosine on age-induced changes in senescence-accelerated mice Yuneva M.O.; Bulygina E.R.; Gallant S.C.; Kramarenko G.G.; Stvolinsky S.L.; Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 605
Semyonova M.L.; Boldyrev A.A. Prof. A.A. Boldyrev, Department of Biochemistry, School of Biology, Moscow State University, Vorobjovy Gory, 119899 Moscow Russian Federation Author Email: aab@1.biocenter.bio.msu.ru Journal of Anti-Aging Medicine ( J. ANTI-AGING MED. ) ( United States ) 1999 , 2/4 (337-342) The effect of carnosine on the life span and several brain biochemical characteristics in senescence-accelerated mice-prone 1 (SAMP1) was investigated. A 50% survival rate of animals treated with carnosine increased by 20% as compared to controls. Moreover, the number of animals that lived to an old age significantly increased. The effect of carnosine on life span was accompanied by a decrease in the level of 2'-tiobarbituric acid reactive substances (TBARS), monoamine oxidase b (MAO b), and Na/K-ATPase activity. There was also an increase in glutamate binding to N-methyl-D-aspartate receptors. These observations are consistent with the conclusion that carnosine increases life span and quality of life by diminishing production of lipid peroxides and reducing the influence of reactive oxygen species (ROS) on membrane proteins. 18. Salganik R.I.; Dikalova A.; Dikalov S.; La D.; Bulygina E.; Stvolinsky S.; Boldyrev A. Dr. R.I. Salganik, 2217B, McGavran-Greenberg Hall, School of Public Health, University of North Carolina, Chapel Hill, NC 27599 United States Author Email: rsalganik@unc.edu Journal of Anti-Aging Medicine ( J. ANTI-AGING MED. ) ( United States ) 2001 , 4/1 (49-54) Impairment of long-term memory is characteristic of aging and some neurodegenerative diseases associated with the increased generation of reactive oxygen species (ROS). An inbred OXYS rat strain was developed from Wistar rats with an inherited overproduction of ROS, manifesting impairment of long-term memory and oxidative damage of cell structures and functions. A highly inbred OYXR strain harboring oxidative patterns close to normal Wistar rats served as a control. Alterations of brain neurochemical functions in OXYS rats and the possibility of protecting them with different antioxidants were studied. Assaying the oxidative DNA lesion, 8-hydroxydeoxyguanine (8-OHdG), and lipid peroxidation-induced etheno-DNA adducts in rat liver DNA indicated a high oxidative stress in OXYS rats. We found that the Na/K-ATPase activity, N-methyl-Daspartate (NMDA) receptors, and the integrity of sulfhydryl (SH) groups, parameters associated with memory-related neurochemical mechanisms, were altered in OXYS rat brains compared to that of control OXYR rats. Protection of neurochemical functions was investigated by long-term treatment of OXYS rats with different antioxidants, namely, 2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene; BHT), 2,6-dimethyl-3hydroxypyridine (emoxipine), and beta-alanyl-L-histidine (carnosine). We determined that BHT protected rat brains from the oxidative alteration of Na/K-ATPase but did not protect NMDA receptors and SH groups. Emoxipine protected rat brain from oxidative Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 606
impairment of SH group, but did not protect NMDA receptors and Na/K-ATPase. Carnosine protected from oxidative impairment rat brain NMDA receptors, Na/KATPase, and protein SH groups. 19. Biochemistry (Mosc). 2000 Jul;65(7):807-16. Interactions between carnosine and zinc and copper: implications for neuromodulation and neuroprotection. Trombley PQ, Horning MS, Blakemore LJ. Biomedical Research Facility, Department of Biological Science, Florida State University, Tallahassee, Florida 32306-4340, USA. trombley@neuro.fsu.edu. This review examines interactions in the mammalian central nervous system (CNS) between carnosine and the endogenous transition metals zinc and copper. Although the relationship between these substances may be applicable to other brain regions, the focus is on the olfactory system where these substances may have special significance. Carnosine is not only highly concentrated in the olfactory system, but it is also contained in neurons (in contrast to glia cells in most of the brain) and has many features of a neurotransmitter. Whereas the function of carnosine in the CNS is not well understood, we review evidence that suggests that it may act as both a neuromodulator and a neuroprotective agent. Although zinc and/or copper are found in many neuronal pathways in the brain, the concentrations of zinc and copper in the olfactory bulb (the target of afferent input from sensory neurons in the nose) are among the highest in the CNS. Included in the multitude of physiological roles that zinc and copper play in the CNS is modulation of neuronal excitability. However, zinc and copper also have been implicated in a variety of neurologic conditions including Alzheimer's disease, Parkinson's disease, stroke, and seizures. Here we review the modulatory effects that carnosine can have on zinc and copper's abilities to influence neuronal excitability and to exert neurotoxic effects in the olfactory system. Other aspects of carnosine in the CNS are reviewed elsewhere in this issue. 20. Brain Res. 2000 Jan 3;852(1):56-61. Endogenous mechanisms of neuroprotection: role of zinc, copper, and carnosine. Horning MS, Blakemore LJ, Trombley PQ. Biomedical Research Facility, Department of Biological Science, Florida State University, Tallahassee 32306-4340, USA. horning@neuro.fsu.edu Zinc and copper are endogenous transition metals that can be synaptically released during neuronal activity. Synaptically released zinc and copper probably function to modulate neuronal excitability under normal conditions. However, zinc and copper also can be neurotoxic, and it has been proposed that they may contribute to the neuropathology associated with a variety of conditions, such as Alzheimer's disease, stroke, and seizures. Recently, we demonstrated that carnosine, a dipeptide expressed in glial cells throughout the brain as well as in neuronal pathways of the visual and olfactory systems, can Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 607
modulate the effects of zinc and copper on neuronal excitability. This result led us to hypothesize that carnosine may modulate the neurotoxic effects of zinc and copper as well. Our results demonstrate that carnosine can rescue neurons from zinc- and copper-mediated neurotoxicity and suggest that one function of carnosine may be as an endogenous neuroprotective agent. 21. Neuroscience. 1999;94(2):571-7. Carnosine protects against excitotoxic cell death independently of effects on reactive oxygen species. Boldyrev A, Song R, Lawrence D, Carpenter DO. International Center for Biotechnology and Center for Molecular Medicine, MV Lomonosov Moscow State University, Department of Biochemistry, School of Biology, Russia. The role of carnosine, N-acetylcarnosine and homocarnosine as scavengers of reactive oxygen species and protectors against neuronal cell death secondary to excitotoxic concentrations of kainate and N-methyl-D-aspartate was studied using acutely dissociated cerebellar granule cell neurons and flow cytometry. We find that carnosine, N-acetylcarnosine and homocarnosine at physiological concentrations are all potent in suppressing fluorescence of 2',7'-dichlorofluorescein, which reacts with intracellularly generated reactive oxygen species. However, only carnosine in the same concentration range was effective in preventing apoptotic neuronal cell death, studied using a combination of the DNA binding dye, propidium iodide, and a fluorescent derivative of the phosphatidylserine-binding dye, Annexin-V. Our results indicate that carnosine and related compounds are effective scavengers of reactive oxygen species generated by activation of ionotropic glutamate receptors, but that this action does not prevent excitotoxic cell death. Some other process which is sensitive to carnosine but not the related compounds is a critical factor in cell death. These observations indicate that at least in this system reactive oxygen species generation is not a major contributor to excitotoxic neuronal cell death. 22. Cell Mol Neurobiol. 1999 Feb;19(1):45-56. Carnosine: an endogenous neuroprotector in the ischemic brain. Stvolinsky SL, Kukley ML, Dobrota D, Matejovicova M, Tkac I, Boldyrev AA. Institute of Neurology, Russian Academy of Medical Sciences, Moscow, Russia. 1. The biological effects of carnosine, a natural hydrophilic neuropeptide, on the reactive oxygen species (ROS) pathological generation are reviewed. 2. We describe direct antioxidant action observed in the in vitro experiments. 3. Carnosine was found to effect metabolism indirectly. These effects are reflected in ROS turnover regulation and lipid peroxidation (LPO) processes. 4. During brain ischemia carnosine acts as a neuroprotector, contributing to better cerebral blood flow restoration, electroencephalography (EEG) normalization, decreased lactate accumulation, and enzymatic protection against ROS. 5. The Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 608
data presented demonstrate that carnosine is a specific regulator of essential metabolic pathways in neurons supporting brain homeostasis under unfavorable conditions. 23. Surgery. 1986 Nov;100(5):815-21. Action of carnosine and beta-alanine on wound healing. Nagai K, Suda T, Kawasaki K, Mathuura S. In rats treat-given hydrocortisone to suppress healing, tensile strength of the skin at the site of an incision wound was significantly higher in rats locally treated with carnosine than in untreated animals. Similar effects on the tensile strength of the skin were observed by the administration of beta-alanine and histidine, but not of beta-alanine alone. Exogenous carnosine was degraded in the body by carnosinase and histidine decarboxylase to yield histamine. Since beta-alanine, the other degradation product of carnosine, was found to stimulate the biosynthesis of nucleic acids and collagen, histamine derived from carnosine is considered to have enhanced the process of wound healing by stimulating effusion at the initial stage of inflammation. Thus, the enhancement by carnosine of wound healing may be ascribed to stimulation of early effusion by histamine and of collagen biosynthesis by beta-alanine. The wound-healing effects of carnosine were further demonstrated by the observation that carnosine significantly increased granulation suppressed by cortisone, mitomycin C, 5-fluorouracil, and bleomycin. 24. Nippon Seirigaku Zasshi. 1986;48(11):735-40. [Immuno-enhancing actions of carnosine and homocarnosine] [Article in Japanese] Nagai K, Suda T. Immuno-enhancing actions of carnosine, beta-alanine, homocarnosine, and gamma-aminobutyric acid were studied in ddY mice by evaluating plaque-forming cell reaction against sheep red blood cells. Animals were administered the test agents in prior to, or simultaneously with, various treatments that are known to reduce immune function such as administration of the anti-tumor agents, mitomycin C and 5-fluorouracil, immunosuppressant cyclophosphamide, antiinflammatory agent hydrocortisone, or cancer implantation and gamma-irradiation. Experiments were performed also in aged mice with reduced immune function. The administration of these drugs showed non-specific immuno-enhancing effects under all conditions examined and on all cell groups that may have been affected by these immunosuppressive stimulus. 25. Nippon Seirigaku Zasshi. 1986;48(11):741-7. [Antineoplastic effects of carnosine and beta-alanine--physiological considerations of its antineoplastic effects] [Article in Japanese] Nagai K, Suda T. Antineoplastic effects of carnosine (CAR) and beta-alanine (ALA), were examined Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 609
in vivo using ddY mice implanted with the solid tumor Sarcoma-180. The sarcoma was treated with trypsin, 10(5) cells were implanted subcutaneously in the back of the animals, and CAR and ALA were administered subcutaneously 2 cm from the implantation site starting on the next day. The animals treated with ALA alone showed prolongation of survival to a T/C value of 132%; the growth of the tumor was inhibited and mortality reduced in those treated with CAR alone. Regression of the tumor was observed in the animals treated with either drug. The effects of these agents were enhanced when administered in combination with the non-specific active immuno-enhancing agent OK-432. More than half the animals treated with CAR and OK-432 survived the observation period (T/C greater than 218%), and survival was prolonged in those treated with ALA and OK-432 to a T/C value of 132%. The agents also showed potent antineoplastic effects on Sarcoma-180 when the tumor had been attenuated in vivo with mitomycin C (MMC). 26. Nippon Seirigaku Zasshi. 1986;48(6):572-9. [Immunoregulative effects of homocarnosine and gamma-aminobuthyric acid] [Article in Japanese] Nagai K, Suda T. The effects of homocarnosine and GABA on antibody production (PFC reaction) and cellular immunity (delayed hypersensitivity reaction, DHR) were examined in vivo. In mice treated with these agents, PFC reaction to 2 X 10(7) SRBC was enhanced but that to 1 X 10(9) SRBC was suppressed; moreover, immunoreaction was reduced in immature mice (2-2.5 weeks old) but was increased in aged mice (30 weeks old or above). These agents had optimal doses on the PFC reaction in mice given 1 X 10(8) SRBC and DHR, and induced recovery of immunofunction suppressed by the administration of MMC. 27. Nippon Seirigaku Zasshi. 1986;48(6):564-71. [Immunoregulative effects of carnosine and beta-alanine] [Article in Japanese] Nagai K, Suda T. Physiological factors involved in immunity and tissue repair with regulate homeostasis, a physiological function of the connective tissue, are as yet unidentified. We earlier detected the granulation-promoting action of carnosine, and reported on the acceleration of tissue repair in experimental as well as clinical studies. In that study, immunoregulatory effects of carnosine and beta-alanine were examined by the plaque-forming cell (PFC) count and delayed hypersensitivity reaction (DHR). The PFC value increased in mice pretreated with these agents. In these mice, PFC reaction to 2 X 10(7) SRBC was enhanced but that to 1 X 10(9) SRBC was suppressed. The agents also suppressed excess immunoreaction in immature mice but increased weakened immunoreaction in aged animals. Furthermore, the agents had the optimal doses for the enhancement of both PFC reaction to 1 X 10(8) SRBC and DHR to 1% picryl chloride. They also induced recovery of immunofunction suppressed by the administration of MMC. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 610
Carnosine and beta-alanine exerts immunoregulatory effects by activating both T and B cells. Our observations indicated that the agents not only promote tissue repair but also help maintain homeostasis and accelerate spontaneous healing. 28. Effects of carnosine on the development of rat sponge-induced granulation tissue. II. Histoautoradiographic observations on collagen biosynthesis. Vizioli MR, Blumen G, Almeida OP, et al. Cell Mol Biol. 1983; 29(1):1-9. No abstract available. 29. Cell Struct Funct. 1999 Apr;24(2):79-87. Carnosine stimulates vimentin expression in cultured rat fibroblasts. Ikeda D, Wada S, Yoneda C, Abe H, Watabe S. Laboratory of Aquatic Molecular Biology and Biotechnology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Bunkyo, Japan. Two-dimensional electrophoretic gel profiles were compared between rat 3Y1 fibroblasts cultured in the presence and absence of 30 mM L-carnosine (beta-alanyl-L-histidine) for one week without any replenishment of medium. While a number of cellular proteins changed their expression levels by the addition of carnosine, we identified one of the most prominently varied proteins as vimentin. Immunoblot analysis with anti-vimentin antibody demonstrated that the vimentin levels increased about 2-fold after one-week culture in the presence of carnosine. We also confirmed that the increase of vimentin expression was dependent on the concentration of carnosine added to the medium. Moreover, when cultured cells were stained with anti-vimentin antibody and observed by light microscopy, most cells grown in the presence of carnosine were found to have markedly developed vimentin filaments. The increase of vimentin expression was also observed by adding with carnosine related dipeptides, N-acetylcarnosine and anserine. 30. Cell Mol Life Sci. 2000 May;57(5):747-53. A possible new role for the anti-ageing peptide carnosine. Hipkiss AR, Brownson C. Biomolecular Sciences Division, GKT School of Biomedical Sciences, King's College London, UK. alan.hipkiss@kcl.ac.uk The naturally occurring dipeptide carnosine (beta-alanyl-L-histidine) is found in surprisingly large amounts in long-lived tissues and can delay ageing in cultured human fibroblasts. Carnosine has been regarded largely as an anti-oxidant and free radical scavenger. More recently, an anti-glycating potential has been discovered whereby carnosine can react with low-molecular-weight compounds that bear carbonyl groups (aldehydes and ketones). Carbonyl groups, arising mostly from the attack of reactive oxygen species and low-molecular-weight aldehydes and ketones, accumulate on proteins Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 611
during ageing. Here we propose, with supporting evidence, that carnosine can react with protein carbonyl groups to produce protein-carbonyl-carnosine adducts ('carnosinylated' proteins). The various possible cellular fates of the carnosinylated proteins are discussed. These proposals may help explain anti-ageing actions of carnosine and its presence in non-mitotic cells of long-lived mammals. 31. Biogerontology. 2000;1(3):217-23. Carnosine reacts with protein carbonyl groups: another possible role for the anti-ageing peptide? Hipkiss AR, Brownson C. Biomolecular Sciences Division, GKT School of Biomedical Sciences, King's College London, Guy's Campus London Bridge, London EC1 1UL, UK. alan.hipkiss@kcl.ac.uk Carnosine (beta-alanyl-L-histidine) can delay senescence and provoke cellular rejuvenation in cultured human fibroblasts. The mechanisms by which such a simple molecule induces these effects is not known despite carnosine's well documented anti-oxidant and oxygen free-radical scavenging activities. Carbonyl groups are generated on proteins post-synthetically by the action of reactive oxygen species and glycating agents and their accumulation is a major biochemical manifestation of ageing. We suggest that, in addition to the prophylactic actions of carnosine, it may also directly participate in the inactivation/disposal of aged proteins possibly by direct reaction with the carbonyl groups on proteins. The possible fates of these 'carnosinylated' proteins including the formation of inert lipofuscin, proteolysis via the proteasome system and exocytosis following interaction with receptors are also discussed. The proposal may point to a hitherto unrecognised mechanism by which cells/organisms normally defend themselves against protein carbonyls. CARNOSINE AND GLYCATION 32. Mech Ageing Dev 2001 Sep 15;122(13):1431-45 Carnosine, the anti-ageing, anti-oxidant dipeptide, may react with protein carbonyl groups. Hipkiss AR, Brownson C, Carrier MJ. Division of Biomolecular Sciences, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, UK. alan.hipkiss@kcl.ac.uk Carnosine (beta-alanyl-L-histidine) is a physiological dipeptide which can delay ageing and rejuvenate senescent cultured human fibroblasts. Carnosine's anti-oxidant, free radical- and metal ion-scavenging activities cannot adequately explain these effects. Previous studies showed that carnosine reacts with small carbonyl compounds (aldehydes and ketones) and protects Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 612
macromolecules against their cross-linking actions. Ageing is associated with accumulation of carbonyl groups on proteins. We consider here whether carnosine reacts with protein carbonyl groups. Our evidence indicates that carnosine can react nonenzymically with protein carbonyl groups, a process termed 'carnosinylation'. We propose that similar reactions could occur in cultured fibroblasts and in vivo. A preliminary experiment suggesting that carnosine is effective in vivo is presented; it suppressed diabetes-associated increase in blood pressure in fructose-fed rats, an observation consistent with carnosine's anti-glycating actions. We speculate that: (i) carnosine's apparent anti-ageing actions result, partly, from its ability to react with carbonyl groups on glycated/oxidised proteins and other molecules; (ii) this reaction, termed 'carnosinylation,' inhibits cross-linking of glycoxidised proteins to normal macromolecules; and (iii) carnosinylation could affect the fate of glycoxidised polypeptides. 33. Biochemistry (Mosc) 2000 Jul;65(7):771-8 Carnosine and protein carbonyl groups: a possible relationship. Hipkiss AR. Division of Biomolecular Sciences, GKT School of Biomedical Sciences, King's College London, London SE1 1UL, UK. alan.hipkiss@kcl.ac.uk. Carnosine has been shown to react with low-molecular-weight aldehydes and ketones and has been proposed as a naturally occurring anti-glycating agent. It is suggested here that carnosine can also react with ("carnosinylate") proteins bearing carbonyl groups, and evidence supporting this idea is presented. Accumulation of protein carbonyl groups is associated with cellular ageing resulting from the effects of reactive oxygen species, reducing sugars, and other reactive aldehydes and ketones. Carnosine has been shown to delay senescence and promote formation of a more juvenile phenotype in cultured human fibroblasts. It is speculated that carnosine may intracellularly suppress the deleterious effects of protein carbonyls by reacting with them to form protein-carbonyl-carnosine adducts, i.e., "carnosinylated" proteins. Various fates of the carnosinylated proteins are discussed including formation of inert lipofuscin and proteolysis via proteosome and RAGE activities. It is proposed that the anti-ageing and rejuvenating effects of carnosine are more readily explainable by its ability to react with protein carbonyls than its well-documented antioxidant activity. 34. Neurosci Lett 1998 Feb 13;242(2):105-8 Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN. Institute of Gerontology, King's College London, UK. j.preston@kcl.ac.uk The effect of a truncated form of the neurotoxin beta-amyloid peptide (A beta25-35) on rat brain vascular endothelial cells (RBE4 cells) was studied in Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 613
cell culture. Toxic effects of the peptide were seen at 200 microg/ml A beta using a mitochondrial dehydrogenase activity (MTT) reduction assay, lactate dehydrogenase release and glucose consumption. Cell damage could be prevented completely at 200 microg/ml A beta and partially at 300 microg/ml A beta, by the dipeptide carnosine. Carnosine is a naturally occurring dipeptide found at high levels in brain tissue and innervated muscle of mammals including humans. Agents which share properties similar to carnosine, such as beta-alanine, homocarnosine, the anti-glycating agent aminoguanidine, and the antioxidant superoxide dismutase (SOD), also partially rescued cells, although not as effectively as carnosine. We postulate that the mechanism of carnosine protection lies in its anti-glycating and antioxidant activities, both of which are implicated in neuronal and endothelial cell damage during Alzheimer's disease. Carnosine may therefore be a useful therapeutic agent. 35. Biochemistry (Mosc) 1997 Oct;62(10):1119-23 Change in the functional properties of actin by its glycation in vitro. Kuleva NV, Kovalenko ZS. Department of Biochemistry, School of Biology and Soil Sciences, St. Petersburg State University, Universitetskaya Naberezhnaya 7/9, Vasil'evskii Ostrov, St. Petersburg, Russia. The influence of glycation (non-enzymatic glycosylation) on structural and functional properties of actin of rabbit skeletal muscle and the effects of the natural anti-glycating dipeptide carnosine were studied. Glucose (0.5 M), fructose (0.5 M), and glyceraldehyde (0.05 M) were used as glycating agents. Marked changes in the structural and functional properties were observed in the presence of glyceraldehyde when high-molecular-weight components appear. This was followed by a decrease in the ability of actin to activate myosin ATPase, to polymerize, and to inhibit DNase I. In the presence of 0.05 M carnosine, the quantity of high-molecular-weight products decreased and myosin ATPase activation was retained. Since muscle tissue contains millimolar quantities of carnosine, glycation of actin associated with changes in its properties is evidently more likely to occur in non-muscle cells. CARNOSINE AND DEGENERATIVE 36. Biochim Biophys Acta. 2000 Dec 15;1524(2-3):162-70. Enhanced oxidative damage by the familial amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutants. Kang JH, Eum WS. Department of Genetic Engineering, Division of Natural Sciences, Chongju University, 360-764, Chongju, South Korea. jhkang@chongiu.ac.kr Some cases of familial amyotrophic lateral sclerosis (FALS), a degenerative disorder of motor neurons, is associated with mutation in the Cu,Zn-superoxide Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 614
dismutase (SOD) gene SOD1. The purified FALS mutant and wild-type Cu,Zn-SODs expressed in Escherichia coli cells have identical dismutation activity whereas the hydroxyl radical formation of FALS mutants was enhanced relative to that of the wild-type enzyme. These higher free radical-generating activities of mutants facilitated the release of copper ions from their own molecules. The reaction of the mutants with hydrogen peroxide enhanced DNA strand breaks and lipid peroxidation. The results suggested that the enhanced oxidative damage of macromolecules is mediated in the Cu,Zn-SOD mutants and hydrogen peroxide system via the generation of hydroxyl radicals by a combination of the higher free radical-generating activities of mutants and a Fenton-like reaction of copper ions released from oxidatively damaged Cu,Zn-SODs. Carnosine has been proposed to act as antioxidant in vivo. We investigated whether carnosine could protect the oxidative damage induced by FALS mutants. Carnosine effectively inhibited the DNA cleavage and lipid peroxidation. These results suggest that the higher free radical-generating function of FALS mutants can lead to increased oxidative damage of macromolecules which further implicates free radical-mediated motor neuronal injury in the pathogenesis of FALS and carnosine may be explored as potential therapeutic agents for FALS patients. GLYCATION AND CARNOSINE SEARCH 37. Life Sci. 2003 Apr 25;72(23):2603-16. The polyamines spermine and spermidine protect proteins from structural and functional damage by AGE precursors: a new role for old molecules? Gugliucci A, Menini T. Biochemistry Laboratory, Division of Basic Medical Sciences, Touro University, College of Osteopathic Medicine, 1310 Johnson Lane, Mare Island, Vallejo, CA 94592, USA. agugliuc@touro.edu Due to the importance of glycation in the genesis of diabetic complications, an intense search for synthetic new antiglycation agents is ongoing. However, a somewhat neglected avenue is the search for endogenous compounds that may inhibit the process and be a source of protodrugs. Based on their ubiquity, their polycationic nature, their essential role in growth, their relatively high concentrations in tissues, and their high concentrations in sperm, we hypothesized that polyamines inhibit glycation and that might be one of their so far elusive functions. In this study we demonstrate a potent antiglycation effect of physiological concentrations of the polyamines spermine and spermidine. We employed two approaches: in the first, we monitored structural changes on histones and ubiquitin in which polyamines inhibit glycation-induced dimer and polymer formation. In the second we monitored functional impairment of catalytic activity of antithrombin III and plasminogen. Protection is afforded against glycation by hexoses, trioses and dicarbonyls AGE precursors and is comparable to those of aminoguanidine and carnosine. 38. Biochem Biophys Res Commun. 2003 Jan 3;300(1):75-80. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 615
Carnosine promotes the heat denaturation of glycated protein. Yeargans GS, Seidler NW. Department of Biochemistry, University of Health Sciences, 1750 Independence Avenue, Kansas City, MO 64106-1453, USA. Glycation alters protein structure and decreases biological activity. Glycated proteins, which accumulate in affected tissue, are reliable markers of disease. Carnosine, which prevents glycation, may also play a role in the disposal of glycated protein. Carnosinylation tags glycated proteins for cell removal. Since thermostability determines cell turnover of proteins, the present study examined carnosine's effect on thermal denaturation of glycated protein using cytosolic aspartate aminotransferase (cAAT). Glycated cAAT (500 microM glyceraldehyde for 72h at 37 degrees C) increased the T(0.5) (temperature at which 50% denaturation occurs) and the Gibbs free energy barrier (DeltaG) for denaturation. The enthalpy of denaturation (DeltaH) for glycated cAAT was also higher than that for unmodified cAAT, suggesting that glycation changes the water accessible surface. Carnosine enhanced the thermal unfolding of glycated cAAT as evidenced by a decreased T(0.5) and a lowered Gibbs free energy barrier. Additionally, carnosine decreased the enthalpy of denaturation, suggesting that carnosine may promote hydration during heat denaturation of glycated protein. 39. Life Sci. 2002 Mar 1;70(15):1789-99. Effects of thermal denaturation on protein glycation. Seidler NW, Yeargans GS. Department of Biochemistry, University of Health Sciences, Kansas City, MO 64106, USA. nseidler@uhs.edu Protein denaturation occurs at sites of inflammation. We hypothesized that denatured protein may provide a more susceptible target for glycation, which is a known mediator of inflammation. We examined the effects of thermal denaturation on the susceptibility of protein glycation using glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and aspartate aminotransferase (AAT) as our target proteins. GAPDH and AAT are ubiquitous proteins that exhibited very different thermal stabilities. Glycating agents, methylglyoxal (MG) and glyceraldehyde (Glyc), caused an increase in the formation of advanced glycation endproducts (AGEs) in native and denatured GAPDH and AAT. The effects of the glycating agents were more pronounced with the denatured proteins. In addition to nitroblue tetrazolium (NBT)- reactivity, our measured endpoints were absorbance (lambda = 365 nm) and fluorescence (lambda(ex) = 370 nm; lambda(em) = 470 nm) properties that are typically associated with protein glycation. We also looked at carnosine's ability to prevent glycation of native and denatured protein. Carnosine, an endogenous histidine dipeptide, exhibits anti-inflammatory activity presumably due to its anti-oxidant and anti-glycation properties. Carnosine prevented Glyc-induced AGE formation in both native and denatured AAT suggesting that carnosine's anti-inflammatory activity may be due in part to carnosine's ability to prevent glycation of denatured protein. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 616
40. Ann N Y Acad Sci. 2002 Apr;959:285-94. Reaction of carnosine with aged proteins: another protective process? Hipkiss AR, Brownson C, Bertani MF, Ruiz E, Ferro A. GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London SE1 1UL, United Kingdom. alan.hipkiss@kcl.ac.uk Cellular aging is often associated with an increase in protein carbonyl groups arising from oxidation- and glycation-related phenomena and suppressed proteasome activity. These "aged" polypeptides may either be degraded by 20S proteasomes or cross-link to form structures intractable to proteolysis and inhibitory to proteasome activity. Carnosine (beta-alanyl-l-histidine) is present at surprisingly high levels (up to 20 mM) in muscle and nervous tissues in many animals, especially long-lived species. Carnosine can delay senescence in cultured human fibroblasts and reverse the senescent phenotype, restoring a more juvenile appearance. As better antioxidants/free-radical scavengers than carnosine do not demonstrate these antisenescent effects, additional properties of carnosine must contribute to its antisenescent activity. Having shown that carnosine can react with protein carbonyls, thereby generating "carnosinylated" polypeptides using model systems, we propose that similar adducts are generated in senescent cells exposed to carnosine. Polypeptide-carnosine adducts have been recently detected in beef products that are relatively rich in carnosine, and carnosine's reaction with carbonyl functions generated during amino acid deamidation has also been described. Growth of cultured human fibroblasts with carnosine stimulated proteolysis of long-labeled proteins as the cells approached their "Hayflick limit," consistent with the idea that carnosine ameliorates the senescence-associated proteolytic decline. We also find that carnosine suppresses induction of heme-oxygenase-1 activity following exposure of human endothelial cells to a glycated protein. The antisenescent activity of the spin-trap agent alpha-phenyl-N-t-butylnitrone (PBN) towards cultured human fibroblasts resides in N-t-butyl-hydroxylamine, its hydrolysis product. As hydroxylamines are reactive towards aldehydes and ketones, the antisenescent activity of N-t-butyl-hydroxylamine and other hydroxylamines may be mediated, at least in part, by reactivity towards macromolecular carbonyls, analogous to that proposed for carnosine. 41. Biosci Biotechnol Biochem. 2002 Jan;66(1):36-43. Effect of carnosine and related compounds on the inactivation of human Cu,Zn-superoxide dismutase by modification of fructose and glycolaldehyde. Ukeda H, Hasegawa Y, Harada Y, Sawamura M. Department of Bioresources Science, Faculty of Agriculture, Kochi University, Nankoku, Japan. hukeda@cc.kochi-u.ac.jp Glycolaldehyde, an intermediate of the Maillard reaction, and fructose, which is mainly derived from the polyol pathway, rapidly inactivate human Cu,Zn-superoxide dismutase (SOD) at the physiological concentration. We employed Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 617
this inactivation with these carbonyl compounds as a model glycation reaction to investigate whether carnosine and its related compounds could protect the enzyme from inactivation. Of eight derivatives examined, histidine, Gly-His, carnosine and Ala-His inhibited the inactivation of the enzyme by fructose (p<0.001), and Gly-His, Ala-His, anserine, carnosine, and homocarnosine exhibited a marked protective effect against the inactivation by glycolaldehyde (p<0.001). The carnosine-related compounds that showed this highly protective effect against the inactivation by glycolaldehyde had high reactivity with glycolaldehyde and high scavenging activity toward the hydroxyl radical as common properties. On the other hand, the carnosine-related compounds that had a protective effect against the inactivation by fructose showed significant hydroxyl radical-scavenging ability. These results indicate that carnosine and such related compounds as Gly-His and Ala-His are effective anti-glycating agents for human Cu,Zn-SOD and that the effectiveness is based not only on high reactivity with carbonyl compounds but also on hydroxyl radical scavenging activity. 42. J Biol Chem. 2001 Dec 28;276(52):48967-72. Epub 2001 Oct 24. Chelating activity of advanced glycation end-product inhibitors. Price DL, Rhett PM, Thorpe SR, Baynes JW. Department of Chemistry and Biochemistry, University of South Carolina, Columbia, South Carolina 29208, USA. The advanced glycation end-product (AGE) hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications. The two most commonly measured AGEs, N(epsilon)-(carboxymethyl)lysine and pentosidine, are glycoxidation products, formed from glucose by sequential glycation and autoxidation reactions. Although several compounds have been developed as AGE inhibitors and are being tested in animal models of diabetes and in clinical trials, the mechanism of action of these inhibitors is poorly understood. In general, they are thought to function as nucleophilic traps for reactive carbonyl intermediates in the formation of AGEs; however alternative mechanisms of actions, such as chelation, have not been rigorously examined. To distinguish between the carbonyl trapping and antioxidant activity of AGE inhibitors, we have measured the chelating activity of the inhibitors by determining the concentration required for 50% inhibition of the rate of copper-catalyzed autoxidation of ascorbic acid in phosphate buffer. All AGE inhibitors studied were chelators of copper, as measured by inhibition of metal-catalyzed autoxidation of ascorbate. Apparent binding constants for copper ranged from approximately 2 mm for aminoguanidine and pyridoxamine, to 10-100 microm for carnosine, phenazinediamine, OPB-9195 and tenilsetam. The AGE-breakers, phenacylthiazolium and phenacyldimethylthiazolium bromide, and their hydrolysis products, were among the most potent inhibitors of ascorbate oxidation. We conclude that, at millimolar concentrations of AGE inhibitors used in many in vitro studies, inhibition of AGE formation results primarily from the chelating or antioxidant activity of the AGE inhibitors, rather than their carbonyl trapping activity. Further, at therapeutic Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 618
concentrations, the chelating activity of AGE inhibitors and AGE-breakers may contribute to their inhibition of AGE formation and protection against development of diabetic complications. 43. Free Radic Biol Med. 2000 May 15;28(10):1564-70. Carnosine reacts with a glycated protein. Brownson C, Hipkiss AR. Division of Biomolecular Science, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London, UK. Oxidation and glycation induce formation of carbonyl (CO) groups in proteins, a characteristic of cellular aging. The dipeptide carnosine (beta-alanyl-L-histidine) is often found in long-lived mammalian tissues at relatively high concentrations (up to 20 mM). Previous studies show that carnosine reacts with low-molecular-weight aldehydes and ketones. We examine here the ability of carnosine to react with ovalbumin CO groups generated by treatment of the protein with methylglyoxal (MG). Incubation of MG-treated protein with carnosine accelerated a slow decline in CO groups as measured by dinitrophenylhydrazine reactivity. Incubation of [(14)C]-carnosine with MG-treated ovalbumin resulted in a radiolabeled precipitate on addition of trichloroacetic acid (TCA); this was not observed with control, untreated protein. The presence of lysine or N-(alpha)-acetylglycyl-lysine methyl ester caused a decrease in the TCA-precipitable radiolabel. Carnosine also inhibited cross-linking of the MG-treated ovalbumin to lysine and normal, untreated alpha-crystallin. We conclude that carnosine can react with protein CO groups (termed "carnosinylation") and thereby modulate their deleterious interaction with other polypeptides. It is proposed that, should similar reactions occur intracellularly, then carnosine's known "anti-aging" actions might, at least partially, be explained by the dipeptide facilitating the inactivation/removal of deleterious proteins bearing carbonyl groups. 44. J Biochem Mol Toxicol. 2000;14(4):215-20. Carnosine prevents the glycation-induced changes in electrophoretic mobility of aspartate aminotransferase. Seidler NW. University of Health Sciences, Department of Biochemistry, Kansas City, MO 64106-1453, USA. NSEIDLER@fac1.uhs.edu Carbohydrate-derived aldehydes cause irreversible loss of protein function via glycation. We previously observed that glyceraldehyde 3-phosphate (Glyc3P) abolishes the enzyme activity of cardiac aspartate aminotransferase (cAAT). We also examined the protective effects of carnosine against Glyc3P-induced loss of enzyme activity. The present study looked at carnosine's prevention of Glyc3P-induced change in protein structure. Purified cAAT (2 mg protein/mL) was incubated with various concentrations of carnosine (1-20 mM) in the presence of Glyc3P (500 microM) for 4 days at 37 degrees C. Following incubation, samples Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 619
were analyzed by SDS-polyacrylamide gel electrophoresis. Carnosine showed prevention of protein modification at carnosine-to-Glyc3P ratios of 10:1 or greater. There was a progressive loss of the unmodified cAAT protein band as Glyc3P concentration was increased. Additionally, the gel position of the Glyc3P-modified cAAT protein varied over time. The apparent molecular weight (MWapp) of the Glyc3P-modified cAAT protein that formed after 1 day at 37 degrees C (500 microM) was greater than its MWapp after 2 days, suggesting that a chemical rearrangement of the initial adduct occurs. These observations support the hypothesis that carnosine is an antiglycation agent and that its mechanism of action involves prevention of protein modification. 45. Tsitologiia. 2000;42(1):66-71. [Nonenzymatic glycosylation of and oxidative damage to actin in vitro and in vivo] [Article in Russian] Kuleva NV, Zalesova ZS. St. Petersburg State University. A study was made the influence exerted by non-enzymatic glycosylation (glycation) and oxidative destruction on structural and functional parameters of actin (free NH2-groups, advanced glycation end product and bityrosine cross-linking content, DNase inhibition by G-actin and myosin Mg(2+)-ATPase activation by F-actin). The functional properties of actin were shown to change under high molecular weight product formation and oxidative destruction: the extent of DNAase I inhibition decreases (from 70 to 40%) and the extent of myosin Mg(2+)-ATPase decreases (by 40%). Carnosine prevents actin oligomer formation and oxidative destruction which favours preservation of the protein functional properties. 46. Arch Toxicol. 1999 Aug;73(6):307-9. Carnosine prevents glyceraldehyde 3-phosphate-mediated inhibition of aspartate aminotransferase. Swearengin TA, Fitzgerald C, Seidler NW. Department of Biochemistry, University of Health Sciences, 1750 Independence Boulevard, Kansas City, MO 64106-1453, USA. Post-mitotic tissues, such as the heart, exhibit high concentrations (20 mM) of carnosine (beta-alanyl-l-histidine). Carnosine may have aldehyde scavenging properties. We tested this hypothesis by examining its protective effects against inhibition of enzyme activity by glyceraldehyde 3-phosphate (Glyc3P). Glyc3P is a potentially toxic triose; Glyc3P inhibits the cardiac aspartate aminotransferase (cAAT) by non-enzymatic glycosylation (or glycation) of the protein. cAAT requires pyridoxal 5-phosphate (PyP) for catalysis. We observed that carnosine (20 mM) completely prevents the inhibition of cAAT activity by Glyc3P (5 mM) after brief incubation (30 min at 37 degrees C). After a prolonged incubation (3.25 h) of cAAT with Glyc3P (0.5 mM) at 37 degrees C, the protection by carnosine (20 mM) persisted but PyP availability was affected. In the absence Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 620
of PyP from the assay medium, cAAT activities (plus Glyc3P) were 95 +/- 18.2 micromol/min per mg protein (mean +/- SD), minus carnosine and 100 +/- 2.4, plus carnosine; control activity was 172 +/- 3.9. When PyP (1.0 microM) was included in the assay medium, cAAT activities (plus Glyc3P) were 93 +/- 14.8, minus carnosine and 151 +/- 16.8, plus carnosine, P < 0. 001; control activity was 180 +/- 17.7. These data, which showed carnosine moderating the effects of both Glyc3P and PyP, suggest that carnosine may be an endogenous aldehyde scavenger. 47. Int J Biochem Cell Biol. 1998 Aug;30(8):863-8. Carnosine, a protective, anti-ageing peptide? Hipkiss AR. Molecular Biology and Biophysics Group, King's College London, Strand, UK. Carnosine (beta-alanyl-L-histidine) has protective functions additional to anti-oxidant and free-radical scavenging roles. It extends cultured human fibroblast life-span, kills transformed cells, protects cells against aldehydes and an amyloid peptide fragment and inhibits, in vitro, protein glycation (formation of cross-links, carbonyl groups and AGEs) and DNA/protein cross-linking. Carnosine is an aldehyde scavenger, a likely lipofuscin (age pigment) precursor and possible modulator of diabetic complications, atherosclerosis and Alzheimer's disease.
Magnesium - 570 CITATIONS

1: Zausinger S, Scholler K, Plesnila N, Schmid-Elsaesser R. Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Stroke. 2003 Sep;34(9):2246-51. Epub 2003 Jul 31. PMID: 12893947 2: Dube L, Granry JC. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review. Can J Anaesth. 2003 Aug-Sep;50(7):732-46. PMID: 12944451 3: Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol. 2003 Jul;102(1):181-92. PMID: 12850627 4: Hughes R, Goldkorn A, Masoli M, Weatherall M, Burgess C, Beasley R. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 621
Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial. Lancet. 2003 Jun 21;361(9375):2114-7. PMID: 12826434 5: Bucca C, Rolla G. Nebulised magnesium in asthma: the right solution for an old remedy? Lancet. 2003 Jun 21;361(9375):2095-6. PMID: 12826427 6: Jian W, Su L, Yiwu L. The effects of magnesium prime solution on magnesium levels and potassium loss in open heart surgery. Anesth Analg. 2003 Jun;96(6):1617-20, table of contents. PMID: 12760983 7: Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen. Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. PMID: 12730554 8: Geleijnse JM, Grobbee DE. Nutrition and healthhypertension. Ned Tijdschr Geneeskd. 2003 May 24;147(21):996-1000. PMID: 12811968 9: Suresh S, Lozono S, Hall SC. Large-dose intravenous methotrexate-induced cutaneous toxicity: can oral magnesium oxide reduce pain? Anesth Analg. 2003 May;96(5):1413-4, table of contents. PMID: 12707144 10: Sigman-Grant M, Warland R, Hsieh G. Selected lower-fat foods positively impact nutrient quality in diets of free-living Americans. J Am Diet Assoc. 2003 May;103(5):570-6. PMID: 12728214 11: Haupt H, Scheibe F, Mazurek B. Therapeutic efficacy of magnesium in acoustic trauma in the guinea pig. ORL J Otorhinolaryngol Relat Spec. 2003 May-Jun;65(3):134-9. PMID: 12925813 12: Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW.
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The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat. Brain Res Bull. 2003 Apr 15;60(1-2):105-14. PMID: 12725898 13: Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya T, Okamura M, Kim S, Iwao H, Miura K. Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation. Transplantation. 2003 Apr 15;75(7):1040-4. PMID: 12698095 14: Sharkey JR, Giuliani C, Haines PS, Branch LG, Busby-Whitehead J, Zohoori N. Summary measure of dietary musculoskeletal nutrient (calcium, vitamin D, magnesium, and phosphorus) intakes is associated with lower-extremity physical performance in homebound elderly men and women. Am J Clin Nutr. 2003 Apr;77(4):847-56. PMID: 12663282 15: Seguro AC, de Araujo M, Seguro FS, Rienzo M, Magaldi AJ, Campos SB. Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) nephrotoxicity in rats. Clin Nephrol. 2003 Apr;59(4):267-72. PMID: 12708566 16: Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. Development of ionized hypomagnesemia is associated with higher mortality rates. Crit Care Med. 2003 Apr;31(4):1082-7. PMID: 12682476 17: Ilich JZ, Brownbill RA, Tamborini L. Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density. Eur J Clin Nutr. 2003 Apr;57(4):554-65. PMID: 12700617 18: Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider M, Chachashvily S, Averbukh Z, Golik A, Chen-Levy Z, Modai D. Serum magnesium aberrations in furosemide (frusemide) treated patients with congestive heart failure: pathophysiological correlates and prognostic evaluation. Heart. 2003 Apr;89(4):411-6. PMID: 12639869
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19: Lin PH, Aickin M, Champagne C, Craddick S, Sacks FM, McCarron P, MostWindhauser MM, Rukenbrod F, Haworth L; Dash-Sodium Collaborative Research Group. Food group sources of nutrients in the dietary patterns of the DASH-Sodium trial. J Am Diet Assoc. 2003 Apr;103(4):488-96. PMID: 12669013 20: Onagawa T, Ohkuchi A, Ohki R, Izumi A, Matsubara S, Sato I, Suzuki M, Minakami H. Woman with postpartum ventricular tachycardia and hypomagnesemia. J Obstet Gynaecol Res. 2003 Apr;29(2):92-5. PMID: 12755529 21: Singhi SC, Singh J, Prasad R. Hypo- and hypermagnesemia in an Indian Pediatric Intensive Care Unit. J Trop Pediatr. 2003 Apr;49(2):99-103. PMID: 12729292 22: van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. Acta Neurochir (Wien). 2003 Mar;145(3):195-9; discussion 199. Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for long term treatment. PMID: 12632115 23: Higgins JC. The 'crashing astimatic.' Am Fam Physician. 2003 Mar 1;67(5):997-1004. PMID: 12643359 24: Roy SR, Milgrom H. Managing outpatient asthma exacerbations. Curr Allergy Asthma Rep. 2003 Mar;3(2):179-89. PMID: 12562559 25: Cappell MS. Gastric and duodenal ulcers during pregnancy. Gastroenterol Clin North Am. 2003 Mar;32(1):263-308. PMID: 12635419 26: Igondjo-Tchen S, Pages N, Bac P, Godeau G, Durlach J. Marfan syndrome, magnesium status and medical prevention of cardiovascular complications by hemodynamic treatments and antisense gene therapy. Magnes Res. 2003 Mar;16(1):59-64. PMID: 12735484 27: Caron MF, Kluger J, Tsikouris JP, Ritvo A, Kalus JS, White CM. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 624
Pharmacotherapy. 2003 Mar;23(3):296-300. Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide. PMID: 12627926 28: Ferrari L, Meschi M, Musini S, Frattini A, Savazzi GM. Recenti Prog Med. 2003 Mar;94(3):136-41. Etiopathogenesis and clinical aspects of nephrolithiasis--at present. PMID: 12677782 29: Touyz RM. Role of magnesium in the pathogenesis of hypertension. Mol Aspects Med. 2003 Feb 6;24(1-3):107-36. PMID: 12537992 30: Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P. Effect of intra-operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Anaesthesia. 2003 Feb;58(2):131-5. PMID: 12562408 31: Pamnani MB, Bryant HJ, Clough DL, Schooley JF. Increased dietary potassium and magnesium attenuate experimental volume dependent hypertension possibly through endogenous sodium-potassium pump inhibitor. Clin Exp Hypertens. 2003 Feb;25(2):103-15. PMID: 12611422 32: Czajkowski K, Wojcicka-Bentyn J, Grymowicz M, Smolarczyk R, MalinowskaPolubiec A, Romejko E. Calcium-phosphorus-magnesium homeostasis in pregnant women after renal transplantation. Int J Gynaecol Obstet. 2003 Feb;80(2):111-6. PMID: 12566182 33: Hata M, Miyao M, Mizuno Y. Osteoporosis as a lifestyle-related disease. Nippon Rinsho. 2003 Feb;61(2):305-13. PMID: 12638226 34: Zhang Y, Davies LR, Martin SM, Bawaney IM, Buettner GR, Kerber RE. Magnesium reduces free radical concentration and preserves left ventricular function after direct current shocks. Resuscitation. 2003 Feb;56(2):199-206. PMID: 12589995
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35: Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. N Engl J Med. 2003 Jan 23;348(4):304-11. PMID: 12540643 36: Vink R, O'Connor CA, Nimmo AJ, Heath DL. Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats. Neurosci Lett. 2003 Jan 9;336(1):41-4. PMID: 12493598 37: Averbukh Z, Rosenberg R, Galperin E, Berman S, Cohn M, Cohen N, Modai D, Efrati S, Weissgarten J. Cell-associated magnesium and QT dispersion in hemodialysis patients. Am J Kidney Dis. 2003 Jan;41(1):196-202. PMID: 12500237 38: Meram I, Balat O, Tamer L, Ugur MG. Trace elements and vitamin levels in menopausal women receiving hormone replacement therapy. Clin Exp Obstet Gynecol. 2003;30(1):32-4. PMID: 12731741 39: Duley L, Gulmezoglu AM, Henderson-Smart DJ. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Cochrane Database Syst Rev. 2003;(2):CD000025. PMID: 12804383 40: Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. Adenosine triphosphate-magnesium chloride: relevance for intensive care. Intensive Care Med. 2003 Jan;29(1):10-8. Epub 2002 Nov 02. PMID: 12528016 41: Margolin A, Kantak K, Copenhaver M, Avants SK. A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. J Addict Dis. 2003;22(2):49-61. PMID: 12703668 42: Egami I, Wakai K, Kunitomo H, Tamakoshi A, Ando M, Nakayama T, Ohno Y. Associations of lifestyle factors with bone mineral density among male university students in Japan. J Epidemiol. 2003 Jan;13(1):48-55. PMID: 12587613
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43: Cisse CT, Faye Dieme ME, Ngabo D, Mbaye M, Diagne PM, Moreau JC. Therapeutics indications and prognosis of eclampsia at Dakar University Teaching Hospital. J Gynecol Obstet Biol Reprod (Paris). 2003;32(3 Pt 1):239-45. PMID: 12773926 44: Darvish D. Magnesium may help patients with recessive hereditary inclusion body myopathy, a pathological review. Med Hypotheses. 2003 Jan;60(1):94-101. PMID: 12450772 45: Kato Y, Tamaki G, Tokumitsu M, Yamaguchi S, Yachiku S, Okuyama M. A case of urolithiasis associated with short bowel syndrome. Nippon Hinyokika Gakkai Zasshi. 2003 Jan;94(1):33-6. PMID: 12638204 46: Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. The use of magnesium to prevent laryngospasm after tonsillectomy and adenoidectomy: a preliminary study. Paediatr Anaesth. 2003 Jan;13(1):43-7. PMID: 12535038 47: Byrd RP Jr, Roy TM. Magnesium: its proven and potential clinical significance. South Med J. 2003 Jan;96(1):104. PMID: 12602735 48: Kidd PM. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Altern Med Rev. 2002 Dec;7(6):472-99. PMID: 12495373 49: Carlin Schooley M, Franz KB. Magnesium deficiency during pregnancy in rats increases systolic blood pressure and plasma nitrite. Am J Hypertens. 2002 Dec;15(12):1081-6. PMID: 12460704 50: Imazu M. Hypertension and insulin disorders. Curr Hypertens Rep. 2002 Dec;4(6):477-82. PMID: 12419178 51: Grzybek A, Klosiewicz-Latoszek L, Targosz U. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 627
Changes in the intake of vitamins and minerals by men and women with hyperlipidemia and overweight during dietetic treatment. Eur J Clin Nutr. 2002 Dec;56(12):1162-8. PMID: 12494300 52: Gryspeerdt S, Lefere P, Dewyspelaere J, Baekelandt M, van Holsbeeck B. Optimisation of colon cleansing prior to computed tomographic colonography. JBR-BTR. 2002 Dec;85(6):289-96. PMID: 12553658 53: Bhatia R, Prabhakar S, Grover VK. Tetanus. Neurol India. 2002 Dec;50(4):398-407. PMID: 12577086 54: Murck H. Magnesium and affective disorders. Nutr Neurosci. 2002 Dec;5(6):375-89. PMID: 12509067 55: Haas KM, Suzuki S, Yamaguchi N, Kato I, Ban K, Tanaka T, Fukuda S, Togari H. Nitric oxide further attenuates pulmonary hypertension in magnesium-treated piglets. Pediatr Int. 2002 Dec;44(6):670-4. PMID: 12421268 56: Minami T, Adachi T, Fukuda K. An effective use of magnesium sulfate for intraoperative management of laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient. Anesth Analg. 2002 Nov;95(5):1243-4, table of contents. PMID: 12401602 57: Nakatani T, Asai T. Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity. Hinyokika Kiyo. 2002 Nov;48(11):699-705. PMID: 12512145 58: Blackwell SC, Redman ME, Whitty JE, Refuerzo JS, Berry SM, Sorokin Y, Russell E, Cotton DB. The effect of intrapartum magnesium sulfate therapy on fetal cardiac troponin I levels at delivery. J Matern Fetal Neonatal Med. 2002 Nov;12(5):327-31. PMID: 12607765
628
59: Unachak K, Louthrenoo O, Katanyuwong K. Primary hypomagnesemia in Thai infants: a case report with 7 years follow-up and review of literature. J Med Assoc Thai. 2002 Nov;85(11):1226-31. PMID: 12546321 60: Berger R, Garnier Y, Jensen A. Perinatal brain damage: underlying mechanisms and neuroprotective strategies. J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28. PMID: 12445595 61: Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. New migraine preventive options: an update with pathophysiological considerations. Rev Hosp Clin Fac Med Sao Paulo. 2002 Nov-Dec;57(6):293-8. Epub 2003 Feb 17. PMID: 12612763 62: Milionis HJ, Rizos E, Liamis G, Nikas S, Siamopoulos KC, Elisaf MS. Acid-base and electrolyte disturbances in patients with hypercalcemia. South Med J. 2002 Nov;95(11):1280-7. PMID: 12539994 63: Rao GN. Diet and kidney diseases in rats. Toxicol Pathol. 2002 Nov-Dec;30(6):651-6. PMID: 12512864 64: Anderson RA. A complementary approach to urolithiasis prevention. World J Urol. 2002 Nov;20(5):294-301. Epub 2002 Oct 17. PMID: 12522585 65: Paskitti M, Reid KH. Use of an adenosine triphosphate-based 'cocktail' early in reperfusion substantially improves brain protein synthesis after global ischemia in rats. Neurosci Lett. 2002 Oct 18;331(3):147-50. PMID: 12383918 66: Gaby AR. Intravenous nutrient therapy: the "Myers' cocktail". Altern Med Rev. 2002 Oct;7(5):389-403. PMID: 12410623
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67: Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia. Anesth Analg. 2002 Oct;95(4):828-34, table of contents. PMID: 12351253 68: Davis GK, Homer CS, Brown MA. Hypertension in pregnancy: do consensus statements make a difference? Aust N Z J Obstet Gynaecol. 2002 Oct;42(4):369-73. PMID: 12403283 69: Ichiba H, Tamai H, Negishi H, Ueda T, Kim TJ, Sumida Y, Takahashi Y, Fujinaga H, Minami H; Kansai Magnesium Study Group. Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia. Pediatr Int. 2002 Oct;44(5):505-9. PMID: 12225549 70: Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation. 2002 Sep 27;74(6):784-91. PMID: 12364856 71: Plasma exchange in severe postpartum HELLP syndrome. Forster JG, Peltonen S, Kaaja R, Lampinen K, Pettila V. Acta Anaesthesiol Scand. 2002 Sep;46(8):955-8. PMID: 12190795 72: Kantas E, Cetin A, Kaya T, Cetin M. Effect of magnesium sulfate, isradipine, and ritodrine on contractions of myometrium: pregnant human and rat. Acta Obstet Gynecol Scand. 2002 Sep;81(9):825-30. PMID: 12225296 73: Memis D, Turan A, Karamanlioglu B, Sut N, Pamukcu Z. The use of magnesium sulfate to prevent pain on injection of propofol. Anesth Analg. 2002 Sep;95(3):606-8, table of contents. PMID: 12198045 74: Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Anesth Analg. 2002 Sep;95(3):661-6, table of contents. PMID: 12198056
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75: Forlani S, De Paulis R, de Notaris S, Nardi P, Tomai F, Proietti I, Ghini AS, Chiariello L. Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg. 2002 Sep;74(3):720-5; discussion 725-6. PMID: 12238830 76: Tramer MR, Glynn CJ. Magnesium Bier's block for treatment of chronic limb pain: a randomised, double-blind, cross-over study. Pain. 2002 Sep;99(1-2):235-41. PMID: 12237201 77: Patrick L. Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Altern Med Rev. 2002 Aug;7(4):276-91. PMID: 12197781 78: Attygalle D, Rodrigo N. Magnesium as first line therapy in the management of tetanus: a prospective study of 40 patients. Anaesthesia. 2002 Aug;57(8):811-7. PMID: 12133096 79: Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S; Acute Asthma/Magnesium Study Group. IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest. 2002 Aug;122(2):489-97. PMID: 12171821 80: Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. Effect of formulation variables on the floating properties of gastric floating drug delivery system. Drug Dev Ind Pharm. 2002 Aug;28(7):783-93. PMID: 12236064 81: van den Bergh WM, Zuur JK, Kamerling NA, van Asseldonk JT, Rinkel GJ, Tulleken CA, Nicolay K. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage. J Neurosurg. 2002 Aug;97(2):416-22. PMID: 12186471 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 631
82: Garcia MC, Byrd RP Jr, Roy TM. Lethal iatrogenic hypermagnesemia. Tenn Med. 2002 Aug;95(8):334-6. PMID: 12174756 83: Patel S, Martinez-Ripoll M, Blundell TL, Albert A. J Mol Biol. 2002 Jul 26;320(5):1087-94. Structural enzymology of Li(+)-sensitive/Mg(2+)-dependent phosphatases. PMID: 12126627 84: Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. Combined systemic administration of morphine and magnesium sulfate attenuates painrelated behavior in mononeuropathic rats. Brain Res. 2002 Jul 5;943(1):101-4. PMID: 12088843 85: Dagdelen S, Toraman F, Karabulut H, Alhan C. The value of P dispersion on predicting atrial fibrillation after coronary artery bypass surgery: effect of magnesium on P dispersion. Ann Noninvasive Electrocardiol. 2002 Jul;7(3):211-8. PMID: 12167181 86: Streetman DD, Bhatt-Mehta V, Johnson CE. Management of acute, severe asthma in children. Ann Pharmacother. 2002 Jul-Aug;36(7-8):1249-60. PMID: 12086560 87: Kaye P, O'Sullivan I. The role of magnesium in the emergency department. Emerg Med J. 2002 Jul;19(4):288-91. PMID: 12101132 88: Yamori Y, Liu L, Mu L, Zhao H, Pen Y, Hu Z, Kuga S, Negishi H, Ikeda K; Japan-China Cooperative Study Group: Chongqing Project. Diet-related factors, educational levels and blood pressure in a Chinese population sample: findings from the Japan-China Cooperative Research Project. Hypertens Res. 2002 Jul;25(4):559-64. PMID: 12358141 89: Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic liver cirrhosis -- relation to spironolactone. J Intern Med. 2002 Jul;252(1):56-63. PMID: 12074739 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 632
90: Malluche HH, Mawad H. Management of hyperphosphataemia of chronic kidney disease: lessons from the past and future directions. Nephrol Dial Transplant. 2002 Jul;17(7):1170-5. PMID: 12105237 91: Gordin A, Goldenberg D, Golz A, Netzer A, Joachims HZ. Magnesium: a new therapy for idiopathic sudden sensorineural hearing loss. Otol Neurotol. 2002 Jul;23(4):447-51. PMID: 12170143 92. Ozkaya O, Kalman S, Bakkaloglu S, Buyan N, Soylemezoglu O. Cyclosporine-associated facial paralysis in a child with renal transplant. Pediatr Nephrol. 2002 Jul;17(7):544-6. Epub 2002 Jun 18. PMID: 12172772 93: Guh JY, Chen HC, Chuang HY, Huang SC, Chien LC, Lai YH. Risk factors and risk for mortality of mild hypoparathyroidism in hemodialysis patients. Am J Kidney Dis. 2002 Jun;39(6):1245-54. PMID: 12046038 94: Gohda T, Shou I, Fukui M, Funabiki K, Horikoshi S, Shirato I, Tomino Y. Parathyroid hormone gene polymorphism and secondary hyperparathyroidism in hemodialysis patients. Am J Kidney Dis. 2002 Jun;39(6):1255-60. PMID: 12046039 95: Lozo E, Riecke K, Schwabe R, Vormann J, Stahlmann R. Synergistic effect of ofloxacin and magnesium deficiency on joint cartilage in immature rats. Antimicrob Agents Chemother. 2002 Jun;46(6):1755-9. PMID: 12019086 96: Bigal ME, Bordini CA, Speciali JG. Efficacy of three drugs in the treatment of migrainous aura: a randomized placebo-controlled study. Arq Neuropsiquiatr. 2002 Jun;60(2-B):406-9. PMID: 12131941 97: Petridou E, Zavras AI, Lefatzis D, Dessypris N, Laskaris G, Dokianakis G, Segas J, Douglas CW, Diehl SR, Trichopoulos D. The role of diet and specific micronutrients in the etiology of oral carcinoma. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 633
Cancer. 2002 Jun 1;94(11):2981-8. PMID: 12115387 98: Matsusaka T, Hasebe N, Jin YT, Kawabe J, Kikuchi K. Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism in rabbits. Cardiovasc Res. 2002 Jun;54(3):568-75. PMID: 12031702 99: Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia. 2002 Jun;22(5):345-53. PMID: 12110110 100: Advanced life support drugs: do they really work? Nolan JP, De Latorre FJ, Steen PA, Chamberlain DA, Bossaert LL. Curr Opin Crit Care. 2002 Jun;8(3):212-8. PMID: 12386499 101: Morimatsu H, Uchino S, Bellomo R, Ronco C. Continuous veno-venous hemodiafiltration or hemofiltration: impact on calcium, phosphate and magnesium concentrations. Int J Artif Organs. 2002 Jun;25(6):512-9. PMID: 12117290 102: Cho MS, Lee KS, Lee YK, Ma SK, Ko JH, Kim SW, Kim NH, Choi KC. Relationship between the serum parathyroid hormone and magnesium levels in continuous ambulatory peritoneal dialysis (CAPD) patients using low-magnesium peritoneal dialysate. Korean J Intern Med. 2002 Jun;17(2):114-21. PMID: 12164088 103: Magpie Trial Collaboration Group. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Lancet. 2002 Jun 1;359(9321):1877-90. PMID: 12057549 104: Karapinar K, Ulus AT, Kaplan S, Tutun U, Saritas A, Aksoyek A, Apaydn N, Saritas Z, Katircioglu SF. Mg++SO4 treatment improves the hemodynamics following the acute myocardial ischemia and reperfusion. Panminerva Med. 2002 Jun;44(2):129-33. PMID: 12032431 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 634
105: Hoane MR, Barth TM. The window of opportunity for administration of magnesium therapy following focal brain injury is 24 h but is task dependent in the rat. Physiol Behav. 2002 Jun 1;76(2):271-80. PMID: 12044600 106: Sidani M, Campbell J. Gynecology: select topics. Prim Care. 2002 Jun;29(2):297-321, vi. PMID: 12391713 107: Jaber R. Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Prim Care. 2002 Jun;29(2):231-61. PMID: 12391710 108: van der Sijs IH, Ho-Dac-Pannekeet MM. The treatment of hypomagnesemia. Ned Tijdschr Geneeskd. 2002 May 18;146(20):934-8. PMID: 12051060 109: Pharmacokinetics of ionized versus total magnesium in subjects with preterm labor and preeclampsia Taber EB, Tan L, Chao CR, Beall MH, Ross MG Am J Obstet Gynecol. 2002 May;186(5):1017-21. PMID: 12015530 110: Baghdadli A, Gonnier V, Aussilloux C. Encephale. 2002 May-Jun;28(3 Pt 1):248-54. Review of psychopharmacological treatments in adolescents and adults with autistic disorders. PMID: 12091786 111: Chia RY, Hughes RS, Morgan MK. Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. J Clin Neurosci. 2002 May;9(3):279-81. PMID: 12093134 112: Lukaski HC, Nielsen FH. Dietary magnesium depletion affects metabolic responses during submaximal exercise in postmenopausal women. J Nutr. 2002 May;132(5):930-5. PMID: 11983816 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 635
113: Toll J, Erb H, Birnbaum N, Schermerhorn T. Prevalence and incidence of serum magnesium abnormalities in hospitalized cats. J Vet Intern Med. 2002 May-Jun;16(3):217-21. PMID: 12041648 114: Lees KR. Management of acute stroke. Lancet Neurol. 2002 May;1(1):41-50. PMID: 12849544 115: Roffe C, Sills S, Crome P, Jones P. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Med Sci Monit. 2002 May;8(5):CR326-30. PMID: 12011773 116: Stoll ML, Listman JA. Nephrolithiasis in a neonate with transient renal wasting of calcium and magnesium. Pediatr Nephrol. 2002 May;17(5):386-9. PMID: 12042901 117: Rukshin V, Shah PK, Cercek B, Finkelstein A, Tsang V, Kaul S. Comparative antithrombotic effects of magnesium sulfate and the platelet glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in a canine model of stent thrombosis. Circulation. 2002 Apr 23;105(16):1970-5. PMID: 11997285 118: Dorsch NW. Therapeutic approaches to vasospasm in subarachnoid hemorrhage. Curr Opin Crit Care. 2002 Apr;8(2):128-33. PMID: 12386513 119: van der Heyden JJ, Standley CA. Maternal-fetal effects of magnesium sulfate on serum osmolality in pre-eclampsia. J Matern Fetal Neonatal Med. 2002 Apr;11(4):270-4. PMID: 12375684 120: Gulliksson H, AuBuchon JP, Vesterinen M, Sandgren P, Larsson S, Pickard CA, Herschel I, Roger J, Tracy JE, Langweiler M; Biomedical Excellence for Safer Transfusion Working Party of the International Society of Blood Transfusion. Storage of platelets in additive solutions: a pilot in vitro study of the effects of potassium and magnesium. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 636
Vox Sang. 2002 Apr;82(3):131-6. PMID: 11952987 1: Stroke. 2003 Sep;34(9):2246-51. Epub 2003 Jul 31. Combination drug therapy and mild hypothermia after transient focal cerebral ischemia in rats. Zausinger S, Scholler K, Plesnila N, Schmid-Elsaesser R. PMID: 12893947 2: Can J Anaesth. 2003 Aug-Sep;50(7):732-46. The therapeutic use of magnesium in anesthesiology, intensive care and emergency medicine: a review: [L'usage therapeutique du magnesium en anesthesiologie, reanimation et medecine d'urgence]. Dube L, Granry JC. PMID: 12944451 3: Obstet Gynecol. 2003 Jul;102(1):181-92. Diagnosis and management of gestational hypertension and preeclampsia. Sibai BM. PMID: 12850627 4: Lancet. 2003 Jun 21;361(9375):2114-7. Comment in: Lancet. 2003 Jun 21;361(9375):2095-6. Use of isotonic nebulised magnesium sulphate as an adjuvant to salbutamol in treatment of severe asthma in adults: randomised placebo-controlled trial. Hughes R, Goldkorn A, Masoli M, Weatherall M, Burgess C, Beasley R. PMID: 12826434 5: Lancet. 2003 Jun 21;361(9375):2095-6. Comment on: Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 637
Lancet. 2003 Jun 21;361(9375):2114-7. Nebulised magnesium in asthma: the right solution for an old remedy? Bucca C, Rolla G. PMID: 12826427 6: Anesth Analg. 2003 Jun;96(6):1617-20, table of contents. The effects of magnesium prime solution on magnesium levels and potassium loss in open heart surgery. Jian W, Su L, Yiwu L. PMID: 12760983 7: Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen. Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. PMID: 12730554 8: Ned Tijdschr Geneeskd. 2003 May 24;147(21):996-1000. [Nutrition and health--hypertension] [Article in Dutch] Geleijnse JM, Grobbee DE. PMID: 12811968 9: Anesth Analg. 2003 May;96(5):1413-4, table of contents. Large-dose intravenous methotrexate-induced cutaneous toxicity: can oral magnesium oxide reduce pain? Suresh S, Lozono S, Hall SC. PMID: 12707144 10: J Am Diet Assoc. 2003 May;103(5):570-6. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 638
Selected lower-fat foods positively impact nutrient quality in diets of free-living Americans. Sigman-Grant M, Warland R, Hsieh G. PMID: 12728214 11: ORL J Otorhinolaryngol Relat Spec. 2003 May-Jun;65(3):134-9. Therapeutic efficacy of magnesium in acoustic trauma in the guinea pig. Haupt H, Scheibe F, Mazurek B. PMID: 12925813 12: Brain Res Bull. 2003 Apr 15;60(1-2):105-14. The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat. Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. PMID: 12725898 13: Transplantation. 2003 Apr 15;75(7):1040-4. Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation. Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya T, Okamura M, Kim S, Iwao H, Miura K. PMID: 12698095 14: Am J Clin Nutr. 2003 Apr;77(4):847-56. Summary measure of dietary musculoskeletal nutrient (calcium, vitamin D, magnesium, and phosphorus) intakes is associated with lower-extremity physical performance in homebound elderly men and women. Sharkey JR, Giuliani C, Haines PS, Branch LG, Busby-Whitehead J, Zohoori N. PMID: 12663282 15: Clin Nephrol. 2003 Apr;59(4):267-72. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 639
Effects of hypokalemia and hypomagnesemia on zidovudine (AZT) and didanosine (ddI) nephrotoxicity in rats. Seguro AC, de Araujo M, Seguro FS, Rienzo M, Magaldi AJ, Campos SB. PMID: 12708566 16: Crit Care Med. 2003 Apr;31(4):1082-7. Development of ionized hypomagnesemia is associated with higher mortality rates. Soliman HM, Mercan D, Lobo SS, Melot C, Vincent JL. PMID: 12682476 17: Eur J Clin Nutr. 2003 Apr;57(4):554-65. Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density. Ilich JZ, Brownbill RA, Tamborini L. PMID: 12700617 18: Heart. 2003 Apr;89(4):411-6. Serum magnesium aberrations in furosemide (frusemide) treated patients with congestive heart failure: pathophysiological correlates and prognostic evaluation. Cohen N, Almoznino-Sarafian D, Zaidenstein R, Alon I, Gorelik O, Shteinshnaider M, Chachashvily S, Averbukh Z, Golik A, Chen-Levy Z, Modai D. PMID: 12639869 19: J Am Diet Assoc. 2003 Apr;103(4):488-96. Food group sources of nutrients in the dietary patterns of the DASH-Sodium trial. Lin PH, Aickin M, Champagne C, Craddick S, Sacks FM, McCarron P, MostWindhauser MM, Rukenbrod F, Haworth L; Dash-Sodium Collaborative Research Group. PMID: 12669013 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 640
20: J Obstet Gynaecol Res. 2003 Apr;29(2):92-5. Woman with postpartum ventricular tachycardia and hypomagnesemia. Onagawa T, Ohkuchi A, Ohki R, Izumi A, Matsubara S, Sato I, Suzuki M, Minakami H. PMID: 12755529 21: J Trop Pediatr. 2003 Apr;49(2):99-103. Hypo- and hypermagnesemia in an Indian Pediatric Intensive Care Unit. Singhi SC, Singh J, Prasad R. PMID: 12729292 22: Acta Neurochir (Wien). 2003 Mar;145(3):195-9; discussion 199. Magnesium therapy after aneurysmal subarachnoid haemorrhage a dose-finding study for long term treatment. van den Bergh WM, Albrecht KW, Berkelbach van der Sprenkel JW, Rinkel GJ. PMID: 12632115 23: Am Fam Physician. 2003 Mar 1;67(5):997-1004. The 'crashing astimatic.'. Higgins JC. PMID: 12643359 24: Curr Allergy Asthma Rep. 2003 Mar;3(2):179-89. Managing outpatient asthma exacerbations. Roy SR, Milgrom H. PMID: 12562559 25: Gastroenterol Clin North Am. 2003 Mar;32(1):263-308. Gastric and duodenal ulcers during pregnancy. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 641
Cappell MS. PMID: 12635419 26: Magnes Res. 2003 Mar;16(1):59-64. Marfan syndrome, magnesium status and medical prevention of cardiovascular complications by hemodynamic treatments and antisense gene therapy. Igondjo-Tchen S, Pages N, Bac P, Godeau G, Durlach J. PMID: 12735484 27: Pharmacotherapy. 2003 Mar;23(3):296-300. Effects of intravenous magnesium sulfate on the QT interval in patients receiving ibutilide. Caron MF, Kluger J, Tsikouris JP, Ritvo A, Kalus JS, White CM. PMID: 12627926 28: Recenti Prog Med. 2003 Mar;94(3):136-41. [Etiopathogenesis and clinical aspects of nephrolithiasis--at present] Ferrari L, Meschi M, Musini S, Frattini A, Savazzi GM. PMID: 12677782 29: Mol Aspects Med. 2003 Feb 6;24(1-3):107-36. Role of magnesium in the pathogenesis of hypertension. Touyz RM. PMID: 12537992 30: Anaesthesia. 2003 Feb;58(2):131-5. Effect of intra-operative magnesium sulphate on pain relief and patient comfort after major lumbar orthopaedic surgery. Levaux Ch, Bonhomme V, Dewandre PY, Brichant JF, Hans P.
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PMID: 12562408 31: Clin Exp Hypertens. 2003 Feb;25(2):103-15. Increased dietary potassium and magnesium attenuate experimental volume dependent hypertension possibly through endogenous sodium-potassium pump inhibitor. Pamnani MB, Bryant HJ, Clough DL, Schooley JF. PMID: 12611422 32: Int J Gynaecol Obstet. 2003 Feb;80(2):111-6. Calcium-phosphorus-magnesium homeostasis in pregnant women after renal transplantation. Czajkowski K, Wojcicka-Bentyn J, Grymowicz M, Smolarczyk R, Malinowska-Polubiec A, Romejko E. PMID: 12566182 33: Nippon Rinsho. 2003 Feb;61(2):305-13. [Osteoporosis as a lifestyle-related disease] Hata M, Miyao M, Mizuno Y. PMID: 12638226 34: Resuscitation. 2003 Feb;56(2):199-206. Magnesium reduces free radical concentration and preserves left ventricular function after direct current shocks. Zhang Y, Davies LR, Martin SM, Bawaney IM, Buettner GR, Kerber RE. PMID: 12589995 35: N Engl J Med. 2003 Jan 23;348(4):304-11. A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia. Belfort MA, Anthony J, Saade GR, Allen JC Jr; Nimodipine Study Group. PMID: 12540643 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 643
36: Neurosci Lett. 2003 Jan 9;336(1):41-4. Magnesium attenuates persistent functional deficits following diffuse traumatic brain injury in rats. Vink R, O'Connor CA, Nimmo AJ, Heath DL. PMID: 12493598 37: Am J Kidney Dis. 2003 Jan;41(1):196-202. Cell-associated magnesium and QT dispersion in hemodialysis patients. Averbukh Z, Rosenberg R, Galperin E, Berman S, Cohn M, Cohen N, Modai D, Efrati S, Weissgarten J. PMID: 12500237 38: Clin Exp Obstet Gynecol. 2003;30(1):32-4. Trace elements and vitamin levels in menopausal women receiving hormone replacement therapy. Meram I, Balat O, Tamer L, Ugur MG. PMID: 12731741 39: Cochrane Database Syst Rev. 2003;(2):CD000025. Magnesium sulphate and other anticonvulsants for women with pre-eclampsia. Duley L, Gulmezoglu AM, Henderson-Smart DJ. PMID: 12804383 40: Intensive Care Med. 2003 Jan;29(1):10-8. Epub 2002 Nov 02. Adenosine triphosphate-magnesium chloride: relevance for intensive care. Nalos M, Asfar P, Ichai C, Radermacher P, Leverve XM, Froba G. PMID: 12528016 41: J Addict Dis. 2003;22(2):49-61.
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A preliminary, controlled investigation of magnesium L-aspartate hydrochloride for illicit cocaine and opiate use in methadone-maintained patients. Margolin A, Kantak K, Copenhaver M, Avants SK. PMID: 12703668 42: J Epidemiol. 2003 Jan;13(1):48-55. Associations of lifestyle factors with bone mineral density among male university students in Japan. Egami I, Wakai K, Kunitomo H, Tamakoshi A, Ando M, Nakayama T, Ohno Y. PMID: 12587613 43: J Gynecol Obstet Biol Reprod (Paris). 2003;32(3 Pt 1):239-45. [Therapeutics indications and prognosis of eclampsia at Dakar University Teaching Hospital] Cisse CT, Faye Dieme ME, Ngabo D, Mbaye M, Diagne PM, Moreau JC. PMID: 12773926 44: Med Hypotheses. 2003 Jan;60(1):94-101. Magnesium may help patients with recessive hereditary inclusion body myopathy, a pathological review. Darvish D. PMID: 12450772 45: Nippon Hinyokika Gakkai Zasshi. 2003 Jan;94(1):33-6. [A case of urolithiasis associated with short bowel syndrome] Kato Y, Tamaki G, Tokumitsu M, Yamaguchi S, Yachiku S, Okuyama M. PMID: 12638204 46: Paediatr Anaesth. 2003 Jan;13(1):43-7. The use of magnesium to prevent laryngospasm after tonsillectomy and adenoidectomy: a preliminary study. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 645
Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. PMID: 12535038 47: South Med J. 2003 Jan;96(1):104. Magnesium: its proven and potential clinical significance. Byrd RP Jr, Roy TM. PMID: 12602735 48: Altern Med Rev. 2002 Dec;7(6):472-99. Autism, an extreme challenge to integrative medicine. Part 2: medical management. Kidd PM. PMID: 12495373 49: Am J Hypertens. 2002 Dec;15(12):1081-6. Magnesium deficiency during pregnancy in rats increases systolic blood pressure and plasma nitrite. Carlin Schooley M, Franz KB. PMID: 12460704 50: Curr Hypertens Rep. 2002 Dec;4(6):477-82. Hypertension and insulin disorders. Imazu M. PMID: 12419178 51: Eur J Clin Nutr. 2002 Dec;56(12):1162-8. Changes in the intake of vitamins and minerals by men and women with hyperlipidemia and overweight during dietetic treatment. Grzybek A, Klosiewicz-Latoszek L, Targosz U.
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PMID: 12494300 52: JBR-BTR. 2002 Dec;85(6):289-96. Optimisation of colon cleansing prior to computed tomographic colonography. Gryspeerdt S, Lefere P, Dewyspelaere J, Baekelandt M, van Holsbeeck B. PMID: 12553658 53: Neurol India. 2002 Dec;50(4):398-407. Tetanus. Bhatia R, Prabhakar S, Grover VK. PMID: 12577086 54: Nutr Neurosci. 2002 Dec;5(6):375-89. Magnesium and affective disorders. Murck H. PMID: 12509067 55: Pediatr Int. 2002 Dec;44(6):670-4. Nitric oxide further attenuates pulmonary hypertension in magnesium-treated piglets. Haas KM, Suzuki S, Yamaguchi N, Kato I, Ban K, Tanaka T, Fukuda S, Togari H. PMID: 12421268 56: Anesth Analg. 2002 Nov;95(5):1243-4, table of contents. An effective use of magnesium sulfate for intraoperative management of laparoscopic adrenalectomy for pheochromocytoma in a pediatric patient. Minami T, Adachi T, Fukuda K. PMID: 12401602 57: Hinyokika Kiyo. 2002 Nov;48(11):699-705.
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[Non-immunologic factor: immunosuppressive drug-induced nephrotoxicity] Nakatani T, Asai T. PMID: 12512145 58: J Matern Fetal Neonatal Med. 2002 Nov;12(5):327-31. The effect of intrapartum magnesium sulfate therapy on fetal cardiac troponin I levels at delivery. Blackwell SC, Redman ME, Whitty JE, Refuerzo JS, Berry SM, Sorokin Y, Russell E, Cotton DB. PMID: 12607765 59: J Med Assoc Thai. 2002 Nov;85(11):1226-31. Primary hypomagnesemia in Thai infants: a case report with 7 years follow-up and review of literature. Unachak K, Louthrenoo O, Katanyuwong K. PMID: 12546321 60: J Soc Gynecol Investig. 2002 Nov-Dec;9(6):319-28. Perinatal brain damage: underlying mechanisms and neuroprotective strategies. Berger R, Garnier Y, Jensen A. PMID: 12445595 61: Rev Hosp Clin Fac Med Sao Paulo. 2002 Nov-Dec;57(6):293-8. Epub 2003 Feb 17. New migraine preventive options: an update with pathophysiological considerations. Bigal ME, Rapoport AM, Sheftell FD, Tepper SJ. PMID: 12612763 62: South Med J. 2002 Nov;95(11):1280-7. Acid-base and electrolyte disturbances in patients with hypercalcemia. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 648
Milionis HJ, Rizos E, Liamis G, Nikas S, Siamopoulos KC, Elisaf MS. PMID: 12539994 63: Toxicol Pathol. 2002 Nov-Dec;30(6):651-6. Diet and kidney diseases in rats. Rao GN. PMID: 12512864 64: World J Urol. 2002 Nov;20(5):294-301. Epub 2002 Oct 17. A complementary approach to urolithiasis prevention. Anderson RA. PMID: 12522585 65: Neurosci Lett. 2002 Oct 18;331(3):147-50. Use of an adenosine triphosphate-based 'cocktail' early in reperfusion substantially improves brain protein synthesis after global ischemia in rats. Paskitti M, Reid KH. PMID: 12383918 66: Altern Med Rev. 2002 Oct;7(5):389-403. Intravenous nutrient therapy: the "Myers' cocktail". Gaby AR. PMID: 12410623 67: Anesth Analg. 2002 Oct;95(4):828-34, table of contents. Correction of ionized plasma magnesium during cardiopulmonary bypass reduces the risk of postoperative cardiac arrhythmia. Wilkes NJ, Mallett SV, Peachey T, Di Salvo C, Walesby R. PMID: 12351253 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 649
68: Aust N Z J Obstet Gynaecol. 2002 Oct;42(4):369-73. Hypertension in pregnancy: do consensus statements make a difference? Davis GK, Homer CS, Brown MA. PMID: 12403283 69: Pediatr Int. 2002 Oct;44(5):505-9. Randomized controlled trial of magnesium sulfate infusion for severe birth asphyxia. Ichiba H, Tamai H, Negishi H, Ueda T, Kim TJ, Sumida Y, Takahashi Y, Fujinaga H, Minami H; Kansai Magnesium Study Group. PMID: 12225549 70: Transplantation. 2002 Sep 27;74(6):784-91. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K. PMID: 12364856 71: Acta Anaesthesiol Scand. 2002 Sep;46(8):955-8. Plasma exchange in severe postpartum HELLP syndrome. Forster JG, Peltonen S, Kaaja R, Lampinen K, Pettila V. PMID: 12190795 72: Acta Obstet Gynecol Scand. 2002 Sep;81(9):825-30. Effect of magnesium sulfate, isradipine, and ritodrine on contractions of myometrium: pregnant human and rat. Kantas E, Cetin A, Kaya T, Cetin M. PMID: 12225296
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73: Anesth Analg. 2002 Sep;95(3):606-8, table of contents. The use of magnesium sulfate to prevent pain on injection of propofol. Memis D, Turan A, Karamanlioglu B, Sut N, Pamukcu Z. PMID: 12198045 74: Anesth Analg. 2002 Sep;95(3):661-6, table of contents. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. PMID: 12198056 75: Ann Thorac Surg. 2002 Sep;74(3):720-5; discussion 725-6. Combination of sotalol and magnesium prevents atrial fibrillation after coronary artery bypass grafting. Forlani S, De Paulis R, de Notaris S, Nardi P, Tomai F, Proietti I, Ghini AS, Chiariello L. PMID: 12238830 76: Pain. 2002 Sep;99(1-2):235-41. Magnesium Bier's block for treatment of chronic limb pain: a randomised, double-blind, cross-over study. Tramer MR, Glynn CJ. PMID: 12237201 77: Altern Med Rev. 2002 Aug;7(4):276-91. Nonalcoholic fatty liver disease: relationship to insulin sensitivity and oxidative stress. Treatment approaches using vitamin E, magnesium, and betaine. Patrick L. PMID: 12197781 78: Anaesthesia. 2002 Aug;57(8):811-7. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 651
Magnesium as first line therapy in the management of tetanus: a prospective study of 40 patients. Attygalle D, Rodrigo N. PMID: 12133096 79: Chest. 2002 Aug;122(2):489-97. IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S; Acute Asthma/Magnesium Study Group. PMID: 12171821 80: Drug Dev Ind Pharm. 2002 Aug;28(7):783-93. Effect of formulation variables on the floating properties of gastric floating drug delivery system. Li S, Lin S, Daggy BP, Mirchandani HL, Chien YW. PMID: 12236064 81: J Neurosurg. 2002 Aug;97(2):416-22. Role of magnesium in the reduction of ischemic depolarization and lesion volume after experimental subarachnoid hemorrhage. van den Bergh WM, Zuur JK, Kamerling NA, van Asseldonk JT, Rinkel GJ, Tulleken CA, Nicolay K. PMID: 12186471 82: Tenn Med. 2002 Aug;95(8):334-6. Lethal iatrogenic hypermagnesemia. Garcia MC, Byrd RP Jr, Roy TM. PMID: 12174756 83: J Mol Biol. 2002 Jul 26;320(5):1087-94. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 652
Structural enzymology of Li(+)-sensitive/Mg(2+)-dependent phosphatases. Patel S, Martinez-Ripoll M, Blundell TL, Albert A. PMID: 12126627 84: Brain Res. 2002 Jul 5;943(1):101-4. Combined systemic administration of morphine and magnesium sulfate attenuates pain-related behavior in mononeuropathic rats. Ulugol A, Aslantas A, Ipci Y, Tuncer A, Hakan Karadag C, Dokmeci I. PMID: 12088843 85: Ann Noninvasive Electrocardiol. 2002 Jul;7(3):211-8. The value of P dispersion on predicting atrial fibrillation after coronary artery bypass surgery: effect of magnesium on P dispersion. Dagdelen S, Toraman F, Karabulut H, Alhan C. PMID: 12167181 86: Ann Pharmacother. 2002 Jul-Aug;36(7-8):1249-60. Management of acute, severe asthma in children. Streetman DD, Bhatt-Mehta V, Johnson CE. PMID: 12086560 87: Emerg Med J. 2002 Jul;19(4):288-91. The role of magnesium in the emergency department. Kaye P, O'Sullivan I. PMID: 12101132 88: Hypertens Res. 2002 Jul;25(4):559-64. Diet-related factors, educational levels and blood pressure in a Chinese population sample: findings from the Japan-China Cooperative Research Project.
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Yamori Y, Liu L, Mu L, Zhao H, Pen Y, Hu Z, Kuga S, Negishi H, Ikeda K; Japan-China Cooperative Study Group: Chongqing Project. PMID: 12358141 89: J Intern Med. 2002 Jul;252(1):56-63. Muscle strength, Na,K-pumps, magnesium and potassium in patients with alcoholic liver cirrhosis -- relation to spironolactone. Aagaard NK, Andersen H, Vilstrup H, Clausen T, Jakobsen J, Dorup I. PMID: 12074739 90: Nephrol Dial Transplant. 2002 Jul;17(7):1170-5. Management of hyperphosphataemia of chronic kidney disease: lessons from the past and future directions. Malluche HH, Mawad H. PMID: 12105237 91: Otol Neurotol. 2002 Jul;23(4):447-51. Magnesium: a new therapy for idiopathic sudden sensorineural hearing loss. Gordin A, Goldenberg D, Golz A, Netzer A, Joachims HZ. PMID: 12170143 92. Pediatr Nephrol. 2002 Jul;17(7):544-6. Epub 2002 Jun 18. Cyclosporine-associated facial paralysis in a child with renal transplant. Ozkaya O, Kalman S, Bakkaloglu S, Buyan N, Soylemezoglu O. PMID: 12172772 93: Am J Kidney Dis. 2002 Jun;39(6):1245-54. Risk factors and risk for mortality of mild hypoparathyroidism in hemodialysis patients. Guh JY, Chen HC, Chuang HY, Huang SC, Chien LC, Lai YH.
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PMID: 12046038 94: Am J Kidney Dis. 2002 Jun;39(6):1255-60. Parathyroid hormone gene polymorphism and secondary hyperparathyroidism in hemodialysis patients. Gohda T, Shou I, Fukui M, Funabiki K, Horikoshi S, Shirato I, Tomino Y. PMID: 12046039 95: Antimicrob Agents Chemother. 2002 Jun;46(6):1755-9. Synergistic effect of ofloxacin and magnesium deficiency on joint cartilage in immature rats. Lozo E, Riecke K, Schwabe R, Vormann J, Stahlmann R. PMID: 12019086 96: Arq Neuropsiquiatr. 2002 Jun;60(2-B):406-9. [Efficacy of three drugs in the treatment of migrainous aura: a randomized placebo-controlled study] Bigal ME, Bordini CA, Speciali JG. PMID: 12131941 97: Cancer. 2002 Jun 1;94(11):2981-8. The role of diet and specific micronutrients in the etiology of oral carcinoma. Petridou E, Zavras AI, Lefatzis D, Dessypris N, Laskaris G, Dokianakis G, Segas J, Douglas CW, Diehl SR, Trichopoulos D. PMID: 12115387 98: Cardiovasc Res. 2002 Jun;54(3):568-75. Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism in rabbits. Matsusaka T, Hasebe N, Jin YT, Kawabe J, Kikuchi K. PMID: 12031702 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 655
99: Cephalalgia. 2002 Jun;22(5):345-53. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Bigal ME, Bordini CA, Tepper SJ, Speciali JG. PMID: 12110110 100: Curr Opin Crit Care. 2002 Jun;8(3):212-8. Advanced life support drugs: do they really work? Nolan JP, De Latorre FJ, Steen PA, Chamberlain DA, Bossaert LL. PMID: 12386499 101: Int J Artif Organs. 2002 Jun;25(6):512-9. Continuous veno-venous hemodiafiltration or hemofiltration: impact on calcium, phosphate and magnesium concentrations. Morimatsu H, Uchino S, Bellomo R, Ronco C. PMID: 12117290 102: Korean J Intern Med. 2002 Jun;17(2):114-21. Relationship between the serum parathyroid hormone and magnesium levels in continuous ambulatory peritoneal dialysis (CAPD) patients using low-magnesium peritoneal dialysate. Cho MS, Lee KS, Lee YK, Ma SK, Ko JH, Kim SW, Kim NH, Choi KC. PMID: 12164088 103: Lancet. 2002 Jun 1;359(9321):1877-90. Do women with pre-eclampsia, and their babies, benefit from magnesium sulphate? The Magpie Trial: a randomised placebo-controlled trial. Magpie Trial Collaboration Group. PMID: 12057549
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104: Panminerva Med. 2002 Jun;44(2):129-33. Mg++SO4 treatment improves the hemodynamics following the acute myocardial ischemia and reperfusion. Karapinar K, Ulus AT, Kaplan S, Tutun U, Saritas A, Aksoyek A, Apaydn N, Saritas Z, Katircioglu SF. PMID: 12032431 105: Physiol Behav. 2002 Jun 1;76(2):271-80. The window of opportunity for administration of magnesium therapy following focal brain injury is 24 h but is task dependent in the rat. Hoane MR, Barth TM. PMID: 12044600 106: Prim Care. 2002 Jun;29(2):297-321, vi. Gynecology: select topics. Sidani M, Campbell J. PMID: 12391713 107: Prim Care. 2002 Jun;29(2):231-61. Respiratory and allergic diseases: from upper respiratory tract infections to asthma. Jaber R. PMID: 12391710 108: Ned Tijdschr Geneeskd. 2002 May 18;146(20):934-8. [The treatment of hypomagnesemia] van der Sijs IH, Ho-Dac-Pannekeet MM. PMID: 12051060 109: Am J Obstet Gynecol. 2002 May;186(5):1017-21.
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Pharmacokinetics of ionized versus total magnesium in subjects with preterm labor and preeclampsia. Taber EB, Tan L, Chao CR, Beall MH, Ross MG. PMID: 12015530 110: Encephale. 2002 May-Jun;28(3 Pt 1):248-54. [Review of psychopharmacological treatments in adolescents and adults with autistic disorders] Baghdadli A, Gonnier V, Aussilloux C. PMID: 12091786 111: J Clin Neurosci. 2002 May;9(3):279-81. Magnesium: a useful adjunct in the prevention of cerebral vasospasm following aneurysmal subarachnoid haemorrhage. Chia RY, Hughes RS, Morgan MK. PMID: 12093134 112: J Nutr. 2002 May;132(5):930-5. Dietary magnesium depletion affects metabolic responses during submaximal exercise in postmenopausal women. Lukaski HC, Nielsen FH. PMID: 11983816 113: J Vet Intern Med. 2002 May-Jun;16(3):217-21. Prevalence and incidence of serum magnesium abnormalities in hospitalized cats. Toll J, Erb H, Birnbaum N, Schermerhorn T. PMID: 12041648 114: Lancet Neurol. 2002 May;1(1):41-50. Management of acute stroke.
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Lees KR. PMID: 12849544 115: Med Sci Monit. 2002 May;8(5):CR326-30. Randomised, cross-over, placebo controlled trial of magnesium citrate in the treatment of chronic persistent leg cramps. Roffe C, Sills S, Crome P, Jones P. PMID: 12011773 116: Pediatr Nephrol. 2002 May;17(5):386-9. Nephrolithiasis in a neonate with transient renal wasting of calcium and magnesium. Stoll ML, Listman JA. PMID: 12042901 117: Circulation. 2002 Apr 23;105(16):1970-5. Comparative antithrombotic effects of magnesium sulfate and the platelet glycoprotein IIb/IIIa inhibitors tirofiban and eptifibatide in a canine model of stent thrombosis. Rukshin V, Shah PK, Cercek B, Finkelstein A, Tsang V, Kaul S. PMID: 11997285 118: Curr Opin Crit Care. 2002 Apr;8(2):128-33. Therapeutic approaches to vasospasm in subarachnoid hemorrhage. Dorsch NW. PMID: 12386513 119: J Matern Fetal Neonatal Med. 2002 Apr;11(4):270-4. Maternal-fetal effects of magnesium sulfate on serum osmolality in pre-eclampsia. van der Heyden JJ, Standley CA. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 659
PMID: 12375684 120: Vox Sang. 2002 Apr;82(3):131-6. Storage of platelets in additive solutions: a pilot in vitro study of the effects of potassium and magnesium. Gulliksson H, AuBuchon JP, Vesterinen M, Sandgren P, Larsson S, Pickard CA, Herschel I, Roger J, Tracy JE, Langweiler M; Biomedical Excellence for Safer Transfusion Working Party of the International Society of Blood Transfusion. PMID: 11952987 121: Stroke. 2003 Jun;34(6):1526-32. Epub 2003 May 01. Neuroprotection in transient focal cerebral ischemia by combination drug therapy and mild hypothermia: comparison with customary therapeutic regimen. Zausinger S, Westermaier T, Plesnila N, Steiger HJ, Schmid-Elsaesser R. PMID: 12730554 122: Brain Res Bull. 2003 Apr 15;60(1-2):105-14. The behavioral effects of magnesium therapy on recovery of function following bilateral anterior medial cortex lesions in the rat. Hoane MR, Knotts AA, Akstulewicz SL, Aquilano M, Means LW. PMID: 12725898 123: Transplantation. 2003 Apr 15;75(7):1040-4. Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: role in beneficial effects of magnesium supplementation. Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya T, Okamura M, Kim S, Iwao H, Miura K. PMID: 12698095 124: Am J Cardiol. 2003 Mar 1;91(5):517-21. Effects of oral magnesium therapy on exercise tolerance, exercise-induced chest pain, and quality of life in patients with coronary artery disease. Shechter M, Bairey Merz CN, Stuehlinger HG, Slany J, Pachinger O, Rabinowitz B. PMID: 12615252 125: Clin Exp Hypertens. 2003 Feb;25(2):103-15. Increased dietary potassium and magnesium attenuate experimental volume dependent hypertension possibly through endogenous sodium-potassium pump inhibitor. Pamnani MB, Bryant HJ, Clough DL, Schooley JF. PMID: 12611422
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126: Med Hypotheses. 2003 Jan;60(1):94-101. Magnesium may help patients with recessive hereditary inclusion body myopathy, a pathological review. Darvish D. PMID: 12450772 127: Paediatr Anaesth. 2003 Jan;13(1):43-7. The use of magnesium to prevent laryngospasm after tonsillectomy and adenoidectomy: a preliminary study. Gulhas N, Durmus M, Demirbilek S, Togal T, Ozturk E, Ersoy MO. Department of Anaesthesia, Inonu University School of Medicine, Turkey. PMID: 12535038 128: South Med J. 2003 Jan;96(1):104. Magnesium: its proven and potential clinical significance. Byrd RP Jr, Roy TM. PMID: 12602735 129: Brain Res. 2002 Nov 15;955(1-2):133-7. Magnesium pre-treatment reduces neuronal apoptosis in newborn rats in hypoxia-ischemia. Turkyilmaz C, Turkyilmaz Z, Atalay Y, Soylemezoglu F, Celasun B. PMID: 12419529 130: Transplantation. 2002 Sep 27;74(6):784-91. Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K, Nakao T, Okamura M, Kim S, Iwao H, Miura K. PMID: 12364856 131: Anesth Analg. 2002 Sep;95(3):661-6, table of contents. Intrathecal magnesium prolongs fentanyl analgesia: a prospective, randomized, controlled trial. Buvanendran A, McCarthy RJ, Kroin JS, Leong W, Perry P, Tuman KJ. PMID: 12198056 132: Am J Hypertens. 2002 Aug;15(8):691-6. The effect of magnesium supplementation on blood pressure: a meta-analysis of randomized clinical trials. Jee SH, Miller ER 3rd, Guallar E, Singh VK, Appel LJ, Klag MJ. PMID: 12160191 133: Thorac Cardiovasc Surg. 2002 Aug;50(4):208-15. Initial reperfusion with magnesium after cardioplegic arrest attenuates myocardial reperfusion injury. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 661
Fuchs F, Messmer K, Kuppe H, Habazettl H. PMID: 12165870 134: Cardiovasc Res. 2002 Jun;54(3):568-75. Magnesium reduces myocardial infarct size via enhancement of adenosine mechanism in rabbits. Matsusaka T, Hasebe N, Jin YT, Kawabe J, Kikuchi K. PMID: 12031702 135: Physiol Behav. 2002 Jun 1;76(2):271-80. The window of opportunity for administration of magnesium therapy following focal brain injury is 24 h but is task dependent in the rat. Hoane MR, Barth TM. PMID: 12044600 136: Ned Tijdschr Geneeskd. 2002 May 18;146(20):934-8. [The treatment of hypomagnesemia] van der Sijs IH, Ho-Dac-Pannekeet MM. PMID: 12051060 137: Eur J Pharmacol. 2002 May 10;442(3):241-50. Dietary Mg(2+) supplementation restores impaired vasoactive responses in isolated rat aorta induced by chronic ethanol consumption. Brown RA, Ilg KJ, Chen AF, Ren J. PMID: 12065078 138: Eur J Clin Nutr. 2002 May;56(5):409-14. Dietary magnesium intake in type 2 diabetes. Walti MK, Zimmermann MB, Spinas GA, Jacob S, Hurrell RF. PMID: 12001011 139: J Nutr. 2002 May;132(5):930-5. Dietary magnesium depletion affects metabolic responses during submaximal exercise in postmenopausal women. Lukaski HC, Nielsen FH. PMID: 11983816 140: Am J Clin Nutr. 2002 Mar;75(3):550-4. Low dietary magnesium increases supraventricular ectopy. Klevay LM, Milne DB. PMID: 11864862 141: Magnes Res. 2002 Mar;15(1-2):27-36. Therapeutic effect of parenteral magnesium on noise-induced hearing loss in the guinea pig. Scheibe F, Haupt H, Ising H, Cherny L. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 662
PMID: 12030420 142: Med Hypotheses. 2002 Mar;58(3):213-20. Unexpected benefit of sorbitol placebo in Mg intervention study of premenstrual symptoms: implications for choice of placebo in RCTs. Walker AF, De Souza MC, Marakis G, Robinson PA, Morris AP, Bolland KM. PMID: 12018972 143: Ann Pharmacother. 2002 Feb;36(2):255-60. High-dose oral magnesium treatment of chronic, intractable erythromelalgia. Cohen JS. PMID: 11847944 144: Am J Epidemiol. 2002 Jan 15;155(2):125-31. Dietary magnesium, potassium, sodium, and children's lung function. Gilliland FD, Berhane KT, Li YF, Kim DH, Margolis HG. PMID: 11790675 145: Am J Hypertens. 2002 Jan;15(1 Pt 1):10-5. Magnesium infusion improves endothelium-dependent vasodilation in the human forearm. Haenni A, Johansson K, Lind L, Lithell H. PMID: 11824853 146: Ann Thorac Surg. 2002 Jan;73(1):112-8. Magnesium-supplemented warm blood cardioplegia in patients undergoing coronary artery revascularization. Yeatman M, Caputo M, Narayan P, Lotto AA, Ascione R, Bryan AJ, Angelini GD. PMID: 11833996 147: Asia Pac J Clin Nutr. 2002;11(4):268-73. Impact of supplementary high calcium milk with additional magnesium on parathyroid hormone and biochemical markers of bone turnover in postmenopausal women. Green JH, Booth C, Bunning R. PMID: 12495258 148: J Nutr Health Aging. 2002;6(2):147-53. Magnesium and trace elements in the elderly: intake, status and recommendations. Vaquero MP. PMID: 12166371 149: Pediatr Cardiol. 2002 Jan-Feb;23(1):41-8. Epub 2002 Feb 19. Studies of magnesium in congenital long QT syndrome. Hoshino K, Ogawa K, Hishitani T, Kitazawa R. PMID: 11922507 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 663
150: Prog Cardiovasc Dis. 2002 Jan-Feb;44(4):267-74. The importance of effect mechanism in the design and interpretation of clinical trials: the role of magnesium in acute myocardial infarction. Woods KL, Abrams K. PMID: 12007082 151: Metabolism. 2001 Dec;50(12):1409-17. Magnesium reduces insulin-stimulated glucose uptake and serum lipid concentrations in type 1 diabetes. Djurhuus MS, Klitgaard NA, Pedersen KK, Blaabjerg O, Altura BM, Altura BT, Henriksen JE. PMID: 11735085 152: South Med J. 2001 Dec;94(12):1195-201. Magnesium: its proven and potential clinical significance. Fox C, Ramsoomair D, Carter C. PMID: 11811859 153: Arch Cardiol Mex. 2001 Oct-Dec;71(4):335-44. [Magnesium in the treatment of acute myocardial infarction. Review and controversies] Juarez U, Antman EM. PMID: 11806038 154: Magnes Res. 2001 Sep;14(3):173-9. Mechanisms of action of the anti-atherogenic effect of magnesium: lessons from a mouse model. Sherer Y, Bitzur R, Cohen H, Shaish A, Varon D, Shoenfeld Y, Harats D. PMID: 11599549 155: Magnes Res. 2001 Sep;14(3):211-6. Dietary intakes of Mg, Ca and P with whole-day food rations from Cracovie, Lodz, Olsztyn and Poznan, Poland. Skibniewska KA. PMID: 11599554 156: J Nutr. 2001 Jul;131(7):1875-8. Dairy food consumption, blood pressure and stroke. Massey LK. PMID: 11435500 157: Ann N Y Acad Sci. 2001 Jun;939:271-82. Non-pharmacologic (physiologic) neuroprotection in the treatment of brain ischemia. Auer RN. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 664
PMID: 11462780 158: Blood Coagul Fibrinolysis. 2001 Jun;12(4):223-8. Intravenous magnesium does not influence the activity of the coagulation cascade. Ravn HB, Lassen JF, Bergenhem N, Kristensen AT. PMID: 11460004 159: Nutr Metab Cardiovasc Dis. 2001 Jun;11(3):158-67. Diet enrichment with calcium and magnesium enhances the cholesterol-lowering effect of plant sterols in obese Zucker rats. Vaskonen T, Mervaala E, Seppanen-Laakso T, Karppanen H. PMID: 11590991 160: Indian J Pediatr. 2001 May;68(5):417-9. Neuronal protection with magnesium. Gathwala G. PMID: 11407156 161: Magnes Res. 2001 Mar;14(1-2):51-63. The behavioral and anatomical effects of MgCl2 therapy in an electrolytic lesion model of cortical injury in the rat. Hoane MR, Barth TM. PMID: 11300622 162: Cerebrovasc Dis. 2001;11(1):44-50. Effect of nicardipine and magnesiumon cerebral infarction - brain surface perfusion technique. Mikami C, Suzuki M, Tsuiki K, Ogawa A. PMID: 11173793 163: CNS Drugs. 2001;15(12):921-30. Magnesium for neuroprotection in ischaemic stroke: rationale for use and evidence of effectiveness. Muir KW. PMID: 11735612 164: Crit Care Clin. 2001 Jan;17(1):155-73, viii. Hypomagnesemic disorders. Dacey MJ. PMID: 11219227 165: J Nutr Health Aging. 2001;5(4):253-5. Dietary intake of calcium, magnesium and phosphorus in an elderly population using duplicate diet sampling vs food composition tables. Moreno-Torres R, Ruiz-Lopez MD, Artacho R, Oliva P, Baena F, Baro L, Lopez C. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 665
PMID: 11753488 166: Magnes Res. 2000 Dec;13(4):233-7. Effect of magnesium on fibrin formation from lower molecular weight (LMW) fibrinogen. Lipinski B, Lipinska I. PMID: 11153893 167: Magnes Res. 2000 Dec;13(4):275-84. Beneficial antithrombotic effects of the association of pharmacological oral magnesium therapy with aspirin in coronary heart disease patients. Shechter M, Merz CN, Paul-Labrador M, Meisel SR, Rude RK, Molloy MD, Dwyer JH, Shah PK, Kaul S. PMID: 11153897 168: Magnes Res. 2000 Dec;13(4):265-73. Cerebral palsy and experimental hypoxia-induced perinatal brain injury: is magnesium protective? Oorschot DE. PMID: 11153896 169: Magnes Res. 2000 Dec;13(4):249-64. Long-term excessive magnesium supplementation is deleterious whereas suboptimal supply is beneficial for bones in rats. Riond JL, Hartmann P, Steiner P, Ursprung R, Wanner M, Forrer R, Spichiger UE, Thomsen JS, Mosekilde L. PMID: 11153895 170: Circulation. 2000 Nov 7;102(19):2353-8. Oral magnesium therapy improves endothelial function in patients with coronary artery disease. Shechter M, Sharir M, Labrador MJ, Forrester J, Silver B, Bairey Merz CN. PMID: 11067788 171: Eur J Neurol. 2000 Nov;7(6):741-4. The effect of magnesium oral therapy on spasticity in a patient with multiple sclerosis. Rossier P, van Erven S, Wade DT. PMID: 11136367 172: J Cardiothorac Vasc Anesth. 2000 Oct;14(5):524-30. Postoperative atrial tachyarrhythmias in patients undergoing coronary artery bypass graft surgery without cardiopulmonary bypass: a role for intraoperative magnesium supplementation. Maslow AD, Regan MM, Heindle S, Panzica P, Cohn WE, Johnson RG. PMID: 11052432 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 666
173: Magnes Res. 2000 Sep;13(3):197-203. Are low magnesium levels in type 1 diabetes associated with electromyographical signs of polyneuropathy? Engelen W, Bouten A, De Leeuw I, De Block C. PMID: 11008927 174: Med Hypotheses. 2000 Sep;55(3):263-5. Magnesium and potassium supplementation in the prevention of diabetic vascular disease. Whang R, Sims G. PMID: 10985921 175: J Acoust Soc Am. 2000 Jul;108(1):453-6. The role of magnesium in the susceptibility of soldiers to noise-induced hearing loss. Walden BE, Henselman LW, Morris ER. PMID: 10923909 176: Neuroepidemiology. 2000 Jul-Aug;19(4):210-6. Dietary intake of calcium, magnesium and antioxidants in relation to risk of amyotrophic lateral sclerosis. Longnecker MP, Kamel F, Umbach DM, Munsat TL, Shefner JM, Lansdell LW, Sandler DP. PMID: 10859501 177: Thromb Res. 2000 Jul 1;99(1):61-9. Intravenously and topically applied magnesium in the prevention of arterial thrombosis. Toft G, Ravn HB, Hjortdal VE. PMID: 10904104 178: J Am Coll Nutr. 2000 Jun;19(3):374-82. Magnesium status and parameters of the oxidant-antioxidant balance in patients with chronic fatigue: effects of supplementation with magnesium. Manuel y Keenoy B, Moorkens G, Vertommen J, Noe M, Neve J, De Leeuw I. PMID: 10872900 179: Psychopharmacology (Berl). 2000 Jun;150(2):220-5. The effects of an oral multivitamin combination with calcium, magnesium, and zinc on psychological well-being in healthy young male volunteers: a double-blind placebo-controlled trial. Carroll D, Ring C, Suter M, Willemsen G. PMID: 10907676 180: Med Pregl. 2000 May-Jun;53(5-6):319-24. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 667
[Magnesium in cardiology] Topalov V, Kovacevic D, Topalov A, Kovacevic D. PMID: 11089379 181: Am Heart J. 2000 Apr;139(4):703. Benefits of magnesium in acute myocardial infarction: timing is crucial. Gyamlani G, Parikh C, Kulkarni AG. PMID: 10740162 182: J Womens Health Gend Based Med. 2000 Mar;9(2):131-9. A synergistic effect of a daily supplement for 1 month of 200 mg magnesium plus 50 mg vitamin B6 for the relief of anxiety-related premenstrual symptoms: a randomized, double-blind, crossover study. De Souza MC, Walker AF, Robinson PA, Bolland K. PMID: 10746516 183: Pathobiology. 2000 Mar-Apr;68(2):93-8. Suppression of atherogenesis in female low-density lipoprotein receptor knockout mice following magnesium fortification of drinking water: the importance of diet. Sherer Y, Shoenfeld Y, Shaish A, Levkovitz H, Bitzur R, Harats D. PMID: 10878506 184: Psychiatry Res. 2000 Feb 14;93(1):83-7. Magnesium oxide augmentation of verapamil maintenance therapy in mania. Giannini AJ, Nakoneczie AM, Melemis SM, Ventresco J, Condon M. PMID: 10699232 185: Eur Arch Otorhinolaryngol. 2000;257(7):355-61. Preventive magnesium supplement reduces ischemia-induced hearing loss and blood viscosity in the guinea pig. Scheibe F, Haupt H, Vlastos GA. PMID: 11052244 186: Gynecol Obstet Invest. 2000;49(4):231-5. Comparison of magnesium and methyldopa for the control of blood pressure in pregnancies complicated with hypertension. Rudnicki M, Frolich A, Pilsgaard K, Nyrnberg L, Moller M, Sanchez M, Fischer-Rasmussen W. PMID: 10828704 187: J Intern Med. 2000 Jan;247(1):78-86. Hypomagnesemia in heart failure with ventricular arrhythmias. Beneficial effects of magnesium supplementation. Ceremuzynski L, Gebalska J, Wolk R, Makowska E. PMID: 10672134 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 668
188: Wien Med Wochenschr. 2000;150(15-16):335-41. Interrelationship of magnesium and congestive heart failure. Seelig MS. PMID: 11105329 189: Wien Med Wochenschr. 2000;150(15-16):325-9. [Magnesium in coronary artery disease--is there evidence?] Kiss K, Stuhlinger HG, Glogar HD, Smetana R. PMID: 11105327 190: Wien Med Wochenschr. 2000;150(15-16):330-4. [Significance of magnesium in cardiac arrhythmias] Stuhlinger HG, Kiss K, Smetana R. PMID: 11105328 191: Wien Med Wochenschr. 2000;150(15-16):343-7. The role of magnesium as antithrombotic therapy. Shechter M. PMID: 11105330 192: J Hum Hypertens. 1999 Nov;13(11):777-80. Effect of a mineral salt diet on 24-h blood pressure monitoring in elderly hypertensive patients. Katz A, Rosenthal T, Maoz C, Peleg E, Zeidenstein R, Levi Y. PMID: 10578223 193: J Neurosci Res. 1999 Nov 1;58(3):442-8. Mexiletine and magnesium independently, but not combined, protect against permanent focal cerebral ischemia in Wistar rats. Lee EJ, Ayoub IA, Harris FB, Hassan M, Ogilvy CS, Maynard KI. PMID: 10518118 194: Panteleeva GP, Bondar' VV, Krasnikova NI, Raiushkin VA. [Cerebrolysin and magnesium-B6 in the treatment of side effects of psychotropic drugs] Zh Nevrol Psikhiatr Im S S Korsakova. 1999;99(1):37-41. Russian. PMID: 11530457 195: Kawasaki T, Itoh K, Kawasaki M. Reduction in blood pressure with a sodium-reduced, potassium- and magnesium-enriched mineral salt in subjects with mild essential hypertension. Hypertens Res. 1998 Dec;21(4):235-43. PMID: 9877516 196: Durlach J, Bac P, Bara M, Guiet-Bara A. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 669
Is the pharmacological use of intravenous magnesium before preterm cerebroprotective or deleterious for premature infants? Possible importance of the use of magnesium sulphate. Magnes Res. 1998 Dec;11(4):323-5. Review. PMID: 9884990 197: van den Broek FA, Beynen AC. The influence of dietary phosphorus and magnesium concentrations on the calcium content of heart and kidneys of DBA/2 and NMRI mice. Lab Anim. 1998 Oct;32(4):483-91. PMID: 9807763 198: Ascherio A, Rimm EB, Hernan MA, Giovannucci EL, Kawachi I, Stampfer MJ, Willett WC. Intake of potassium, magnesium, calcium, and fiber and risk of stroke among US men. Circulation. 1998 Sep 22;98(12):1198-204. PMID: 9743511 199: Ram L, Schonewille JT, Martens H, Van't Klooster AT, Beynen AC. Magnesium absorption by wethers fed potassium bicarbonate in combination with different dietary magnesium concentrations. J Dairy Sci. 1998 Sep;81(9):2485-92. PMID: 9785240 200: Fonseca FA, Paiva TB, Silva EG, Ihara SS, Kasinski N, Martinez TL, Filho EE. Dietary magnesium improves endothelial dependent relaxation of balloon injured arteries in rats. Atherosclerosis. 1998 Aug;139(2):237-42. PMID: 9712329 201: Zorbas YG, Kakurin AG, Kuznetsov NK, Federov MA, Yaroshenko YY. Magnesium loading effect on magnesium deficiency in endurance-trained subjects during prolonged restriction of muscular activity. Biol Trace Elem Res. 1998 Aug;63(2):149-66. PMID: 9823441 202: Kawano Y, Matsuoka H, Takishita S, Omae T. Effects of magnesium supplementation in hypertensive patients: assessment by office, home, and ambulatory blood pressures. Hypertension. 1998 Aug;32(2):260-5. PMID: 9719052 203: Garcia LA, Dejong SC, Martin SM, Smith RS, Buettner GR, Kerber RE. Magnesium reduces free radicals in an in vivo coronary occlusion-reperfusion Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 670
model. J Am Coll Cardiol. 1998 Aug;32(2):536-9. PMID: 9708488 204: Dimai HP, Porta S, Wirnsberger G, Lindschinger M, Pamperl I, Dobnig H, Wilders-Truschnig M, Lau KH. Daily oral magnesium supplementation suppresses bone turnover in young adult males. J Clin Endocrinol Metab. 1998 Aug;83(8):2742-8. PMID: 9709941 205: Hornyak M, Voderholzer U, Hohagen F, Berger M, Riemann D. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep. 1998 Aug 1;21(5):501-5. PMID: 9703590 206: Ramirez JE, Alvarez EG, Montano M, Shen Y, Zinn RA. Influence of dietary magnesium level on growth-performance and metabolic responses of Holstein steers to laidlomycin propionate. J Anim Sci. 1998 Jul;76(7):1753-9. PMID: 9690629 207: Serebruany VL, Atar D, Dalesandro MR, O'Connor CM, Gurbel PA. Changes in hemostasis after parenteral magnesium in myocardial ischemia-reperfusion: from animal studies to clinical trials. Magnes Res. 1998 Jun;11(2):133-40. Review. PMID: 9675757 208: Seelig MS, Elin RJ, Antman EM. Magnesium in acute myocardial infarction: still an open question. Can J Cardiol. 1998 May;14(5):745-9. Review. PMID: 9627532 209: Lima Mde L, Cruz T, Pousada JC, Rodrigues LE, Barbosa K, Cangucu V. The effect of magnesium supplementation in increasing doses on the control of type 2 diabetes. Diabetes Care. 1998 May;21(5):682-6. PMID: 9589224 210: Ahn EK, Bai SJ, Cho BJ, Shin YS. The infusion rate of mivacurium and its spontaneous neuromuscular recovery in magnesium-treated parturients. Anesth Analg. 1998 Mar;86(3):523-6. PMID: 9495406
671
211: Ichikawa S. [Magnesium and calcium changes in serum and atrial muscle caused by open heart surgery and the effect of preoperative oral magnesium administration] Jpn J Thorac Cardiovasc Surg. 1998 Mar;46(3):287-98. Japanese. PMID: 9584479 212: Muir KW. New experimental and clinical data on the efficacy of pharmacological magnesium infusions in cerebral infarcts. Magnes Res. 1998 Mar;11(1):43-56. Review. PMID: 9595548 213: Schindler R, Thoni H, Classen HG. The role of magnesium in the generation and therapy of benign muscle cramps. Combined in-vivo/in-vitro studies on rat phrenic nerve-diaphragm preparations. Arzneimittelforschung. 1998 Feb;48(2):161-6. PMID: 9541727 214: Yang CY, Cheng MF, Tsai SS, Hsieh YL. Calcium, magnesium, and nitrate in drinking water and gastric cancer mortality. Jpn J Cancer Res. 1998 Feb;89(2):124-30. PMID: 9548438 215: McCord JK, Borzak S, Davis T, Gheorghiade M. Usefulness of intravenous magnesium for multifocal atrial tachycardia in patients with chronic obstructive pulmonary disease. Am J Cardiol. 1998 Jan 1;81(1):91-3. PMID: 9462615 216: Ford ES. Race, education, and dietary cations: findings from the Third National Health And Nutrition Examination Survey. Ethn Dis. 1998 Winter;8(1):10-20. PMID: 9595243 217: Harari M, Barzillai R, Shani J. Magnesium in the management of asthma: critical review of acute and chronic treatments, and Deutsches Medizinisches Zentrum's (DMZ's) clinical experience at the Dead Sea. J Asthma. 1998;35(7):525-36. Review. PMID: 9777879 218: Bren A, Kmetec A, Kveder R, Kaplan-Pavlovcic S. Magnesium hydrogen carbonate natural mineral water enriched with K(+)-citrate and vitamin B6 improves urinary abnormalities in patients with calcium oxalate nephrolithiasis. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 672
Urol Int. 1998;60(2):105-7. PMID: 9563149 219: Ravn HB, Kristensen SD, Hjortdal VE, Thygesen K, Husted SE. Early administration of intravenous magnesium inhibits arterial thrombus formation. Arterioscler Thromb Vasc Biol. 1997 Dec;17(12):3620-5. PMID: 9437213 220: Galan P, Preziosi P, Durlach V, Valeix P, Ribas L, Bouzid D, Favier A, Hercberg S. Dietary magnesium intake in a French adult population. Magnes Res. 1997 Dec;10(4):321-8. PMID: 9513928 221: Kummerow FA, Mahfouz M, Zhou Q. Cholesterol metabolism in human umbilical arterial endothelial cells cultured in low magnesium media. Magnes Res. 1997 Dec;10(4):355-60. Review. PMID: 9513931 222: Itoh K, Kawasaka T, Nakamura M. The effects of high oral magnesium supplementation on blood pressure, serum lipids and related variables in apparently healthy Japanese subjects. Br J Nutr. 1997 Nov;78(5):737-50. PMID: 9389897 223: Iannello S, Prestipino M, Cavalleri A, Spina S, Belfiore F. [Precordial discomfort and ECG changes of repolarization associated with hypomagnesemia in a young women following colectomy for diffuse colonic lipomatosis] Minerva Cardioangiol. 1997 Nov;45(11):581-6. Review. Italian. PMID: 9549292 224: Faintuch JJ, Menezes MS. [Magnesium and myocardial infarction. Brazilian aspects] Rev Hosp Clin Fac Med Sao Paulo. 1997 Nov-Dec;52(6):333-6. Review. Portuguese. PMID: 9629745 225: Hill J, Micklewright A, Lewis S, Britton J. Investigation of the effect of short-term change in dietary magnesium intake in asthma. Eur Respir J. 1997 Oct;10(10):2225-9. PMID: 9387944 226: De Franceschi L, Bachir D, Galacteros F, Tchernia G, Cynober T, Alper S, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 673
Platt O, Beuzard Y, Brugnara C. Oral magnesium supplements reduce erythrocyte dehydration in patients with sickle cell disease. J Clin Invest. 1997 Oct 1;100(7):1847-52. PMID: 9312186 227: Chugh SN, Kolley T, Kakkar R, Chugh K, Sharma A. A critical evaluation of anti-peroxidant effect of intravenous magnesium in acute aluminium phosphide poisoning. Magnes Res. 1997 Sep;10(3):225-30. PMID: 9483483 228: Sasaki R, Hirota K, Nakamaru K, Masuda A, Satone T, Ito Y. [Influence of fluid replacement on serum magnesium concentration and proper magnesium supplementation during general anesthesia] Masui. 1997 Sep;46(9):1179-85. Japanese. PMID: 9311207 229: Altura BM, Gebrewold A, Zhang A, Altura BT, Gupta RK. Short-term reduction in dietary intake of magnesium causes deficits in brain intracellular free Mg2+ and [H+]i but not high-energy phosphates as observed by in vivo 31P-NMR. Biochim Biophys Acta. 1997 Aug 21;1358(1):1-5. PMID: 9296515 230: De Franceschi L, Brugnara C, Beuzard Y. Dietary magnesium supplementation ameliorates anemia in a mouse model of beta-thalassemia. Blood. 1997 Aug 1;90(3):1283-90. PMID: 9242563 231: Haberl R. [Medicamentous anti-arrhythmia therapy. Is oral adjuvant therapy with electrolytes of value?] Herz. 1997 Jun;22 Suppl 1:77-80. Review. German. PMID: 9333595 232: Zehender M, Meinertz T, Just H. [Magnesium deficiency and magnesium substitution. Effect on ventricular cardiac arrhythmias of various etiology] Herz. 1997 Jun;22 Suppl 1:56-62. Review. German. PMID: 9333593 233: Vester EG. [Clinico-electrophysiologic effects of magnesium, especially in supraventricular tachycardia] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 674
Herz. 1997 Jun;22 Suppl 1:40-50. Review. German. PMID: 9333591 234: McCully JD, Levitsky S. Mechanisms of in vitro cardioprotective action of magnesium on the aging myocardium. Magnes Res. 1997 Jun;10(2):157-68. Review. PMID: 9368237 235: Soldatovic D, Vujanovic D, Matovic V, Plamenac Z. Compared effects of high oral Mg supplements and of EDTA chelating agent on chronic lead intoxication in rabbits. Magnes Res. 1997 Jun;10(2):127-33. PMID: 9368233 236: Starobrat-Hermelin B, Kozielec T. The effects of magnesium physiological supplementation on hyperactivity in children with attention deficit hyperactivity disorder (ADHD). Positive response to magnesium oral loading test. Magnes Res. 1997 Jun;10(2):149-56. PMID: 9368236 237: Zehender M, Meinertz T, Faber T, Caspary A, Jeron A, Bremm K, Just H. Antiarrhythmic effects of increasing the daily intake of magnesium and potassium in patients with frequent ventricular arrhythmias. Magnesium in Cardiac Arrhythmias (MAGICA) Investigators. J Am Coll Cardiol. 1997 Apr;29(5):1028-34. PMID: 9120155 238: Lichodziejewska B, Klos J, Rezler J, Grudzka K, Dluzniewska M, Budaj A, Ceremuzynski L. Clinical symptoms of mitral valve prolapse are related to hypomagnesemia and attenuated by magnesium supplementation. Am J Cardiol. 1997 Mar 15;79(6):768-72. PMID: 9070556 239: Mervaala EM, Pere AK, Lindgren L, Laakso J, Teravainen TL, Karjala K, Vapaatalo H, Ahonen J, Karppanen H. Effects of dietary sodium and magnesium on cyclosporin A-induced hypertension and nephrotoxicity in spontaneously hypertensive rats. Hypertension. 1997 Mar;29(3):822-7. PMID: 9052902 240: Matkovics B, Kiss I, Kiss SA. The activation by magnesium treatment of anti-oxidants eliminating the oxygen free radicals in Drosophila melanogaster in vivo. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 675
Magnes Res. 1997 Mar;10(1):33-8. PMID: 9339836 241: Nilsson CG, Lagerlof H. [Forced fibrinolysis causes damage to the myocardium. Magnesium therapy is considerate in myocardial infarction] Lakartidningen. 1997 Jan 15;94(3):148-50. Review. Swedish. PMID: 9053633 242: Davis M, Perry RH, Mendelow AD. The effect of non-competitive N-methyl-D-aspartate receptor antagonism on cerebral oedema and cerebral infarct size in the aging ischaemic brain. Acta Neurochir Suppl (Wien). 1997;70:30-3. PMID: 9416269 243: Bar-Dayan Y, Shoenfeld Y. Magnesium fortification of water. A possible step forward in preventive medicine? Ann Med Interne (Paris). 1997;148(6):440-4. Review. PMID: 9538378 244: Alavalkama K. [Who forgot magnesium] Duodecim. 1997;113(8):767. Finnish. PMID: 11466877 245: Mervaala E. [Magnesium, an electrolyte worth noticing] Duodecim. 1997;113(2):97-8. Finnish. PMID: 11370049 246: Marx A, Neutra RR. Magnesium in drinking water and ischemic heart disease. Epidemiol Rev. 1997;19(2):258-72. Review. PMID: 9494787 247: Lopez Martinez J, Sanchez Castilla M, Garcia de Lorenzo y Mateos A, Culebras Fernandez JM. [Magnesium: metabolism and requirements] Nutr Hosp. 1997 Jan-Feb;12(1):4-14. Review. Spanish. PMID: 9147537 248: Benzer W. [Significance of supraphysiologic administration of magnesium after myocardial infarct] Wien Klin Wochenschr Suppl. 1997;2:38-41. Review. German. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 676
PMID: 9340922 249: Sanjuliani AF, de Abreu Fagundes VG, Francischetti EA. Effects of magnesium on blood pressure and intracellular ion levels of Brazilian hypertensive patients. Int J Cardiol. 1996 Oct 11;56(2):177-83. PMID: 8894790 250: Kolev ST, Leman P, Kite GC, Stevenson PC, Shaw D, Murray VS. Toxicity following accidental ingestion of Aconitum containing Chinese remedy. Hum Exp Toxicol. 1996 Oct;15(10):839-42. PMID: 8906434 251: Kimura Y, Murase M, Nagata Y. Change in glucose homeostasis in rats by long-term magnesium-deficient diet. J Nutr Sci Vitaminol (Tokyo). 1996 Oct;42(5):407-22. PMID: 8981248 252: Gawaz M. [Antithrombocytic effectiveness of magnesium] Fortschr Med. 1996 Sep 20;114(26):329-32. Review. German. PMID: 8999005 253: Shils ME, Rude RK. Deliberations and evaluations of the approaches, endpoints and paradigms for magnesium dietary recommendations. J Nutr. 1996 Sep;126(9 Suppl):2398S-2403S. PMID: 8811804 254: Arsenian MA, New PS, Cafasso CM. Safety, tolerability, and efficacy of a glucose-insulin-potassium-magnesium-carnitine solution in acute myocardial infarction. Am J Cardiol. 1996 Aug 15;78(4):477-9. PMID: 8752197 255: Gilleran G, O'Leary M, Bartlett WA, Vinall H, Jones AF, Dodson PM. Effects of dietary sodium substitution with potassium and magnesium in hypertensive type II diabetics: a randomised blind controlled parallel study. J Hum Hypertens. 1996 Aug;10(8):517-21. PMID: 8895035 256: Peikert A, Wilimzig C, Kohne-Volland R. Prophylaxis of migraine with oral magnesium: results from a prospective, multi-center, placebo-controlled and double-blind randomized study. Cephalalgia. 1996 Jun;16(4):257-63. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 677
PMID: 8792038 257: Geleijnse JM, Witteman JC, den Breeijen JH, Hofman A, de Jong PT, Pols HA, Grobbee DE. Dietary electrolyte intake and blood pressure in older subjects: the Rotterdam Study. J Hypertens. 1996 Jun;14(6):737-41. PMID: 8793696 258: Ravn HB, Vissinger H, Kristensen SD, Wennmalm A, Thygesen K, Husted SE. Magnesium inhibits platelet activity--an infusion study in healthy volunteers. Thromb Haemost. 1996 Jun;75(6):939-44. PMID: 8822590 259: Roth A, Kornowski R, Agmon Y, Vardinon N, Sheps D, Graph E, Burke M, Laniado S, Yust I. High-dose intravenous magnesium attenuates complement consumption after acute myocardial infarction treated by streptokinase. Eur Heart J. 1996 May;17(5):709-14. PMID: 8737101 260: Singh RB, Singh NK, Niaz MA, Sharma JP. Effect of treatment with magnesium and potassium on mortality and reinfarction rate of patients with suspected acute myocardial infarction. Int J Clin Pharmacol Ther. 1996 May;34(5):219-25. PMID: 8738859 261: Dietch D, Wilson A, Thomas A. Magnesium is underused in acute atrial fibrillation. BMJ. 1996 Apr 27;312(7038):1101. PMID: 8616439 262: Navas FJ, Cordova A. Effect of magnesium supplementation and training on magnesium tissue distribution in rats. Biol Trace Elem Res. 1996 Summer;53(1-3):137-45. Erratum in: Biol Trace Elem Res 1996 Oct-Nov;55(1-2):213. PMID: 8862744 263: Martyka Z, Kotela I, Blady-Kotela A. [Clinical use of magnesium] Przegl Lek. 1996;53(3):155-8. Review. Polish. PMID: 8754371 264: Meinertz T. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 678
[Magnesium: current studies--critical evaluation--consequences] Z Kardiol. 1996;85 Suppl 6:147-51. Review. German. PMID: 9064959 265: Zehender M. [Magnesium as an anti-arrhythmic therapy principle in supraventricular and ventricular cardiac arrhythmias] Z Kardiol. 1996;85 Suppl 6:135-45. Review. German. PMID: 9064958 266: Beuckelmann DJ. [Value of magnesium in acute myocardial infarct] Z Kardiol. 1996;85 Suppl 6:129-34. Review. German. PMID: 9064957 267: Van Leer EM, Seidell JC, Kromhout D. Dietary calcium, potassium, magnesium and blood pressure in the Netherlands. Int J Epidemiol. 1995 Dec;24(6):1117-23. PMID: 8824852 268: Sueta CA, Patterson JH, Adams KF Jr. Antiarrhythmic action of pharmacological administration of magnesium in heart failure: a critical review of new data. Magnes Res. 1995 Dec;8(4):389-401. Review. PMID: 8861138 269: Herzog WR, Schlossberg ML, MacMurdy KS, Edenbaum LR, Gerber MJ, Vogel RA, Serebruany VL. Timing of magnesium therapy affects experimental infarct size. Circulation. 1995 Nov 1;92(9):2622-6. PMID: 7586365 270: Seelig MS. ISIS 4: clinical controversy regarding magnesium infusion, thrombolytic therapy, and acute myocardial infarction. Nutr Rev. 1995 Sep;53(9):261-4. Review. PMID: 8577409 271: Landmark K, Abdelnoor M. [Magnesium therapy in acute myocardial infarction. New points of view] Tidsskr Nor Laegeforen. 1995 Aug 10;115(18):2268-70. Review. Norwegian. PMID: 7652726 272: Dahle LO, Berg G, Hammar M, Hurtig M, Larsson L. The effect of oral magnesium substitution on pregnancy-induced leg cramps. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 679
Am J Obstet Gynecol. 1995 Jul;173(1):175-80. PMID: 7631676 273: Leor J, Kloner RA. An experimental model examining the role of magnesium in the therapy of acute myocardial infarction. Am J Cardiol. 1995 Jun 15;75(17):1292-3. PMID: 7778564 274: Lonnerdal B. Magnesium nutrition of infants. Magnes Res. 1995 Mar;8(1):99-105. Review. PMID: 7669512 275: Bac P, Pages N, Herrenknecht C, Teste JF. Inhibition of mouse-killing behaviour in magnesium-deficient rats: effect of pharmacological doses of magnesium pidolate, magnesium aspartate, magnesium lactate, magnesium gluconate and magnesium chloride. Magnes Res. 1995 Mar;8(1):37-45. PMID: 7669506 276: Sojka JE, Weaver CM. Magnesium supplementation and osteoporosis. Nutr Rev. 1995 Mar;53(3):71-4. Review. PMID: 7770187 277: Eibl NL, Kopp HP, Nowak HR, Schnack CJ, Hopmeier PG, Schernthaner G. Hypomagnesemia in type II diabetes: effect of a 3-month replacement therapy. Diabetes Care. 1995 Feb;18(2):188-92. PMID: 7729296 278: Drybanska-Kalita A. [Effect of various methods of supplementing magnesium on health status of children under special care] Ann Acad Med Stetin. 1995;41:211-9. Polish. PMID: 8615546 279: Henrotte JG, Aymard N, Allix M, Boulu RG. Effect of pyridoxine and magnesium on stress-induced gastric ulcers in mice selected for low or high blood magnesium levels. Ann Nutr Metab. 1995;39(5):285-90. PMID: 8585697 280: Salem M, Kasinski N, Munoz R, Chernow B. Progressive magnesium deficiency increases mortality from endotoxin challenge: protective effects of acute magnesium replacement therapy. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 680
Crit Care Med. 1995 Jan;23(1):108-18. PMID: 8001362 281: Heesch CM, Eichhorn EJ. Magnesium in acute myocardial infarction. Ann Emerg Med. 1994 Dec;24(6):1154-60. Review. PMID: 7978600 282: Bubeck J, Haussecker H, Disch G, Spatling L, Classen HG. Potentiation of magnesium-deficiency-induced foetotoxicity by concomitant iron deficiency and its prevention by adequate supply via drinking water. Magnes Res. 1994 Dec;7(3-4):245-54. PMID: 7786687 283: Colonna F, Giorgi R, Ciana G, Benettoni A. [Efficacy of magnesium in a case of neonatal pulmonary hypertension refractory to the usual therapies] Minerva Pediatr. 1994 Dec;46(12):553-5. Italian. PMID: 7731416 284: Atar D, Serebruany V, Poulton J, Godard J, Schneider A, Herzog WR. Effects of magnesium supplementation in a porcine model of myocardial ischemia and reperfusion. J Cardiovasc Pharmacol. 1994 Oct;24(4):603-11. PMID: 7528843 285: Schmitt HJ, Barth GR, Thierauf P. Neuronal protection by intraischemic brain perfusion: an electron microscopy study in the rat. J Neurosurg Anesthesiol. 1994 Oct;6(4):265-74. PMID: 8000201 286: Spisak V. [Treatment of acute myocardial infarct with magnesium] Vnitr Lek. 1994 Oct;40(10):649-53. Slovak. PMID: 7810083 287: Roth A, Eshchar Y, Keren G, Kerbel S, Harsat A, Villa Y, Laniado S, Miller HI. Effect of magnesium on restenosis after percutaneous transluminal coronary angioplasty: a clinical and angiographic evaluation in a randomized patient population. A pilot study. The Ichilov Magnesium Study Group. Eur Heart J. 1994 Sep;15(9):1164-73. PMID: 7982415 288: Geleijnse JM, Witteman JC, Bak AA, den Breeijen JH, Grobbee DE. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 681
Reduction in blood pressure with a low sodium, high potassium, high magnesium salt in older subjects with mild to moderate hypertension. BMJ. 1994 Aug 13;309(6952):436-40. PMID: 7920126 289: Shils ME, Rude RK. Deliberations and evaluations of the approaches, endpoints and paradigms for magnesium dietary recommendations. J Nutr. 1996 Sep;126(9 Suppl):2398S-2403S. PMID: 8811804 290: Dorup I, Skajaa K, Thybo NK. [Oral magnesium supplementation to patients receiving diuretics--normalization of magnesium, potassium and sodium, and potassium pumps in the skeletal muscles] Ugeskr Laeger. 1994 Jul 4;156(27):4007-10, 4013. Danish. PMID: 8066894 291: Balon TW, Jasman A, Scott S, Meehan WP, Rude RK, Nadler JL. Dietary magnesium prevents fructose-induced insulin insensitivity in rats. Hypertension. 1994 Jun;23(6 Pt 2):1036-9. PMID: 8206589 292: Paolisso G, Scheen A, Cozzolino D, Di Maro G, Varricchio M, D'Onofrio F, Lefebvre PJ. Changes in glucose turnover parameters and improvement of glucose oxidation after 4-week magnesium administration in elderly noninsulin-dependent (type II) diabetic patients. J Clin Endocrinol Metab. 1994 Jun;78(6):1510-4. PMID: 8200955 293: Lasserre B, Spoerri M, Moullet V, Theubet MP. Should magnesium therapy be considered for the treatment of coronary heart disease? II. Epidemiological evidence in outpatients with and without coronary heart disease. Magnes Res. 1994 Jun;7(2):145-53. PMID: 7999529 294: Kurita T. Antiarrhythmic effect of parenteral magnesium on ventricular tachycardia associated with long QT syndrome. Magnes Res. 1994 Jun;7(2):155-7. Review. PMID: 7999530 295: Weiss M, Lasserre B. Should magnesium therapy be considered for the treatment of coronary heart disease? I. A critical appraisal of current facts and hypotheses. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 682
Magnes Res. 1994 Jun;7(2):135-44. Review. PMID: 7999528 296: Thomas J, Tomb E, Thomas E, Faure G. Migraine treatment by oral magnesium intake and correction of the irritation of buccofacial and cervical muscles as a side effect of mandibular imbalance. Magnes Res. 1994 Jun;7(2):123-7. PMID: 7999526 297: Rob PM, Lebeau A, Schmid H, Sack K, Classen HG. Cyclosporin induces magnesium deficiency in rats and thereby aggravates its own nephrotoxicity: benefit of magnesium supplementation. Transplant Proc. 1994 Jun;26(3):1736-7. PMID: 8030111 298: Olerich MA, Rude RK. Should we supplement magnesium in critically ill patients? New Horiz. 1994 May;2(2):186-92. Review. PMID: 7922443 299: Singh RB, Rastogi SS, Ghosh S, Niaz MA. Dietary and serum magnesium levels in patients with acute myocardial infarction, coronary artery disease and noncardiac diagnoses. J Am Coll Nutr. 1994 Apr;13(2):139-43. PMID: 8006295 300: Orlov MV, Brodsky MA, Douban S. A review of magnesium, acute myocardial infarction and arrhythmia. J Am Coll Nutr. 1994 Apr;13(2):127-32. Review. PMID: 8006293 301: Casthely PA, Yoganathan T, Komer C, Kelly M. Magnesium and arrhythmias after coronary artery bypass surgery. J Cardiothorac Vasc Anesth. 1994 Apr;8(2):188-91. PMID: 7515706 302: Williams JM, Hammad A, Cottington EC, Harchelroad FC. Intravenous magnesium in the treatment of hydrofluoric acid burns in rats. Ann Emerg Med. 1994 Mar;23(3):464-9. PMID: 8135420 303: Rahman MI, Chagoury ME. Selections from current literature: magnesium, myocardial infarction and meta-analysis. Fam Pract. 1994 Mar;11(1):96-101. PMID: 8034161 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 683
304: Howard JM, Davies S, Hunnisett A. Red cell magnesium and glutathione peroxidase in infertile women--effects of oral supplementation with magnesium and selenium. Magnes Res. 1994 Mar;7(1):49-57. PMID: 8054261 305: Corica F, Allegra A, Di Benedetto A, Giacobbe MS, Romano G, Cucinotta D, Buemi M, Ceruso D. Effects of oral magnesium supplementation on plasma lipid concentrations in patients with non-insulin-dependent diabetes mellitus. Magnes Res. 1994 Mar;7(1):43-7. PMID: 8054260 306: Hampton EM, Whang DD, Whang R. Intravenous magnesium therapy in acute myocardial infarction. Ann Pharmacother. 1994 Feb;28(2):212-9. Review. PMID: 8173140 307: Sueta CA, Clarke SW, Dunlap SH, Jensen L, Blauwet MB, Koch G, Patterson JH, Adams KF Jr. Effect of acute magnesium administration on the frequency of ventricular arrhythmia in patients with heart failure. Circulation. 1994 Feb;89(2):660-6. PMID: 7508827 308: Simko F. Pathophysiological aspects of the protective effect of magnesium in myocardial infarction (review). Acta Med Hung. 1994;50(1-2):55-64. Review. PMID: 7638042 309: McLean RM. Magnesium and its therapeutic uses: a review. Am J Med. 1994 Jan;96(1):63-76. Review. PMID: 8304365 310: Retta TM, Afre GM, Randall OS. Dietary management of blood pressure. J Assoc Acad Minor Phys. 1994;5(4):147-51. Review. PMID: 7812082 311: Takahashi S, Okada K, Yanai M. Magnesium and parathyroid hormone changes to magnesium-free dialysate in continuous ambulatory peritoneal dialysis patients. Perit Dial Int. 1994;14(1):75-8. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 684
PMID: 8312420 312: Hix CD. Magnesium in congestive heart failure, acute myocardial infarction and dysrhythmias. J Cardiovasc Nurs. 1993 Oct;8(1):19-31. Review. PMID: 8106895 313: Miturzynska-Stryjecka H, Bielak G. [Beneficial effects of magnesium salts used in acute myocardial infarction] Wiad Lek. 1993 Oct;46(19-20):766-9. Review. Polish. PMID: 7975622 314: Stella PR, Kan G. [Magnesium: a promising addition to the therapy in acute myocardial infarct] Ned Tijdschr Geneeskd. 1993 Sep 25;137(39):1958-61. Review. Dutch. PMID: 8413703 315: Teo KK, Yusuf S. Role of magnesium in reducing mortality in acute myocardial infarction. A review of the evidence. Drugs. 1993 Sep;46(3):347-59. Review. PMID: 7693427 316: Mass H, Santoni F, Pirazzi B. On the use of parenteral magnesium salts in the treatment of acute ischaemic heart disease: a brief review. Magnes Res. 1993 Sep;6(3):275-89. Review. PMID: 8292502 317: Driessens FC. [Prevention of osteoporosis and pathological calcifications] Ned Tijdschr Tandheelkd. 1993 Sep;100(9):412, 413-4. Dutch. PMID: 11917878 318: Scheller S, Krol W, Skirmuntt K, Zydowicz G, Shani J. Antitumoral effect of bleomycin+dolomite combination treatment, in mice bearing Ehrlich ascites carcinoma. Z Naturforsch [C]. 1993 Sep-Oct;48(9-10):818-20. PMID: 7504493 319: Shaheen BE, Cornish LA. Magnesium in the treatment of acute myocardial infarction. Clin Pharm. 1993 Aug;12(8):588-96. Review. PMID: 8222523
685
320: Heimburger DC. Marked resistance of normal subjects to tube-feeding-induced diarrhea: the role of magnesium. JPEN J Parenter Enteral Nutr. 1993 Jul-Aug;17(4):394. PMID: 8271368 321: Soldatovic D, Matovic V, Vujanovic D. Prophylactic effect of high magnesium intake in rabbits exposed to prolonged lead intoxication. Magnes Res. 1993 Jun;6(2):145-8. PMID: 8274359 322: Gullestad L, Birkeland K, Molstad P, Hoyer MM, Vanberg P, Kjekshus J. The effect of magnesium versus verapamil on supraventricular arrhythmias. Clin Cardiol. 1993 May;16(5):429-34. PMID: 8504578 323: Matz R. Magnesium: deficiencies and therapeutic uses. Hosp Pract (Off Ed). 1993 Apr 30;28(4A):79-82, 85-7, 91-2. PMID: 8473371 324: Kummerow FA, Wasowicz E, Smith T, Yoss NL, Thiel J. Plasma lipid physical properties in swine fed margarine or butter in relation to dietary magnesium intake. J Am Coll Nutr. 1993 Apr;12(2):125-32. PMID: 8463511 325: Luo SQ, Plowman MC, Hopfer SM, Sunderman FW Jr. Mg(2+)-deprivation enhances and Mg(2+)-supplementation diminishes the embryotoxic and teratogenic effects of Ni2+, Co2+, Zn2+, and Cd2+ for frog embryos in the FETAX assay. Ann Clin Lab Sci. 1993 Mar-Apr;23(2):121-9. PMID: 8457141 326: Rudnicki PM, Frolich A, Fischer-Rasmussen W. [Magnesium therapy in pregnancy-induced hypertension and pre-eclampsia] Ugeskr Laeger. 1993 Feb 15;155(7):460-3. Review. Danish. PMID: 8465449 327: Dorup I, Skajaa K, Thybo NK. Oral magnesium supplementation restores the concentrations of magnesium, potassium and sodium-potassium pumps in skeletal muscle of patients receiving diuretic treatment. J Intern Med. 1993 Feb;233(2):117-23. PMID: 8381850 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 686
328: Lichodziejewska B, Klos J. [Magnesium in cardiology. Instant success of an undervalued ion] Kardiol Pol. 1993 Feb;38(2):126-30. Review. Polish. PMID: 8230983 329: Moesgaard B, Larsen IE, Quistorff B, Therkelsen I, Christensen VG, Jorgensen PF. Effect of dietary magnesium on post mortem phosphocreatine utilization in skeletal muscle of swine: a non-invasive study using 31P-NMR spectroscopy. Acta Vet Scand. 1993;34(4):397-404. PMID: 8147293 330: Widman L, Wester PO, Stegmayr BK, Wirell M. The dose-dependent reduction in blood pressure through administration of magnesium. A double blind placebo controlled cross-over study. Am J Hypertens. 1993 Jan;6(1):41-5. PMID: 8427660 331: Spatling L. [Magnesium in obstetrics and gynecology] Gynakol Geburtshilfliche Rundsch. 1993;33(2):85-91. Review. German. PMID: 8400911 332: Joachims Z, Netzer A, Ising H, Rebentisch E, Attias J, Weisz G, Gunther T. Oral magnesium supplementation as prophylaxis for noise-induced hearing loss: results of a double blind field study. Schriftenr Ver Wasser Boden Lufthyg. 1993;88:503-16. English, German. PMID: 8460390 333: Orita H, Fukasawa M, Hirooka S, Minowa T, Uchino H, Washio M. Prevention of postischemic reperfusion injury: the improvement of myocardial tissue blood flow after ischemia by terminal nicorandil-Mg cardioplegia. Surg Today. 1993;23(4):344-9. PMID: 8318789 334: England MR, Gordon G, Salem M, Chernow B. Magnesium administration and dysrhythmias after cardiac surgery. A placebo-controlled, double-blind, randomized trial. JAMA. 1992 Nov 4;268(17):2395-402. PMID: 1404796 335: Haga H. Effects of dietary magnesium supplementation on diurnal variations of blood pressure and plasma Na+, K(+)-ATPase activity in essential hypertension. Jpn Heart J. 1992 Nov;33(6):785-800. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 687
PMID: 1338597 336: Chau AC, Gabert HA, Miller JM Jr. A prospective comparison of terbutaline and magnesium for tocolysis. Obstet Gynecol. 1992 Nov;80(5):847-51. PMID: 1407926 337: Gullestad L, Dolva LO, Soyland E, Manger AT, Falch D, Kjekshus J. Oral magnesium supplementation improves metabolic variables and muscle strength in alcoholics. Alcohol Clin Exp Res. 1992 Oct;16(5):986-90. PMID: 1443440 338: Paolisso G, Di Maro G, Cozzolino D, Salvatore T, D'Amore A, Lama D, Varricchio M, D'Onofrio F. Chronic magnesium administration enhances oxidative glucose metabolism in thiazide treated hypertensive patients. Am J Hypertens. 1992 Oct;5(10):681-6. PMID: 1418829 339: Horner SM. Efficacy of intravenous magnesium in acute myocardial infarction in reducing arrhythmias and mortality. Meta-analysis of magnesium in acute myocardial infarction. Circulation. 1992 Sep;86(3):774-9. PMID: 1387591 340: Facchinetti F, Battaglia C, Benatti R, Borella P, Genazzani AR. Oral magnesium supplementation improves fetal circulation. Magnes Res. 1992 Sep;5(3):179-81. PMID: 1467155 341: Martin M, Diaz-Rubio E, Casado A, Lopez Vega JM, Sastre J, Almenarez J. Intravenous and oral magnesium supplementations in the prophylaxis of cisplatin-induced hypomagnesemia. Results of a controlled trial. Am J Clin Oncol. 1992 Aug;15(4):348-51. PMID: 1514533 342: Luo L, Tong JM, Huang JC. Effects of dietary chloride and magnesium on the incidence of tibial dyschondroplasia in chickens fed on Chinese practical diets. Br Poult Sci. 1992 Jul;33(3):603-11. PMID: 1643524 343: Paolisso G, Sgambato S, Gambardella A, Pizza G, Tesauro P, Varricchio M, D'Onofrio F. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 688
Daily magnesium supplements improve glucose handling in elderly subjects. Am J Clin Nutr. 1992 Jun;55(6):1161-7. PMID: 1595589 344: Brilla LR, Haley TF. Effect of magnesium supplementation on strength training in humans. J Am Coll Nutr. 1992 Jun;11(3):326-9. PMID: 1619184 345: del Castillo Rueda A, Recarte Garcia-Andrade C, Torres Segovia FJ. [Magnesium: therapeutic usefulness in emergency situations] An Med Interna. 1992 May;9(5):246-50. Review. Spanish. PMID: 1504208 346: Holecek V, Holecek T. [New findings on the clinical significance of magnesium] Cas Lek Cesk. 1992 Mar 4;131(4):101-3. Review. Czech. PMID: 1581935 347: McIntosh TK. Pharmacologic strategies in the treatment of experimental brain injury. J Neurotrauma. 1992 Mar;9 Suppl 1:S201-9. Review. PMID: 1588609 348: Landmark K, Urdal P. [Magnesium therapy in acute myocardial infarction] Tidsskr Nor Laegeforen. 1992 Feb 10;112(4):495-7. Review. Norwegian. PMID: 1553701 349: Hsieh ST, Sano H, Saito K, Kubota Y, Yokoyama M. Magnesium supplementation prevents the development of alcohol-induced hypertension. Hypertension. 1992 Feb;19(2):175-82. PMID: 1737652 350: Teo KK, Yusuf S, Collins R, Held PH, Peto R. Effects of intravenous magnesium in suspected acute myocardial infarction: overview of randomised trials. BMJ. 1991 Dec 14;303(6816):1499-503. PMID: 1838289 351: Koo WW, Tsang RC. Mineral requirements of low-birth-weight infants. J Am Coll Nutr. 1991 Oct;10(5):474-86. Review. PMID: 1955624
689
352: Birch RF, Lake CL. Pro: magnesium is a valuable therapy in the cardiac surgical patient. J Cardiothorac Vasc Anesth. 1991 Oct;5(5):518-21. Review. PMID: 1932660 353: Touyz RM. Magnesium supplementation as an adjuvant to synthetic calcium channel antagonists in the treatment of hypertension. Med Hypotheses. 1991 Oct;36(2):140-1. PMID: 1664038 354: Facchinetti F, Borella P, Sances G, Fioroni L, Nappi RE, Genazzani AR. Oral magnesium successfully relieves premenstrual mood changes. Obstet Gynecol. 1991 Aug;78(2):177-81. PMID: 2067759 355: Leor J, Harman M, Rabinowitz B, Mozes B. Giant U waves and associated ventricular tachycardia complicating astemizole overdose: successful therapy with intravenous magnesium. Am J Med. 1991 Jul;91(1):94-7. PMID: 1677532 356: Singh RB, Rastogi SS, Mani UV, Seth J, Devi L. Does dietary magnesium modulate blood lipids? Biol Trace Elem Res. 1991 Jul;30(1):59-64. PMID: 1718369 357: Finlayson DC. Magnesium: its time has come. J Cardiothorac Vasc Anesth. 1991 Jun;5(3):199-200. PMID: 1863737 358: Davydenko NV, Vasilenko IG. [Magnesium level in food rations and the prevalence of ischemic heart disease among the population] Gig Sanit. 1991 May;(5):44-6. Russian. PMID: 1916337 359: Facchinetti F, Sances G, Borella P, Genazzani AR, Nappi G. Magnesium prophylaxis of menstrual migraine: effects on intracellular magnesium. Headache. 1991 May;31(5):298-301. PMID: 1860787 360: Saggese G, Federico G, Bertelloni S, Baroncelli GI, Calisti L. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 690
Hypomagnesemia and the parathyroid hormone-vitamin D endocrine system in children with insulin-dependent diabetes mellitus: effects of magnesium administration. J Pediatr. 1991 Feb;118(2):220-5. PMID: 1993948 361: Rudnicki M, Frolich A, Rasmussen WF, McNair P. The effect of magnesium on maternal blood pressure in pregnancy-induced hypertension. A randomized double-blind placebo-controlled trial. Acta Obstet Gynecol Scand. 1991;70(6):445-50. PMID: 1763608 362: Steidl L, Ditmar R. Treatment of soft tissue calcifications with magnesium. Acta Univ Palacki Olomuc Fac Med. 1991;130:273-87. PMID: 1838878 363: Gullestad L, Oystein Dolva L, Birkeland K, Falch D, Fagertun H, Kjekshus J. Oral versus intravenous magnesium supplementation in patients with magnesium deficiency. Magnes Trace Elem. 1991-92;10(1):11-6. PMID: 1814318 364: Mathew R, Altura BM. The role of magnesium in lung diseases: asthma, allergy and pulmonary hypertension. Magnes Trace Elem. 1991-92;10(2-4):220-8. Review. PMID: 1844555 365: Rudnicki M, Frolich A, Fischer-Rasmussen W. Magnesium supplement in pregnancy-induced hypertension: effects on maternal and neonatal magnesium and calcium homeostasis. Miner Electrolyte Metab. 1991;17(6):399-403. PMID: 1823392 366: Itokawa Y. Cardiovascular disease and magnesium: epidemiological and experimental data. Proc Finn Dent Soc. 1991;87(4):651-7. Review. PMID: 1775493 367: Ogata H, Izumo Y. [Mortality reduction in mice administered a single abundant dose of zinc, manganese or magnesium after irradiation by gamma-rays at sublethal doses] Radioisotopes. 1990 Dec;39(12):573-6. Japanese. PMID: 2290996 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 691
368: Donoghue DJ, Krueger WF, Donoghue AM, Byrd JA, Ali DH, el Halawani ME. Magnesium-aspartate-hydrochloride reduces weight loss in heat-stressed laying hens. Poult Sci. 1990 Nov;69(11):1862-8. PMID: 2087447 369: Netten PM, de Mulder PH, Theeuwes AG, Willems JL, Kohler BE, Wagener DT. Intravenous magnesium supplementation during cisdiammine-dichloroplatinum administration prevents hypomagnesemia. Ann Oncol. 1990 Sep;1(5):369-72. PMID: 1702009 370: Seelig MS. Increased need for magnesium with the use of combined oestrogen and calcium for osteoporosis treatment. Magnes Res. 1990 Sep;3(3):197-215. Review. PMID: 2132751 371: Ogawa Y, Yamaguchi K, Morozumi M. Effects of magnesium salts in preventing experimental oxalate urolithiasis in rats. J Urol. 1990 Aug;144(2 Pt 1):385-9. PMID: 2374212 372: Mathew R, Gloster ES, Altura BT, Altura BM. Pulmonary vasculature in monocrotaline-induced hypertensive rats on magnesium therapy. Microcirc Endothelium Lymphatics. 1990 Aug-Oct;6(4-5):267-83. PMID: 2149161 373: Hara A, Matsumura H, Abiko Y. Beneficial effect of magnesium on the isolated perfused rat heart during reperfusion after ischaemia: comparison between pre-ischaemic and post-ischaemic administration of magnesium. Naunyn Schmiedebergs Arch Pharmacol. 1990 Jul;342(1):100-6. PMID: 2402298 374: Keren A, Tzivoni D. Magnesium therapy in ventricular arrhythmias. Pacing Clin Electrophysiol. 1990 Jul;13(7):937-45. Review. PMID: 1695751 375: Iseri LT. Role of magnesium in cardiac tachyarrhythmias. Am J Cardiol. 1990 Jun 19;65(23):47K-50K. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 692
PMID: 2353670 376: Tzivoni D, Keren A. Suppression of ventricular arrhythmias by magnesium. Am J Cardiol. 1990 Jun 1;65(20):1397-9. Review. PMID: 2188497 377: Demory JE, Firmin JM, Parot P. [The value of magnesium pyrrolidone carboxylate in true cervix dystocia. A double blind versus placebo study] Rev Fr Gynecol Obstet. 1990 Jun;85(6):413-6. French. PMID: 2389112 378: Wu HW, Wen JX, Qu GR. [Changes in fluorine metabolism during the treatment with calcium-magnesium preparation in 60 cases of endemic fluorosis] Zhonghua Nei Ke Za Zhi. 1990 Jun;29(6):357-9, 383. Chinese. PMID: 2269037 379: Abraham GE, Grewal H. A total dietary program emphasizing magnesium instead of calcium. Effect on the mineral density of calcaneous bone in postmenopausal women on hormonal therapy. J Reprod Med. 1990 May;35(5):503-7. PMID: 2352244 380: Fontana-Klaiber H, Hogg B. [Therapeutic effects of magnesium in dysmenorrhea] Schweiz Rundsch Med Prax. 1990 Apr 17;79(16):491-4. German. PMID: 2349410 381: Classen HG, Nowitzki S. [The clinical importance of magnesium. 2. The indications for supplementation and therapy] Fortschr Med. 1990 Apr 10;108(10):198-200. Review. German. PMID: 2187780 382: Huang QF, Gebrewold A, Altura BT, Altura BM. Cocaine-induced cerebral vascular damage can be ameliorated by Mg2+ in rat brain. Neurosci Lett. 1990 Feb 5;109(1-2):113-6. PMID: 2314626 383: Bacon JA, Bell MC, Miller JK, Ramsey N, Mueller FJ. Effect of magnesium administration route on plasma minerals in Holstein calves receiving either adequate or insufficient magnesium in their diets. J Dairy Sci. 1990 Feb;73(2):470-3. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 693
PMID: 2329207 384: Singh RB. Effect of dietary magnesium supplementation in the prevention of coronary heart disease and sudden cardiac death. Magnes Trace Elem. 1990;9(3):143-51. PMID: 2248695 385: Huang QF, Gebrewold A, Altura BT, Altura BM. Mg2+ protects against PCP-induced cerebrovasospasms and vascular damage in rat brain. Magnes Trace Elem. 1990;9(1):44-6. PMID: 2158788 386: Singh RB, Rastogi SS, Sharma VK, Saharia RB, Kulshretha SK. Can dietary magnesium modulate lipoprotein metabolism? Magnes Trace Elem. 1990;9(5):255-64. PMID: 2130823 387: Abraham AS. Treatment of patients with acute myocardial infarction with intravenous magnesium. Magnes Trace Elem. 1990;9(4):177-85. Review. PMID: 2095160 388: Ising H, Rebentisch E, Bertschat F, Gunther T. Correlations between ventricular arrhythmias and electrolyte disturbances after acute myocardial infarction. Magnes Trace Elem. 1990;9(4):205-11. PMID: 2095164 389: Singh RB, Sircar AR, Rastogi SS, Garg V. Magnesium and potassium administration in acute myocardial infarction. Magnes Trace Elem. 1990;9(4):198-204. PMID: 2095163 390: Chouinard G, Beauclair L, Geiser R, Etienne P. A pilot study of magnesium aspartate hydrochloride (Magnesiocard) as a mood stabilizer for rapid cycling bipolar affective disorder patients. Prog Neuropsychopharmacol Biol Psychiatry. 1990;14(2):171-80. PMID: 2309035 391: Ploceniak C. [Bruxism and magnesium, my clinical experiences since 1980] Rev Stomatol Chir Maxillofac. 1990;91 Suppl 1:127. French. PMID: 2130443 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 694
392: Martineau J, Barthelemy C, Roux S, Garreau B, Lelord G. Electrophysiological effects of fenfluramine or combined vitamin B6 and magnesium on children with autistic behaviour. Dev Med Child Neurol. 1989 Dec;31(6):721-7. PMID: 2599266 393: Hauser SP, Braun PH. [Intravenous magnesium administration in bronchial asthma] Schweiz Med Wochenschr. 1989 Nov 18;119(46):1633-5. German. PMID: 2609133 394: Laubach HE. Effect of dietary magnesium on Ascaris suum infections of mice. Biochem Med Metab Biol. 1989 Oct;42(2):95-104. PMID: 2789853 395: Chiossi M, Rosati U, Renna S, Lattere M, De Santis L. [Theophylline poisoning in childhood: depurative therapy using a combination of activated charcoal and a saline cathartic] Minerva Pediatr. 1989 Oct;41(10):535-7. Italian. PMID: 2615728 396: Inui K, Kobayashi M, Orita H, Shimanuki T, Kohno M, Fukasawa M, Abe K, Kuraoka S, Washio M. [Effect of magnesium containing cardioplegic solution on the cases of extended aortic cross clamping] Rinsho Kyobu Geka. 1989 Oct;9(5):468-71. Japanese. PMID: 9301958 397: Grases F, Genestar C, Conte A, March P, Costa-Bauza A. Inhibitory effect of pyrophosphate, citrate, magnesium and chondroitin sulphate in calcium oxalate urolithiasis. Br J Urol. 1989 Sep;64(3):235-7. PMID: 2553195 398: Kinnunen O, Salokannel J. Comparison of the effects of magnesium hydroxide and a bulk laxative on lipids, carbohydrates, vitamins A and E, and minerals in geriatric hospital patients in the treatment of constipation. J Int Med Res. 1989 Sep-Oct;17(5):442-54. PMID: 2553511 399: Durlach J. Recommended dietary amounts of magnesium: Mg RDA. Magnes Res. 1989 Sep;2(3):195-203. Review. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 695
PMID: 2701269 400: Mletzko R, Jung W, Manz M, Kamradt T, Vogel F, Luderitz B. [Arrhythmogenic effect of flecainide--treatment with i.v. magnesium] Z Kardiol. 1989 Sep;78(9):602-6. German. PMID: 2510412 401: Paolisso G, Passariello N, Pizza G, Marrazzo G, Giunta R, Sgambato S, Varricchio M, D'Onofrio F. Dietary magnesium supplements improve B-cell response to glucose and arginine in elderly non-insulin dependent diabetic subjects. Acta Endocrinol (Copenh). 1989 Jul;121(1):16-20. PMID: 2662695 402: Ditmar R, Steidl L. [The importance of magnesium in orthopedics. VI. The importance of magnesium in the treatment of ectopic calcification and ossification] Acta Chir Orthop Traumatol Cech. 1989 Jun;56(3):190-200. Czech. PMID: 2502888 403: Calvani M. [Magnesium and hypomagnesemia in childhood] Recenti Prog Med. 1989 Jun;80(6):338-43. Review. Italian. PMID: 2672198 404: Green SM, Naftel J. Antiarrhythmic efficacy of magnesium in the setting of life-threatening digoxin toxicity. Am J Emerg Med. 1989 May;7(3):347-8. PMID: 2712905 405: Rasmussen HS, Aurup P, Goldstein K, McNair P, Mortensen PB, Larsen OG, Lawaetz H. Influence of magnesium substitution therapy on blood lipid composition in patients with ischemic heart disease. A double-blind, placebo controlled study. Arch Intern Med. 1989 May;149(5):1050-3. PMID: 2719498 406: Roden DM. Magnesium treatment of ventricular arrhythmias. Am J Cardiol. 1989 Apr 18;63(14):43G-46G. Review. PMID: 2650516 407: Nowson CA, Morgan TO. Magnesium supplementation in mild hypertensive patients on a moderately low sodium diet. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 696
Clin Exp Pharmacol Physiol. 1989 Apr;16(4):299-302. PMID: 2663263 408: Pastorfide GB, Gorgonio NM, Ganzon AR, Alberto RM. Zinc chloride spray--magnesium hydroxide ointment dual topical regimen in the treatment of obstetric and gynecologic incisional wounds. Clin Ther. 1989 Mar-Apr;11(2):258-63. PMID: 2660997 409: Kohvakka A, Luurila O, Gordin A, Sundberg S. Comparison of potassium alone and potassium-magnesium supplementation in patients with heart failure using hydrochlorothiazide. Magnesium. 1989;8(2):71-6. PMID: 2755214 410: Rasmussen HS. Clinical intervention studies on magnesium in myocardial infarction. Magnesium. 1989;8(5-6):316-25. Review. PMID: 2693849 411: Iseri LT, Allen BJ, Brodsky MA. Magnesium therapy of cardiac arrhythmias in critical-care medicine. Magnesium. 1989;8(5-6):299-306. Review. PMID: 2693848 412: Mathew R, Altura BT, Altura BM. Strain differences in pulmonary hypertensive response to monocrotaline alkaloid and the beneficial effect of oral magnesium treatment. Magnesium. 1989;8(2):110-6. PMID: 2526910 413: Chaudry IH. ATP-MgCl2 and liver blood flow following shock and ischemia. Prog Clin Biol Res. 1989;299:19-31. Review. PMID: 2657790 414: Seifert B, Wagler P, Dartsch S, Schmidt U, Nieder J. [Magnesium--a new therapeutic alternative in primary dysmenorrhea] Zentralbl Gynakol. 1989;111(11):755-60. German. PMID: 2675496 415: Keren A, Dorian P, Davy JM, Opie LH. Effects of magnesium on ischemic and reperfusion arrhythmias in the rat heart and electrophysiologic effects of hypermagnesemia in the anesthetized dog. Cardiovasc Drugs Ther. 1988 Dec;2(5):637-45. PMID: 3154638 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 697
416: Rasmussen HS, Larsen OG, Meier K, Larsen J. Hemodynamic effects of intravenously administered magnesium on patients with ischemic heart disease. Clin Cardiol. 1988 Dec;11(12):824-8. PMID: 3233812 417: Mathew R, Gloster ES, Altura BT, Altura BM. Magnesium aspartate hydrochloride attenuates monocrotaline-induced pulmonary artery hypertension in rats. Clin Sci (Lond). 1988 Dec;75(6):661-7. PMID: 2974771 418: Pinkham CS, Kubena KS. Consequences of low dietary magnesium and high dietary calcium on pregnancy outcome and tissue mineralization in rats. Magnes Res. 1988 Dec;1(3-4):147-53. PMID: 3275202 419: Kovacs L, Molnar BG, Huhn E, Bodis L. [Magnesium substitution in pregnancy. A prospective, randomized double-blind study] Geburtshilfe Frauenheilkd. 1988 Aug;48(8):595-600. German. PMID: 3063587 420: Rasmussen HS. Justification for intravenous magnesium therapy in acute myocardial infarction. Magnes Res. 1988 Jul;1(1-2):59-73. Review. PMID: 3079204 421: Rasmussen HS, Gronbaek M, Cintin C, Balslov S, Norregard P, McNair P. One-year death rate in 270 patients with suspected acute myocardial infarction, initially treated with intravenous magnesium or placebo. Clin Cardiol. 1988 Jun;11(6):377-81. PMID: 3396238 422: Hallson PC, Rose GA. Reduction of the urinary risk factors of urolithiasis with magnesium and tartrate mixture: a new treatment. Br J Urol. 1988 May;61(5):382-4. PMID: 3395794 423: Moser PB, Reynolds RD, Acharya S, Howard MP, Andon MB. Calcium and magnesium dietary intakes and plasma and milk concentrations of Nepalese lactating women. Am J Clin Nutr. 1988 Apr;47(4):735-9. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 698
PMID: 3354499 424: Dyckner T, Wester PO, Widman L. Effects of peroral magnesium on plasma and skeletal muscle electrolytes in patients on long-term diuretic therapy. Int J Cardiol. 1988 Apr;19(1):81-7. PMID: 3372076 425: Spatling L, Spatling G. Magnesium supplementation in pregnancy. A double-blind study. Br J Obstet Gynaecol. 1988 Feb;95(2):120-5. PMID: 3349001 426: Oster JR, Epstein M. Management of magnesium depletion. Am J Nephrol. 1988;8(5):349-54. Review. PMID: 3071142 427: Mathew R, Altura BM. Magnesium and the lungs. Magnesium. 1988;7(4):173-87. Review. PMID: 3072451 428: Sjogren A, Floren CH, Nilsson A. Oral administration of magnesium hydroxide to subjects with insulin-dependent diabetes mellitus: effects on magnesium and potassium levels and on insulin requirements. Magnesium. 1988;7(3):117-22. PMID: 3054347 429: Critelli G, Reale A. [Magnesium and cardiac arrhythmias. Revived interest for an old substance] Cardiologia. 1987 Sep;32(9):989-98. Review. Italian. PMID: 3319159 430: Rasmussen HS, Suenson M, McNair P, Norregard P, Balslev S. Magnesium infusion reduces the incidence of arrhythmias in acute myocardial infarction. A double-blind placebo-controlled study. Clin Cardiol. 1987 Jun;10(6):351-6. PMID: 3297445 431: Floriot C, Delacour JL, Bourscheid D, Wagschal G, Daoudal P, Ory JP, Guyon B. [Value of magnesium chloride in supraventricular paroxysmal tachycardia and tachycardia caused by auricular fibrillation] Presse Med. 1987 May 9;16(17):829. French. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 699
PMID: 2954105 432: Abraham AS, Rosenmann D, Kramer M, Balkin J, Zion MM, Farbstien H, Eylath U. Magnesium in the prevention of lethal arrhythmias in acute myocardial infarction. Arch Intern Med. 1987 Apr;147(4):753-5. PMID: 3548627 433: Joffres MR, Reed DM, Yano K. Relationship of magnesium intake and other dietary factors to blood pressure: the Honolulu heart study. Am J Clin Nutr. 1987 Feb;45(2):469-75. PMID: 3812346 434: Martin RW, Gaddy DK, Martin JN Jr, Lucas JA, Wiser WL, Morrison JC. Tocolysis with oral magnesium. Am J Obstet Gynecol. 1987 Feb;156(2):433-4. PMID: 3826180 435: Penev I, Marinov B, Ruseva R, Vlasova D. [Importance of magnesium in preventing late pregnancy toxicoses (pre-eclampsia) (preliminary report)] Akush Ginekol (Sofiia). 1987;26(4):31-4. Bulgarian. PMID: 3674320 436: Kinnunen O, Salokannel J. Constipation in elderly long-stay patients: its treatment by magnesium hydroxide and bulk-laxative. Ann Clin Res. 1987;19(5):321-3. PMID: 3126699 437: Classen HG, Fischer G, Marx J, Schimatschek H, Schmid C, Stein C. Prevention of stress-induced damage in experimental animals and livestock by monomagnesium-L-aspartate hydrochloride. Magnesium. 1987;6(1):34-9. PMID: 3821173 438: Breuer J, Moniz C, Baldwin D, Parsons V. The effects of zero magnesium dialysate and magnesium supplements on ionised calcium concentration in patients on regular dialysis treatment. Nephrol Dial Transplant. 1987;2(5):347-50. PMID: 3122112 439: Roujouleh H, Lavaud S, Toupance O, Melin JP, Chanard J. [Magnesium hydroxide treatment of hyperphosphatemia in chronic hemodialysis Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 700
patients with an aluminum overload] Nephrologie. 1987;8(2):45-50. French. PMID: 3614505 440: Goldberg P, Fleming MC, Picard EH. Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D. Med Hypotheses. 1986 Oct;21(2):193-200. PMID: 3537648 441: Bradley RJ. Calcium or magnesium concentration affects the severity of organophosphate-induced neuromuscular block. Eur J Pharmacol. 1986 Aug 15;127(3):275-8. PMID: 3019732 442: Willox JC, McAllister EJ, Sangster G, Kaye SB. Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: a randomised trial. Br J Cancer. 1986 Jul;54(1):19-23. PMID: 3524645 443: Luthringer C, Berthelot A. [Dietary magnesium and mineralocorticoid DOCA-salt hypertension in the rat. Effect on the metabolism of sodium and magnesium] Arch Mal Coeur Vaiss. 1986 Jun;79(6):871-4. French. PMID: 3099703 444: O'Donovan R, Baldwin D, Hammer M, Moniz C, Parsons V. Substitution of aluminium salts by magnesium salts in control of dialysis hyperphosphataemia. Lancet. 1986 Apr 19;1(8486):880-2. PMID: 2870354 445: Rasmussen HS, McNair P, Norregard P, Backer V, Lindeneg O, Balslev S. Intravenous magnesium in acute myocardial infarction. Lancet. 1986 Feb 1;1(8475):234-6. PMID: 2868254 446: Laban E, Charbon GA. Magnesium and cardiac arrhythmias: nutrient or drug? J Am Coll Nutr. 1986;5(6):521-32. Review. PMID: 3537078 447: Fehlinger R, Mielke U, Fauk D, Seidel K. Rheographic indications for reduced cerebral vasoconstriction after oral Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 701
magnesium medication in tetanic patients, a double-blind, placebo-controlled trial. Magnesium. 1986;5(2):60-5. PMID: 3713254 448: Iseri LT. Magnesium and cardiac arrhythmias. Magnesium. 1986;5(3-4):111-26. Review. PMID: 3523053 449: Marier JR. Magnesium content of the food supply in the modern-day world. Magnesium. 1986;5(1):1-8. Review. PMID: 3515057 450: Rude RK, Adams JS, Ryzen E, Endres DB, Niimi H, Horst RL, Haddad JG Jr, Singer FR. Low serum concentrations of 1,25-dihydroxyvitamin D in human magnesium deficiency. J Clin Endocrinol Metab. 1985 Nov;61(5):933-40. PMID: 3840173 451: Clemens MG, McDonagh PF, Chaudry IH, Baue AE. Hepatic microcirculatory failure after ischemia and reperfusion: improvement with ATP-MgCl2 treatment. Am J Physiol. 1985 Jun;248(6 Pt 2):H804-11. PMID: 3923842 452: Fuss M, Cogan E, Gillet C, Karmali R, Geurts J, Bergans A, Brauman H, Bouillon R, Corvilain J. Magnesium administration reverses the hypocalcaemia secondary to hypomagnesaemia despite low circulating levels of 25-hydroxyvitamin D and 1,25-dihydroxy vitamin D. Clin Endocrinol (Oxf). 1985 Jun;22(6):807-15. PMID: 3874724 453: Martineau J, Barthelemy C, Garreau B, Lelord G. Vitamin B6, magnesium, and combined B6-Mg: therapeutic effects in childhood autism. Biol Psychiatry. 1985 May;20(5):467-78. PMID: 3886023 454: Delhumeau A, Victor J, Granry JC, Monrigal JP, Chapillon M, Cavellat M. [Anti-arrhythmia effects of magnesium salts. 4 cases] Presse Med. 1985 Mar 16;14(11):629-32. French. PMID: 3157950 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 702
455: O'Sullivan G, Sear JW, Bullingham RE, Carrie LE. The effect of magnesium trisilicate mixture, metoclopramide and ranitidine on gastric pH, volume and serum gastrin. Anaesthesia. 1985 Mar;40(3):246-53. PMID: 2986474 456: Hirasawa H, Soeda K, Ohtake Y, Oda S, Kobayashi S, Odaka M, Sato H. Effects of ATP-MgCl2 and ATP-Na2 administration on renal function and cellular metabolism following renal ischemia. Circ Shock. 1985;16(4):337-46. PMID: 3836026 457: Morgan KJ, Stampley GL, Zabik ME, Fischer DR. Magnesium and calcium dietary intakes of the U.S. population. J Am Coll Nutr. 1985;4(2):195-206. PMID: 4019942 458: Corby DG, McCullen AH, Chadwick EW, Decker WJ. Effect of orally administered magnesium hydroxide in experimental iron intoxication. J Toxicol Clin Toxicol. 1985-86;23(7-8):489-99. PMID: 3831376 459: Cohen L, Kitzes R. Early radiation-induced proctosigmoiditis responds to magnesium therapy. Magnesium. 1985;4(1):16-9. PMID: 4033202 460: Marier JR, Neri LC. Quantifying the role of magnesium in the interrelationship between human mortality/morbidity and water hardness. Magnesium. 1985;4(2-3):53-9. PMID: 4046646 461: Conradt A, Weidinger H, Algayer H. Magnesium therapy decreased the rate of intrauterine fetal retardation, premature rupture of membranes and premature delivery in risk pregnancies treated with betamimetics. Magnesium. 1985;4(1):20-8. PMID: 2863425 462: Pignide L, Hersch R. [Efficacy and limits of magnesium therapy in extrasystole] Magnesium. 1985;4(5-6):272-9. French. PMID: 2422503 Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 703
463: Ulmann A, Hadj S, Lacour B, Bourdeau A, Bader C. Renal magnesium and phosphate wastage in a patient with hypercalciuria and nephrocalcinosis: effect of oral phosphorus and magnesium supplements. Nephron. 1985;40(1):83-7. PMID: 4000339 464: Lakshmanan FL, Rao RB, Kim WW, Kelsay JL. Magnesium intakes, balances, and blood levels of adults consuming self-selected diets. Am J Clin Nutr. 1984 Dec;40(6 Suppl):1380-9. PMID: 6507359 465: Jonas C, Etienne T, Barthelemy C, Jouve J, Mariotte N. [Clinical and biochemical value of Magnesium + vitamin B6 combination in the treatment of residual autism in adults] Therapie. 1984 Nov-Dec;39(6):661-9. French. PMID: 6397868 466: Reynolds CK, Bell MC, Sims MH. Changes in plasma, red blood cell and cerebrospinal fluid mineral concentrations in calves during magnesium depletion followed by repletion with rectally infused magnesium chloride. J Nutr. 1984 Jul;114(7):1334-41. PMID: 6737093 467: Vacanti FX, Ames A 3rd. Mild hypothermia and Mg++ protect against irreversible damage during CNS ischemia. Stroke. 1984 Jul-Aug;15(4):695-98. PMID: 6464063 468: Lewis LD, Morris ML Jr. Treatment and prevention of feline struvite urolithiasis. Vet Clin North Am Small Anim Pract. 1984 May;14(3):649-60. Review. PMID: 6377667 469: Mills BJ, Broghamer WL, Higgins PJ, Lindeman RD. Inhibition of tumor growth by magnesium depletion of rats. J Nutr. 1984 Apr;114(4):739-45. PMID: 6716176 470: Conradt A, Weidinger H, Algayer H. [Reduced frequency of gestoses in beta-mimetic treated risk pregnancies with added magnesium therapy] Geburtshilfe Frauenheilkd. 1984 Feb;44(2):118-23. German. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 704
PMID: 6564044 471: Schaumann E, Bergmann W. [Magnesium, an essential factor in the pathogenesis and therapy of diseases of civilization] Z Gesamte Hyg. 1984 Feb;30(2):84-7. German. PMID: 6711060 472: Johansson BW. Magnesium infusion in decompensated hypomagnesemic patients. Acta Pharmacol Toxicol (Copenh). 1984;54 Suppl 1:125-8. PMID: 6711328 473: Suau A, Dominguez Martin A, Ferrando Cucarella J, Juncosa Iglesias L, Munoz Benitez J, Nieto Calvet M, Perez Gieb J, Perez Mota A, Pineda Garcia A, Rodriguez Sanchez E, et al. Treatment of gastric pyrosis with almagate in patients with and without endoscopically demonstrable duodenal ulcer. A multicentre clinical trial. Arzneimittelforschung. 1984;34(10A):1380-3. PMID: 6548926 474: Llupia J, Lumachi B, Beckett PR, Roberts DJ. Protective action of almagate against bile-facilitated gastric ulceration in the pylorus-ligated (Shay) rat. Arzneimittelforschung. 1984;34(10A):1373-5. PMID: 6548924 475: Spatling L. [Additional magnesium therapy in tocolysis: clinico-chemical monitoring parameters] Geburtshilfe Frauenheilkd. 1984 Jan;44(1):19-24. German. PMID: 6559720 476: Karppanen H, Tanskanen A, Tuomilehto J, Puska P, Vuori J, Jantti V, Seppanen ML. Safety and effects of potassium- and magnesium-containing low sodium salt mixtures. J Cardiovasc Pharmacol. 1984;6 Suppl 1:S236-43. PMID: 6204148 477: Dyckner T, Wester PO. Intra-/extracellular shifts of potassium after the administration of Mg in patients with cardiovascular diseases. Magnesium. 1984;3(4-6):339-45. PMID: 6536841
705
478: Luoma H, Koskinen M, Tuomisto J, Collan Y. Reduction of the lethality and the nephrocalcinotic effect of single fluoride doses by magnesium in rats. Magnesium. 1984;3(2):81-7. PMID: 6503359 479: Moe BH. On the therapeutic mechanism of Mg2+ in digitoxic arrhythmias and the role of cardiac glycosides in Mg depletion. Magnesium. 1984;3(1):8-20. PMID: 6482510 480: Morton BC, Nair RC, Smith FM, McKibbon TG, Poznanski WJ. Magnesium therapy in acute myocardial infarction--a double-blind study. Magnesium. 1984;3(4-6):346-52. PMID: 6399346 481: Cohen L, Laor A, Kitzes R. Reversible retinal vasospasm in magnesium-treated hypertension despite no significant change in blood pressure. Magnesium. 1984;3(3):159-63. PMID: 6392763 482: Buck DR, Bales J. Maternal dietary magnesium effects on lactation success and on milk yield and composition in the rat. J Nutr. 1983 Dec;113(12):2421-31. PMID: 6655508 483: Marie PJ, Travers R, Delvin EE. Influence of magnesium supplementation on bone turnover in the normal young mouse. Calcif Tissue Int. 1983 Sep;35(6):755-61. PMID: 6652550 484: Conradt A, Weidinger H, Algayer H. [Reduction of low weight birth, premature amniotic rupture and premature labor following additional magnesium therapy in high risk pregnancy treated with beta mimetics and cerclage] Geburtshilfe Frauenheilkd. 1983 Jun;43(6):355-62. German. PMID: 6554207 485: Atteh JO, Leeson S. Influence of increasing the calcium and magnesium content of the drinking water on performance and bone and plasma minerals of broiler chickens. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 706
Poult Sci. 1983 May;62(5):869-74. PMID: 6878125 486: Conradt A, Weidinger H, Algayer H. [The importance of betamimetics and magnesium for the outcome of pregnancy: I. Reduction of intrauterine growth retardation, premature rupture of membranes and premature birth after supplemental magnesium therapy] Z Geburtshilfe Perinatol. 1983 May-Jun;187(3):127-37. Review. German. PMID: 6137118 487: Malestein A. [Does the supply of magnesium affect the feed intake in ruminants?] Tijdschr Diergeneeskd. 1983 Mar 15;108(6):250-3. Dutch. PMID: 6573812 488: Berthelot A, Esposito J. Effects of dietary magnesium on the development of hypertension in the spontaneously hypertensive rat. J Am Coll Nutr. 1983;2(4):343-53. PMID: 6317730 489: Bartl W, Riss P. [Pathophysiology and therapy of magnesium deficiency in pregnancy] Z Geburtshilfe Perinatol. 1982 Nov-Dec;186(6):335-7. German. PMID: 6891868 490: Salducci J, Planche D. [A therapeutic trial in patients with spasmophilia] Sem Hop. 1982 Oct 7;58(36):2097-100. French. PMID: 6294844 491: Harwood EJ. The influence of dietary magnesium on reduction of nephrocalcinosis in rats fed purified diet. Lab Anim. 1982 Oct;16(4):314-8. PMID: 7176523 492: Luoma AR, Koskinen M, Olkkonen H, Luoma H. Caries reduction in rats through F + Mg supplementation of dietary sucrose with observations on bone mineral density and soft and hard tissue minerals. Scand J Dent Res. 1982 Oct;90(5):345-53. PMID: 6960464 493: Wischnik A, Mendler N, Schroll A, Heimisch W, Weidenbach A. [The cardiac hazard of tocolysis and antagonizing possibilities. II. Communication: protection of the myocardium by means of substitution of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 707
magnesium] Geburtshilfe Frauenheilkd. 1982 Jul;42(7):537-42. German. PMID: 6922076 494: Lelord G, Callaway E, Muh JP. Clinical and biological effects of high doses of vitamin B6 and magnesium on autistic children. Acta Vitaminol Enzymol. 1982;4(1-2):27-44. PMID: 7124567 495: Chaudry IH, Kupper TS, Schleck S, Clemens MG, Baue AE. Impairment of reticuloendothelial function following thermal injury and its restoration with ATP-MgCl2 administration. Circ Shock. 1982;9(3):297-305. PMID: 7094221 496: Dyckner T, Wester PO. Magnesium treatment of diuretic-induced hyponatremia with a preliminary report of a new aldosterone-antagonist. J Am Coll Nutr. 1982;1(2):149-53. PMID: 7185847 497: Johansson G, Backman U, Danielson BG, Fellstrom B, Ljunghall S, Wikstrom B. Effects of magnesium hydroxide in renal stone disease. J Am Coll Nutr. 1982;1(2):179-85. PMID: 6764473 498: Guillot AP, Hood VL, Runge CF, Gennari FJ. The use of magnesium-containing phosphate binders in patients with end-stage renal disease on maintenance hemodialysis. Nephron. 1982;30(2):114-7. PMID: 7099318 499: Gullner HG, Gill JR Jr, Bartter FC. Correction of hypokalemia by magnesium repletion in familial hypokalemic alkalosis with tubulopathy. Am J Med. 1981 Oct;71(4):578-82. PMID: 7025624 500: Harris JC, Rumack BH, Bregman DJ. Comparative efficacy of injectable calcium and magnesium salts in the therapy of hydrofluoric acid burns. Clin Toxicol. 1981 Sep;18(9):1027-32. PMID: 7318388 501: Stromme JH, Steen-Johnsen J, Harnaes K, Hofstad F, Brandtzaeg P. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 708
Familial hypomagnesemia--a follow-up examination of three patients after 9 to 12 years of treatment. Pediatr Res. 1981 Aug;15(8):1134-9. PMID: 7267188 502: Krasner BS, Girdwood R, Smith H. The effect of slow releasing oral magnesium chloride on the QTc interval of the electrocardiogram during open heart surgery. Can Anaesth Soc J. 1981 Jul;28(4):329-33. PMID: 7260710 503: Gurvich DB, Korovina NA. [Effect of a magnesium-enriched diet on electrolyte metabolism and oxalate excretion in kidney diseases in children] Vopr Pitan. 1981 Jul-Aug;(4):27-30. Russian. PMID: 7293102 504: Lelord G, Muh JP, Barthelemy C, Martineau J, Garreau B, Callaway E. Effects of pyridoxine and magnesium on autistic symptoms--initial observations. J Autism Dev Disord. 1981 Jun;11(2):219-30. PMID: 6765503 505: Dyckner T, Wester PO. Effects of magnesium infusions in diuretic induced hyponatraemia. Lancet. 1981 Mar 14;1(8220 Pt 1):585-6. PMID: 6110822 506: Spatling L. [Oral magnesium therapy in cases of preterm labour (author's transl)] Geburtshilfe Frauenheilkd. 1981 Feb;41(2):101-2. German. PMID: 6908857 507: Singh RB, Singh VP, Cameron EA. Magnesium in atherosclerotic cardiovascular disease and sudden death. Acta Cardiol. 1981;36(6):411-29. PMID: 6977957 508: Karppanen H. Epidemiological studies on the relationship between magnesium intake and cardiovascular diseases. Artery. 1981;9(3):190-9. PMID: 7305668 509: Mesmer M, Fischer G, Classen HG. [Inhibition of stress reactions by magnesium. Beneficial effects of parenteral magnesium therapy on the development of stress ulcers in rats (author's transl)] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 709
Arzneimittelforschung. 1981;31(2):389-91. German. PMID: 7194659 510: Knox D, Cowey CB, Adron JW. Studies on the nutrition of salmonid fish. The magnesium requirement of rainbow trout (Salmo gairdneri). Br J Nutr. 1981 Jan;45(1):137-48. PMID: 7470429 511: Brundig P, Berg W, Schneider HJ. The influence of magnesium chloride on blood and urine parameters in calcium oxalate stone patients. Eur Urol. 1981;7(2):97-9. PMID: 7461010 512: Main AN, Morgan RJ, Russell RI, Hall MJ, MacKenzie JF, Shenkin A, Fell GS. Mg deficiency in chronic inflammatory bowel disease and requirements during intravenous nutrition. JPEN J Parenter Enteral Nutr. 1981 Jan-Feb;5(1):15-9. PMID: 6785467 513: Cobden I, McMahon MJ, Dixon MF, Axon AT. Double-blind clinical, endoscopic and histological comparison of hydrotalcite/dimethicone suspension and magnesium hydroxide/aluminum hydroxide suspension in the treatment of symptomatic gastritis. Pharmatherapeutica. 1981;2(9):607-12. PMID: 7267678 514: Bac P. [Audiogenic seizure in the mouse according to strain and sex: the effect of the magnesium ration and neuromediators] Reprod Nutr Dev. 1981;21(3):429-40. French. PMID: 6130580 515: Horn B. Magnesium-it's about time. West J Med. 1981 Jan;134(1):72-3. PMID: 7210668 516: Johansson G, Backman U, Danielson BG, Fellstrom B, Ljunghall S, Wikstrom B. Biochemical and clinical effects of the prophylactic treatment of renal calcium stones with magnesium hydroxide. J Urol. 1980 Dec;124(6):770-4. PMID: 7441826 517: Landahl S, Graffner C, Jagenburg R, Lundborg P, Steen B. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 710
Prevalence and treatment of hypomagnesemia in the elderly studies in a representative in 70-year-old population and in geriatric patients. Aktuelle Gerontol. 1980 Sep;10(9):397-402. PMID: 6110376 518: Siegel NJ, Glazier WB, Chaudry IH, Gaudio KM, Lytton B, Baue AE, Kashgarian M. Enhanced recovery from acute renal failure by the postischemic infusin of adenine nucleotides and magnesium chloride in rats. Kidney Int. 1980 Mar;17(3):338-49. PMID: 7401453 519: Binswanger U, Schiffl H, Huggler M, Becker C. 1,25 dihydroxycholecalciferol treatment of uraemic rats after high magnesium feeding. Proc Eur Dial Transplant Assoc. 1980;17:563-8. PMID: 6894642 520: Maksimovich IaB, Gaidenko AI, Aksel'rod LB, Malakhova OP. [Mechanism of the anti-arrhythmia action of potassium and magnesium nicotinates] Farmakol Toksikol. 1979 Sep-Oct;42(5):501-4. Russian. PMID: 488322 521: Brautbar N, Lee DB, Coburn JW, Kleeman CR. Influence of dietary magnesium in experimental phosphate depletion: bone and soft tissue mineral changes. Am J Physiol. 1979 Aug;237(2):E152-7. PMID: 464091 522: Chaudry IH, Hirasawa H, Baue AE. Impairment of reticuloendothelial system function with sepsis and its improvement with ATP-MgCl2 plus glucose administration. Adv Shock Res. 1979;2:153-62. PMID: 262800 523: Menotti A, Signoretti P. [Characteristics of drinking water and coronary heart disease. An epidemiological experience (author's transl)] G Ital Cardiol. 1979;9(7):674-7. Italian. PMID: 540698 524: Hirasawa H, Ohkawa M, Odaka M, Sato H. Improved survival, RES function, and ICG test with ATP-MgCl2 following hepatic ischemia. Surg Forum. 1979;30:158-60. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 711
PMID: 538581 525: Wiberg JJ, Turner GG, Nuttall FQ. Effect of phosphate or magnesium cathartics on serum calcium: observations in normocalcemic patients. Arch Intern Med. 1978 Jul;138(7):1114-6. PMID: 666471 526: Binet P, Miocque M, Pechery C, Roux M, Rinjard P. [Comparative corrective effect of magnesium 2-pyrrolidone carboxylate and magnesium chloride on skin and hematological disorders in experimental magnesium deficiency in the rat] Therapie. 1978 Jul-Aug;33(4):491-500. French. PMID: 734628 527: Hirasawa H, Chaundry IH, Baue AE. Improved hepatic function and survival with adenosine triphosphate-magnesium chloride after hepatic ischemia. Surgery. 1978 Jun;83(6):655-62. PMID: 644458 528: Moore MJ, Flink EB. Magnesium deficiency as a cause of serious arrhythmias. Arch Intern Med. 1978 May;138(5):825-6. PMID: 646549 529: Borges LF, Gucer G. Effect of magnesium on epileptic foci. Epilepsia. 1978 Feb;19(1):81-91. PMID: 414910 530: Holdsworth JD. A fresh look at magnesium trisilicate. J Int Med Res. 1978;6 Suppl 1:70-6. PMID: 35427 531: Lytton B, Glazier WB, Chaudry IH, Baue AE. The use of adenosine triphosphate with magnesium chloride in the treatment of post ischemic renal injury. Trans Am Assoc Genitourin Surg. 1978;70:145-8. PMID: 753014 532: Schneider HJ, Hesse A, Berg W, Kirsten J, Nickel H. [Animal-experiment studies on the effect of magnesium and vitamin B 6 on calcium-oxalate nephrolithiasis] Z Urol Nephrol. 1977 Jun;70(6):419-27. German. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 712
PMID: 906678 533: Jorgensen I, Schjelderup-Mathiesen PM. [Magnesium--an alternative in treatment resistant tachyarrhythmias] Tidsskr Nor Laegeforen. 1977 May 30;97(15):770-769. Norwegian. PMID: 867390 534: Bletry O, Certin M, Herreman G, Wechsler B, Godeau P. [Hypokalemia and hypomagnesemia in a cirrhotic patient. Correction of metabolic disorders by magnesium] Sem Hop. 1977 May 23;53(20):1175-8. French. PMID: 198892 535: Berthelot A, Miss-Pages C, Gairard A. [Calcium metabolism and mineralocorticoid-induced hypertension: effects of parathormone and exogenous thyrocalcitonin and of variations in dietary calcium and magnesium] C R Seances Soc Biol Fil. 1977;171(5):1101-6. French. PMID: 146554 536: Freeman JB, Wittine MF. Magnesium requirements are increased during total parenteral nutrition. Surg Forum. 1977;28:61-2. PMID: 103228 537: Hutchinson BR. Preoperative magnesium trisilicate in infants. Anaesth Intensive Care. 1976 Aug;4(3):192-5. PMID: 9840 538: Anast C, David L, Winnacker J, Glass R, Baskin W, Brubaker L, Burns T. Serum calcitonin-lowering effect of magnesium in patients with medullary carcinoma of the thyroid. J Clin Invest. 1975 Dec;56(6):1615-21. PMID: 1202087 539: Hadlich M, Kolb E. [Calcium, magnesium, phosphorus, chloride and glucose in the blood of cattle following intravenous infusion of solutions with various calcium and magnesium concentration aimed at improving the treatment of hypomagnesemia] Arch Exp Veterinarmed. 1975 Jun;29(3):379-95. German. PMID: 1190966 540: Pointillart A, Meslin JC. [Effect of dietary magnesium levels on cardiac lesions in rats fed a diet rich in rapeseed oil] Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 713
Nutr Metab. 1975;19(1-2):10-9. French. PMID: 1226266 541: Catto GR, MacLeod M, Pelc B, Kodicek E. The investigation and treatment of renal osteodystrophy. Proc Eur Dial Transplant Assoc. 1975;11:473-80. PMID: 1197272 542: Slezak J, Tribulova N. Morphological changes after combined administration of isoproterenol and K+,Mg2+-aspartate as a physiological Ca2+ antagonist. Recent Adv Stud Cardiac Struct Metab. 1975;6:75-84. PMID: 1197902 543: Janke J, Fleckenstein A, Hein B, Leder O, Sigel H. Prevention of myocardial Ca overload and necrotization by Mg and K salts or acidosis. Recent Adv Stud Cardiac Struct Metab. 1975;6:33-42. PMID: 743 544: Classen HG, Marquardt P, Spath M, Ebel H, Schumacher KA. Improvement by chlorine of the intestinal absorption of inorganic and organic Mg compounds and of their protective effect against adrenergic cardiopathy. Recent Adv Stud Cardiac Struct Metab. 1975;6:11-9. PMID: 128076 545: Ghani MF, Smith JR. The effectiveness of magnesium chloride in the treatment of ventricular tachyarrhythmias due to digitalis intoxication. Am Heart J. 1974 Nov;88(5):621-6. PMID: 4419576 546: Izawa H, Imura M, Kuroda M, Takeda R. Proceedings: Effect of magnesium on secondary hyperparathyroidism in chronic hemodialysis: a case with soft tissue calcification improved by high Mg dialysate. Calcif Tissue Res. 1974;15(2):162. PMID: 4844404 547: Levin MP, Yearwood LL, Carpenter WN. The desensitizing effect of calcium hydroxide and magnesium hydroxide on hypersensitive dentin. Oral Surg Oral Med Oral Pathol. 1973 May;35(5):741-6. PMID: 4573138 548: Rosler A, Rabinowitz D. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 714
Magnesium-induced reversal of vitamin-D resistance in hypoparathyroidism. Lancet. 1973 Apr 14;1(7807):803-4. PMID: 4121224 549: Prikryl P. [Positive therapeutic effect of K-Mg asparaginate in Prinzmetal's angina pectoris and Adams-Stokes syndrome] Cas Lek Cesk. 1973 Feb;112(6):186. Czech. PMID: 4726977 550: Szelenyi I. Magnesium and its significance in cardiovascular and gastro-intestinal disorders. World Rev Nutr Diet. 1973;17:189-224. Review. PMID: 4570425 551: Ringenbach MG. [Decrease in transfusion reactions by the use of magnesium thiosulfate] Bord Med. 1972 Dec;5(20):2743-6. French. PMID: 4660157 552: Fernandez PC, Kovnat PJ. Metabolic acidosis reversed by the combination of magnesium hydroxide and a cation-exchange resin. N Engl J Med. 1972 Jan 6;286(1):23-4. PMID: 5006921 553: Tokumaru M, Takaoka A, Inoue H, Tateichi K. [Effective treatment of tetany in a newborn infant by combined administration of magnesium and calcium] Nippon Shonika Gakkai Zasshi. 1971 Oct;75(10):913-6. Japanese. PMID: 5169738 554: Wenzel E. [The therapeutic effect of kavain and magnesium orotate on traumatic and vascular brain lesions] Wien Med Wochenschr. 1971 Mar 20;121(12):226-36. German. PMID: 5556378 555: Casucci N, Girardi F, Argentieri R, Venezia L. [On a case of grave disorders of cardiac rhythm caused by hyper-potassemia, in a patient in hemodialytic therapy, controlled with Mg ascorbate] Minerva Nefrol. 1970 Nov-Dec;17(6):208-12. Italian. PMID: 5516057 556: Villanyi P, Votin J, Rahlfs V. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 715
[Arteriosclerosis, myocardial infarct and blood lipids, their therapeutic modification by magnesium orotate] Wien Med Wochenschr. 1970 Jan 31;120(5):76-83. German. PMID: 5513887 557: Golber LM, Anan'eva KA, Kandror VI, Kriukova IV, Negovskaia AV. [The importance of magnesium in preventing myocardial metabolic disorders in thyrotoxicosis] Biull Eksp Biol Med. 1969 Mar;67(3):23-6. Russian. PMID: 5821450 558: Stein DG, Brink JJ. Prevention of retrograde amnesia by injection of magnesium pemoline in dimethylsulfoxide. Psychopharmacologia. 1969;14(3):240-7. PMID: 5389242 559: Szulc EJ. [Clinical studies on the therapeutic effect of potassium-magnesium aspartate in coronary disease] Wiad Lek. 1968 Sep 1;21(17):1509-14. Polish. PMID: 4882478 560: Combes-Hamelle A, Stelian Y. [Value of magnesium bromoglutamate syrup for problems of behavior and psychomotor development of the child] Ann Pediatr (Paris). 1968 Aug-Sep;15(8):585-6. French. PMID: 5685048 561: Bertharion G. [Magnesium lactate used as protective agent against hyperoxemia convulsions in white rats] J Physiol (Paris). 1968;60 Suppl 2:348. French. PMID: 5734904 562: [No authors listed] Magnesium--its nutritional and pharmacologic effects. Med Lett Drugs Ther. 1967 Nov 17;9(23):93-4. PMID: 6054465 563: Atlan D, Regis H, Gastaut H. Treatment of spasmophilia in the adult by magnesium lactate. Electroencephalogr Clin Neurophysiol. 1967 Oct;23(4):388. PMID: 4167803
716
564: Reichertz PL, Noell G, Hemmati A. [Therapy of disorders of myocardial metabolism with potassium-magnesium aspartate] Med Welt. 1967 Sep 23;38:2236-43. German. PMID: 5614953 565: Atlan D, Regis H, Gastaut H. [Treatment of spasmophilia of the adult by magnesium lactate] Rev Neurol (Paris). 1967 Jul;117(1):170-7. French. PMID: 4863462 566: de Alencastro GG, da Fonseca JP. [Therapy of sickle cell anemia by alkalies and magnesium salts. Presentation of a case] Hospital (Rio J). 1967 Jun;71(6):1771-4. Portuguese. PMID: 5304212 567: Durlach J. [The physiologic role of magnesium. Phlebothrombotic disease due to magnesium deficiency] Coeur Med Interne. 1967 Apr;6(2):213-32. French. PMID: 5618969 568: Guerrier Y. [Magnesium lactate in the treatment of pharyngo-laryngeal paresthesia] J Fr Otorhinolaryngol Audiophonol Chir Maxillofac. 1967 Apr;16(4):289-90. French. PMID: 4241457 569: Kwitko ML, Wener J, Simon MA, Pintar K. The inhibition of iris lipidosis in rabbits with oral magnesium. Can J Ophthalmol. 1966 Jul;1(3):240-8. PMID: 5914355 570: Dumont M. [Treatment of uterine pain in pregnancy with magnesium lactate] Lyon Med. 1965 May 23;213(21):1571-82. French. PMID: 5828798
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Quercetin - 30 ABSTRACTS
1. Pharmacology. 2003 Oct;69(2):59-67. Protective Effect of Flavonoids against Agingand Lipopolysaccharide-Induced Cognitive Impairment in Mice.Patil CS, Singh VP, Satyanarayan PS, Jain NK, Singh A, Kulkarni SK. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Flavonoids, naturally occurring polyphenolic compounds, are known to inhibitboth lipopolysaccharide (LPS) stimulated tumor necrosis factor alpha and interleukin 6 release which modulate the proinflammatory molecules that have been reported in many progressive neurodegenerative disorders, including Alzheimer's disease (AD), viral and bacterial meningitis, AIDS dementia complex,and stroke. The present experiments were performed to study the possible effects of exogenously administered flavonoids (apigenin-7-glucoside and quercetin) on the cognitive performance in aged and LPStreated mice (an animal model for AD) using passive avoidance and elevated plus-maze tasks. Aged and LPS-treated mice showed poor retention of memory in step-through passive avoidance and in plus-maze tasks. Chronic administration of the flavonoids apigenin-7-glucoside (5-20 mg/kg i.p.) and quercetin (25-100 mg/kg i.p.) dose dependently reversed the age-induced and LPS-induced retention deficits in both test paradigms. However, flavonoids after chronic administration in young mice did not show any improvement of memory retention in both paradigms. Apigenin-7-glucoside showed more efficacy as compared with quercetin in both models that may be probably due to its greater efficacy to inhibit cyclooxygenase-2 and inducible nitric oxide synthase. Chronic treatment with flavonoids did not alter the locomotor activity in both young and aged mice; however, aged mice showed improvement of performance on Rota-Rod test. The results showed that chronic treatment with flavonoids reverses cognitive deficits in aged and LPS-intoxicated mice which suggests that modulation of cyclooxygenase-2 and inducible nitric synthase by flavonoids may be important in the prevention of memory deficits, one of the symptoms related to AD. Copyright 2003 S. Karger AG, Basel 2. Clin Pharmacokinet. 2003;42(5):437-59. Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress. Schwedhelm E, Maas R, Troost R, Boger RH. Institute of Experimental and Clinical Pharmacology, Clinical Pharmacology Unit, University Hospital of Hamburg-Eppendorf, Hamburg, Germany. schwedhelm@uke-hamburg.de Dietary antioxidants play a major role in maintaining the homeostasis of the oxidative balance. They are believed to protect humans from disease and aging. Vitamin C (ascorbic acid), vitamin E (tocopherol), beta-carotene and other
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micronutrients such as carotenoids, polyphenols and selenium have been evaluated as antioxidant constituents in the human diet. This article addresses data provided from clinical trials, highlighting the clinical pharmacokinetics of vitamin C, vitamin E, beta-carotene, lycopene, lutein, quercetin, rutin, catechins and selenium. The bioavailability of vitamin C is dose-dependent. Saturation of transport occurs with dosages of 200-400 mg/day. Vitamin C is not protein-bound and is eliminated with an elimination half-life (t((1/2))) of 10 hours. In Western populations plasma vitamin C concentrations range from 54-91 micro mol/L. Serum alpha- and gamma-tocopherol range from 21 micro mol/L (North America) to 27 micro mol/L (Europe) and from 3.1 micro mol/L to 1.5 micro mol/L, respectively. alpha-Tocopherol is the most abundant tocopherol in human tissue. The bioavailability of all-rac-alpha-tocopherol is estimated to be 50% of R,R,R-alphatocopherol. The hepatic alpha-tocopherol transfer protein (alpha-TTP) together with the tocopherol-associated proteins (TAP) are responsbile for the endogenous accumulation of natural alpha-tocopherol. Elimination of alpha-tocopherol takes several days with a t((1/2)) of 81 and 73 hours for R,R,R-alpha-tocopherol and all-rac-alpha-tocopherol, respectively. The t((1/2)) of tocotrienols is short, ranging from 3.8-4.4 hours for gamma- and alpha-tocotrienol, respectively. gamma-Tocopherol is degraded to 2, 7, 8-trimethyl-2-(beta-carboxyl)-6-hyrdoxychroman by the liver prior to renal elimination. Blood serum carotenoids in Western populations range from 0.28-0.52 micro mol/L for beta-carotene, from 0.2-0.28 for lutein, and from 0.29-0.60 for lycopene. Alltrans-carotenoids have a better bioavailability than the 9-cis-forms. Elimination of carotenoids takes several days with a t((1/2)) of 5-7 and 2-3 days for beta-carotene and lycopene, respectively. The bioconversion of betacarotene to retinal is dose-dependent, and ranges between 27% and 2% for a 6 and 126mg dose, respectively. Several oxidised metabolites of carotenoids are known. Flavonols such as quercetin glycosides and rutin are predominantly absorbed as aglycones, bound to plasma proteins and subsequently conjugated to glucuronide, sulfate, and methyl moieties. The t((1/2)) ranges from 12-19 hours. The bioavailabillity of catechins is low and they are eliminated with a t((1/2)) of 2-4 hours. Catechins are degraded to several gamma-valerolactone derivatives and phase II conjugates have also been identified. Only limited clinical pharmacokinetic data for other polyphenols such as resveratrol have been reported to date. 3. Neurobiol Aging. 2002 Sep-Oct;23(5):891-97. Natural extracts as possible protective agents of brain aging. Bastianetto S, Quirion R. Department of Psychiatry and Pharmacology and Therapeutics, Douglas Hospital Research Centre, McGill University, 6875 LaSalle Boulevard, Verdun, Que, Canada H4H 1R3. A growing number of studies suggest that natural extracts and phytochemicals have a positive impact on brain aging. We examined the potential of the Ginkgo Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 719
biloba extract EGb 761 and red wine-derived constituents on cell death produced by beta-amyloid (Abeta) peptides and oxidative stress, with respect to their possible deleterious role in age-related neurological disorders. We found that EGb 761, possibly through the antioxidant properties of its flavonoids, was able to protect hippocampal cells against toxic effects induced by Abeta peptides. Moreover, we showed that an exposure of rat hippocampal cells to the nitric oxide (NO) donor sodium nitroprusside (SNP) resulted in a decrease in cell survival and increase in reactive oxygen species (ROS) accumulation. However, EGb 761 and red wine-derived polyphenols protected against these events, due to their antioxidant activities, and their ability to block SNP-stimulated activity of protein kinase C (PKC). Taken together, these results support the hypothesis that dietary intake of natural substances may be beneficial in normal aging of the brain. Copyright 2002 Elsevier Science Inc. 4. Mol Biol Cell. 2002 Jul;13(7):2502-17. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Volonte D, Zhang K, Lisanti MP, Galbiati F. Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15261, USA. Caveolae are vesicular invaginations of the plasma membrane. Caveolin-1 is the principal structural component of caveolae in vivo. Several lines of evidence are consistent with the idea that caveolin-1 functions as a "transformation suppressor" protein. In fact, caveolin-1 mRNA and protein expression are lost or reduced during cell transformation by activated oncogenes. Interestingly, the human caveolin-1 gene is localized to a suspected tumor suppressor locus (7q31.1). We have previously demonstrated that overexpression of caveolin-1 arrests mouse embryonic fibroblasts in the G(0)/G(1) phase of the cell cycle through activation of a p53/p21-dependent pathway, indicating a role of caveolin-1 in mediating growth arrest. However, it remains unknown whether overexpression of caveolin-1 promotes cellular senescence in vivo. Here, we demonstrate that mouse embryonic fibroblasts transgenically overexpressing caveolin-1 show: 1) a reduced proliferative lifespan; 2) senescence-like cell morphology; and 3) a senescence-associated increase in beta-galactosidase activity. These results indicate for the first time that the expression of caveolin-1 in vivo is sufficient to promote and maintain the senescent phenotype. Subcytotoxic oxidative stress is known to induce premature senescence in diploid fibroblasts. Interestingly, we show that subcytotoxic level of hydrogen peroxide induces premature senescence in NIH 3T3 cells and increases endogenous caveolin-1 expression. Importantly, quercetin and vitamin E, two antioxidant agents, successfully prevent the premature senescent phenotype and the up-regulation of caveolin-1 induced by hydrogen peroxide. Also, we demonstrate that hydrogen peroxide alone, but not in combination with quercetin, stimulates the caveolin-1 promoter activity. Interestingly, premature senescence induced by hydrogen peroxide is greatly reduced in Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 720
NIH 3T3 cells harboring antisense caveolin-1. Importantly, induction of premature senescence is recovered when caveolin-1 levels are restored. Taken together, these results clearly indicate a central role for caveolin-1 in promoting cellular senescence and they suggest the hypothesis that premature senescence may represent a tumor suppressor function mediated by caveolin-1 in vivo. 5. Mech Ageing Dev. 2000 Dec 20;121(1-3):217-30. Antioxidants may contribute in the fight against ageing: an in vitro model. Hu HL, Forsey RJ, Blades TJ, Barratt ME, Parmar P, Powell JR. Molecular Physiology, Unilever Research Laboratory Colworth, Sharnbrook, Bedford MK44 1LQ, UK. Elderly humans have altered cellular redox levels and dysregulated immune responses, both of which are key events underlying the progression of chronic degenerative diseases of ageing, such as atherosclerosis and Alzeimer's disease. Poorly maintained cellular redox levels lead to elevated activation of nuclear transcription factors such as NFkB and AP-1. These factors are co-ordinately responsible for a huge range of extracellular signalling molecules responsible for inflammation, tissue remodelling, oncogenesis and apoptosis, progessess that orchestrate many of the degenerative processess associated with ageing. It is now clear that levels of endogenous anti-oxidants such as GSH decrease with age. This study aimed to investigate the potential of exogenous anti-oxidants to influence inflammatory responses and the ageing process itself. We investigated the potential of the dietary antioxidant, quercetin, to reverse the age related influences of GSH depletion and oxidative stress using in vitro human umbilical vein endothelial cells (HUVEC) and human skin fibroblast (HSF) cell models. Oxidative stress-induced inflammatory responses were investigated in a GSH depletion and a Phorbol 12-myristate 13-acetate (PMA)-induced stress model. As measured with a sensitive HPLC fluorescence method, GSH in HUVEC was depleted by the addition of L-buthionine-[S,R]-sulfoxiniine (BSO), a gamma-glutamylcysteine synthetase inhibitor, to the culture medium at a concentration of 0.25 mM. Time course studies revealed that the GSH half-life was 4.6 h in HUVEC. GSH depletion by BSO for 24 h led to a slight increase in intracellular adhesion molecule 1 (ICAM1) expression and prostaglandin E2 (PGE2) secretion in both types of cells. However, GSH depletion markedly enhanced PMA-induced ICAM and PGE2 production in HUVEC. Responses were progressively elevated following prolonged BSO treatment. Inhibition studies showed that 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7), a protein kinase C (PKC) inhibitor, not only abolished most of PMA-induced ICAM-1 expression and PGE2, production, but also eliminated GSH depletion-enhanced PMA stimulation. This enhancement was also inhibited by supplementation with quercetin. The results clearly demonstrate that GSH depletion increased the susceptibility of vascular endothelial cells and fibroblasts to oxidative stress associated inflammatory stimuli. This increased in vitro susceptibility may be extrapolated to the in vivo situation of ageing, providing a useful model to study the influence of micronutrients on the ageing process. In conclusion, these data suggest that dietary antioxidants could play a significant role in the reduction of inflammatory responses. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 721
6. Eur J Clin Nutr. 2000 May;54(5):415-7. Quercetin intake and the incidence of cerebrovascular disease. Knekt P, Isotupa S, Rissanen H, Heliovaara M, Jarvinen R, Hakkinen S, Aromaa A, Reunanen A. National Public Health Institute, Helsinki, Finland. paul.knekt@ktl.fi OBJECTIVE: To study the relation between intake of the antioxidant flavonoid quercetin and subsequent incidence of cerebrovascular disease (CVA). DESIGN: A cohort study carried out among 9208 Finnish men and women 15 y or more of age and initially free from cardiovascular disease. During a 28 y follow-up period in 1967-1994, a total of 824 cases with CVA were diagnosed. METHODS: Food consumption data were collected using a dietary history interview method covering the total habitual diet during the previous year. RESULTS: Quercetin intake was not associated with CVA incidence. The relative risk of CVA adjusted for age, serum cholesterol, body mass index, smoking, hypertension, diabetes, geographical area, occupation and intake of beta-carotene, vitamin E, vitamin C, fibre, various fatty acids, and energy between the highest and lowest quartiles of quercetin intake was 0.99 (95% confidence interval (CI)=0.71-1.38) for men and 0.85 (CI=0.60-1.21) for women. In contrast, apples, the major source of quercetin in the study population, showed a significant inverse associationn both in men and women, mainly due to an association with thrombotic or embolic stroke. The relative risks of thrombotic stroke after further adjustment for quercetin intake were 0.59 (CI=0.35-0.99; P=0.45) and 0.61 (CI=0.33-1.12: P for trend=0.02) for men and women, respectively. CONCLUSIONS: The results suggest that the intake of apples is related to a decreased risk of thrombotic stroke. This association apparently is not due to the presence of the antioxidant flavonoid quercetin. 7. Free Radic Biol Med. 1997;22(4):669-78. Quercetin protects cutaneous tissue-associated cell types including sensory neurons from oxidative stress induced by glutathione depletion: cooperative effects of ascorbic acid. Skaper SD, Fabris M, Ferrari V, Dalle Carbonare M, Leon A. Researchlife S.c.p.A., Castelfranco Veneto, Italy. Oxidation reactions are essential biological reactions necessary for the formation of high-energy compounds used to fuel metabolic processes, but can be injurious to cells when produced in excess. Cutaneous tissue is especially susceptible to damage mediated by reactive oxygen species and low-density lipoprotein oxidation, triggered by dysmetabolic diseases, inflammation, environmental factors, or aging. Here we have examined the ability of the flavonoid quercetin to protect cutaneous tissue-associated cell types from injury induced by oxidative stress, and possible cooperative effects of ascorbic acid. Human skin fibroblasts, keratinocytes, and endothelial cells were cultured in the presence of buthionine sulfoximine (BSO), an irreversible inhibitor of Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 722
glutathione (GSH) synthesis. Depletion of intracellular levels of GSH leads to an accumulation of cellular peroxides and eventual cell death. Quercetin concentration-dependently (EC50: 30-40 microM) reduced oxidative injury of BSO to all cell types, and was also effective when first added after BSO washout. BSO caused marked decreases in the intracellular level of GSH, which remained depressed in quercetin-protected cells. Ascorbic acid, while by itself not cytoprotective synergized with quercetin, lowered the quercetin EC50 and prolonged the window for cytoprotection. The related flavonoids rutin and dihydroquercetin also decreased BSO-induced injury to dermal fibroblasts, albeit less efficaciously so than quercetin. The cytoprotective effect of rutin, but not that of dihydroquercetin, was enhanced in the presence of ascorbic acid. Further, quercetin rescued sensory ganglion neurons from death provoked by GSH depletion. Direct oxidative injury to this last cell type has not been previously demonstrated. The results show that flavonoids are broadly protective for cutaneous tissue-type cell populations subjected to a chronic intracellular form of oxidative stress. Quercetin in particular, paired with ascorbic acid, may be of therapeutic benefit in protecting neurovasculature structures in skin from oxidative damage. 8. Exp Gerontol. 1982;17(3):213-7. Quercetin, flavonoids and the life-span of mice. Jones E, Hughes RE. A dietary supplement of 0.1% quercetin significantly reduced the life span of mice. The effect was predominantly on the 'shorter living' males. A blackcurrant juice extract, containing a mixture of flavonoids in addition to quercetin, prolonged significantly the life span of the 'older dying' females. The significance of these results vis-a-vis aging mechanisms and the dietary intake of quercetin is discussed. 9. Biochem Pharmacol. 1992 Mar 17;43(6):1167-79. Effects of flavonoids on immune and inflammatory cell functions. Middleton E Jr, Kandaswami C. Department of Medicine, State University of New York, Buffalo 14203. No doubt can remain that the flavonoids have profound effects on the function of immune and inflammatory cells as determined by a large number and variety of in vitro and some in vivo observations. That these ubiquitous dietary chemicals may have significant in vivo effects on homeostasis within the immune system and on the behavior of secondary cell systems comprising the inflammatory response seems highly likely but more work is required to strengthen this hypothesis. Ample evidence indicates that selected flavonoids, depending on structure, can affect (usually inhibit) secretory processes, mitogenesis, and cell-cell interactions including possible effects on adhesion molecule expression and function. The possible action of flavonoids on the function of cytoskeletal elements is suggested by their effects on secretory processes. Moreover, Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 723
evidence indicates that certain flavonoids may affect gene expression and the elaboration and effects of cytokines and cytokine receptors. How all of these effects are mediated is not yet clear but one important mechanism may be the capacity of flavonoids to stimulate or inhibit protein phosphorylation and thereby regulate cell function. Perhaps the counterbalancing effect of cellular protein tyrosine phosphatases will also be found to be affected by flavonoids. Some flavonoid effects can certainly be attributed to their recognized antioxidant and radical scavenging properties. A potential mechanism of action that requires scrutiny, particularly in relation to enzyme inhibition, is the redox activity of appropriately configured flavonoids. Finally, in a number of cell systems it seems that resting cells are not affected significantly by flavonoids but once a cell becomes activated by a physiological stimulus a flavonoid-sensitive substance is generated and interaction of flavonoids with that substance dramatically alters the outcome of the activation process. 10. Thromb Res. 1991 Oct 1;64(1):91-100. Inhibition of platelet aggregation by some flavonoids. Tzeng SH, Ko WC, Ko FN, Teng CM. Department of Pharmacology, Taipei Medical College, Taiwan. The inhibitory effects of five flavonoids on the aggregation and secretion of platelets were studied. These flavonoids inhibited markedly platelet aggregation and ATP release of rabbit platelets induced by arachidonic acid or collagen, and slightly those by platelet-activating factor. ADP-induced platelet aggregation was also suppressed by myricetin, fisetin and quercetin. The IC50 on arachidonic acid-induced platelet aggregation was: fisetin, 22 microM; kaempferol, 20 microM; quercetin, 13 microM; morin, 150 microM less than IC50 less than 300 microM. The thromboxane B2 formations were also inhibited by flavonoids in platelets challenged with arachidonic acid. Fisetin, kaempferol, morin and quercetin antagonized the aggregation of washed platelets induced by U46619, a thromboxane A2/prostaglandin endoperoxides mimetic receptor agonist. In human platelet-rich plasma, quercetin prevented the secondary aggregation and blocked ATP release from platelets induced by epinephrine or ADP. These results demonstrate that the major antiplatelet effect of flavonoids tested may be due to both the inhibition of thromboxane formation and thromboxane receptor antagonism. 11. Am J Clin Nutr. 2000 Nov;72(5):1150-5. Erratum in: Am J Clin Nutr 2001 Feb;73(2):360. The flavonoids quercetin and catechin synergistically inhibit platelet function by antagonizing the intracellular production of hydrogen peroxide. Pignatelli P, Pulcinelli FM, Celestini A, Lenti L, Ghiselli A, Gazzaniga PP, Violi F. Department of Experimental Medicine and Pathology, Institute of 1st Clinical Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 724
Medicine, University La Sapienza, National Institute for Nutrition, Rome, Italy. gazzaniga@uniroma1.it BACKGROUND: Epidemiologic studies have shown an inverse relation between moderate consumption of red wine and cardiovascular disease. Studies have shown that red wine and its component flavonoids inhibit in vivo platelet activation, but the underlying mechanism has not yet been identified. OBJECTIVE: Because we showed previously that collagen-induced platelet aggregation is associated with a burst of hydrogen peroxide, which in turn contributes to stimulating the phospholipase C pathway, the aim of this study was to investigate whether flavonoids synergize in inhibiting platelet function and interfere with platelet function by virtue of their antioxidant effect. DESIGN: We tested the effect of 2 flavonoids, quercetin and catechin, on collagen-induced platelet aggregation and hydrogen peroxide and on platelet adhesion to collagen. RESULTS: Catechin (50-100 micromol/L) and quercetin (10-20 micromol/L) inhibited collagen-induced platelet aggregation and platelet adhesion to collagen. The combination of 25 micromol catechin/L and 5 micromol quercetin/L, neither of which had any effect on platelet function when used alone, significantly inhibited collagen-induced platelet aggregation and platelet adhesion to collagen. Such a combination strongly inhibited collagen-induced hydrogen peroxide production, calcium mobilization, and 1,3,4-inositol triphosphate formation. CONCLUSIONS: These data indicate that flavonoids inhibit platelet function by blunting hydrogen peroxide production and, in turn, phospholipase C activation and suggest that the synergism among flavonoids could contribute to an understanding of the relation between the moderate consumption of red wine and the decreased risk of cardiovascular disease. 12. Lancet. 1993 Oct 23;342(8878):1007-11. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. National Institute of Public Health and Environment Protection, Bilthoven, Netherlands. Flavonoids are polyphenolic antioxidants naturally present in vegetables, fruits, and beverages such as tea and wine. In vitro, flavonoids inhibit oxidation of low-density lipoprotein and reduce thrombotic tendency, but their effects on atherosclerotic complications in human beings are unknown. We measured the content in various foods of the flavonoids quercetin, kaempferol, myricetin, apigenin, and luteolin. We then assessed the flavonoid intake of 805 men aged 65-84 years in 1985 by a cross-check dietary history; the men were then followed up for 5 years. Mean baseline flavonoid intake was 25.9 mg daily. The major sources of intake were tea (61%), onions (13%), and apples (10%). Between 1985 and 1990, 43 men died of coronary heart disease. Fatal or non-fatal myocardial infarction occurred in 38 of 693 men with no history of myocardial Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 725
infarction at baseline. Flavonoid intake (analysed in tertiles) was significantly inversely associated with mortality from coronary heart disease (p for trend = 0.015) and showed an inverse relation with incidence of myocardial infarction, which was of borderline significance (p for trend = 0.08). The relative risk of coronary heart disease mortality in the highest versus the lowest tertile of flavonoid intake was 0.42 (95% CI 0.20-0.88). After adjustment for age, body-mass index, smoking, serum total and high-density-lipoprotein cholesterol, blood pressure, physical activity, coffee consumption, and intake of energy, vitamin C, vitamin E, beta-carotene, and dietary fibre, the risk was still significant (0.32 [0.15-0.71]). Intakes of tea, onions, and apples were also inversely related to coronary heart disease mortality, but these associations were weaker. Flavonoids in regularly consumed foods may reduce the risk of death from coronary heart disease in elderly men. 13. Arch Intern Med. 1996 Mar 25;156(6):637-42. Dietary flavonoids, antioxidant vitamins, and incidence of stroke: the Zutphen study. Keli SO, Hertog MG, Feskens EJ, Kromhout D. Department of Chronic Disease and Environmental Epidemiology, National Institute of Public Health and Environmental Protection, Bilthoven, The Netherlands. BACKGROUND: Epidemiological studies suggested that consumption of fruit and vegetables may protect against stroke. The hypothesis that dietary antioxidant vitamins and flavonoids account for this observation is investigated in a prospective study. METHODS: A cohort of 552 men aged 50 to 69 years was examined in 1970 and followed up for 15 years. Mean nutrient and food intake was calculated from cross-check dietary histories taken in 1960, 1965, and 1970. The association between antioxidants, selected foods, and stroke incidence was assessed by Cox proportional hazards regression analysis. Adjustment was made for confounding by age, systolic blood pressure, serum cholesterol, cigarette smoking, energy intake, and consumption of fish and alcohol. RESULTS: Forty-two cases of first fatal or nonfatal stroke were documented. Dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence after adjustment for potential confounders, including antioxidant vitamins. The relative risk (RR) of the highest vs the lowest quartile of flavonoid intake ( > or = 28.6 mg/d vs <18.3 mg/d) was 0.27 (95% confidence interval [CI], 0.11 to 0.70). A lower stroke risk was also observed for the highest quartile of beta-carotene intake (RR, 0.54; 95% CI, 0.22 to 1.33). The intake of vitamin C and vitamin E was not associated with stroke risk. Black tea contributed about 70% to flavonoid intake. The RR for a daily consumption of 4.7 cups or more of tea vs less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84). CONCLUSION: The habitual intake of flavonoids and their major source (tea) may protect against stroke.
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14. Surgery. 2002 Feb;131(2):198-204. Quercetin inhibits human vascular smooth muscle cell proliferation and migration. Alcocer F, Whitley D, Salazar-Gonzalez JF, Jordan WD, Sellers MT, Eckhoff DE, Suzuki K, Macrae C, Bland KI. Department of Surgery, University of Alabama at Birmingham, 35294-0007, USA. BACKGROUND: The French paradox has been associated with regular intake of red wine, which is enriched with flavonoids. Quercetin, a flavonoid present in the human diet, exerts cardiovascular protection through its antioxidant properties. We hypothesized that the beneficial effect of quercetin also could be related to the inhibition of vascular smooth muscle cell proliferation and migration. METHODS: Human aortic smooth muscle cells (AoSMC) were grown in culture in the presence of serum. Quercetin inhibited the serum-induced proliferation of AoSMC. This inhibition was dose-dependent and not attributed to toxicity. Cell cycle analysis revealed that quercetin arrested AoSMC in the G(0)/G(1) phase. The effect of quercetin on AoSMC migration was examined using explant migration and Transwell migration assays. Quercetin significantly decreased migration in both assays in a consistent manner. Finally, Western blot analysis of AoSMC exposed to quercetin demonstrated a significant reduction in the activation of mitogen-activated protein kinase, a signaling pathway associated with the migration of vascular smooth muscle cells. CONCLUSIONS: Quercetin inhibits the proliferation and migration of AoSMC, concomitant with inhibition of mitogen-activated protein kinase phosphorylation. These findings provide new insights and a rationale for the potential use of quercetin in the prophylaxis of cardiovascular diseases. 15. Mol Pharmacol. 2001 Oct;60(4):656-65. Quercetin inhibits Shc- and phosphatidylinositol 3-kinase-mediated c-Jun N-terminal kinase activation by angiotensin II in cultured rat aortic smooth muscle cells. Yoshizumi M, Tsuchiya K, Kirima K, Kyaw M, Suzaki Y, Tamaki T. Department of Pharmacology, The University of Tokushima School of Medicine, Tokushima, Japan. yoshizu@basic.med.tokushima-u.ac.jp Angiotensin II (Ang II) induces vascular smooth muscle cell (VSMC) hypertrophy, which results in various cardiovascular diseases. Ang II-induced cellular events have been implicated, in part, in the activation of mitogen-activated protein (MAP) kinases. Although it has been proposed that daily intake of bioflavonoids belonging to polyphenols reduces the incidence of ischemic heart diseases (known as "French paradox"), the precise mechanisms of efficacy have not been elucidated. Thus, we hypothesized that bioflavonoids may affect Ang II-induced MAP kinase activation in cultured rat aortic smooth muscle cells (RASMC). Our findings showed that Ang II stimulated rapid and significant activation of extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK), and p38 in RASMC. Ang II-induced JNK activation was inhibited by Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 727
3,3',4',5,7-pentahydroxyflavone (quercetin), a major bioflavonoid in foods of plant origin, whereas ERK1/2 and p38 activation by Ang II were not affected by quercetin. Ang II caused a rapid tyrosine phosphorylation of Src homology and collagen (Shc), which was inhibited by quercetin. Quercetin also inhibited Ang II-induced Shc.p85 association and subsequent activation of phosphatidylinositol 3-kinase (PI3-K)/Akt pathway in RASMC. Furthermore, LY294002, a PI3-K inhibitor and a quercetin derivative, inhibited Ang II-induced JNK activation as well as Akt phosphorylation. Finally, Ang II-induced [(3)H]leucine incorporation was abolished by both quercetin and LY294002. These findings suggest that the preventing effect of quercetin on Ang II-induced VSMC hypertrophy are attributable, in part, to its inhibitory effect on Shc- and PI3-K-dependent JNK activation in VSMC. Thus, inhibition of JNK by quercetin may imply its usefulness for the treatment of cardiovascular diseases relevant to VSMC growth. 16. Br J Pharmacol. 2001 May;133(1):117-24. Antihypertensive effects of the flavonoid quercetin in spontaneously hypertensive rats. Duarte J, Perez-Palencia R, Vargas F, Ocete MA, Perez-Vizcaino F, Zarzuelo A, Tamargo J. Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada, Spain. 1. The effects of an oral daily dose (10 mg kg(-1)) of the flavonoid quercetin for 5 weeks in spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY) were analysed. 2. Quercetin induced a significant reduction in systolic (-18%), diastolic (-23%) and mean (-21%) arterial blood pressure and heart rate (-12%) in SHR but not in WKY rats. 3. The left ventricular weight index and the kidney weight index in vehicle-treated SHR were significantly greater than in control WKY and these parameters were significantly reduced in quercetin-treated SHR in parallel with the reduction in systolic blood pressure. 4. Quercetin had no effect on the vasodilator responses to sodium nitroprusside or to the vasoconstrictor responses to noradrenaline or KCl but enhanced the endothelium-dependent relaxation to acetylcholine (E(max)=58+/-5% vs 78+/-5%, P<0.01) in isolated aortae. 5. The 24 h urinary isoprostane F(2 alpha) excretion and the plasma malonyldialdehyde (MDA) levels in SHR rats were increased as compared to WKY rats. However, in quercetin-treated SHR rats both parameters were similar to those of vehicle-treated WKY. 6. These data demonstrate that quercetin reduces the elevated blood pressure, the cardiac and renal hypertrophy and the functional vascular changes in SHR rats without effect on WKY. These effects were associated with a reduced oxidant status due to the antioxidant properties of the drug. 17. Free Radic Biol Med. 2002 Jun 1;32(11):1220-8. Mitochondrial function in response to cardiac ischemia-reperfusion after oral Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 728
treatment with quercetin. Brookes PS, Digerness SB, Parks DA, Darley-Usmar V. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2180, USA. brookes@uab.edu Polyphenolic compounds present in red wines, such as the flavonol quercetin, are thought capable of cardioprotection through mechanisms not yet clearly defined. It has been established that mitochondria play a critical role in myocardial recovery from ischemia-reperfusion (I-R) damage, and in vitro experiments indicate that quercetin can exert a variety of direct effects on mitochondrial function. The effects of quercetin at concentrations typically found in 1-2 glasses of red wine on cardiac I-R and mitochondrial function in vivo are not known. Quercetin was administered to rats (0.033 mg/kg per day by gavage for 4 d). Isolated Langendorff perfused hearts were subjected to I-R, and cardiac functional parameters determined both before and after I-R. Mitochondria were isolated from post-I-R hearts and their function assessed. Compared to an untreated control group, quercetin treatment significantly decreased the impairment of cardiac function following I-R. This protective effect was associated with improved mitochondrial function after I-R. These results indicate that oral low dose quercetin is cardioprotective, possibly via a mechanism involving protection of mitochondrial function during I-R. 18. Proc Natl Acad Sci U S A. 2000 Aug 1;97(16):9052-7. The NF-kappa B signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Hajra L, Evans AI, Chen M, Hyduk SJ, Collins T, Cybulsky MI. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto General Research Institute, Toronto, Ontario, M5G 2C4, Canada. Atherosclerotic lesions form at distinct sites in the arterial tree, suggesting that hemodynamic forces influence the initiation of atherogenesis. If NF-kappaB plays a role in atherogenesis, then the activation of this signal transduction pathway in arterial endothelium should show topographic variation. The expression of NF-kappaB/IkappaB components and NF-kappaB activation was evaluated by specific antibody staining, en face confocal microscopy, and image analysis of endothelium in regions of mouse proximal aorta with high and low probability (HP and LP) for atherosclerotic lesion development. In control C57BL/6 mice, expression levels of p65, IkappaBalpha, and IkappaBbeta were 5- to 18-fold higher in the HP region, yet NF-kappaB was activated in a minority of endothelial cells. This suggested that NF-kappaB signal transduction was primed for activation in HP regions on encountering an activation stimulus. Lipopolysaccharide treatment or feeding low-density lipoprotein receptor knockout mice an atherogenic diet resulted in NF-kappaB activation and up-regulated expression of NFkappaB-inducible genes predominantly in HP region endothelium. Preferential regional activation of endothelial NF-kappaB by systemic stimuli, including
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hypercholesterolemia, may contribute to the localization of atherosclerotic lesions at sites with high steady-state expression levels of NF-kappaB/IkappaB components. 19. Clin Exp Allergy. 2000 Apr;30(4):501-8. Effects of luteolin, quercetin and baicalein on immunoglobulin E-mediated mediator release from human cultured mast cells. Kimata M, Shichijo M, Miura T, Serizawa I, Inagaki N, Nagai H. Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan. BACKGROUND: Flavonoids have a variety of activities including anti-allergic activities, and are known to inhibit histamine release from human basophils and murine mast cells. OBJECTIVE: The effects of luteolin, a flavone, on the immunoglobulin (Ig) E-mediated allergic mediator release from human cultured mast cells (HCMCs) were investigated and compared with those of baicalein and quercetin. METHODS: HCMCs were sensitized with IgE, and then treated with flavonoids before challenge with antihuman IgE. The amount of released mediators was determined as was mobilization of intracellular Ca2+ concentration, protein kinase C (PKC) translocation and phosphorylation of intracellular proteins were detected after anti-IgE stimulation. RESULTS: Luteolin, baicalein and quercetin inhibited the release of histamine, leukotrienes (LTs), prostaglandin D2 (PGD2), and granulocyte macrophage-colony stimulating factor (GM-CSF) from HCMC in a concentration-dependent manner. Additionally, the three flavonoids inhibited A23187-induced histamine release. As concerns Ca2+ signalling, luteolin and quercetin inhibited Ca2+ influx strongly, although baicalein did slightly. With regard to PKC signalling, luteolin and quercetin inhibited PKC translocation and PKC activity strongly, although baicalein did slightly. The suppression of Ca2+ and PKC signallings might contribute to the inhibition of mediator release. The activation of extracellular signal-regulated kinases (ERKs) and c-Jun NH2terminal kinase (JNK), that were activated just before the release of LTs and PGD2 and GM-CSF mRNA expression in IgE-mediated signal transduction events, were clearly suppressed by luteolin and quercetin. In contrast, the flavonoids did not affect the activation of p38 mitogen-activated protein kinase (p38 MAPK) pathway. CONCLUSION: These results indicate that luteolin is a potent inhibitor of human mast cell activation through the inhibition of Ca2+ influx and PKC activation. 20. Res Commun Chem Pathol Pharmacol. 1992 Nov;78(2):211-8. Changes in the xanthine dehydrogenase/xanthine oxidase ratio in the rat kidney subjected to ischemia-reperfusion stress: preventive effect of some flavonoids. Sanhueza J, Valdes J, Campos R, Garrido A, Valenzuela A. Unidad de Bioquimica Farmacologica y Lipidos, INTA, Universidad de Chile, Santiago. The enzyme xanthine oxidase has been implicated in the tissue oxidative injury after ischemia-reperfusion. This enzyme, which is a source of oxygen free radicals, is formed from a dehydrogenase form during ischemia. The ratio Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 730
dehydrogenase/oxidase of rat kidney homogenates decreases during the ischemia and the reperfusion. Two flavonoids, quercetin and silybin, characterized as free radical scavengers, exert a protective effect preventing the decrease in the dehydrogenase/oxidase ratio observed during ischemia-reperfusion. The mechanism of this effect and the role of flavonoids in the ischemia-reperfusion tissue damage is discussed. 21. Methods Find Exp Clin Pharmacol. 2001 May;23(4):175-81. Quercetin, a bioflavonoid, protects against oxidative stress-related renal dysfunction by cyclosporine in rats. Satyanarayana PS, Singh D, Chopra K. Pharmacology Division, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India. Nephrotoxicity is the most common and clinically important side effect of cyclosporine (CsA). Recent evidence suggests that reactive oxygen species (ROS) play an important role in CsA nephrotoxicity. This study was designed to demonstrate the role of oxidative stress and its relation to renal dysfunction and to investigate the effects of quercetin, a bioflavonoid with antioxidant properties, in CsA-induced nephrotoxicity. Quercetin (0.5 and 2.0 mg/kg i.p.) was administered 24 h before and concurrently with CsA (20 mg/kg s.c.) for 21 days. Tissue lipid peroxidation was measured as thiobarbituric acid reacting substances (TBARS). Renal function was assessed by estimating plasma creatinine, blood urea nitrogen (BUN), creatinine and urea clearance. Renal morphological alterations were assessed histopathologically. Pretreatment with CsA (20 mg/kg s.c.) for 21 days produced elevated levels of TBARS and deteriorated renal function as assessed by increased plasma creatinine, BUN and decreased creatinine and urea clearance as compared to vehicle-treated rats. The kidneys of CsA-treated rats showed severe striped interstitial fibrosis, arteriopathy, glomerular basement thickening, tubular vacuolization and hyaline casts. Quercetin (2 mg/kg) markedly reduced elevated levels of TBARS and significantly attenuated renal dysfunction and morphological changes in CsA-treated rats. It is likely that quercetin, due to its antioxidant properties, prevented CsA-induced ROS and consequently CsA nephrotoxicity. These results clearly demonstrate the pivotal role of oxidative stress and its relation to renal dysfunction, and also point to the therapeutic potential of the natural antioxidant quercetin in CsA-induced nephrotoxicity. 22. Free Radic Biol Med. 2002 Jul 1;33(1):63-70. Quercetin metabolism in the lens: role in inhibition of hydrogen peroxide induced cataract. Cornish KM, Williamson G, Sanderson J. School of Biological Sciences, University of East Anglia, Norwich, Norfolk, UK. Oxidative stress is implicated in the initiation of maturity onset cataract. Quercetin, a major flavonol in the diet, inhibits lens opacification in a lens organ culture oxidative Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 731
model of cataract. The aim of this research was to investigate the metabolism of quercetin in the lens and show how its metabolism affects the ability to prevent oxidation-induced opacity. The LOCH model (Free Radical Biology & Medicine 26:639; 1999) was employed, using rat lenses to investigate the effects of quercetin and metabolites on hydrogen peroxide-induced opacification. High-performance liquid chromatography analysis showed that the intact rat lens is capable of converting quercetin aglycone to 3'O-methyl quercetin (isorhamnetin). Over a 6 h culture period no further metabolism of the 3'-O-methyl quercetin occurred. Loss of quercetin in the lens was accounted for by the increase in 3'-O-methyl quercetin. Incubation with 3,5-dinitrocatechol (10 microM), a catechol-O-methyltransferase (COMT) inhibitor, prevented the conversion of quercetin to 3'-O-methyl quercetin. The presence of both membrane-bound and soluble COMT was confirmed by immunoblotting. The results demonstrate that in the rat lens COMT methylates quercetin and that the product accumulates within the lens. Quercetin (10 microM) and 3'-O-methyl quercetin (10 microM) both inhibited hydrogen peroxide- (500 microM) induced sodium and calcium influx and lens opacification. Incubation of lenses with quercetin in the presence of COMT inhibitor revealed that the efficacy of quercetin is not dependent on its metabolism to 3'-O-methyl quercetin. The results indicate dietary quercetin and metabolites are active in inhibiting oxidative damage in the lens and thus could play a role in prevention of cataract formation. 23. Free Radic Biol Med. 1999 Sep;27(5-6):683-94. Structure-activity relationships of quercetin in antagonizing hydrogen peroxide-induced calcium dysregulation in PC12 cells. Wang H, Joseph JA. Jean Mayer United States Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA. wang_us@hnrc.tufts.edu Oxidative stress can induce neurotoxic insults by increasing intracellular calcium (Ca2+), which has been implicated in various neurodegenerative diseases in aging. Previously, we showed that hydrogen peroxide induced calcium dysregulation in PC12 cells, as evidenced by (i) an increase in calcium baselines, (ii) a decrease in depolarization-induced calcium influx, and (iii) a failure to recover the Ca2+ levels. In the present experiments, we investigated whether a dietary flavonoid, quercetin, can antagonize the effects of hydrogen peroxide in the same cell model. We also investigated the possible structure-activity relationships of quercetin by comparing the results with four other flavonoids, each having a slightly different structure from quercetin. Our results indicated that two structural components, including (i) 3', 4'-hydroxyl (OH) groups in the B ring and (ii) a 2,3-double bond in conjugation with a 4-oxo group in the C ring, along with the polyphenolic structures were crucial for the protection. These structural components are found in quercetin, and this compound was also the most efficacious in reducing both the H2O2-induced Ca2+ dysregulation in cells and oxidative stress assessed via the dichlorofluorescein Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 732
assay. Collectively, these data indicated that the particular polyphenolic structural components of quercetin provided its strong antioxidant property of protecting cells against H2O2-induced oxidative stress and calcium dysregulation. 24. Zhongguo Yao Li Xue Bao. 1999 May;20(5):426-30. Quercetin decreased heart rate and cardiomyocyte Ca2+ oscillation frequency in rats and prevented cardiac hypertrophy in mice. Wang Y, Wang HY, Yuan ZK, Zhao XN, Wang JX, Zhang ZX. School of Medicine, State Key Laboratory of Coordination Chemistry, Nanjing University, China. AIM: To study the effects of quercetin (Que) on myocardial excitation-contraction coupling and cardiac remodeling. METHODS: Left ventricles and femoral arteries of rats were cannulated for hemodynamic recording. Mouse cardiac hypertrophy was induced by abdominal aortic coarctation (AAC). Cultured myocardial cells in neonatal rats were loaded with Fura 2-AM. The intracellular calcium ([Ca2+]i) and spontaneous [Ca2+]i oscillations ([Ca2+]i-SO) were tested by AR-CM-MIC cation measurement system. RESULTS: Que 3 or 25 mg.kg-1 i.v. in rats decreased heart rate from (420 +/- 19) to (390 +/- 15) and (314 +/- 18) beat.min-1, respectively, companied with very modest changes in both left ventricular pressures (LVP) and its differential dpLV/dtmax. Que 10, 50, 250 mumol.L-1 concentration-dependently slowed the frequency of [Ca2+]i-SO in cultured myocardial cells from (26 +/- 4) to (25 +/- 3), (18 +/- 4), and (12 +/- 3) time.min-1, respectively, but did not change their resting [Ca2+]i or amplitudes of [Ca2+]i-SO. Similarly, the increases in frequency of [Ca2+]i-SO caused by either isoproterenol (Iso) or ouabain (Oua) were prevented by Que 100 mumol.L-1, while the simultaneous increases in amplitude of [Ca2+]i-SO remained. Besides, [Ca2+]i rises excited by angiotensin II (Ang II) but not high [K+]o were prevented by Que 100 mumol.L-1. Daily administration of Que 120 mg.kg-1 i.g. for 5 d markedly prevented the cardiac hypertrophy in AAC mice, without effects on the ventricular mass to body weight ratio (VM/BW) in sham-operated mice. CONCLUSION: Quercetin decreased myocardial [Ca2+]i-oscillation frequency and prevented cardiac remodeling, but had no direct effect on cardiac excitation-contraction coupling. 25. Zhongguo Yao Li Xue Bao. 1995 May;16(3):223-6. Effects of quercetin on aggregation and intracellular free calcium of platelets. Xiao D, Gu ZL, Bai JP, Wang Z. Department of Pharmacology, Suzhou Medical College, China. AIM: To study the effects of Que on the intraplatelet free calcium concentration and the effects of calcium on the inhibition of platelet aggregation by Que. METHODS: Using Quin-2 fluorescence technique. RESULTS: Que inhibited the platelet aggregation and the rise of [Ca2+]i induced by thrombin in platelets. The values of IC50 and 95% confidence interval were 146.2 (92.4 - 231.3) and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 733
78.5 (49.5 - 124.4) mumol.L-1, respectively. The inhibitory effects of Que on platelet aggregation induced by thrombin were reduced by adding calcium to the medium, and Que had no effect on thrombin-induced internal Ca2+ release from dense tubular system. CONCLUSION: The inhibitory effects of Que on aggregation and the rise of [Ca2+]i in platelets was mainly due to an inhibition of Ca2+ influx. 26. Antiproliferative potency of structurally distinct dietary flavonoids on human colon cancer cells Kuo SM. Nutrition Program, State University of New York at Buffalo, 14214, USA. smkuo@acsu.buffalo.edu Cancer Letters (Ireland), 1996, 110/1-2 (41-48) Dietary flavonoids are known to be antiproliferative and may play an important role in cancer chemoprevention, especially cancers of the gastrointestinal tract, because of a direct contact with food. This study was designed to compare the antiproliferative potency of several structurally distinct dietary flavonoids in colon cancer cells, Caco-2 and HT-29, and in rat nontransformed intestinal crypt cells, IEC-6. Flavonoids varied significantly in their antiproliferative potency depending on the structural features but the observations were consistent among the three cell lines studied. Of the two most potent flavonoids, quercetin and genistein, the effect was found to be dose-dependent and chromatin condensation, an indication of apoptosis, was noticed. Quercetin was found to distribute throughout the cell with higher amounts in the perinuclear and nucleoli areas. The lack of specific cell membrane enrichment by quercetin was consistent with its lack of effect on the transepithelial resistance. While several flavonoids including quercetin were found to be unstable, the chemical instability did not correlate with the antiproliferative potency, although it may contribute to the antiproliferative effect. 27. Preferential requirement for protein tyrosine phosphatase activity in the 12-Otetradecanoylphorbol-13-acetate-induced differentiation of human colon cancer cells. Kuo ML, Huang TS, Lin JK. Institute of Toxicology, College of Medicine, National Taiwan University, Taipei. Biochem Pharmacol; 50(8):1217-22 1995 Some lines of colon cancer cells are forced to undergo differentiation by 12-Otetradecanoylphorbol-13-acetate (TPA). The increases in activities of both protein tyrosine phosphatase (PTP) and protein tyrosine kinase (PTK) have been reported to be associated with the TPA-induced differentiation of HL-60 leukemia cells. In the present study, a 2-fold increase in PTP activity was observed in SW620 human colon cancer cells after 30 min of TPA treatment; a maximal level (4- to 5-fold) was reached at 60 min and continued for more than 6 hr. In addition, two TPA-induced differentiated characteristics, morphological alteration and release of cellular surface proteoglycan, were effectively blocked by PTP inhibitors, such as sodium orthovanadate (50 microM), zinc chloride (100 microM), and iodoacetate (250 microM), but not by the protein serine/threonine phosphatase inhibitor okadaic acid (20 nM). On the other hand, although TPA induced a Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 734
transient slight increase in PTK activity (1.4-fold) at 60 min, four PTK inhibitors (genistein, herbimycin A, tyrphostin-23 and quercetin) had different effects on the TPAinduced release of cell surface proteoglycan. Genistein (60 microM) potentiated this process, but in contrast, quercetin (45 microM) could partially inhibit the TPA effect. Taken together, these observations suggest that both PTP and PTK activities were increased in SW620 cells in response to TPA; however, the activation of PTP seems to be preferentially required for the TPA-induced differentiation of SW620 human. 28. Effect of Quercitrin on acute and chronic experimental colitis in the rat De Medina F.S.; Galvez L.-H.; Romero J.A.; Zarzuelo A. F.S. De Medina, Department of Pharmacology, School of Pharmacy, University of Granada, 18071 Granada Spain Journal of Pharmacology and Experimental Therapeutics (USA) , 1996, 278/2 (771-779) Quercitrin was tested for acute and chronic anti-inflammatory activity in trinitrobenzenesulfonic acid-induced rat colitis. The inflammatory status was evaluated by myeloperoxidase, alkaline phosphatase and total glutathione levels, leukotriene B4 synthesis, in vivo colonic fluid absorption, macroscopical damage and occurrence of diarrhea and adhesions. Treatment with 1 or 5 mg/kg of quercitrin by the oral route reduced myeloperoxidase and alkaline phosphatase levels, preserved normal fluid absorption, counteracted glutathione depletion and ameliorated colonic damage at 2 days. Increasing or lowering the dose of the flavonoid resulted in marked loss of effect. The acute anti-inflammatory effect of quercitrin is unrelated to impairment of neutrophil function or lipoxygenase inhibition, and it may be caused by mucosal protection or enhancement of mucosal repair secondary to increased defense against oxidative insult and/or preservation of normal colonic absorptive function. When tested in chronic colitis (2 and 4 weeks), quercitrin treatment (1 or 5 mg/kg . day) decreased colonic damage score and the incidence of diarrhea, and normalized the colonic fluid transport. All other parameters were unaffected. The chronic effect of the flavonoid is apparently related to its action on colonic absorption, although it can be partly secondary to its acute beneficial effect. 29. Inhibition of human breast cancer cell proliferation and delay of mammary tumorigenesis by flavonoids and citrus juices So FV, Guthrie N, Chambers AF, Moussa M, Carroll KK. Department of Pharmacology and Toxicology, University of Western Ontario, London, Canada. Nutrition and Cancer (USA) , 1996, 26/2 (167-181)
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Two citrus flavonoids, hesperetin and naringenin, found in oranges and grapefruit, respectively, and four noncitrus flavonoids, baicalein, galangin, genistein, and quercetin, were tested singly and in one-to-one nd growth of a human breast carcinoma cell line, MDA-MB-435. The concentration at which cell proliferation was inhibited by 50% (IC50), based on incorporation of (3H)thymidine, varied from 5.9 to 140 microg/ml for the single flavonoids, with the most potent being baicalein. IC50 values for the one-to-one combinations ranged from 4. 7 microg/ml (quercetin + hespererin, quercetin + naringenin) to 22.5 microg/ml (naringenin + hespererin). All the flavonoids showed low cytotoxicity (>500 microg/ml for 50% cell death). Naringenin is present in grapefruit mainly as its glycosylated form, naringin. These compounds, as well as grapefruit and orange juice concentrates, were tested for their ability to inhibit development of mammary tumors induced by 7,12-dimethylbenz(a)anthracene (DMBA) in female Sprague-Dawley rats. Two experiments were conducted in which groups of 21 rats were fed a semipurified diet containing 5% corn oil and were given a 5-mg dose of DMBA intragastrically at approximately 50 days of age while in diestrus. One week later, individual groups were given double- strength grapefruit juice or orange juice or fed naringin or naringenin at levels comparable to that provided by the grapefruit juice; in the second experiment, the rats were fed a semipurified diet containing 20% corn oil at that time. As expected, rats fed the high-fat diet developed more tumors than rats fed the low-fat diet, but in both experiments tumor development was delayed in the groups given orange juice or fed the naringin-supplemented diet compared with the other three groups. Although tumor incidence and tumor burden (grams of tumor/rat) were somewhat variable in the different groups, rats given orange juice had a smaller tumor burden than controls, although they grew better than any of the other groups. These experiments provide evidence of anticancer properties of orange juice and indicate that citrus flavonoids are effective inhibitors of human breast cancer cell proliferation in vitro, especially when paired with quercetin, which is widely distributed in other foods. 30. Quercetin glycosides inhibit lipoxygenase-induced LDL oxidation Inhibition of mammalian 15-lipoxygenase-dependent lipid peroxidation in low-density lipoprotein by quercetin and quercetin monoglucosides. Luiz da Silva E, Tsushida T, Terao J. National Food Research Institute, Ministry of Agriculture, Forestry, and Fisheries, Ibaraki, Japan. Arch Biochem Biophys. 1998 Jan 15;349(2):313-20. Lipoxygenase is suggested to be involved in the early event of atherosclerosis by inducing plasma low-density lipoprotein (LDL) oxidation in the subendothelial space of the arterial wall. Since flavonoids such as quercetin are recognized as lipoxygenase inhibitors and they occur mainly in the glycoside form, we assessed the effect of quercetin and its glycosides (quercetin 3-O-beta-glucopyranoside, Q3G; quercetin 4'O-beta-glucopyranoside, Q4'G; quercetin 7-O-beta-glucopyranoside, Q7G) on rabbit reticulocyte 15-lipoxygenase (15-LOX)-induced human LDL lipid peroxidation and Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 736
compared it with the inhibition obtained by ascorbic acid and alpha-tocopherol, the main water-soluble and lipid-soluble antioxidants in blood plasma, respectively. Quercetin inhibited the formation of cholesteryl ester hydroperoxides (CE-OOH) and endogenous alpha-tocopherol consumption effectively throughout the incubation period of 6 h. Ascorbic acid exhibited an effective inhibition only in the initial stage and LDL preloaded with fivefold alpha-tocopherol did not affect the formation of CE-OOH compared with the native LDL. CE-OOH formation was inhibited by both quercetin and quercetin monoglucosides in a concentration-dependent manner. Quercetin, Q3G, and Q7G exhibited a higher inhibitory effect than Q4'G (IC50: 0.3-0.5 microM for quercetin, Q3G, and Q7G and 1.2 microM for Q4'G). While endogenous alpha-tocopherol was completely depleted after 2 h of LDL oxidation, quercetin, Q7G, and Q3G prevented the consumption of alpha-tocopherol. Quercetin and its monoglucosides were also exhausted during the LDL oxidation. These results indicate that quercetin glycosides as well as its aglycone are capable of inhibiting lipoxygenase-induced LDL oxidation more efficiently than ascorbic acid and alpha-tocopherol.
L-Carnosine - 15 Studies
1. Bull Exp Biol Med. 2003 Feb;135(2):130-2. Protective effect of carnosine on Cu,Zn-superoxide dismutase during impaired oxidative metabolism in the brain in vivo. Stvolinskii SL, Fedorova TN, Yuneva MO, Boldyrev AA. Institute of Neurology, Russian Academy of Medical Sciences, Moscow. sls@bio.inevro.msk.ru 2. Bull Exp Biol Med. 2002 Jun;133(6):559-61. Effect of carnosine on Drosophila melanogaster lifespan. Yuneva AO, Kramarenko GG, Vetreshchak TV, Gallant S, Boldyrev AA. M. V. Lomonosov Moscow State University, Moscow. 3. Biogerontology. 2001;2(1):19-34. AGES in brain ageing: AGE-inhibitors as neuroprotective and antidementia drugs? Dukic-Stefanovic S, Schinzel R, Riederer P, Munch G. Physiological Chemistry I, Biocenter, University of Wurzburg, Germany. 4. Proc Natl Acad Sci U S A. 1996 May 14;93(10):4765-9. Age-related losses of cognitive function and motor skills in mice are associated with oxidative protein damage in the brain. Forster MJ, Dubey A, Dawson KM, Stutts WA, Lal H, Sohal RS. Department of Pharmacology, University of North Texas Health Science Center, Fort Worth, 76107, USA.
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5. J Histochem Cytochem. 1998 Jun;46(6):731-5. Cytochemical demonstration of oxidative damage in Alzheimer disease by immunochemical enhancement of the carbonyl reaction with 2,4dinitrophenylhydrazine. Smith MA, Sayre LM, Anderson VE, Harris PL, Beal MF, Kowall N, Perry G. Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. 6. Neurosci Lett. 1998 Feb 13;242(2):105-8. Toxic effects of beta-amyloid(25-35) on immortalised rat brain endothelial cell: protection by carnosine, homocarnosine and beta-alanine. Preston JE, Hipkiss AR, Himsworth DT, Romero IA, Abbott JN. Institute of Gerontology, King's College London, UK. j.preston@kcl.ac.uk 7. FEBS Lett. 1995 Aug 28;371(1):81-5. Non-enzymatic glycosylation of the dipeptide L-carnosine, a potential anti-protein-cross-linking agent. Hipkiss AR, Michaelis J, Syrris P. Division of Biomolecular Engineering, CSIRO, North Ryde, NSW, Australia. 8. Biochim Biophys Acta. 1997 Feb 27;1360(1):17-29. Influence of advanced glycation end-products and AGE-inhibitors on nucleation-dependent polymerization of beta-amyloid peptide. Munch G, Mayer S, Michaelis J, Hipkiss AR, Riederer P, Muller R, Neumann A, Schinzel R, Cunningham AM. Theodor-Boveri-Institute (Biocenter), Wurzburg, Germany. muench@biozentrum.uni-wuerzburg.de 9. Biochem Biophys Res Commun. 1998 Jul 9;248(1):28-32. Carnosine protects proteins against methylglyoxal-mediated modifications. Hipkiss AR, Chana H. Molecular Biology and Biophysics Group, King's College London, United Kingdom. alan.hipkiss@kcl.ac.uk 10. Free Radic Biol Med. 2000 May 15;28(10):1564-70. Carnosine reacts with a glycated protein. Brownson C, Hipkiss AR. Division of Biomolecular Science, GKT School of Biomedical Sciences, King's College London, Guy's Campus, London Bridge, London, UK. 11.Neurosci Lett. 1997 Dec 5;238(3):135-8. Protective effects of carnosine against malondialdehydeinduced toxicity towards cultured rat brain endothelial cells. Hipkiss AR, Preston JE, Himswoth DT, Worthington VC, Abbot NJ. Molecular Biology and Biophysics Group, King's College London, Strand, UK.
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12. Cell Mol Neurobiol. 1997 Apr;17(2):259-71. Biochemical and physiological evidence that carnosine is an endogenous neuroprotector against free radicals. Boldyrev AA, Stvolinsky SL, Tyulina OV, Koshelev VB, Hori N, Carpenter DO. M. V. Lomonosov Moscow State University, Moscow, Russia. 13. Ann N Y Acad Sci. 1998 Nov 20;854:37-53. Pluripotent protective effects of carnosine, a naturally occurring dipeptide. Hipkiss AR, Preston JE, Himsworth DT, Worthington VC, Keown M, Michaelis J, Lawrence J, Mateen A, Allende L, Eagles PA, Abbott NJ. Molecular Biology and Biophysics Group, King's College London, Strand, United Kingdom. alan.hipkiss@kcl.ac.uk 14. Exp Cell Res. 1994 Jun;212(2):167-75. Retardation of the senescence of cultured human diploid fibroblasts by carnosine. McFarland GA, Holliday R. CSIRO Division of Biomolecular Engineering, Sydney Laboratory, NSW, Australia. 15. Exp Gerontol. 1999 Jan;34(1):35-45. Further evidence for the rejuvenating effects of the dipeptide Lcarnosine on cultured human diploid fibroblasts. McFarland GA, Holliday R. CSIRO Division of Molecular Science, Sydney Laboratory, North Ryde, Australia.
Cayenne 267 Studies

1. Allison DB, Fontaine KR, Heshka S, Mentore JL, Heymsfield SB. Alternative treatments for weight loss: a critical review. Crit Rev Food Sci Nutr. 2001;41(1):1-28; discussion 39-40. 2. Attal N. Chronic neuropathic pain: mechanisms and treatment [Review]. Clin J Pain 2000;16(3 Suppl):S118-30. 3. Bouraoui A, Toumi A, Mustapha HB, et al. Effects of capsicum fruit on theophylline absorption and bioavailability in rabbits. Drug-Nutrient Interact. 1988;5:345350. 4. Blumenthal M, Goldberg A, Brinckmann J. Herbal Medicine: Expanded Commission E Monographs. Newton, MA: Integrative Medicine Communications; 2000:52-56. 5. D'Alonzo AJ, Grover GJ, Darbenzio RB, et al. In vitro effects of capsaicin: antiarrhythmic and antiischemic activity. Eur J Pharmacol. 1995;272(2-3):269-278. 6. Deal CL, Schnitzer TJ, Lipstein E, et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther. 1991;13(3):383-395. 7. Egger G, Cameron-Smith D, Stanton R. The effectiveness of popular, non-prescription weight loss supplements. Medical Journal of Australia. 1999;171(11-12):604-608. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 739
8. Ellison N, Loprinzi CL, Kugler J, et al. Phase III placebo-controlled trial of capsaicin cream in the management of surgical neuropathic pain in cancer patients. J Clin Oncol. 1997;15(8):2974-2980. 9. Fusco BM, Giacovazzo M. Peppers and pain. The promise of capsaicin. Drugs. 1997;53(6):909-914. 10. Fusco BM, Marabini S, Maggi CA, Fiore G, Geppetti P. Preventative effect of repeated nasal applications of capsaicin in cluster headache. Pain. 1994;59(3):321-325 11. Gallo R, Cozzani E, Guarrera M. Sensitization to pepper (Capsicum annuum) in a latex-allergic patient. Contact Dermatitis. 1997;37(1):36-37. 12. Hakas JF Jr. Topical capsaicin induces cough in patient receiving ACE inhibitor. Ann Allergy. 1990;65:322. 13. Hautkappe M, Roizen MF, Toledano A, Roth S, Jeffries JA, Ostermeier AM. Review of the effectiveness of capsaicin for painful cutaneous disorders and neural dysfunction. [Review]. Clin J Pain. 1998;14(2):97-106. 14. Jensen PG, Larson JR. Management of painful diabetic neuropathy [Review]. Drugs Aging. 2001;18(10):737-749. 15. Kang JY, Yeoh KG, Chia HP, Lee HP, Chia YW, Guan R, Yap I. Chili--protective factor against peptic ulcer? Dig Dis Sci. 1995;40(3):576-9 16. Kenney JK, Jamjian C, Wheeler MM. Prevention and management of pain associated with Herpes zoster. Journal of Pharmaceutical Care in Pain and Symptom Control. 1999;7(3):7-26. 17. Nicholas JJ. Physical modalities in rheumatological rehabilitation. Archives of Physical and Medical Rehabilitation. 1994;75(9):994-1001. 18. Paice JA, Ferrens CE, Lashley FR, Shott S, Vizgirda V, Pitrak D. Topical capsaicin in the management of HIV-associated peripheral neuropathy. J Pain Symtom Manage. 2000;19(1):45-52. 19. Petersen KL, Fields HL, Brennum J, Sandroni P, Rowbotham MC. Capsaicin evoked pain and allodynia in post-herpetic neuralgia. Pain. 2000;88:125-133. 20. Rains C, Bryson HM. Topical Capsaicin. A review of its pharmacological properties and therapeutic potential in post-herpetic neuralgia, diabetic neuropathy and osteoarthritis. Drugs and Aging. 1998;7(4):317-328. 21. Robbins W. Clinical applications of capsaicinoids [Review]. Clin J Pain. 2000;16(2 Suppl):S86-89. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 740
22. Rosenstein ED. Topical agents in the treatment of rheumatic disorders. Rheum Dis Clin North Am. 1999;25(4):899-913. 23. Stander S, Luger T, Metze D. Treatment of prurigo nodularis with topical capsaicin. J Am Acad Dermatol. 2001;44(3):471-478. 24. Stankus SJ, Dlugopolski M, Packer D. Management of herpes zoster (shingles) and postherpetic neuralgia. [Review]. Am Fam Physician. 2000;61(8):2437-44, 2447-2448. 25. Volmink J, Lancaster T, Gray S, Silagy C. Treatments for postherpetic neuralgia--a systematic review of randomized controlled trials. Fam Pract. 1996;13(1):84-91. 25. Yeoh KG, Kang JY, Yap I, et al. Chili protects against aspirin-induced gastroduodenal mucosal injury in humans. Dig Dis Sci. 1995;40:580583. 26. Yoshioka M, St-Pierre S, Suzuki M, Tremblay A. Effects of red pepper added to high-fat and high-carbohydrate meals on energy metabolism and substrate utilization in Japanese women. Br J Nutr. 1998;80(6):503-510. 27. Zhang WY, Li Wan Po A. The effectiveness of topically applied capsaicin. Eur J Clin Pharmacol. 1994;46:517-522.
Phosphatidylserine 19 Studies
1. Palmieri, G., et al., Double-blind controlled trial of phosphatidylserine in patients with senile mental deterioration. Clin. Trials J. 1987;24:73-83. 2. Delwaide PJ, et al. Double-blind randomized controlled study of phosphatidylserine in senile demented patients. Acta Neurol Scand 1986 Feb;73(2):136-40. 3. Crook TH, et al. Effects of phosphatidylserine in age-associated memory impairment. Neurology 1991 May;41(5):644-649. 4. Cenacchi T, et al. Cognitive decline in the elderly: a double-blind, placebo-controlled multicenter study on efficacy of phosphatidylserine administration. Aging (Milano) 1993 Apr;5(2):123-33. 5. Funfgeld EW, et al. Double-blind study with phosphatidylserine (PS) in parkinsonian patients with senile dementia of Alzheimer's type (SDAT). Prog Clin Biol Res 1989;317:1235-46. 6. (no authors listed) Phosphatidylserine in the treatment of clinically diagnosed Alzheimer's disease. The SMID Group. J Neural Transm Suppl 1987;24:287-92. 7. Amenta F, et al. Treatment of cognitive dysfunction associated with Alzheimer's disease with cholinergic precursors. Ineffective treatments or inappropriate approaches? Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 741
Mech Ageing Dev 2001 Nov;122(16):2025-40. 8. Heiss WD, et al. Activation PET as an instrument to determine therapeutic efficacy in Alzheimer's disease. Ann N Y Acad Sci 1993 Sep 24;695:327-31. 9. Crook T, et al. Effects of Phosphatidylserine in Alzheimer's Disease. Psychopharmacol Bull 1992;28(1):61-66. 10. Engel RR, Double-blind cross-over study of phosphatidylserine vs. placebo in patients with early dementia of the Alzheimer type. Eur Neuropsychopharmacol 1992 Jun;2(2):149-55. 11. Maggioni M, et al. Effects of Phosphatidylserine Therapy in Geriatric Patients With Depressive Disorders. Acta Psychiatr Scand 1990;81:265-270. 12. Monteleone P, et al. Blunting by chronic phosphatidylserine administration of the stress-induced activation of the hypothalamo-pituitary-adrenal axis in healthy men. Eur J Clin Pharmacol 1992;42(4):385-388. 13. Monteleone P, et al. Effects of phosphatidylserine on the neuroendocrine response to physical stress in humans. Neuroendocrinology 1990 Sep;52(3):243-8. 14. Benton D, et al. The influence of phosphatidylserine supplementation on mood and heart rate when faced with an acute stressor. Nutr Neurosci 2001;4(3):169-78. 15. Gindin, J., et al. 1990, Effect of Soy Lecithin Phosphatidylserine (PS) Treatment on Daily Functioning and Self-Reported General Condition in Patients with Alzheimer's Disease, The Geriatric Institute of Education and Research Kaplan Medical Centre, Rehovot, and Hadassah Medical School, Hebrew University of Jerusalem, Israel. 16. Sakai M, et al. Pharmacological effects of phosphatidylserine enzymatically synthesized from soybean lecithin on brain functions in rodents. J Nutr Sci Vitaminol (Tokyo) 1996 Feb;42(1):47-54. 17. Schreiber S, et al. An open trial of plant-source derived phosphatidylserine for treatment of age-related cognitive decline. Isr J Psychiatry Relat Sci 2000;37(4):302-7. 18. Suzuki S, et al. Oral administration of soybean lecithin transphosphatidylated phosphatidylserine improves memory impairment in aged rats. J Nutr 2001 Nov;131(11):2951-6. 19. Van den Besselaar AM. Phosphatidylethanolamine and phosphatidylserine synergistically promote heparin's anticoagulant effect. Blood Coagul Fibrinolysis 1995;6:239-244.
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Ginkgo Biloba Leaf Powder 25 Studies

1. Blumenthal M, ed. The ABC Clinical Guide to Herbs. Austin, TX: American Botanical Council; 2003 2. Blumenthal M, Goldberg A, Brinckmann J, eds. Herbal Medicine. Expanded Commission E Monographs. 1st ed. Newton, MA: Integrative Medicine Communications; 2000. 3. Cooper R. Gin(kgo) and tonicwith a twist! J Altern Complement Med. 2003 Oct;9(5):599-601. 4. Cieza A, Maier P, Poppel E. Effects of Gink- go biloba on mental functioning in healthy volunteers. Arch Med Res. 2003 Sep;34(5):373-81. 5. Trick L, Boyle J, Hindmarch I. The effects of Ginkgo biloba extract (LI 1370) supplementation and discontinuation on activities of daily living and mood in free living older volunteers. Phytother Res. 2004 Jul;18(7):531-7. 6. Smith JV, Luo Y. Studies on molecular mechanisms of Ginkgo biloba extract. Appl Microbiol Biotechnol. 2004 May;64(4):465-72. 7. McKenna DJ, Jones K, Hughes K. Efficacy, safety, and use of ginkgo biloba in clinical and preclinical applications. Altern Ther Health Med. 2001 Sep;7(5):70-90. 8. Davies JA, Johns L, Jones FA. Effects of bilobalide on cerebral amino acid neurotransmission. Pharmacopsychiatry. 2003 Jun;36 Suppl 1S84-8. 9. Auguet M, Delaflotte S, Hellegouarch A, Clostre F. Pharmacological bases of the vascular impact of Ginkgo biloba extract. Presse Med. 1986 Sep 25;15(31):1524-28. 10. Yoshikawa T, Naito Y, Kondo M. Ginkgo biloba leaf extract: review of biological actions and clinical applications. Antioxid Redox Signal. 1999;1(4):469-80. 11. Huang SY, Jeng C, Kao SC, Yu JJ, Liu DZ. Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy. Clin Nutr. 2004 Aug;23(4):615-21. 12. Evans JG, Wilcock G, Birks J. Evidence-based pharmacotherapy of Alzheimers disease. Int J Neuropsychopharmacol. 2004 Sep;7(3):351-69. 13. Kurz A, Van Baelen B. Ginkgo biloba compared with cholinesterase inhibitors in the treatment of dementia: a review based on meta-analyses by the cochrane collaboration. Dement Geriatr Cogn Disord. 2004;18(2):217-26. Copyright Gary Null & Associates, Inc., 2005 All Rights Reserved 743
14. Jacoby D, Mohler ER, III. Drug treatment of intermittent claudication. Drugs. 2004;64(15):1657-70. 15. Horsch S, Walther C. Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD)a review based on randomized, controlled studies. Int J Clin Pharmacol Ther. 2004 Feb;42(2):63-72. 16. McKay D. Nutrients and botanicals for erectile dysfunction: examining the evidence. Altern Med Rev. 2004 Mar;9(1):4-16. 17. Cohen AJ, Bartlik B. Ginkgo biloba for antidepressant-induced sexual dysfunction. J Sex Marital Ther. 1998 Apr;24(2):139-43. 18. Chao JC, Hung HC, Chen SH, Fang CL. Effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer. World J Gastroenterol. 2004 Feb 15;10(4):560-6. 19. Abdel-Salam OM, Baiuomy AR, El batran S, Arbid MS. Evaluation of the antiinflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat. Pharmacol Res. 2004 Feb;49(2):133-42. 20. Colciaghi F, Borroni B, Zimmermann M, et al. Amyloid precursor protein metabolism is regulated toward alpha-secretase pathway by Ginkgo biloba extracts. Neurobiol Dis. 2004 Jul;16(2):454-60.
21. Antagonistic effects of extract from leaves of Ginkgo biloba on glutamate neurotoxicity. Zhu L Wu J Liao H Gao J Zhao XN Zhang ZX Acta Pharmacol Sin 1997 JUL;18(4):344 Zhu L, Nanjing Univ, Sch Med, Nanjing 210093, PEOPLES R CHINA 22. Attenuation of salicylate-induced tinnitus by Ginkgo biloba extract in rats. Jastreboff PJ Zhou ST Jastreboff MM Kwapisz U Gryczynska U Audiol Neuro Otol 1997 JUL-AUG;2(4):197-212 Jastreboff PJ, Univ Maryland, Sch Med, Dept Surg, Tinnitus & Hyperacusis Ctr, 10 S Pine St, Mstf Bldg, RM 436, Baltimore,MD 21201 USA
23. Phospholipid breakdown and choline release under hypoxic conditions: Inhibition by bilobalide, a constituent of Ginkgo biloba. Klein J Chatterjee SS Loffelholz K Brain Res 1997 MAY 2;755(2):347-350 Klein J, Univ Mainz, Dept Pharmacol, Obere Zahlbacher Str 67, D 55101 Mainz, GERMANY 24. Proof of efficacy of the Ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multiinfarct dementia (Reprinted f rom Pharmacopsychiat, vol 29, pg 47-56, 1996). Kanowski S Herrmann WM Stephan K Wierich W Horr R
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Phytomedicine 1997 MAR;4(1):3-13 Kanowski S, Free Univ Berlin, Klinikum Benjamin Franklin, ABT Gerontopsychiat, Dept Gerontopsychiat, D 14050 Berlin, GERMANY 25. Effect of Ginkgo biloba extract (EGb 761) on the vasospastic response of mouse cutaneous arterioles to platelet activation. Stucker O Pons C Duverger JP Drieu K DArbigny P Int J Microcirc Clin Exp 1997 MAR-APR;17(2):61-66 Stucker O, Cerom, 155 Rue Faubourg St Denis, F 75010 Paris, FRANCE
Linoleic Acid 29 Studies
1. Conjugated linoleic acid: A powerful anticarcinogen from animal fat sources Ip C.; Scimeca J.A.; Thompson H.J. Department of Surgical Oncology, Roswell Park Center Institute, Elm and Carlton Streets, Buffalo, NY 14263 USA CANCER (USA) , 1994, 74/3 (1050-1054) 2. Conjugated linoleic acid and atherosclerosis in rabbits Lee K.N.; Kritchevsky D.; Pariza M.W. Food Research Institute, Dept. Food Microbiology/Toxicology, University of WisconsinMadison, 1925 Willow Drive, Madison, WI 53706 USA Atherosclerosis (Ireland), 1994, 108/1 (19-25) 3. Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid Chin S.F.; Storkson J.M.; Liu W.; Albright K.J.; Pariza M.W. Food Microbiology/Toxicology Dept., Food Research Institute, University of Wisconsin, Madison, WI 53706 USA J. NUTR. (USA) , 1994, 124/5 (694-701) 4. Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells Shultz TD; Chew BP; Seaman WR; Luedecke LO Cancer Lett (NETHERLANDS) Apr 15 1992, 63 (2) p125-33, 5. Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat Ip C; Singh M; Thompson HJ; Scimeca JA Cancer Res (UNITED STATES) Mar 1 1994, 54 (5) p1212-5,
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6. Conjugated linoleic acid suppresses mammary carcinogenesis and proliferative activity of the mammary gland in the rat CANCER RES. (USA) , 1994, 54/5 (1212-1215) 7. Effect of cheddar cheese consumption on plasma conjugated linoleic acid concentrations in men NUTR. RES. (USA) , 1994, 14/3 (373-386) 8. Differential stimulatory and inhibitory responses of human MCF-7 breast cancer cells to linoleic acid and conjugated linoleic acid in culture ANTICANCER RES. (Greece) , 1992, 12/6 B (2143-2145) pronounced (8 - 81%) than LA. These in vitro results suggest that CLA is cytotoxic to MCF-7 cells. 9. Inhibitory effect of conjugated dienoic derivatives of linoleic acid and beta-carotene on the in vitro growth of human cancer cells CANCER LETT. (Ireland) , 1992, 63/2 (125-133) 10. Inhibition of Listeria monocytogenes by fatty acids and monoglycerides APPL. ENVIRON. MICROBIOL. (USA) , 1992, 58/2 (624-629) 11. Recognition of cervical neoplasia by the estimation of a free-radical reaction product (octadeca-9,11-dienoic acid) in exfoliated cells CLIN. CHIM. ACTA (NETHERLANDS) , 1987, 163/2 (149-152) 12. Feeding conjugated linoleic acid to animals partially overcomes catabolic responses due to endotoxin injection BIOCHEM. BIOPHYS. RES. COMMUN. (USA) , 1994, 198/3 (1107-1112) 13. Conjugated linoleic acid (9,11- and 10,12-octadecadienoic acid) is produced in conventional but not germ-free rats fed linoleic acid J. NUTR. (USA) , 1994, 124/5 (694-701) 14. Conjugated linoleic acid and atherosclerosis in rabbits ATHEROSCLEROSIS (Ireland) , 1994, 108/1 (19-25) 15. Conjugated linoleic acid is a growth factor for rats as shown by enhanced weight gain and improved feed efficiency J. NUTR. (USA) , 1994, 124/12 (2344-2349) 16. Cows' milk fat components as potential anticarcinogenic agents Journal of Nutrition (USA) , 1997, 127/6 (1055-1060) 17. Suppression of voltage-gated L-type Ca2+ currents by polyunsaturated fatty acids in adult and neonatal rat ventricular myocytes
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Proceedings of the National Academy of Sciences of the United States of America (USA) , 1997, 94/8 (4182-4187) 18. Effects of dietary conjugated linoleic acid on lymphocyte function and growth of mammary tumors in mice Anticancer Research (Greece) , 1997, 17/2 A (987-993) 19. Conjugated linoleic acid suppresses the growth of human breast adenocarcinoma cells in SCID mice Anticancer Research (Greece) , 1997, 17/2 A (969-973) 20. Lymphatic recovery, tissue distribution, and metabolic effects of conjugated lioleic acid in rats Journal of Nutritional Biochemistry (USA) , 1997, 8/1 (38-43) 21. Proliferative responses of normal human mammary and MCF-7 breast cancer cells to linoleic acid, conjugated linoleic acid and eicosanoid synthesis inhibitors in culture Anticancer Research (Greece) , 1997, 17/1 A (197-203) 22. Conjugated linoleic acid modulates hepatic lipid composition in mice Lipids (USA) , 1997, 32/2 (199-204) 23. Dietary conjugated linoleic acid modulation of phorbol ester skin tumor promotion Nutrition and Cancer (USA) , 1996, 26/2 (149-157) 24. The efficacy of conjugated linoleic acid in mammary cancer prevention is independent of the level or type of fat in the diet Carcinogenesis (United Kingdom) , 1996, 17/5 (1045-1050) 25. Dietary modifiers of carcinogenesis Environmental Health Perspectives (USA) , 1995, 103/SUPPL. 8 (177-184) 26. Effects of C18 fatty acid isomers on DNA synthesis in hepatoma and breast cancer cells Anticancer Research (Greece) , 1995, 15/5 B (2017-2021) 27. Effect of timing and duration of dietary conjugated linoleic acid on mammary cancer prevention Nutrition and Cancer (USA) , 1995, 24/3 (241-247) 28. The role of phenolics, conjugated linoleic acid, carnosine, and pyrroloquinoline quinone as nonessential dietary antioxidants Nutrition Reviews (USA) , 1995, 53/3 (49-58)
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29. Dietary conjugated linoleic acid reduces plasma lipoproteins and early aortic atharosclerosis in hypercholasterolemic hamsters Artery (USA) , 1997, 22/5 (266-277)
Inositol 6 Studies
1. Can intervention in inositol phosphate signalling pathways improve therapy for cystic fibrosis? Expert Opin Ther Targets. 2005 Dec;9(6):1307-17. PMID: 16300477
2. 1. Levine J, Barak Y, Gonzalves M, et al. Double-blind, controlled trial of inositol treatment of depression. Am J Psychiatry 1995;152:7924.
3. Levine J, Barak Y, Kofman O, Belmaker RH. Follow-up and relapse analysis of an inositol study of depression. Isr J Psychiatry Relat Sci 1995;32:1421.
4. Benjamin J, Levine J, Fux M, et al. Double-blind, placebo-controlled, crossover trial of inositol treatment for panic disorder. Am J Psychiatry 1995;152:10846. 5. Fux M, Levine J, Aviv A, Belmaker RH. Inositol treatment of obsessive-compulsive disorder. Am J Psychiatry 1996;153:121921. 6. Colodny L, Hoffman RL. InositolClinical applications for exogenous use. Altern Med Rev 1998;3:43247.
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Gary Null Anti-Aging Protocol For Nursing Homes - Studies

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Gary Nulls Anti-Aging Protocol for Nursing Homes: Nutrients Scientifically Proven to be Beneficial to Cognition and the Overall

Prepared by: Gary Null, Ph.D., and Doug Henderson, Esq.

Nursing Home Intervention Study: Introduction

NURSING HOMES, DYING FROM NEGLECT 16 References

2. Mortality associated with nosocomial infections: analysis of multiple causeof-death data.

ANTIDEPRESSANTS 109 Studies

PSYCHOTROPIC DRUGS USED FOR ADULTS AND THE ELDERLY

PSYCHOTROPIC DRUGS IN PREGNANCY

DRUGS, FALLS AND HIP FRACTURES

PSYCHOTROPIC DRUGS AND MOTOR VEHICLE ACCIDENTS

THE HIGH COST OF MEDICAL CARE 49 Studies

MEDICAL ERRORS & ADVERSE DRUG REACTIONS 76 Studies

ADVERSE DRUG REACTIONS AND ADVERSE EVENTS

ADVERSE DRUG REACTIONS AND ERRORS IN CHILDREN

NURSING HOME PROTOCOL

Vitamin B1 120 Studies

Vitamin B12 64 Studies

Pantothenic Acid (B5) 47 Studies

Calcium Carbonate - 86 Studies

Ginkgo Biloba 33 Studies

Choline Bitartrate 63 Studies

Blue Cohosh Root 2 Studies

Siberian Ginseng Root 40 Studies

Rosemary Leaves 17 Studies

Apsartic Acid 21 Studies

Linoleic Acid 56 Studies

Linolenic Acid 10 Studies

Caprylic Acid - 9 Studies

Pregenolone -23 Studies

SUPER ANTIOXIDANTS Vitamin A 41 STUDIES

1. Traber MG. Utilization of vitamin E. Biofactors. 1999;10(2-3):115-120. (PubMed)

Ann Surg Oncol. 2002 Dec;9(10):1023-32. PMID: 12464597

Rosemary Leaf Powder - 20 STUDIES

Raspberry Leaf Powder - 10 Studies

Citrus Bioflavonoids 11 STUDIES

Chronic Fatigue Syndrome

Cardiocascular and EYE

Bilberry High in Quercetin

Red Wine Concentrate 14 STUDIES

J Altern Complement Med. 2004 Apr;10(2):235-9.

Grape Skin Extract 48 STUDIES

China Green Tea Leaf Powder - 100 Studies

Reduced L-Glutathione - 13 CITATIONS

Coenzyme Q10 43 STUDIES

N-Acetylcysteine (NAC) - 40 STUDIES

Alpha Lipoic Acid 20 STUDIES

Superroxide Dismutase 51 STUDIES

8. Phytother Res. 2002 Sep;16(6):567-71. Treatment of melasma with Pycnogenol.

Licorice Root 21 STUDIES

BroccolI Stem - 26 STUDIES

Cabbage Leaf 10 STUDIES

8. Aggarwal BB, Ichikawa H.

Carrot Root - 11 STUDIES

Milk Thistle Leaf - 27 STUDIES

Alpha Lipoic Acid - 70 ABSTRACTS

ALPHA LIPOIC ACID: 70 RESEARCH ABSTRACTS

Mixed Tocopherols - 398 Studies

Pharmacol Biochem Behav 1992 Feb;41(2):445-8

CARNOSINE: 47 RESEARCH ABSTRACTS

Magnesium - 570 CITATIONS

Cayenne 267 Studies

Ginkgo Biloba Leaf Powder 25 Studies