Herbal Antimalerial

CONTENTS
S.No. 1. 1.1 1.2 1.3 1.4 1.5 1.6 2. 3. 3.1 3.2 3.3 3.4
3.1
3.2
Title Introduction History of Malaria Distribution of Malaria Parasite and vector of Malaria Life Cycle of Plasmodium Resistance History of Treatment and Prophylaxis Antimalarial Drugs Herbal Antimalarial Drugs Cinchona (Quinine) Artemisia Vulgaris Cryptolepis Yingzhaosu Cinchona (Quinine) Source, and History of cinchona A. Properties and Action B. Phytochemical Study C. Pharmacological Study D. Uses and Application E. Biological Activities and Clinical Research F. Formulation Artemisia Vulgaris
Page No. 1 20 15 6 6 7 10 10 11 12 - 20 21 24 25
Source and Properties

A. Morphological Study and Cultivation B. Production Profile C. Market and Market Potential Cryptolepis A. History B. Nomenclature and Taxonomy C. Morphological Study D. Pharmacological Study
E. Uses 3.4
3.3
4. 5.
Yingzhaosu Conclusion References
26 37 26 28 29 30 31 31 32 32 33 34 35 - 37 38 45 41 42 42 44 44 45 45 46 57 46 46 47 47 48 48 54 54 57 58 59 60 61 - 66
1. INTRODUCTION
The term malaria comes from 'mal' 'aria', or bad air. The Romans noticed that they got sick when they took walks in the night air. Approximately 100 years ago, Dr. Ronald Ross, a British Medical Officer in Hyderabad, India discovered that mosquitoes transmitted malaria. He first recognized that the black pigment associated with human disease was also present in the gut of the mosquito and later showed that when infected mosquitoes bit chickens the disease was indeed transmitted. For his studies he received the 1902 Nobel Prize in Medicine. Malaria remains one of the most serious tropical diseases in many parts of the world. The malaria situation is deteriorating in many areas impairing the prevention and treatment of malaria, despite major control becoming more widespread.
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campaigns.
Resistance of the malaria parasite to antimalarial drugs is increasing and The incidence of travel-related malaria is increasing, especially in visitors to endemic African countries. 2,4,6,8 The eradication of malaria in the Midwestern United States was achieved by (i) breeding fish that ate mosquito larvae and (ii) increasing the standard of living. The female Anopheline mosquito is highly prevalent in the Southern United States. Thus, the emergence of drug resistant parasites elsewhere and more frequent international travel increases the risk of malaria in the US. The CDCP predicts that the highest risk of entry is Florida, due to immigration from Haiti. The blood stages of infection are responsible for all of the clinical symptoms and pathoglogies associated with malaria. These stages are our main focus of interest. The parasite has a complex life as shown in Figure 3 (below). When a mosquito bites a human host, sporozoites are released from the salivary glands of the mosquito into the bloodstream. These reach the liver and undergo a cycle of development in hepatocytes. The resulting merozoites lyse out of liver cells and subsequently infect erythrocytes to undergo asexual proliferation as shown
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in Figure 4 (below). Here a single merozoite gives rise to ~16 daugther cells, which then re-infected red cells and thereby maintain the asexual cycle. The length of the cycle determines the periodicity of the fevers and chills associated with malaria. In falciparum malaria, the parasite development in the red cell takes 48 hours. Fever occurs concomitant with release of merozoites into the blood stream, every two days. 1.1 History of Malaria
Deadly fevers - probably malaria - have been recorded since the beginning of the written word (6000-5500 B.C.) References can be found in the Vedic writings of 1600 B.C. in India and by Hippocrates some 2500 years ago.
There are no references to malaria in the "medical books" of the Mayans or Aztecs. It is likely that European settlers and slavery brought malaria to the New World and the awaiting anophelines within the last 500 years.
Quinine, a toxic plant alkaloid made from the bark of the Cinchona tree in South America, was used to treat malaria more than 350 years ago.
Jesuit missionaries in South America learned of the anti-malarial properties of the bark of the Cinchona tree and had introduced it into Europe by the 1630s and into India by 1657.
Malaria existed in parts of the United States from colonial times to the 1940s. One of the first military expenditures of the Continental Congress, around 1775, was for $300 to buy quinine to protect General Washington's troops.
In the summer of 1828 "swamp fever" broke out in the settlement of Bytown (Ottawa) and along the construction route of the Rideau Canal. According to some accounts, the "malaria" was not native to North
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America but had been introduced by infected British soldiers who had returned from India. Numerous deaths had occurred by the time the epidemic subsided in September when the mosquitoes disappeared.
During the American Civil War (1861-65), one half of the white troops and 80% of the black soldiers of the Union Army got malaria annually.
More than an estimated 600,000 cases of malaria occurred in the U.S. in 1914, according to information from the Centers for Disease Control and Prevention in Atlanta, Georgia.
In 1927, J. Wagner von Jauregg was awarded the Nobel Prize in Medicine for his work in treating syphilis using malaria. Patients were inoculated with a type of malaria to produce fevers that would literally burn up the temperature-sensitive syphilis bacteria. After three or four cycles of the fever, the patient was administered quinine for a relatively rapid parasitological cure for the malaria.
Malaria therapy for syphilis, using monkey and human parasites, continued until the mid-1950s when it was replaced by antibiotic chemotherapy.
The Dutch bought Cinchona seeds from British trader, Charles Leger, who brought them from Peru. They established Cinchona plantations in Java (Indonesia) in the mid 1800s and soon had a virtual monopoly on quinine.
When the Japanese captured Java during the second World War, quinine, except for some old stocks became unavailable. The need for a new synthetic antimalarial became a priority at that time.
In 1880, the first true sighting of the malaria parasite was made in Algeria by a French Army physician, Charles-Louis-Alphonse Laveran, while
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viewing blood slides under a microscope. Laveran's discovery was rejected by the medical community and it was not until 1886 that his discovery was accepted by Italian scientists, the leaders in the field at the time.
In 1882 the mosquito transmission hypothesis - guilt by association - was first made.
The December 18, 1897 issue of the British Medical Journal reported that Dr. Ronald Ross discovered malaria cysts in the stomach wall of anopheline mosquitoes that fed on a malaria patient. While it was recognised that the Anopheles mosquito played a key role in the transmission of the disease it was not until 1948 that all the stages in its life cycle were identified. The parasite undergoes a development stage in the mosquito and the female of the species requires a blood meal to mature her eggs. She bites a human and injects material from her salivary glands, which contains primitive malarial parasites called sporozoites, before feeding. These sporozoites circulate in the blood for a short time and then settle in the liver where they enter the parenchymal cells and multiply; this stage is known as preerythrocytic schizogony. After about 12 days there may be many thousands of young parasites known as merozoites in one liver cell, the cell ruptures and the free merozoites enter red blood cells. The blood stages of the four species of malaria can be seen in the section on Diagnosis. In the case of P. vivax, and P.ovale the liver cycle continues and requires a course of primaquine to eliminate it. P.falciparum on the other hand does not have a continuing liver cycle.1,7,9,12
In the red blood cells the parasites develop into two forms, a sexual and an asexual cycle. The sexual cycle produces male and female gametocytes, which circulate in the blood and are taken up by a female
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mosquito when taking a blood meal. The male and female gametocytes fuse in the mosquito's stomach and form ocysts in the wall of the stomach. These ocysts develop over a period of days and contain large numbers of sporozoites, which move to the salivary glands and are ready to be injected into man when the mosquito next takes a meal. In the asexual cycle the developing parasites form schizonts in the red blood cells which contain many merozoites, the infected red cells rupture and release a batch of young parasites, merozoites, which invade new red cells. In P.vivax, P.ovale and probably P.malariae, all stages of development subsequent to the liver cycle can be observed in the peripheral blood. However, in the case of P.falciparum only ring forms and gametocytes are usually present in the peripheral blood. Developing forms appear to stick in the blood vessels of the large organs such as the brain and restrict the blood flow with serious consequences. 1.2 Distribution of Malaria
GLOBAL DISTRIBUTION Malaria occurs in many parts of the tropics and subtropics in North, Central and South America, Africa, Asia and Oceania (Figure 1). DISTRIBUTION IN SOUTH AFRICA Malaria occurs in limited areas in South Africa. The endemic malaria areas are the low altitude areas (below 1000 metres) of the Northern Province, Mpumalanga, and the north eastern part of KwaZulu-Natal (Figure 2). Occasionally limited focal transmission may develop in the North-West and Northern Cape provinces along the Molopo and Orange Rivers. Infections are very seldom contracted outside the malarious areas and are then possibly a consequence of the importation of infected mosquitoes by motor or other transport.
1.3
Parasite and vector of malaria
Malaria is a protozoal disease transmitted by the Anopheles mosquito, caused by minute parasitic protozoa of the genus Plasmodium, which infect human and insect hosts alternatively. It is a very old disease and prehistoric man is thought to have suffered from malaria. It probably originated in Africa and accompanied human migration to the Mediterranean shores, India and South East Asia. In the past it used to be common in the marshy areas around Rome and the name is derived from the Italian, (mal-aria) or "bad air"; it was also known as Roman fever. Today some 500 hundred million people in Africa, India, South East Asia and South America are exposed to endemic malaria and it is estimated to cause two and a half million deaths annually, one million of which are children. 1.4 Biology of Plasmodium Parasites and Anopheles Mosquitos
The Plasmodium genus of protozoal parasites (mainly P.falciparum, P.vivax, P.ovale, and P.malariae) have a life cycle which is split between a vertebrate host and an insect vector. The Plasmodium species, with the exception of P.malariae (which may affect the higher primates) are exclusively parasites of man. The mosquito is always the vector, and is always an Anopheline mosquito, although, out of the 380 species of Anopheline mosquito, only 60 can transmit malaria. Only female mosquitos are involved as the males do not feed on blood. The basic life cycle of the parasite is shown below:
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Life Cycle of the Malaria Parasite
Malaria is an infectious disease caused by a one-celled parasite known as Plasmodium. The parasite is transmitted to humans by the bite of the female Anopheles mosquito. The Plasmodium parasite spends its life cycle partly in humans and partly in mosquitoes. (A) Mosquito infected with the malaria parasite bites human, passing cells called sporozoites into the humans
bloodstream. (B) Sporozoites travel to the liver. Each sporozoite undergoes asexual reproduction, in which its nucleus splits to form two new cells, called merozoites. (C) Merozoites enter the bloodstream and infect red blood cells. (D) In red blood cells, merozoites grow and divide to produce more merozoites, eventually causing the red blood cells to rupture. Some of the newly released merozoites go on to infect other red blood cells. (E) Some merozoites develop into sex cells known as male and female gametocytes. (F) Another mosquito bites the infected human, ingesting the gametocytes. (G) In the mosquitos stomach, the gametocytes mature. Male and female gametocytes undergo sexual reproduction, uniting to form a zygote. The zygote multiplies to form sporozoites, which travel to the mosquitos salivary glands. (H) If this mosquito bites another human, the cycle begins again.
The spozozoites from the mosquito salivary gland are injected into the human as the mosquito must inject anticoagulant saliva to ensure an even flowing meal. Once in the human bloodstream, the sporozoites arrive in the liver and penetrate hepatocytes, where they remain for 9-16 days, multiplying within the cells. Next they return to the blood and penetrate red blood cells, in which they produce either merozoites, which reinfect the liver, or micro- and macrogametocytes, which have no further activity within the human host. Another mosquito arriving to feed on the blood may suck up these gametocytes into its gut, where exflagellation of microgametocytes occurs, and the macrogametocytes are fertilized. The resulting ookinete penetrates the wall of a cell in the midgut, where it develops into an oocyst. Sporogeny within the oocyst produce many sporozoites and, when the oocyst ruptures, the sporozoites migrate to the salivary gland, for injection into another host. This highly specialised life cycle requires specialised biology on the part of the Plasmodium species. The reason
that not all mosquitos are vectors for Plasmodium parasites is that refractory mosquitos posses substances toxic to Plasmodium within their cells . A higher trypsin-like activity was also found in the midgut of resistant species, possibly inhibiting ookinete development. Plasmodium parasites seem capable of adapting to any suitable anopheline mosquito, given sufficient time and contact. Sporogeny within the mosquito are governed by environmental temperature as Anopheline mosquitos are poikilotherms. Once injected into the human host, all Plasmodium species will penetrate hepatocytes. However, P.falciparum and P.malariae sporozoites trigger immediate schizogony whereas P.ovale and P.vivax sporozoites may either trigger immediate schizogony or have a delayed trigger, resulting in dormant hypnozoites. Some strains, such as the North Korean strain, seem to consist of sporozoites with universally delayed triggers, so they all form long lasting hypnozoites. P.vivax may have an incubation period of up to 10 months. Gametocytes produced in the primary attack seem to contain all the genetic information required to create sporozoites of several different activation times. The same seems true for gametocytes produced in relapses where the hypnozoites become activated. Sexual development of Plasmodium begins as the merozoites invade the erythrocytes after their release from the liver. Within the erythrocyte, shizogony occurs to produce either more merozoites (taking 22 1/2 hours in the case of P.berghei), or the sexual micro and macrogametocytes (taking 26 hours). In P.falciparum, erythrocytic schizogony takes 48 hours and gametocytosis takes 10-12 days. Normally a variable number of cycles of asexual erythrocytiic shizogony occurs before any gametocytes are produced . The immune system may produce antibodies to the gametocytes at this stage.
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1.5
Resistance:-
Drug resistance occurs selectively in the species P. falciparum. The other three species have no documented resistance apart from the regionalized choroquine resistance observed in P. vivax, concentrated largely in Papua New Guinea and Irian Jaya (Indonesia). The reasons for the development and spread of drug resistance involve the interaction of drug-use patterns, characteristics of the drug itself, human host factors, parasite characteristics, and vector and environmental factors. However, only gene mutations confer resistance to the parasites in nature. A summary on the determinants of drug resistance is shown in the Table1. The gene pfmdr1, encoding P-glycoprotein homologue 1 (Pgh1), is linked to chloroquine resistance through mutation. In multi-drug-resistant mammalian cancer cells, the P-glycoprotein is an ATPdependent pump that expels chemotherapeutic agents from the cell. In P. falciparum, the P-glycoprotein is located mainly in the membrane of the digestive vacuole of the parasite and evidence suggests it is involved in nucleotide-dependent transport across the membrane. Mutations in other (unidentified) genes are also required to confer complete resistance to the parasites. Changes in Pgh1 can modulate resistance to quinine, mefloquine and halofantrine. Artemisinin also showed decreased sensitivity against various strains of P. falciparum due to this mutation. Another gene, pfcrt, coding for a vacuolar membrane transporter protein (PfCRT ) is also associated with chloroquine resistance.
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Resistance to chloroquine arises due to the ability of the P. falciparum to release chloroquine 40-50 times more rapidly than a normal susceptible parasite. Calcium channel blockers like verapamil, vinblastine and daunomycin enhanced the accumulation of chloroquine in a resistant parasite and also inhibited the release of chloroquine. These changes were not found in normal susceptible parasites.13 Calcium channel antagonists are thought to interact with the P-glycoprotein transport system in the membrane of the parasite.
1.6
History of Treatment and Prophylaxis Antimalarial drugs fall into several chemical groups and it is useful to have some knowledge of their chemistry. The aim here is to give a brief outline of anti-malarial drugs and their usefulness today, when drug resistant strains of malaria have become a major problem. It is not a comprehensive history nor does it include a number of drugs which are no longer used.
Quinine.
Quinine has been used for more than three centuries and until the 1930's it was the only effective agent for the treatment of malaria. It is one of the four main alkaloids found in the bark of the Cinchona tree and is the only drug which over a long period of time has remained largely effective for treating the disease. It is now only used for treating severe falciparum malaria partly because of undesirable side effects. In Africa in the 1930's and 40's it was known for people to take quinine when they thought they had "a touch of malaria" and the association of repeated infections with falciparum malaria and inadequate treatment with quinine, resulted in the development in some of acute massive intravascular haemolysis and haemoglobinuria ie. black water fever. 12,9,7
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Atebrin(mepacrine).
This drug is a 9-amino-acridine developed in the early 1930's. It was used as a prophylactic on a large scale during the second world war (1939-45) and was then considered a safe drug. It had a major influence in reducing the incidence of malaria in troops serving in South East Asia. It is now considered to have too many undesirable side effects and is no longer used .
Chloroquine.
A very effective 4-amino-quinoline both for treatment and prophylaxis. It was first used in the 1940s shortly after the Second World War and was effective in curing all forms of malaria, with few side effects when taken in the dose prescribed for malaria and it was low in cost. Unfortunately most strains of falciparum malaria are now resistant to chloroquine and more recently chloroquine resistant vivax malaria has also been reported.
Proguanil.
This drug falls into the biguanide class of antimalarials and was first synthesised in 1946. It has a biguanide chain attached at one end to a chlorophenyl ring and it is very close in structure to pyrimethamine. The drug is a folate antagonist and destroys the malarial parasite by binding to the enzyme dihydrofolate reductase in much the same way as pyrimethamine. It is still used as a prophylactic in some countries.
Malarone.
In 1998 a new drug combination was released in Australia called Malarone. This is a combination of proguanil and atovaquone. Atovaquone became available 1992 and was used with success for the treatment of Pneumocystis carrinii. When combined with proguanil there is a synergistic effect and the combination is at the present time a very effective antimalarial treatment. The drug combination has undergone several large clinical trials and has been found
to be 95% effective in otherwise drug resistant falciparum malaria. How long it will be before resistant strains of malaria appear remains to be seen. It has been claimed to be largely free from undesirable side effects but it should be noted that proguanil is an antifolate. This is not likely to be a problem with a single treatment course of the drug but some caution should be exercised when using it for prophylaxis. In Australia it is due to become available for prophylaxis at the end of 1998. At present it is a very expensive drug.
Maloprim.
A combination of dapsone and pyrimethamine. Resistance to this drug is now widespread and its use is no longer recommended
Fansidar.
This is a combination drug, each tablet containing sulphadoxine 500mg. and pyrimethamine 25mg. It acts by interfering with folate metabolism. Resistance to Fansidar is now widespread and serious side effects have been reported. It is no longer recommended.
Mefloquine(Lariam).
First introduced in 1971, this quinoline methanol derivative is related structurally to quinine. The compound was effective against malaria, resistant to other forms of treatment when first introduced and because of its long half life was a good prophylactic, but widespread resistance has now developed and this together with undesirable side effects have resulted in a decline in its use. Because of its relationship to quinine the two drugs must not be used together. There have been reports of various undesirable side effects including several cases of acute brain syndrome, which is estimated to occur in 1 in 10,000 to 1 in 20,000 of the people taking this drug. It usually develops about two weeks after starting mefloquine and generally resolves after a few days.
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Halofantrin(Halfan).
This belongs to a class of compound called the phenanthrene-methanols and is not related to quinine. It is an effective antimalarial introduced in the 1980s, but due to its short half life of 1 to 2 days, is therefore not suitable for use as a prophylactic. Unfortunately resistant forms are increasingly being reported and there is some concern about side effects. Halofantrin has been associated with neuropsychiatric disturbances. It is contraindicated during pregnancy and is not advised in women who are breastfeeding. Abdominal pain, diarrhoea, puritus and skin rash have also been reported.
Artemisinins.
Artemisinin (qinghaosu) is a naturally occurring sesquiterpene lactone peroxide structurally unrelated to any known antimalarial. Qinghaosu, derived from cultivated Artemisia annua, is available as the parent compound artemisinin (oral, parenteral, and suppository formulations) and as three semi-synthetic derivatives: a water-soluble hemisuccinate salt (artesunate) for parenteral or oral administration; and two oil-soluble compounds (artemether and arteether) for intramuscular injection. All are metabolized to a biologically active metabolite, dihydroartemisinin. Artesunate is a prodrug for dihydroartemisinin and as such is the most rapidly active of the derivatives examined to date. All compounds have their antiparasitic effects on the younger ring-form parasites, thereby decreasing the numbers of late parasite forms that can obstruct the hosts microvasculature All artemisinin preparations have been studied and used only for treatment. They are recommended for treatment use only and not for prophylaxis. All compounds are at least as efficacious as quinine in the treatment of severe and
complicated malaria. Qinghaosu and its derivatives lead to faster parasite (mean: 32% faster) and fever (mean: 17% faster) clearance times than do any other anti-malarials. In spite of the more rapid antiparasitic action of qinghaosu compounds, these agents have not been shown to decrease mortality compared with quinine. Artemisinin-related compounds act rapidly against drug-resistant P. falciparum strains but have high recrudescence rates (about 10% to 50%) when used as monotherapy for less than 5 days. Recent3 studies have examined longer durations of therapy (7 days) and combinations of qinghaosu derivatives and mefloquine in order to prevent recrudescence. In vitro synergy has been demonstrated between artemisinin derivatives, mefloquine, and tetracycline. In Thailand, treatment with oral artesunate (over 3 to 5 days) combined with mefloquine (15 to 25 mg/kg) was more effective than mefloquine or artesunate alone. Combination therapy results in > 90% cure rates of primary and recrudescent P. falciparum infections. Malaria Treatment In Respect To Different P.Species.
P.
falciparum.
This species was originally sensitive to chloroquine, however, strains resistant to this and other antimalarial drugs are now commonplace. Because the parasite is able to multiply very rapidly and sequester within the microvasculature, a life threatening illness may develop in a very short space of time. Uncomplicated malaria (where patients can take oral therapy) can be treated with one of three regimens: 1. Quinine sulphate 10 mg salt/kg 8 hourly for seven days plus doxycycline 100 mg daily for 7 days. Patients will usually develop 'cinchonism' (tinnitus, high-tone hearing loss, nausea, dysphoria) after 2-3 days but should be encouraged to complete the full course to avoid recrudescence.
2. MalaroneTM (atovaquone 250 mg plus proguanil 100 mg) 4 tablets daily
for 3 consecutive days. This combination therapy has only recently come on the market and is relatively expensive. Data on efficacy are promising but limited.
3. Mefloquine (LariumTM) given as 15 mg/kg in a divided dose followed by
10 mg/kg the following day. Antipyretic and antiemetic agents may need to be given prior to mefloquine administration to reduce the risk of vomiting.
Choice of regimen is based on :Local cost and availability of antimalarial drugs. Area of malaria acquisition (i.e. drug resistance pattern of P. falciparum). Prior chemoprophylaxis. Known allergies. Concomitant illnesses other than malaria. Age and pregnancy. Likely patient compliance with therapy. Risk of re-exposure to malaria after treatment. In uncomplicated cases in which nausea and vomiting preclude oral therapy, quinine dyhidrochloride 10 mg salt/kg base can be given I.V. in 5% w/v dextrose or normal saline as a 4-hour infusion 8-hourly until the patient can take medication by mouth. Severe malaria. (where patients have coma, jaundice, renal failure, hypoglycaemia, acidosis, severe anaemia, high parasite count, hyperpyrexia) is ideally treated in an intensive care or high dependency unit where patients can be monitored closely both clinically and biochemically. Intravenous quinine is the treatment of choice but rapid injection can lead to hypotension, dysrhythmias and death.
In patients who have not received quinine in the previous 48 hours, one of two regimens can be used: 1. Quinine dihydrochloride 20 mg salt/kg base given I.V. in 5% w/v dextrose or normal saline as a once-only 4 hour infusion followed, 4 hours later, by quinine dihydrochloride 10 mg salt/kg base 4-hour infusions 8 hourly. 2. Where a syringe pump or other accurate infusion device is available, quinine dihydrochloride 7 mg salt/kg base over 30 minutes followed immediately by quinine dihydrochloride 10 mg salt/kg base over 4 hours then, starting 4 hours later, quinine dihydrochloride 10 mg salt/kg base as 4 hour infusions, 8 hourly. P.vivax. Most strains of P. vivax are still sensitive to chloroquine although some chloroquine resistant strains have been reported in Papua New Guinea, Indonesia, Thailand and India. This drug will clear the erythrocyte stages of the parasite but it has no effect on the exo-erythrocytic liver stage and a course of primaquine (an 8-amino-quinoline) is required for radical cure. The Chesson strain of P. vivax found in New Guinea shows some resistance to primaquine and an increased dose of primaquine is required. If primaquine is not given, the patient may suffer a relapse which will occur weeks or months after the original attack. Adult treatment. Based on Chloroquine tablets containing 150mg base. Day 1 Day 2 4 tablets (600mg base) or 10 mg/kg first dose. 2 tablets (300mg base) or 5 mg/kg 6-8 hours later. 2 tablets (300mg base) or 5 mg/kg.
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Day 3 Next 14 days
2 tablets (300mg base) or 5 mg/kg primaquine 2 tablets (each tablet contains 7.5mg base daily with food ).
The primaquine is preferably started after the chloroquine. When the infection is acquired in New Guinea, 3 tablets of primaquine (22.5mg base) should be given daily for 14 days. In the case of a relapse repeat both chloroquine and primaquine treatment. Up to three relapses may occur before the parasite is finally eliminated. Unfortunately there is no other effective treatment. Patients should have their G6PD status checked before primaquine is prescribed. Patients with G6PD deficiency may undergo haemolysis if given a daily dose of primaquine and it is recommended that these patients be given 30-45mg once a week for 8 weeks. P. malariae, P. ovale. Treatment for the eradication of these two strains of malaria is the same as that for P. vivax except it is not necessary to give primaquine to those patients with P. malariae
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2.
ANTIMALARIAL DRUGS
Antimalarials are antiprotozoal drugs that are primarily used to treat malaria. Certain antimalarials are useful in treating other conditions as well, including quinine for leg cramps and hydroxychloroquine for severe cases of rheumatoid arthritis. Classification
A. On the basis of use.
Antimalarial drugs are designed to prevent or treat malaria. There are many of these drugs currently on the market. Here is a partial list. 1. Antimalarial drugs currently used for treatment amodiaquine artemisinin/artemether/artesunate (Artemisinine based on the Artemisia plant) atovaquone chloroquine (Nivaquine, Aralen, Damaral etc.) fansidar (pyrimethamine, sulfadoxine) lumefatrine mefloquine (Lariam ) quinine/quinidine (quinine is derived from the bark of the tropical cinchona tree) 2. Antimalarial drugs currently used for prophylaxis chloroquine doxycycline hydroxychloroquine (Plaquenil) mefloquine proguanil
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pyrimethamine (daraprim) -sulfadoxine (Fansidar) Halofantrine (Halfan) 3. New medicines Malarone DNA/MVA malaria vaccin (under development) 4. 4. Repellents DEET is available as lotion or DEET-spray 5. Mosquito nets
B.On the basis of chemical structure

Antimalarial drugs (P01B) Aminoquinolines Biguanides Methanolquinolines Diaminopyridines derivatives Others Amodiaquine, Chloroquine, Hydroxychloroquine, Pamaquine, Primaquine Proguanil, Cycloguanil embolate Mefloquine, Quinine Pyrimethamine Artenimol Halofantrine, Lumefantrine
Artemisinin{Herbal} Artemisinin, Artemether, Artesunate, Artemotil,
Chloroquine: Many drugs were developed to protect the troops from malaria, particularly during World War II. Chloroquine, Primaquine, Proguanil, amodiaquine and Sulfadoxine/Pyrimethamine were all developed during this time. During World War I, Java and its valuable quinine stores fell into Japanese forces. As a result, the German troops in East Africa suffered heavy casualties
from malaria. In a bid to have their own antimalarial drugs, the German government initiated research into quinine substitutes and entrusted it to Bayer Dye Works. Most of the work was done at Bayer Farbenindustrie A.G. laboratories in Eberfeld, Germany. Several thousands of compounds were tested and some were found to be useful. Plasmochin naphthoate (Pamaquine) in 1926 and quinacrine, mepacrine (Atabrine) in 1932 were the first to be found. Plasmochin, an 8 amino quinoline, was quickly abandoned due to toxicity, although its close structural analog primaquine is now used to treat latent liver parasites of P. vivax and P. ovale. Atabrine, although found superior and persisting in the blood for at least a week, had to be abandoned due to side effects like yellowing of the skin and psychotic reactions. The breakthrough came in 1934 with the synthesis of Resochin (chloroquine) by Hans Andersag, followed by Sontochin or Sontoquine (3 methyl chloroquine). These compounds belonged to a new class of antimalarials known as 4 amino quinolines. But Farben scientists overestimated the compounds toxicity and failed to explore them further. Moreover, they passed the formula for Resochin to Winthrop Stearns, Farbens U.S. sister company, in the late 1930s. Resochin was then forgotten until the outbreak of World War II. Other antimalaria drugs: 1.The formula of Atabrine (mepacrine, a 9-aminoacridine), was also soon solved by Allied chemists and it was produced in large scale in the U.S. It immediately gained widespread acceptance as an excellent therapeutic agent. 2.The success of chloroquine led to the exploration of many (nearly 15000) compounds in the United States and another 4-aminoquinoline Camoquin (amodiaquin) was discovered. Studies on 8-aminoquinolines led to the discovery of Primaquine by Elderfield in 1950. Meanwhile, British investigators at ICI also carried out extensive studies on malaria drugs and Curd, Davey and Rose synthesised antifolate drugs proguanil or Paludrine (chlorguanide hydrochloride) in 1944 and Daraprim or Malocide
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(pyrimethamine) was developed in 1952. However, resistance to proguanil was observed within a year of introduction in Malaya in 1947. 3.Mefloquine was jointly developed by the U.S. Army Medical Research and Development Command, the World Health Organization (WHO/TDR), and Hoffman-La Roche, Inc. After World War II, about 120 compounds were produced at the Walter Reed Army Institute of Research and WR142490 (mefloquine), a 4quinoline methanol was developed. Its efficacy in preventing and treating resistant P. falciparum was proved in 1974-75 and was useful for the US Army in Southeast Asia and South America. By the time the drug became widely available in 1985, evidence of resistance to mefloquine also began to appear in Asia.4.Malarone: In 1998 a new drug combination was released in Australia called Malarone. This is a combination of proguanil and atovaquone. Atovaquone became available 1992 and was used with success for the treatment of Pneumocystis carrinii. The synergistic combination with proguanil is found to be an effective antimalarial treatment.
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3. HERBAL ANTIMALARIAL DRUGS

Herbal medicines have been an important source of natural product drugs and the root of modern pharmocology and drug develepment. Take digoxin as an example. Digoxin is a modern drug used for congestive heart failure. It is a natural molecule occurring in the herb foxglove. Foxglove was originally used in folk herbal remedies consisting of a dozen of herbs. Over 200 years ago it was found to be the active ingredient of the herbal remedies. By 1906, different preparations of foxglove were included in US pharmacopeia. No standard was there. Then standard assays were developed to monitor the bioactivity of foxglove preparations. Eventually, digoxin was identified and became a standard chemical drug.
Generally used herbal antimalarial plant are followings:3.1 3.2

3.3 3.4
CINCHONA [QUININE]. ARTEMISIA VULGARIS.

CRYPTOLEPIS. YINGZHAOSU.
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3.1 Cinchona Officinalis (Quinine)
A. Source and properties, and history of hurb
Family: Rubiaceae Genus: Cinchona Species: officinalis, ledgeriana, succirubra, calisaya Synonyms: Quinaquina officinalis, Quinaquina lancifolia, Quinaquina coccinea Common names: Quinine bark, quina, quinine, kinakina, China bark, cinchona bark, yellow cinchona, red cinchona, Peruvian bark, Jesuit's bark, quina-quina, calisaya bark, fever tree Parts Used: Bark, wood
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History of Cinchona
The cardiac effects of cinchona bark were noted in academic medicine at the end of the 17th century. 1 Quinine was used sporadically through the first half of the 18th century for cardiac problems and arrhythmia and it became a standard of cardiac therapy in the second half of the 19th century.
2
Another alkaloid chemical called quinidine was discovered to be responsible for this beneficial cardiac effect. Quinidine, a compound produced from quinine, is still used in cardiology today, sold as a prescription drug for arrhythmia. The sales demand for this drug still generates the need for harvesting natural quinine bark today because scientists have been unsuccessful in synthesizing this chemical without utilizing the natural quinine found in cinchona bark.
In Brazilian herbal medicine quinine bark is considered tonic, stomachic, and febrifuge. It is used for anemia, indigestion, gastrointestinal disorders, general fatigue, fevers, malaria and as an appetite stimulant. Other folk remedies in South America cite quinine bark as a natural remedy for cancer (breast, glands, liver, mesentery, spleen), amoebiasis, cardidtis, colds, diarrhea, dysentery, dyspepsia, fevers, flu, hangover, lumbago, malaria, neuralgia, pneumonia, sciatica, typhoid, and varicose veins.
In European
herbal
medicine
the bark is considered
antiprotozoal,
antispasmodic, antimalarial, a bitter tonic, and febrifuge. There it is used as an appetite stimulant, for hair loss, alcoholism, liver, spleen, and gallbladder disorders; and to treat arrhythmia, anemia, leg cramps, and fevers of all kinds.
D. Chemical constituents:
Aricine,
caffeic
acid,
cinchofulvic
acid,
cincholic
acid,
cinchonain,
cinchonidine, cinchonine, cinchophyllamine, cinchotannic acid, cinchotine, conquinamine, cuscamidine, cuscamine, cusconidine, cusconine, epicatechin, javanine, paricine, proanthocyanidins, quinacimine, quinamine, quinic acid, quinicine, quinine, quininidine, quinovic acid, quinovin, sucirubine.
.
Table: Alkaloid Content Comparison by Cinchona species Species C. calisaya C. pubescens C. officinalis C. ledgeriana C. succirubra Total Alkaloids (%) 3-7 4.5 - 8.5 5-8 5 -14 6 - 16 Quinine Content (%) 0-4 1-3 2 - 7.5 3 - 13 4 - 14
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B.
Property and Action
QUININE HERBAL PROPERTIES AND ACTIONS Main Actions Other Actions Standard Dosage treats malaria relieves pain Bark kills parasites kills bacteria Decoction: 1/2 to 1 cup reduces fever kills fungi 3 times daily regulated heartbeat dries secretions Capsules: 2 g twice daily Tincture: 1-2 ml twice stimulates digestion calms nerves daily kills germs reduces spasms kills insects
The genus Cinchona contains about forty species of trees. They grow 15-20 meters in height and produce white, pink, or yellow flowers. All cinchonas are indigenous to the eastern slopes of the Amazonian area of the Andes, where they grow from 1,500-3,000 meters in elevation on either side of the equator (from Colombia to Bolivia). They can also be found in the northern part of the Andes (on the eastern slopes of the central and western ranges). They are now widely cultivated in many tropical countries for their commercial value, although they are not indigenous to those areas.
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C. Phytochemical Study : Chemistry Quinine sulfate is an antimalarial drug chemically described as cinchonan-9-ol, 6'- methoxy-, (8a, 9R)-, sulfate (2:1) (salt), dihydrate with a molecular formula of (C20H24N2O2)2H2SO42H2O and a molecular weight of 782.96. The structural formula of quinine sulfate is
Quinine sulfate occurs as a white, crystalline powder that darkens on exposure
to light. It is odorless and has a persistent very bitter taste. It is only slightly soluble in water, alcohol, chloroform Mechanism of action: Quinine acts as a blood schizonticide although it also has gametocytocidal activity against P. vivax and P. malariae. Because it is a weak base, it is concentrated in the food vacuoles of P. falciparum. It is said to act by inhibiting heme polymerase, thereby allowing accumulation of its cytotoxic substrate, heme.
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Food Vacuole
Heme polymerase
Toxic Heme ? Inhibited by Quinine Non Toxic Hemazoin (Malarial Pigment)
Hemoglobin Degradation
As a schizonticidal drug, it is less effective and more toxic than chloroquine. However, it has a special place in the management of severe falciparum malaria in areas with known resistance to chloroquine.
D.
Pharmacological Study
Pharmacokinetics: Quinine is readily absorbed when given orally or intramuscularly. Peak plasma concentrations are achieved within 1 - 3 hours after oral dose and plasma halflife is about 11 hours. In acute malaria, the volume of distribution of quinine contracts and clearance is reduced, and the elimination half-life increases in proportion to the severity of the illness. Therefore, maintenance dose of the drug may have to be reduced if the treatment is continued for more than 48 hours. The drug is extensively metabolised in the liver and only 10% is excreted unchanged in the urine. There is no cumulative toxicity on continued administration.
Side effect.
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The most common adverse reaction to Cinchona alkaloids (quinine and quinidine) in Australia[6] from November 1972 to March 1988 were thrombocytopenia, anorexia, nausea, vomiting, diarrhoea, skin rash, fever, rigors, disturbed liver function, arrhythmia, hypotension, arthralgia, and deaths. The toxic effects of quinine are tinnitus, vertigo, visual impairment, rashes, nausea, vomiting, diarrhoea, abdominal pain, fever, hypotension, convulsions, respiratory depression, cardiac irregularities, weakness, drop in blood pressure, and kidney failure with anuria. Contra indications: Hypersensitivity in the form of rashes, angioedema, visual and auditory symptoms are indications for stopping the treatment. It is contraindicated in patients with tinnitus and optic neuritis. It should be used with caution in patients with atrial fibrillation. Hemolysis is indication for immediately stopping the drug. Availability: It is available as tablets and capsules containing 300 or 600 mg of the base. It is also available as injections, containing 300mg /ml. E. Uses and applications of Quinine Analgesic, anesthetic, antiarrhythmic, antibacterial, antimalarial, antimicrobial, antiparasitic, antipyretic, antiseptic, antispasmodic, antiviral, astringent, bactericide, cytotoxic, febrifuge, fungicide, insecticide, nervine, stomachic, tonic.
Main Uses: Maharishi Arvind College of Pharmacy Page 31
1. for malaria 2. as a bitter digestive aid to stimulate digestive juices 3. for nocturnal leg cramps 4. for intestinal parasites and protozoa 5. for arrhythmia and other heart conditions
WORLDWIDE ETHNOMEDICAL USES
Brazil
for anemia, anorexia, debility, digestive sluggishness, dyspepsia, fatigue, fevers, gastrointestinal disorders, indigestion, malaria for alcoholism, anemia, antimalarial, appetite stimulant, cramps, debility, diarrhea, enlarged spleen, fevers, flatulence, gallbladder disorders, hair loss, irregular heartbeat, leg cramps, liver disorders, malaria, muscle pain, protozoal infections, and as a antiseptic malaria, and as an antiseptic, astringent, and tonic for bacterial infections, colds, digestive disorders, dyspepsia, fevers, flu, headaches, heart palpitations, hemorrhoids, leg cramps, malaria, pain, varicose veins, viral infections, and as an appetite stimulant, astringent and cardiotonic for cancer and malaria for amebic infections, bacterial infections, carditis, colds, contraceptive, cough, dandruff, diarrhea, digestive sluggishness, dysentery, dyspepsia, fever, flu, glandular disorders, hangovers, hemorrhoids, lumbago, malaria, neuralgia, pain, pinworms, pneumonia, sciatica, septic infections, sore throat, stomatitis, tumor (glands), typhoid, varicose veins, and as a insecticide, insect repellent, stimulant, and uterine tonic
Europe
Mexico US
Venezuela Elsewhere
F. Biological Activities And Clinical Research
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Interestingly enough, natural quinine extracted from quinine bark and the use of natural bark tea and/or bark extracts are making a comeback in the management and treatment of malaria. Malaria strains have evolved which have developed a resistance to the synthesized quinine drugs. It was shown in early studies that an effective dose of natural quinine bark extract elicited the same antimalarial activity as an effective dose of the synthesized quinine drug. Scientists are now finding that these new strains of drug-resistant malaria can be treated effectively with natural quinine and/or quinine bark extracts. As evolving pathogens develop widespread resistance to our standard antibiotics, antivirals, and antimalarial drugs, it is of little wonder that the use of the natural medicine in quinine bark is being revisited, even by such giants as the World Health Organization. A recent use for quinine drugs has been for the treatment of muscle spasms and leg cramps. A 1998 study documented the beneficial effects of quinine for leg cramps, with tinnitus being the only documented side effect. In 2002, a doubleblind placebo study was undertaken in which 98 people with nocturnal leg cramps were given 400 mg of quinine daily for 2 weeks. The results stated that quinine administered at this dose effectively reduced the frequency, intensity, and pain of leg cramps without relevant side-effects. This use has fueled the natural product market and more people are looking for natural quinine bark as an alternative to the synthesized prescription drugs for this purpose.
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G. Formulation
A.Quinine
Tablets of quinine hydrochloride, quinine dihydrochloride or quinine sulfate containing 82%, 82% and 82.6% quinine base respectively. Quinine bisulfate formulations, containing 59.2% base are less widely available.
Injectable solutions of quinine hydrochloride, quinine dihydrochloride or quinine sulfate containing 82%, 82% and 82.6% quinine base respectively.
Efficacy Quinine is normally effective against falciparum infections that are resistant to chloroquine and sulfa drug-pyrimethamine combinations. Decreasing sensitivity to quinine has been detected in areas of South-East Asia where it has been extensively used for malaria therapy. This has occurred particularly when therapy was given in an unsupervised and ambulatory setting with regimens longer than 3 days. In these settings, patient adherence to therapy is low, leading to incomplete treatment; this may have led to the selection of resistant parasites. There is some cross-resistance between quinine and mefloquine, suggesting that the wide use of quinine in Thailand might have influenced the development of resistance to mefloquine in that country (31). Strains of P. falciparum from Africa are generally highly sensitive to quinine. Recommended treatment : Quinine can be given by the oral, intravenous or intramuscular routes. Quinine or quinine-containing compounds such as Quinimax should not be given alone for the treatment of malaria as short courses, e.g. 3 days, owing to the possibility of recrudescence (200). When administered to patients with uncomplicated malaria, quinine should be given orally if possible, by one of the following regimens: Areas where parasites are sensitive to quinine:>
Sulfadoxine 1 500 mg or sulfalene 1500 mg plus pyrimethamine 75 mg given on the first day of quinine treatment. Areas with marked decrease in susceptibility of P. falciparum to quinine Quinine 8 mg of base per kg three times daily for 7 days plus Doxycycline 100 mg of salt daily for 7 days (not in children under 8 years of age and not during pregnancy); a pharmacologically superior regimen would include a loading dose of 200 mg of doxycycline followed by 100 mg daily for 6 days. or Tetracycline 250 mg four times daily for 7 days (not in children under 8 years of age and not in pregnancy). Use in pregnancy Quinine is safe in pregnancy. Studies have shown that therapeutic doses of quinine do not induce labour and that the stimulation of contractions and evidence of fetal distress associated with the use of quinine may be attributable to fever and other effects of malarial disease (110). The risk of quinine-induced hypoglycaemia is, however, greater than in non-pregnant women, particularly in severe disease. Special vigilance is therefore required. B. QUINIMAX Quinimax is an association of four cinchona alkaloids: quinine, quinidine, cinchonine and cinchonidine. It was formerly available as tablets of 100 mg, ampoules of 500 mg, 200 mg and 400 mg and suppositories. Each 100 mg tablet contained 96.10 mg of quinine-resorcine bichlorohydrate (59.3 mg of quinine base), 2.55 mg of quinidine-resorcine bichlorohydrate (1.6 mg of quinidine base), 0.68 mg of cinchonine-resorcine bichlorohydrate (0.4 mg of cinchonine base) and 0.67 mg of cinchonidine-resorcine bichlorohydrate (0.4 mg of
cinchonidine base). These have been re-formulated and the preparations now available include tablets of 100 mg and 125 mg of base of all the four components, and ampoules of 125 mg, 250 mg and 500 mg of base of all the four components. Suppositories are no longer available. Quinimax has been shown to be somewhat more effective than quinine in vitro and in animal models, as well as producing somewhat higher plasma levels in humans. A synergistic effect of the association has been claimed but is doubtful. Limited studies show no significant difference between the therapeutic efficacy of Quinimax and that of quinine (205). Intramuscular injection of Quinimax is better tolerated than intramuscular injection of quinine dihydrochloride. Quinimax is used more widely than generic quinine salts in many countries, especially in francophone Africa.
C. QUINIDINE
Quinidine is a distereoisomer of quinine, with similar antimalarial properties. It is available as tablets of 200 mg of quinidine base as the sulfate and as a slowrelease formulation (Quinidine SR ). It is slightly more effective than quinine but has a greater cardiosuppressant effect (110). In other respects the toxicity and drug interactions of quinidine are similar to those of quinine
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3.2
Artemisias
The genus Artemisia spp, includes the herb Tarragon. The plants are herbaceous or suffruticose (woody in the lower part of the stem, but with yearly branches herbaceous) perennials and are rarely shrubs or annual herbs. They posses alternate pinnasect or palmatisect leaves. Racemes or racemose panicles bear numerous small flowerheads. The plants range in height depending on the species, from 30 - 120 cm high. Chemical Constitunets of Artemisias Bitter principals: wormwood coumarins: cronewort, tarragon essential oils (complex, variety specific, with hundreds of components per plant): cronewort (high in camphor, thujone), tarragon, wormwood (high in camphor, thujone) flavonoids: cronewort, tarragon glycosides: cronewort, tarragon hormones: cronewort (sitosterol, stigmasterol) sesquiterpene lactones: cronewort . Species of Artemisias Some of the many Artemisia species that herbalists and gardeners use: A. abrotanum (southernwood) A. absinthium (wormwood) A. afra (African wormwood) A. annua (sweet Annie, qing hao)
A. camphorata (camphor-scented sothernwood) A. drancuncula (tarragon, estragon, little dragon) A. frigida (fringed sagebrush) A. lactiflora (ghost plant) A. ludoviciana (silver queen) A. pontica (Roman wormwood) A. schmidtiana (silver mound) A. stellerana (old woman, dusty miller) A. tridentata (sagebrush; three-toothed sagebrush) A. vulgaris (cronewort, mugwort)
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3.2 Artemisia vulgaris:

Scientific classification
Kingdom: Plantae Division: Magnoliophyta Class: Magnoliopsida Order: Asterales Family: Asteraceae Genus: Artemisia Species: A. vulgaris
Binomial name Artemisia vulgaris L.
Common Name: Botanical Name:
Artemisia Oil ( Armoise Oil ) Artemisia vulgaris L.
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A. Source and Property Geographic origin of the plant: Method of growing: Wild Western Nepal
Introduction / Varity of plant / Method of extraction / Distilled organ: 1. Organoleptic Properties Appearance Color Aroma
The essential oil is obtained by steam distillation of the aerial part of Artemisia vulgaris L.
Fluid liquid. Pale yellow or slightly greenish. Powerful, fresh-camphoraceous, somewhat green & bitter-sweet.
2. Physico-chemical Properties Specific gravity Optical rotation Refractive index Acid number Ester number Ester number after acetylation Solubility 3. Uses (a) In perfumes and as a flavoring agent Insoluble in alcohol 0.8786 to 0.9265 at 25 C [-] 13.25 to [-] 29.35 at 25 C 1.350 to 1.49 at 25 C 2.49 to 6.5 25.05 to 55 65 to 90
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Synonyms : ARMOISE OIL (ARTEMISIA VULGARIS); MUGWORT OIL (ARTEMISIA VULGARIS); YOMUGI OIL (ARTEMISIA VULGARIS); ARTEMISIA VULGARIS OIL; COMMON MUGWORT OIL; A. vulgaris seems to have originated in Eastern Europe and Western Asia. Most of these species are found growing wild and abundantly all over the temperate and cold temperate zones of the world. It is a very common weed in Central Europe, Southeastern Europe, India, China and Japan. This perennial aromatic herb, 60 - 120cm high, has a branching root stock, dark green deeply indented leaves with reddish, grooved and angled, glabrescent or sparsely pubescent stems. The plant's florets are wind pollinated. 28,30,42 B. Morphological Study and Cultivation
Morphology It is a tall herbaceous perennial plant growing 1-2 m (rarely 2.5 m) tall, with a woody root. The leaves are 5-20 cm long, dark green, pinnate, with dense white tomentose hairs on the underside. The erect stem often has a red-purplish tinge. The rather small flowers (5 mm long) are radially symmetrical with many yellow or dark red petals. The narrow and numerous capitula (flower heads) spread out in racemose panicles. It flowers from July to September. Characterstics: Odor Description : Powerful Fresh Cedarleaf Minty Camphor Sage Herbal Bitter-sweet Appearence : Pale Yellow Amber To Almost Colorless Liquid Blends Well With : Patchouli; Rosemary; Clary Sage; 3,3-dimethyl-1,5dioxaspiro[5.5]undecane; 3,3-dimethyl-2-(3-butenyl)norbornanol; Insoluble in : Water;
Some Perfumery Uses : Cedarleaf; Balsam; Lavandin; Fern; Aftershave Fragrances; Traditional use: emollient, soothing agent, muscle relaxant,antimalarial. Geographical source: Perennial herb native to Africa, temperate Asia, and Europe, widely naturalized in most parts of the world. Found growing on hedgebanks and waysides, uncultivated and waste land. . Cultivation aspects:Cultivation is fairly easy Mugwort prefers slightly alkaline, well-drained loamy soil, in a a sunny position. A tall-growing shrubby plant, with angular stems, which are and often purplish, growing 3 feet or more in height. The leaves are smooth and dark green above and covered with a cottony down beneath. They are alternate, pinnately lobed, and segmented. The small greenish yellow flowers are panicled spikes with a cottony appearance. Blooming is from July to October. Mugwort is closely related to Common Wormwood (Absinthe). Gather leaves and stems when in bloom, dry for later herb use. complaints, and diseases of the brain. As a gargle for sore throat, a wash for sores and a poultice for infections, tumors and to stop bleeding. These actions and uses are now backed by scientific studies The leaves have an antibacterial action, inhibiting the growth of Staphococcus aureus, Bacillus typhi, B. dysenteriae, streptococci, E. coli, B. subtilis, and pseudomonas. A weak tea made from the infused plant is a good all-purpose insecticide. The fresh or the dried plant repels insects. 54,56
Chemical constituents:main constituents volatile oils containing 1,8-cineole, artemisin, azulenes sesquiterpene lactones, flavonoids, coumarin derivatives, tannins, thujone and
triterpenes. The plant contains ethereal oils (such as cineole, or wormwood oil, and thujone), flavonoids, triterpenes, and coumarin derivatives. 38,42,45 Use Chewing some leaves will kill the fatigue and stimulate the nervous system. It was also used as an anthelminthic, so it is sometimes confused with wormwood (Artemisia absinthium).
C. Production Profile Current Production and Yields:EU-15 countries currently showing an interest in Artemisia are Austria, Finland, France, Italy Sweden and the UK. Of these France and Sweden are currently running pilot studies on Artemisia. Oil yields - world market tonnage:Plant Artemisia (Wormwood) Tarragon World Tonnage 7 10 market Available oil yield kg/ha 25 12
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Constraints upon Production Southernwood is native to western Asia and has naturalised in Spain, Italy and other Mediterranean countries. It will not set seed and rarely flowers in the UK or in northern Europe. In southern Europe it is rare in the wild, but is cultivated for the perfumeindustry. The plant is extremely aggressive and invasive and will inhibit the growth of nearby plants by the means of root secretions. The plant is spread both by seeds and vegetation; dispersal occurs in most cases by seeds coming from plants in hedges. The severity of mugwort as a weed causes problems in some farming systems as it is so difficult to eradicate once established. The occurrence of volunteers is becoming an increasing worry in such farming systems. D. Markets and Market Potential The leaves and roots of the plant provide a digestive and tonic herb which has a wide variety of traditional uses. It can be taken over the long term at a low dose to improve appetite, digestive function and absorption of nutrients. It can also be taken to eliminate worms. A. vulgaris has traditionally been taken to aid childbirth and its after effects. Mugwort contains a volatile oil, a sequiterpene lactone, flavonoids, coumarin derivatives and triterpenes. Sesquiterpene lactones have many properties which include: Bitter tasting, antibiotic, anthelmintic, anti-inflammatory and phytotoxic. The cytotoxic activities have also been extensively researched (D. Frohne and J. Pfnder, 1984).An essential oil known as Artemisia oil or Armoise oil is obtained by steam distillation of the aerial part of Artemisia vulgaris and is used in perfumes .
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3.3
Cryptolepis:
A. History : The root of the plant cryptolepis (Cryptolepis sanguinolenta (Lindl.) Schlecter, Asclepiadaceae or Periplocaceae) is used in traditional African medicine to treat a variety of diseases, including malaria.Scientific investigations have indicated a number of biological/pharmacological effects of compounds isolated from the plant material, including anti-bacterial, anti-hyperglycemic, anti-inflammatory, anti-plasmodial/anti-malarial, and anti-viral effects Some of these effects have been demonstrated in the crude extract as well as its fractions, including a dosedependent inhibitory effect on the classical pathway of complement fixation. During the past few years, cryptolepis has received additional attention by the phytomedicine division of a pharmaceutical company in Ghana, which developed an herbal tea based on this traditional medicinal herb and recently demonstrated the clinical efficacy of a tea-bag formulation in the treatment of malaria. A preliminary clinical study in 1989 conducted with an aqueous extract of cryptolepis, prepared by boiling powdered cryptolepis roots in water, also suggested the efficacy of the plant material against malaria. B. Nomenclature and Taxonomy:Cryptolepis is derived from the root of Cryptolepis sanguinolenta; syn. C. triangularis N.E. Br., and Pergularia sanguinolenta Lindl. Its common name among the various tribes of Ghana include nibima (among the Twi speaking people), kadze (among the Ewe), and g ngamau (among the Hausa). It is also known as Ghana quinine or yellow-dye root. Although the aqueous extract has a bitter taste, this name is probably based on the common use of the plant as a substitute for the anti-malarial alkaloid quinine, and should not be confused with it. Some decades ago, quinine was the drug of choice for the treatment of
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malaria, and is still in use in areas where there is resistance to chloroquine malaria drugs. In keeping with common practice with popular medicinal botanicals that do not have accepted common names in English, the common name cryptolepis, based on its Latin generic name, will be used throughout this paper. Common Name : Yellow dye Root (Ghane quinine) Botanical Name : Cryptolepis Sanguinolenata Plant Part Used : Root C. Morphological Study : Morphology:Cryptolepis is a thin-stemmed twining and scrambling shrub. The leaves are petiolate, glabrous, elliptic or oblong-elliptic, up to 7 cm long and 3 cm wide. The blades have an acute apex and a symmetrical base. The inflorescence cymes, lateral on branch shoots, are few flowered, with a yellow corolla tube up to 5 mm long. The fruits are paired in linear follicles and are horn-like. The seeds are oblong in shape, small (averaging, 7.4 mm in length and 1.8 mm in the middle), and pinkish, embedded in long silky hairs. Photos on these pages show the root and other plant parts of cryptolepis. Dried cryptolepis has a sweet fragrance. The root, the plant part used for the treatment of malaria, varies from 0.46.6. cm long and 0.311.4 cm wide and has a bitter taste. The root surface is light to medium brown in color. The texture is hard and brittle, longitudinally rigid with occasional cracks and striations. Rootlets are not present. Cut roots show a bright yellow surface, as seen in the photo on this page.
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D. Pharmacological Study Biology and Pharmacology Numerous biological/pharmacological activities have been demonstrated in extracts from the roots of C. sanguinolenta, as well as for the alkaloids isolated from these extracts. They include anti-plasmodial (both chloroquine-sensitive and chloroquine-resistant strains of the malaria parasite), anti-bacterial, antiviral, anti-inflammatory, anti-diabetic and hypotensive effects.
Clinical Trials In a preliminary study aimed at comparing efficacy of an aqueous extract of cryptolepis with that of chloroquine, G.L. Boye, of the University of Ghana, used the WHO extended seven-day in vivo test43 to measure P. falciparum response in a number of patients attending the outpatient clinic of the Centre for Scientific Research into Plant Medicine, a facility in Ghana where orthodox medical practitioners collaborate with traditional medical practitioners. Malarial patients with parasitemia of 1,000 to 100,000 P. falciparum parasites per 8,000 white blood cells, and negative for urinary chloroquine and sulphonamide were recruited into the study. The patients were given either aqueous extract of cryptolepis roots obtained by boiling root powder of the plant in hot water, in a dose as that prescribed by the local herbalist, or chloroquine according to the prescribed dose. After 7 days, the subjects were observed weekly for 3 weeks. The results of this open, randomized, comparative study indicated that the efficacy of cryptolepis in the treatment of malaria was comparable to that of chloroquine1 All 22 patients in the study responded clinically and asexual parasitemia was cleared within 7 days. There was no recurrence of parasitemia during the follow-up period. The mean parasite clearance time in the 12 patients on cryptolepis extract was 3.3 days compared to 2.3 days in the 10 patients on
chloroquine. Of significance in this trial is that the author states that the efficacy of the extract in this study was similar to that of chloroquine. The mean fever clearance time in the cryptolepis extract-treated group was 36 hours, compared to 48 hours for the chloroquine-treated group. Unlike patients in the chloroquine group, patients in the cryptolepis group did not require anti-pyretics (feverreducing drugs). More recently, another open label, uncontrolled clinical trial was conducted by Boye, which demonstrated the clinical efficacy of Phyto-laria, a product of cryptolepis roots formulated as a tea for use in the treatment of acute uncomplicated malaria (Phyto-Riker Pharmaceuticals, Phytomedicine Division, Accra, Ghana).20 Phyto-laria is approved by Ghanas drug regulatory agency, the Food and Drugs Board, and is packaged with instructions on the volume of boiling water to use per tea bag. 59,63 Each patient was given one tea bag, for consumption 3 times a day for 5 days of treatment. The dose administered was based on that calculated from the decoctions prescribed by traditional healers. The results of this study indicated a mean parasite clearance time of 82.3 hours (24144 hours). The mean fever clearance time was 25.4 hours (1296 hours). These figures are comparable to those obtained with chloroquine in Ghana and elsewhere in West Africa. Safety Safety is one of the most important considerations for the assessment of any agent administered for treatment of a disease. Assessment of toxicity is therefore critical in research and development of phytomedicines. Cryptolepine is believed to interact with DNA13 and this could result in toxicity. Evidence of DNA being the direct target of cryptolepine has been provided by Bonjean and his co-workers. Their work has shown that cryptolepine binds tightly to DNA. As is well known, DNA in the nucleus of living organisms
exists as a double helix, two intertwined coils or helices. Some chemical compounds can insert themselves, or intercalate, between the two helices, thereby interfering with the functions of the DNA that depend on this unique double helical structure. One such function is cell division, preceded by replication of the nuclear material and separation of the two sets of nuclear material resulting from the replication. DNA replication occurs through nucleic acid synthesis, using one uncoiled strand of DNA as a template. The reactions responsible for replicating the nuclear material, must therefore involve uncoiling and recoiling of DNA, and are catalyzed by a set of enzymes including those responsible for the unwinding and relaxation of the DNA to remove the tightly coiled helices. One of these enzymes is known as topoisomerase, responsible for the interconversion between the relaxed and coiled forms of DNA. For this interconversion to take place, the DNA must be cut and then rejoined. Topoisomerase I cuts only one strand of the doublestranded DNA and topoisomerase II cuts both strands. When topoisomerases are inhibited, DNA replication ceases to occur. Cryptolepine has been shown to be a potent inhibitor of topoisomerase II. Its effect is to stop the cell from dividing and is probably the basis for its effect on microorganisms, including the malaria parasite. It is also the basis for it being regarded as a promising anti-tumor agent. There have been reports of toxicity of the aqueous extracts of cryptolepis and compounds isolated from the plant material when cell lines usually used to assess anti-tumor activity or in vitro methods of risk assessment were used.43 Cytotoxicity in anti-viral test systems has also been reported. In one study, cytotoxicity, measured as anti-tumor activity (against B16 melanoma cells) did not correlate with toxicity in the in vivo mouse model for malaria used in the same study. Phyto-laria, the cryptolepis product formulated as a tea, was evaluated in vivo by administering it orally to mice, rats, and rabbits and using
the conventional acute toxicity and clinical chemistry tests. This tea bag formulation, which represents an aqueous preparation, was shown to be safe. The LD50 (lethal dose in which 50 percent of test animals died) obtained was above 2,000mg/kg, more than two orders of magnitude higher than the effective dose. It is noteworthy that Luo et al. report the use of cryptolepis extract as a tonic, often taken daily for years without evidence of side effects or toxicity.
IN VITRO:-
In vitro anti-plasmodial activities, which are indicative of anti-malarial activity, have been carried out using inhibition of the incorporation of the malaria parasite into red blood cells. In one study in which both the chloroquinesensitive D6 strain and the chloroquine-resistant K-1 and W-2 strains of the malaria parasite were used, the anti-plasmodial activity was measured using the incorporation of H-hypoxanthine into red blood cells infected with P. falciparum, the standard anti-plasmodial assay. Aqueous, alcoholic, and total alkaloidal extracts, and compounds isolated from the plant material were found to be effective against all three strains of parasite to varying degrees. Of the extracts, the total alkaloid was the most active with mean IC 50 values of 47, 42, and 54 micromolar for the three strains, respectively, compared to values of 2.3, 72, and 68 micromolar, for chloroquine. The aqueous extract was the least active. Of the isolated compounds, cryptolepine was the most effective, with mean IC50 values of 27, 33 and 41 micromolar for the D6 chloroquine-sensitive and K-1 and W-2 chloroquine-resistant strains, respectively. Hydroxycryptolepine was the next best compound with IC50 values of 31, 45, and 59 micromolar, respectively, followed by neocryptolepine. Quindoline, or norcryptolepine, without the methyl group, was the least active anti-plasmodial of the isolated compounds. This is an indication that the methyl group contributes to anti-malarial activity, at least in part. The result of this study with respect to the K-1 strain is in agreement with the work of Noamesi and coworkers, as well
as Kirby and coworkers,who reported the anti-plasmodial activity of cryptolepine against the multi-drug resistant K-1 strain of P. falciparum. In another study, Wright et al., using multi-drug resistant K1 strain of P. falciparum and a method of assessing inhibition of parasite growth based on measurement of lactate dehydrogenase activity, showed that among a number of anhydronium bases, only cryptolepine, the major alkaloid in cryptolepis, had anti-plasmodial activity similar to that of chloroquine. The mean IC50 value, determined from linear regression analysis of doseresponse curves, was 0.114 micromolar for cryptolepine, compared to a mean value of 0.2 micromolar for chloroquine diphosphate. Inhibition of beta-hematin formation in a cell-free system is another in vitro test for anti-plasmodial activity. Reduction or elimination of the characteristic peaks of beta-hematin at 1663 and 1210 cm-1 in an infrared spectrum indicates efficacy. Cryptolepine has been shown to be effective in this model, the peaks disappearing when the reaction mixture was pre-incubated with the alkaloid suggesting that cryptolepines anti-plasmodial effect depended, at least in part, on a quinine-like mode of action. A relatively simple method of measuring betahematin, using absorbance in a simple spectrophotometer, is currently being used in the Department of Biochemistry of the University of Ghana, and could be adopted for assessing the efficacy of extracts of cryptolepis and compounds isolated from them in a research and development effort to develop this particular phytomedicine.Studies have been carried out to evaluate the antimicrobial properties of cryptolepis extracts and compounds isolated from them. In a program of biological evaluation to justify traditional uses of herbal remedies, cryptolepis was studied because of its successful use in treating diarrhea caused by intestinal amoebiasis, and found to be effective in vitro against Entamoeba histolytica. Diarrheal diseases are very common in West
Africa and therefore, any anti-diarrheal remedy is of great interest. Over 100 strains of Campylobacter species, which are causative agents for gastroenteritis, have been used to study the effect of cryptolepis and compounds isolated from it on diarrheal bacteria The finding that cryptolepine was more effective than co-trimoxazole and sulfamethoxazole, just as effective as ampicillin and less effective than erythromycin and streptomycin, the antibiotics usually used against diarrheal diseases, indicates that cryptolepis may be a potential remedy for diarrhea. The ethanolic extract, not the aqueous one, had activity but not as good as that of the isolated alkaloid. The effect of the plant material was not so dramatic when Vibrio cholerae, the causative agent for enteric infections, was used as the test organism. Obviously, cryptolepis could be used as therapy for gastroenteritis although it is not known as such in the region where it is used to manage a number of infections. Some pharmacological effects of cryptolepis, quite unrelated to the use of the plant in folkloric medicine, are its anti-inflammatory and anti-hyperglycemic properties. It has been more than two decades since the anti-inflammatory properties were established, as indicated by inhibition of carageenan-induced edema and that of platelet aggregation (Carageenan-induced edema is a typical pharmacological test for antiinflammatory drugs; carageenan, a gelatinous preparation made from seaweed, is injected into parts, often the paw, of test animals to produce a localized inflammation usually, the type characterized by accumulated fluids, i.e., edema. The tested agent is then measured for its ability to inhibit the resulting inflammation.) The anti-hyperglycemic property has been shown as enhanced insulin-mediated glucose disposal in a mouse model of diabetes and in an in vitro system using the 3T3-L1 glucose transport assay, indicating an effect on Type 2 diabetes Hypotensive properties have also been reported, including effects on cholinergic nerve transmission, alphaadrenoceptors, and muscarinic receptors. Malaria and other infectious diseases
are more prevalent in the West African sub-region and therefore the antiplasmodial and anti-bacterial properties of cryptolepis are more exciting. However, one should not underestimate the potential of cryptolepis in treating some of these other diseases.
E. Traditional Ethnobotanical Use The plant has been shown to be important in West African traditional medicine. Aqueous extract of cryptolepis is used by the Fulani traditional healers in Guinea-Bissau to treat jaundice and hepatitis.1 In Zaire and the Casamance district of Senegal, infusions of the roots are used in the treatment of stomach and intestinal disorders.2,27 In Ghana, dried root decoctions of the herb, prepared by boiling the powdered roots in water, are used in traditional medicine to treat various forms of fevers, including malaria, urinary and upper respiratory tract infections, rheumatism, and venereal diseases. Cryptolepis is used in Congolese traditional medicine for the treatment of amoebiasis. An aqueous decoction of the root bark of cryptolepis is used in Congo for this treatment. The major alkaloid, cryptolepine, was first isolated from C. sanguinolenta in Nigeria and later in Ghana by Dwuma-Badu and his co-workers. According to Ablordeppey et al.,and Tackie et al. this indoloquinoline alkaloid was isolated from the roots of C. triangularis, a plant native to the Belgian Congo and synonymous with C. sanguinolenta. Curiously, cryptolepine was first artificially synthesized in 1906 by Fichter et al., but naturally-occurring cryptolepine from C. triangularis isolated by Clinquart was reported 23 years later in 1929. In addition to cryptolepine, several related minor alkaloids and their salts have been isolated from C. sanguinolenta. These include the hydrochloride (although the hydrochloride salt of a chemical compound is usually not considered a distinct compound) and the 11-hydroxy derivatives of cryptolepine,
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cryptoheptine, iso- and neo-cryptolepine, quindoline, and the dimers biscryptolepine, cryptoquindoline, and cryptospirolepine. The dimers have been found to be less active than the monomers, and they include cryptosanguinolentine, cryptotakienine, and cryptomisrine. Cryptolepine of the ma, the major alkaloid in cryptolepis, is not the only alkaloid with biological/pharmacological activity. Almost all the minor alkaloids also have anti-plasmodial activity. However, the activities of these, based on the inhibition of the chloroquine-sensitive strain laria parasite Plasmodium falciparum, are less than the activity of cryptolepine. Samples of cryptolepis contain cryptolepine at varying concentrations, and since the minor alkaloids also have biological activity, using the content of cryptolepine alone for standardization is questionable. Total alkaloidal content or high performance thin-layer chromatography (HPTLC) with densitometry would be the preferred analytical methods for standardization. 69, 70 Concluding Remarks :In new drug discovery from medicinal botanical preparations, most pharmaceutical companies would use an approach that relies on random, mostly in vitro, mechanism-based, high throughput screening, especially in the initial phases. This approach leads to the formulation of a drug based on a pure chemical compound isolated from a medicinal plant or a derivative of such a compound. An alternative pathway is based on ethnomedical information obtained mainly from traditional medical practitioners (TMPs) and unequivocal biological/pharmacological research results of a number of scientists and clinicians working on the products used by these TMPs. The latter approach is the one used by the Phytomedicine Division of Phyto-Riker, coupled with toxicity as well as clinical confirmatory tests.
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The scientific research that ought to be an important part of this alternative pathway is not merely to inject science into the art of healing that is practiced by indigenous people using medicinal plants, but also to make this art better serve the indigenous and other people. As demonstrated in some of the research work on the biology/pharmacology of cryptolepis, the alcoholic extract is more effective compared to the aqueous extract that the people normally use. It would be worthwhile to carry out appropriate toxicity tests to ensure that the more effective ethanolic extract is just as safe as the aqueous extract, and that it does not extract from the plant compounds that are toxic to humans in addition to extracting more of the effective and safe compounds. When this has been done and the safety of the ethanolic extract assured, a better product could be formulated. As shown in the accompanying Pharmacology article, cryptolepis, or compounds extracted from it, has antimicrobial properties, affecting a number of different microorganisms. In West Africa, where the plant originates, infections from microorganisms are rampant. Malaria is endemic in the subregion as well. A phytomedicine that is capable of treating malarial and other infections could provide an excellent remedy for a whole host of diseases which afflict the majority of the people. It is for this reason that many local health professionals are keen on promoting scientific research efforts required for the development of such a remedy. Quality, safety, and efficacy are obviously key issues. Evaluation of these parameters should be conducted on the plant extract so that standardized remedies of plant materials can be produced without requiring processes that would make the remedy extremely expensive and unaffordable to a large number of people.
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3.4
Yingzhaosu
{Naturally Occurring Antimalarial Endoperoxide} The evolution of malaria strains resistant to standard quinine based drugs has led to a renewed interest in novel antimalarial drugs with a divergent mode of action. Compounds containing an endoperoxide functionality constitute a promising class of antimalarial drugs. Yingzhaosu A (1) was isolated from a herbal extract used in China as a folk remedy against malaria 1 and was subsequently obtained by total synthesis. While many analogues of Yingzhaosu A are known to exhibit antimalarial activity in the low-nanomolar range, 3a,b little is known about the antimalarial properties of Yingzhaosu A itself. This is partly due to the problematic isolation of the compound from natural sources. Also, the only published total synthesis of Yingzhaosu A (1) is long, (15 steps) and lacking in efficiency.
Recently, methodology for the synthesis of highly active antimalarial compounds of type 2 and 3 was developed in our laboratory. We now report an extension of this methodology for a new and efficient total synthesis of Yingzhaosu A (1). Thiol-oxygen-co-oxidation of (S)-limonene was used to introduce the peroxide moiety with concomitant formation of the bicyclic ring in the initial step.3c Special attention was given to the sensitive peroxide functionality, in selecting the reaction conditions for the subsequent steps. These included a high yielding Pummerer reaction, a Mukaiyama-type aldol condensation and a diastereoselective hydrogenation.
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4. CONCLUSION
The pace at which research on quinine is progressing would certainly lead us to a benefiting drug regime for the treatment of malaria. Even through the use of quinine and its salts is not yet prevalent in India, active research on tissue culture, activity and formulation of potent derivatives like quinine sulfate are being carried out. The introduction of comparatively more potent artemisinin and its derivatives, than chloroquin, mefloquin, quinine etc. is an encouraging aspect in this area of increased drug resistant in Plasmodium vivax in Mathura (U.P.) and studies as such would necessitate the use of these drugs. A thorough study on multi drug therapy with quinine and artemisinin oil and other drugs may decrease the incidence of development of quinine resistant strain. Clinical studies on the more potent artemisinin derivatives with low recrudescence rates toxic effects and their formulation would lead to a better therapeutic use of these compounds. The presently available evidence suggest that the supporitory formulation of quinine sulfate and cryptoles is effective and safe in the treatment of uncomplicated and complicated falciparum malaria in adults and children. It is also effective and safe in treating children's as out patients when given as a single dose in combination with mefloquine where is possibility that this treatment regimen, if used for adults and children early in the course of the diseases at the hamletor home level, could improve the physical and economical health of a community and reduce costs to the health care system by decreasing referrals to secondary and tertiary care hospital. Thus, with the emergence of drug resistance in treatment regimens, a new concepts has evolved to combact malaria today. Artemisinin oil and its derivatives have been shown to be effective in the management of chloroquin resistant faciparum malaria. Its therapeutic utility is also greater as it can used
effectively in combination to improve efficacy e.g. with mefloquine. This current drug therapy along with vectory control strategies and other preventive aspects may provide an effective means of management of cerebral malaria. 73
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5. REFERENCES
1. Acton, N., D.L. Klayman, and I.J. Rollman. 1985. Reductive electrochemical HPLC assay for artemisinin (qinghaosu). Planta Med. 51:445446. Bachi, M. D.; Hoos, R.; Korshin, E. E.; Szpilman, A. M. J. Heterocycl. Chem. 2000, 37, 639. Bachi, M. D.; Korshin, E. E. Synlett 1998, 122. Bailey, L.H. and E.Z. Bailey. 1976. Hortus third. MacMillan Publ. Co., New York. Bamgbose SOA, Noamesi, BK. Studies on cryptolepine II: Inhibition of carrageenan-induced oedema by cryptolepine. Planta Med 1981;41:392-6. Bennett, M.D., J.B. Smith, and J.S. Heslop-Harrison. 1982. Nuclear DNA amounts in angiosperms. Proc. Royal Soc. London B 216:179-199. Bierer DE, Fort DM, Mendez CD, et al. Ethnobotanical-directed discovery of the antihyperglycaemic properties of cryptolepine: its isolation from Cryptolepis sanguinolenta, synthesis, and in vitro and in vivo activities. J Med Chem 1998;41: 894-901. Bisset NG. ed. Herbal Drugs and Phytopharmaceuticals. Translated from Second Edition. Boca Raton: CRC Press, 1994. Bloland PB. Drug resistance in malaria. Geneva: World Health Organization; 2001. Blumenthal M, et. al. ed. The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines. Austin: American Botanical Council, 1998. Boakye-Yiadom K, Herman Ackah SM. Cryptolepine hydrochloride: Effect on Staphylococcus aureus. J Pharmaceut Sci 1979;68:1510-4. Boye GL, Ampofo O. Medicinal Plants in Ghana. In: Wagner and Farnsworth NR, editors. Economic and Medicinal Plants Research. Vol. 4. Plants and Traditional Medicine. London: Academic Press; 1990. p 32-3. British Herbal Pharmacopoeia (1996). Fourth Edition. British Herbal Medicine Association Scientific Committee, West Yorks, England. Cardini, F., and W. X. Huang. JAMA 280(18): 1580-1584, November 1998 15. Cardini, F., et al. BJOG 112(6): 743-747, June 2005
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Chen, P. K., Leather, G and Polatnick, M. (1991) Comparative study on artemisinin, 2,4-D and glyphosphate. Journal of Agricultural Food Chemistry (39) pp. 991-994. Chevallier. A. The Encyclopedia of Medicinal Plants Dorling Kindersley. London 1996 ISBN 9-780751-303148 Duke JA, et. al. Handbook of Medicinal Herbs. Second Edition. Boca Raton, FL: CRC Press. 2002.] Duke, S. O., Vaughn, K. C., Croon, E. M. Jr. and Elsohly, H. N., (1987) Artemisinin, a constituent of annual wormwood (Artemisia annua), is a selective phytotoxin. Weed Science (35) pp. 499-505. Duke. J. A. and Ayensu. E. S. Medicinal Plants of China Reference Publications, Inc. 1985 ISBN 0-917256-20-4 Details of over 1,200 medicinal plants of China and brief details of their uses. Often includes an analysis, or at least a list of constituents. Heavy going if you are not into the subject. Engel LW, Straus SE. Development of therapeutics: opportunities within complementary and alternative medicine. Nat Rev Drug Discov. 2002 Mar;1(3):229-37. F. Chittendon. RHS Dictionary of Plants plus Supplement. 1956 Oxford University Press 1951 Comprehensive listing of species and how to grow them. Somewhat outdated, it has been replaces in 1992 by a new dictionary (see [200]). Famin O, Ginsburg H. Differential effects of 4-aminoquinolinecontaining antimalarial drugs on hemoglobin digestion in plasmodium falciparum-infected erythrocytes. Biochemical Pharmacology 2002 ; 63(3):3938. Fernald. M. L. Gray's Manual of Botany. American Book Co. 1950 A bit dated but good and concise flora of the eastern part of N. America. Ferreira, J. F. S. and Janick, J., (1996) Distribution of Artemisinin in Artemisia annua. In: J. Janick (ed.). Progress in new crops. ASHS Press, Arlington, VA. pp. 579-584. Goldman P. Herbal medicines today and the roots of modern pharmacology. Ann Intern Med. 2001 Oct 16;135(8 Pt 1):594-600. Gordon L. A Country Herbal. Devon, England: Webb & Bower (Publishers) Ltd. 1980.
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Gray, A. 1884. Synoptical flora of North America. Vol. 1, Part II. Smithsonian Institution, Washington, DC. Univ. Press, John Wilson and Son, Cambridge. Gruenwald J, et.al. PDR for Herbal Medicines. First Edition. Montvale, NJ: Medical Economics Company, Inc., 1998. Hall, H.M. and F.E. Clements. 1923. The phylogenetic method in taxonomy. The North American species of Artemisia, Chrysothamnus and Atriplex. Carnegie Inst. Wash., Washington. He, X-C., M-Y. Zeng, G-F. Li, and Z. Liang. 1983. Callus induction and regeneration of plantlets from Artemisia annua and changes of qinghaosu contents. Acta Bot. Sin. 25:87-90. http://www.chem.ox.ac.uk/mom/quinine/Quinine.htm http://www.rain-tree.com/quinine.htm Huxley. A. The New RHS Dictionary of Gardening. 1992. MacMillan Press 1992 ISBN 0-333-47494-5 Excellent and very comprehensive, though it contains a number of silly mistakes. Readable yet also very detailed. Jaziri, M., K. Shimomura, K. Yoshimatsu, M.-L. Fauconnier, M. Marlier, and J. Homes. 1995. Establishment of normal and transformed root cultures of Artemisia annua L. for artemisinin production. J. Plant Physiol. 145:175-177. Jellin JM, Batz F, Hitchens K. Natural Medicines Comprehensive Database. Third Edition. Stockton, California: Therapeutic Research Faculty, 2000. plant. p. 242-255. In: A.D. Kinghorn and M.F. Balandrin (eds.), Human Medicinal Agents from Plants. Am. Chem. Soc. Symp. Series. Washington, DC.
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Koehn FE, Carter GT. The evolving role of natural products in drug discovery. Nat Rev Drug Discov. 2005 Mar;4(3):206-20. 39. Krogstad DJ, Gluzman IY, Kyle DE, et al. Efflux of chloroquine from Plasmodium falciparum: mechanism of chloroquine resistance. Science 1987; 238(4831): 1283-85. 40. Liersch, R., H. Soicke, C. Stehr, and H-U. Tllner. 1986. Formation of artemisinin in Artemisia annua during one vegetation period. Planta Med. 52:387-390. Lueng AY, Foster S. Encyclopedia of Common Natural Ingredients Used in Foord, Drugs and Cosmetics. Second Edition. New York, NY: Wiley & Sons, 1996. Lust, J. (2005) "The Herb Book" p.604
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Herbal Antimalerial

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Herbal Antimalerial

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CONTENTS

Source and Properties

Yingzhaosu Conclusion References

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Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Parasite and vector of malaria

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Life Cycle of the Malaria Parasite

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Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

2. MalaroneTM (atovaquone 250 mg plus proguanil 100 mg) 4 tablets daily

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Day 3 Next 14 days

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Maharishi Arvind College of Pharmacy

B.On the basis of chemical structure

Artemisinin{Herbal} Artemisinin, Artemether, Artesunate, Artemotil,

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Maharishi Arvind College of Pharmacy

3. HERBAL ANTIMALARIAL DRUGS

Generally used herbal antimalarial plant are followings:3.1 3.2

CINCHONA [QUININE]. ARTEMISIA VULGARIS.

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3.1 Cinchona Officinalis (Quinine)

A. Source and properties, and history of hurb

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the bark is considered

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Property and Action

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Quinine sulfate occurs as a white, crystalline powder that darkens on exposure

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Maharishi Arvind College of Pharmacy

Main Uses: Maharishi Arvind College of Pharmacy Page 31

F. Biological Activities And Clinical Research

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Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

3.2 Artemisia vulgaris:

Binomial name Artemisia vulgaris L.

Common Name: Botanical Name:

Artemisia Oil ( Armoise Oil ) Artemisia vulgaris L.

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Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

Maharishi Arvind College of Pharmacy

32. 33. 34.

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