Therapeutic Advances in Functional

Gastrointestinal Disease: Irritable

Bowel Syndrome
Alexandru Gaman; Maria Cristina Bucur; Braden Kuo
Authors and Disclosures
Posted: 09/23/2009; Ther Adv Gastroenterol. 2009;2(3):169-
181. © 2009
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• Abstract and Introduction

• Predominantly Central-acting Drugs
• Central and Peripheral-acting Drugs
• 5-HT 3 Modulators
• 5-HT 4 Modulators
• Drugs Acting Predominantly in the Periphery
• Newly Developed Natural Products
• Conclusion

• References

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Abstract and Introduction

Abstract
Reported prevalence rates of irritable bowel syndrome (IBS) are
between 8% to 20% in the US general population with an average
medical expenditure of US$1.35 billion direct and US$205 million
indirect costs. Current pathophysiologic theories are based on
abnormalities of both the brain and gut, thus setting a new stage
for current and future therapeutic approaches. There are
numerous treatment options in IBS acting centrally and
peripherally by influencing motility and visceral sensitivity. Clinical
evidence is variable; however, newer emerging treatments are
being evaluated using better-designed clinical trials. Accurate
assessment of IBS drug efficacy is still hampered by
heterogeneity of the IBS population. Novel methods such as
pharmacogenomics or brain imaging may be helpful in the future
to better understand and characterize IBS patient subtypes, and
this in turn will lead to more specific and efficient therapeutic
options. Patient subpopulation measurement of side effects is
also a clinical challenge and further understanding could improve
treatment efficacy by enhancing the patient compliance.

Introduction

Irritable bowel syndrome (IBS) is a functional gastrointestinal

disorder centered on pain symptoms and changes in bowel habits
such as constipation and diarrhea. It is also associated with
cramping and bloating for at least 6 months prior to diagnosis
(Rome III criteria). Reported prevalence rates of IBS are between
8% and 20% in the US general population with a 2:1 female to
male ratio [Muller-Lissner et al. 2001]. This results in an average
medical expenditure of US$1.35 billion direct and US$205 million
indirect costs [Inadomi et al. 2003]. The pathophysiology of IBS is
considered to be multifactorial, generated by a complex interplay
between genetic, psychosocial and environmental factors that
impact the patient's life quality, by producing abnormalities in
central nervous system processing as well as in the periphery
where they generate abnormal motility and secretory activity
[Roka et al. 2007; Vassallo et al. 1992].

IBS was believed to be mainly a peripheral condition; however,

current pathophysiologic theories are centered on the
abnormalities of both the brain and gut, thus setting a new stage
for current and future therapeutic approaches [Mayer et al. 2002].
Medications can improve the symptoms in IBS by targeting
biochemical and physical mechanisms in the periphery (i.e.
anticholinergic drugs, laxatives, antidiarrheals, antispasmodic
drugs), or possibly with a dual mechanism at the periphery and at
a central level (i.e. selective serotonin reuptake inhibitors (SSRIs),
serotonin receptor modulators, tricyclic antidepressants,
neurokinin antagonists, opioid drugs). This review aims to assess
the developing IBS pharmacological armamentarium that is based
upon emerging research in neuroenteric biology (Table 1).

The IBS clinical trials that led to FDA drug approvals showed
statistically significant improvement of symptoms when the effect
on patients was compared with healthy controls but the clinical
response rate in the population was rarely over 75%. For
example, Camilleri et al. [2000] found a total benefit of 41% in IBS
patients with a therapeutic gain of 12% when compared with
placebo, and a number needed to treat of 7. A French survey
reported that 87% of patients diagnosed with IBS used medication
at some point but only about half (47%) noticed an improvement
[Dapoigny et al. 2004]. These clinical trial results suggest that
despite a significant clinical response this effect may be less
evident when applied to a broader population of IBS patients.
Another limitation that decreases overall use and efficacy of IBS
medications is their side-effect profiles, with reports of ischemic
colitis or cardiovascular problems in some cases.

Philippines

HEALTH AND LIVING STANDARDS

Hospital in Manila
Courtesy Lisowski Collection, Library of Congress

Figure 4. Estimated Population by Age and Sex, 1988

Source: Based on information from Federal Republic of Germany, Statistisches

Bundesamt, Länderbericht, Philippinen, Weisbaden, 1989, 19-20.

The struggle against disease has progressed considerably over the years. Health
conditions in the Philippines in 1990 approximated to those in other Southeast Asian
countries but lagged behind those in the West. Life expectancy, for instance, increased
from 51.2 years in 1960 to 69 years for women and 63 years for men in 1990 (see fig.
4). Infant mortality was 101 per 1,000 in 1950 and had dropped to 51.6 per 1,000 in
1989. In 1923 approximately 76 percent of deaths were caused by communicable
diseases. By 1980 deaths from communicable diseases had declined to about 26
percent.

In 1989 the ratio of physicians and hospitals to the total population was similar to that
in a number of other Southeast Asian countries, but considerably below that in Europe
and North America. Most health care personnel and facilities were concentrated in
urban areas. There was substantial migration of physicians and nurses to the United
States in the 1970s and 1980s, but there are no reliable figures to indicate what effect
this had on the Philippines. Hospital equipment often did not function because there
were insufficient technicians capable of maintaining it, but the 1990 report of the
Department of Health said that centers for the repair and maintenance of hospital
equipment expected to alleviate this problem.

In 1987 a little more than one-half of the infants and children received a complete
series of immunization shots, a major step in preventive medicine, but obviously far
short of a desirable goal. The problem was especially difficult in rural areas. The
Department of Health had made efforts to provide every barangay with at least
minimum health care, but doing so was both difficult and expensive, and the more
remote areas inevitably received less attention.

Although very few Filipinos have been infected with acquired immune deficiency
syndrome (AIDS), concern about the disease has caused authorities to give it
considerable attention. By April 1979, only three people had died from AIDS, two of
whom were overseas Filipinos visiting the homeland and one an American civilian
who had contracted the disease outside the Philippines. In 1985 the Department of
Health and the United States Naval Medical Research unit tested more than 17,000
people, including some 14,000 hospitality girls in Olangapo and a number of other
Filipino cities. They identified twenty-one women as human immunodeficiency virus
(HIV) carriers. The American sponsorship of the study was seized upon as argument
for ending the Military Bases Agreement with the United States (see Foreign Military
Relations , ch. 5). A June 1990 Philippine government study reported that at that time
AIDS was growing at the rate of four cases a month and that twenty people had died
from the disease. The study indicated that most AIDS cases in the Philippines were
transmitted by heterosexual activity. An April 30, 1991, Department of Health report
indicated that 240 Filipinos were infected with AIDS.

Like many other countries, the Philippines has a problem with illicit drugs. Official
Philippine government statistics for 1989 indicate only 1,733 addicts, but the
assumption was that the real number was from ten to a hundred times as great. The
government has instituted both education and treatment programs, but it was uncertain
how effective these programs would be. There also was a problem with inadequatedly
tested legal drugs. In 1983, more than 265 pharmaceutical products were sold in the
Philippines that were banned in many other countries. The Department of Health
succeeded in eliminating 128 of them by 1988. Attempts to eliminate others have been
blocked by the courts, which ruled that the department had acted without due process.

Malnutrition has been a perennial concern of the Philippine government and health
care professionals. In 1987 the Department of Health reported that 2.8 percent of
preschoolers were suffering from third-degree malnutrition and 17.6 percent from
second-degree malnutrition. To alleviate this problem, the government targeted food
assistance for nearly 500,000 preschoolers and lactating mothers.

Nutrition has shown some improvement. In 1955 government statistics estimated the
daily per capita available food supply at only 80 percent of sufficiency. In 1986 it had
improved to 101.8 percent. In the same period, the consumption of milk nearly tripled
and the consumption of fats and oils more than doubled.

The Philippines has a dual health care system consisting of modern (Western) and
traditional medicine. The modern system is based on the germ theory of disease and
has scientifically trained practitioners. The traditional approach assumes that illness is
caused by a breach of taboos set by supernatural forces. It is not unusual for an
individual to alternate between the two forms of medicine. If the benefits of modern
medicine are immediately obvious--eyeglasses, for instance--then there is little
argument. If there is no immediate cure, the impulse to turn to the traditional healer is
often strong.

One type of traditional healer that attracted the attention of foreigners as well as
Filipinos was the so-called psychic surgeon, who professed to be able to operate
without using a scalpel or drawing blood. Some practitioners attracted a considerable
clientele and established lucrative practices. Travel agents in the United States
credited these "surgeons" with generating travel to the Philippines.

Although medical treatment had improved and services had expanded, pervasive
poverty and lack of access to family planning detracted from the general health of the
Philippine people. In 1990 approximately 50 percent of the population was listed
below the poverty line (down from 59 percent in 1985). A high rate of childbirth
tended both to deplete family resources and to be injurious to the health of the mother.
The main general helath hazards were pulmonary, cardivascular, and gastrointestinal
disorders.

The Philippines had a social security system including medicare with wide coverage
of the regularly employed urban workers. It offered a partial shield against disaster,
but was limited both by the generally low level of incomes, which reduced benefits,
and by the exclusion of most workers in agriculture. In April 1989, out of more than
22 million employed individuals, a little more than 10.5 million were covered by
social security. In health care and social security, as with other services, the
Philippines entered the 1990s as a modernizing society struggling with limited success
against heavy odds to apply scarce financial resources to provide its people with a
better life.
* * *
One of the best recent books synthesizing the social and geographic aspects of the
Philippines is Jim Richardson's The Philippines. Robert Youngblood's Marcos
Against the Church gives an excellent overview of contentious issues between church
and government in the Marcos era and beyond. Religion, Politics and Rationality in a
Philippine Community, by Raul Pertierra, is an insightful portrayal of socio-religious
interaction on the barangay level. Kenneth Bauzon'sLiberalism and the Quest for
Islamic Identity in the Philippines clarifies the basic difference in political thinking
between Muslim and Christian, and W.K. Che Man's Muslim Separatism is an
excellent work on that subject.

Language Policy Formulation, Programming, Implementation, and Evaluation in

Philippine Education (1565-1974), by Emma Bernabe, combines a historical approach
to the language controversy with contemporary analysis and The Role of English and
Its Maintenance in the Philippines, edited by Andrew B. Gonzales, provides a detailed
report on that subject.

Philippine Society and the Individual: Selected Essays of Frank Lynch 1949-1976,
edited by Aram A. Yengoyan and Perla Q. Makil, offers a careful treatment of
Philippine values. James F. Eder's On the Road to Extinction: Depopulation,
Deculturation, and Adaptive Well-Being Among the Batak of the Philippinesis a
provocative book on the upland tribes.

For information on the physical setting of the Philippines, the major work is still
Frederick L. Wernstedt and J. E. Spencer's, The Philippine Island World: A Physical,
Cultural, and Regional Geography.

The following periodicals also are excellent sources of information on contemporary

Philippine society: The Philippine Sociological Review, Solidarity, Philippine
Quarterly of Culture and Society, Philippine Studies, and Pilipinas. (For further
references and complete citations, see Bibliography.)

Data as of June 1991