cilansetron and Irritable-Bowel-Syndrome

Irritable bowel syndrome (IBS) is a chronic functional disorder. 5-Hydroxytryptamine (5-HT) is a key modulator of gastrointestinal sensorimotor function. Many patients have IBS that can be difficult to treat, which has led to the development of newer agents, such as 5-HT(3) antagonists and 5-HT(4) agonists. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to estimate the efficacy of all available 5-HT agents in IBS.. MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to June 2008). Trials recruiting adults with IBS in primary, secondary, or tertiary care comparing 5-HT(3) antagonists or 5-HT(4) agonists with placebo were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The number needed to treat (NNT) was calculated from the reciprocal of the risk difference.. The strategic search identified 1,593 citations. A total of 29 RCTs were eligible for inclusion; placebo was compared with 5-HT(3) antagonists in 11 RCTs, with tegaserod in 11, and with mixed 5-HT(3) antagonists/5-HT(4) agonists in 7. The study quality was generally high. The RR of IBS symptoms persisting with 5-HT(3) antagonists vs. placebo was 0.78 (95% CI: 0.71-0.86), with a similar benefit for both alosetron and cilansetron. Tegaserod was also superior to placebo (RR=0.85; 95% CI: 0.80-0.90). Renzapride and cisapride had no benefit in IBS.. Alosetron, cilansetron, and tegaserod are all effective in the treatment of IBS. Serious adverse events were rare in the eligible RCTs included in this systematic review.

Topics: Adult; Age Factors; Aged; Carbazoles; Carbolines; Dose-Response Relationship, Drug; Drug Administration Schedule; Education, Medical, Continuing; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Patient Satisfaction; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Serotonin Antagonists; Severity of Illness Index; Sex Factors; Treatment Outcome

We performed a systematic review and meta-analyses to estimate treatment efficacy and constipation rate of 5-hydroxytryptamine (serotonin) (5-HT(3)) antagonists in patients with nonconstipated (NC) or diarrhea-predominant (D)-irritable bowel syndrome (IBS).. Two reviewers independently searched MEDLINE, EMBASE, and Web of Science (January 1, 1966 to December 15, 2006) for randomized controlled trials of 5-HT(3) antagonists in IBS reporting clinical end points of the IBS symptom complex and safety parameters. Study characteristics, markers of methodologic quality, and outcomes for the intention-to-treat population for each randomized controlled trial were extracted independently.. We found 14 eligible randomized controlled trials of alosetron (n = 3024) or cilansetron (n = 1116) versus placebo (n = 3043) or mebeverine (n = 304). Random-effects meta-analyses found 5-HT(3) antagonists more effective than the comparators in achieving global improvement in IBS symptoms (pooled relative risk, 1.60; 95% confidence interval [CI], 1.49-1.72; I(2) = 0%) and relief of abdominal pain and discomfort (pooled relative risk, 1.30; 95% CI, 1.22-1.39; I(2) = 22%). Benefit was apparent for both agents, in patients of either sex. These agents were more likely to cause constipation (pooled relative risk, 4.28; 95% CI, 3.28-5.60, I(2) = 65%); there was less constipation with 5-HT(3) antagonists in D-IBS patients than in mixed populations (NC-IBS and D-IBS; relative risk ratio, 0.65; 95% CI, 0.41-0.99). Nine patients (0.2%) using 5-HT(3) antagonists had possible ischemic colitis versus none in control groups.. 5-HT(3) antagonists significantly improve symptoms of NC-IBS or D-IBS in men and women. There is an increased risk of constipation with 5-HT(3) antagonists, although the risk is lower in those with D-IBS.

Topics: Administration, Oral; Carbazoles; Carbolines; Constipation; Diarrhea; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Irritable Bowel Syndrome; Male; Phenethylamines; Prognosis; Pyridines; Quality of Life; Randomized Controlled Trials as Topic; Risk Assessment; Serotonin Antagonists; Severity of Illness Index; Treatment Outcome

Information on the 5-hydroxytryptamine type 3 receptor antagonist cilansetron is scarce and most studies have only been published in abstract form. Results from preclinical and two dose-finding studies have suggested that cilansetron could be effective in the treatment of patients with diarrhea-predominant irritable bowel syndrome. Two large efficacy and safety trials extending over 3 and 6 months revealed a superiority of cilansetron 2 mg orally three-times daily over placebo reflected by numbers needed to treat of 4.8 and 5.6, respectively, for the parameter proportion of patients reporting adequate symptom relief. Dose-ranging studies showed no dose-response relationship. Cilansetron tended to induce constipation but, apart from transient ischemic colitis in four out of 1484 cases, no serious adverse effects were observed. Further trials are underway to fully determine the role of cilansetron in the treatment of diarrhea-predominant irritable bowel syndrome.

Topics: Carbazoles; Diarrhea; Humans; Irritable Bowel Syndrome; Pyridines; Serotonin Antagonists

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.

Topics: Carbazoles; Carbolines; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Pyridines; Randomized Controlled Trials as Topic; Serotonin 5-HT3 Receptor Antagonists

Cilansetron is a novel serotonin type-3 (5-hydroxytryptamine; 5-HT) receptor subtype 3 (5-HT(3)) receptor antagonist currently being evaluated for the treatment of female and male patients with irritable bowel syndrome with diarrhoea predominance (IBS-D). 5-HT(3) receptor antagonists such as cilansetron have been shown to affect gastrointestinal motility. Whether cilansetron affects visceral sensation independent of effects on visceral compliance remains controversial. Results from two large, randomised, double-blind, placebo-controlled, parallel-group Phase III clinical trials of cilansetron in patients with IBS-D have recently been presented in abstract form. These studies found that cilansetron was more effective than placebo at improving overall, as well as individual symptoms, including abdominal pain and diarrhoea in female and male IBS-D patients. The most commonly reported side effect with cilansetron has been constipation and, in general, the drug has been well tolerated in clinical trials. Although rare, the most concerning side effect observed with cilansetron has been suspected ischaemic colitis. The event rate for suspected ischaemic colitis associated with cilansetron from clinical trials is 3.77 per 1000 person years of exposure. This rate appears to be greater than that expected in the IBS population and similar to that observed with alosetron, another 5--HT(3) receptor antagonist. All of the cases of suspected ischaemic colitis reported with cilansetron have resolved without serious sequelae. How issues surrounding the safety of cilansetron will affect the approval process in various countries remains to be determined. However, the risk-benefit of cilansetron is likely to be most favourable in patients with IBS-D who have failed to respond to conventional medical therapies. A detailed risk management plan and post-marketing surveillance programme will be required should this drug become available for the treatment of patients with IBS-D.

Topics: Carbazoles; Clinical Trials as Topic; Diarrhea; Humans; Irritable Bowel Syndrome; Pyridines; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists

Cilansetron [KC 9946] is a serotonin-3 receptor (5-HT(3)) antagonist under development with Solvay Pharmaceuticals for the treatment of irritable bowel syndrome with diarrhoea predominance (IBS-D), in both men and women.5-HT(3) antagonists inhibit the 5-HT(3) receptors, resulting in decreased GI motility, secretion and sensation, thereby improving symptoms of IBS-D. Current 5-HT(3) therapy indicated for IBS-D is approved for women only.IBS is one of the most common functional gastrointestinal disorders, affecting an estimated 10-20% of the population in developed countries. Approximately twice as many women as men are diagnosed with IBS; however, this discrepancy may be due to more women seeking medical care. IBS is a chronic and bothersome disorder, and its symptoms, although not life-threatening, have a negative impact on quality of life (QOL), interfering with social activities, relationships and work. The degree to which IBS reduces quality of life appears to be directly related to symptom severity and intensity. In July 2001, Solvay signed an agreement with Quintiles (CRO) in order to optimise clinical research for cilansetron. In April 2004, Solvay Pharmaceuticals submitted a new drug application (NDA) for cilansetron in the UK (for the European Union) for the treatment of irritable bowel syndrome with diarrhoea predominance, in both men and women. In April 2005, Solvay Pharmaceuticals received a 'not-approvable' action letter from the US FDA on its NDA for cilansetron for the treatment of irritable bowel syndrome with diarrhoea predominance (IBS-D), in both men and women. The letter requested additional clinical trials, and Solvay is currently examining its options and will discuss future steps with the FDA. Solvay submitted the NDA for cilansetron in the US in June 2004 and included an extensive Appropriate Use Plan as part of its submission. The NDA submission was based on efficacy and safety studies in around 4000 patients worldwide with IBS-D. The FDA accepted for filing and granted priority review status for this NDA application in September 2004. According to Solvay's first half 2004 results, cilansetron is due to begin phase II clinical trials in Japan for the treatment of irritable bowel syndrome with diarrhoea predominance.

Topics: Animals; Carbazoles; Clinical Trials as Topic; Drugs, Investigational; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Pyridines; Serotonin 5-HT3 Receptor Antagonists

Irritable bowel syndrome is an extremely common disorder affecting approximately 10-20% of the population of North America and Europe. This disorder is characterized by abdominal pain and altered bowel habit. The altered bowel habit can take a number of forms. These include a predominant diarrhea form, a form with constipation and one in which patients alternate between diarrhea and constipated forms of the disorder. Irritable bowel syndrome to date has not been associated with any excess mortality. However, the morbidity associated with irritable bowel syndrome is quite high. This mainly takes on the form of impairment in health-related quality of life, interference with activities of daily living and a considerable degree of human suffering. Likewise, the economic impact of irritable bowel syndrome is not trivial and has been estimated to be between US$20 to 30 billion in the United States alone. In an effort to address this common disabling disorder, a number of new drugs have been developed. One of the latest is cilansetron, which is a competitive type 3 serotonin (5-HT3) receptor antagonist. In phase III trials, cilansetron has been shown to be efficacious for the relief of a wide spectrum of symptoms related to irritable bowel syndrome with diarrhea both in male and female patients. By and large, cilansetron is extremely well tolerated and highly efficacious. The most common side effect of cilansetron is constipation, which is seen in 3-12% of subjects at 6 months. Ischemic colitis, a side effect associated with previous drugs of this class, has been seen in eight subjects (six women and two men) to date. All of these ischemic colitis events have been self-limited and did not require surgery. Because of its high degree of efficacy, the fact that it is well tolerated by the overwhelming majority of patients and that it shows efficacy in both genders, cilansetron represents a major advance in the treatment of irritable bowel syndrome with diarrhea predominance.

Topics: Carbazoles; Clinical Trials, Phase III as Topic; Diarrhea; Humans; Irritable Bowel Syndrome; Pyridines; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists

We examined the pharmacological profile of ramosetron, a 5-HT(3)-receptor antagonist for irritable bowel syndrome with diarrhea, comparing it with those of other 5-HT(3)-receptor antagonists, alosetron and cilansetron, and the anti-diarrheal agent loperamide. Ramosetron showed high affinity for cloned human and rat 5-HT(3) receptors, with K(i) values of 0.091 +/- 0.014 and 0.22 +/- 0.051 nmol/L, respectively, while its affinities for other receptors, transporters, ion channels, and enzymes were negligible. Dissociation of ramosetron from the human 5-HT(3) receptor was extremely slow (t(1/2) = 560 min), while alosetron (t(1/2) = 180 min) and cilansetron (t(1/2) = 88 min) dissociated relatively rapidly. Ramosetron competitively inhibited 5-HT-induced contraction of isolated guinea-pig colon, with pA(2) values of 8.6 (8.5 - 9.0). Ramosetron given orally also dose-dependently inhibited the von Bezold-Jarisch reflex in rats, with an ED(50) value of 1.2 (0.93 - 1.6) microg/kg. In addition, oral ramosetron dose-dependently inhibited restraint stress-induced defecation in rats, with an ED(50) value of 0.62 (0.17 - 1.2) microg/kg. In all of these experiments, the potencies of ramosetron were greater than those of alosetron, cilansetron, or loperamide. These results indicate that ramosetron is a highly potent and selective 5-HT(3)-receptor antagonist, with beneficial effects against stress-induced abnormal defecation in rats.

Topics: Animals; Benzimidazoles; Carbazoles; Carbolines; Carrier Proteins; Colon; Defecation; Gastrointestinal Agents; Guinea Pigs; Humans; Ion Channels; Irritable Bowel Syndrome; Loperamide; Male; Muscle, Smooth; Pyridines; Rats; Rats, Sprague-Dawley; Rats, Wistar; Receptors, Serotonin; Receptors, Serotonin, 5-HT3; Restraint, Physical; Serotonin Antagonists; Stress, Psychological

The aim of this study was to establish a pathophysiologic model of irritable bowel syndrome, and then to evaluate the pharmaceutical efficacy of ramosetron, a potent serotonin 3 (5-HT(3)) receptor antagonist, and other anti-irritable bowel syndrome agents in this model. Rats stressed by a conditioned stress procedure exhibited marked prolongation of freezing time, an index of fear level, and an increase in the frequency of defecation (P<0.01). A corticotropin-releasing factor (CRF) antagonist, alpha-helical CRF, inhibited both defecation and freezing behavior, while the antidiarrheal loperamide inhibited defecation only. The 5-HT(3) receptor antagonists ramosetron, cilansetron and alosetron also inhibited defecation (ED(50) values: 0.012, 0.094, 0.078 mg/kg p.o., respectively) without affecting freezing behavior. Ramosetron showed longer-lasting effect on defecation than cilansetron. Stress also resulted in increases in both proximal and distal colonic transit rates. Ramosetron and other 5-HT(3) receptor antagonists at doses inhibiting stress-induced defecation also ameliorated both stress-stimulated colonic transit rates. These results suggest that ramosetron, as well as agents used for the treatment of irritable bowel syndrome with diarrhea, has beneficial effects against emotional stress-induced colonic dysfunction. Furthermore, this emotional stress model may be useful in evaluation of drugs to treat irritable bowel syndrome presenting with diarrhea.

Topics: Animals; Behavior, Animal; Benzimidazoles; Carbazoles; Carbolines; Colon; Colonic Diseases, Functional; Conditioning, Psychological; Corticotropin-Releasing Hormone; Defecation; Disease Models, Animal; Dose-Response Relationship, Drug; Fear; Gastrointestinal Transit; Immobilization; Irritable Bowel Syndrome; Loperamide; Male; Peptide Fragments; Pyridines; Rats; Rats, Sprague-Dawley; Receptors, Serotonin, 5-HT3; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Stress, Psychological; Time Factors; Treatment Outcome