cilansetron and Diarrhea

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

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

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