Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022104 (irritable bowel syndrome)
 8,033 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Irritable bowel syndrome (IBS) is common and can be disabling. Several drugs that modulate serotonin (5HT) and other neurotransmitters in the gut (neuroenteric modulators) have either become available or are in development, but progress has been slowed by toxicity. Blockade of 5HT(3) receptors slows colonic transit, increases fluid absorption and increases left colon compliance. Alosetron, a potent 5HT(3) receptor antagonist, has, in women but not in men, a clinically significant but modest therapeutic gain over placebo in the relief of abdominal pain and discomfort and bowel-habit disturbance (but not bloating) in diarrhoea-predominant IBS. However, the drug unexpectedly was associated with ischaemic colitis and, very rarely, severe constipation-induced complications, and alosetron has been withdrawn. Cilansetron may have similar efficacy in men and women. 5HT(4) receptor stimulation results in accelerated colonic transit, and tegaserod, a partial 5HT(4) receptor agonist, has modest but clinically significant advantage over placebo in constipation-predominant IBS; the benefit seems to be confined to females. Long-term published data are lacking and safety concerns have been raised. Prucalopride, a full 5HT(4) agonist that has been promising in idiopathic chronic constipation, may also be limited by toxicity. Other 5HT receptor antagonists and agonists are under development for IBS. However, for modulators of single receptors to achieve a substantial therapeutic gain, and to do so safely, drug targets based on the pathophysiology of IBS need to be better defined.
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PMID:Serotoninergic neuroenteric modulators. 1175 32

Cilansetron is a 5-HT3 antagonist tinder development by Solvay Pharmaceuticals as a potential treatment for irritable bowel syndrome (IBS). The compound targets non-constipated men and women with IBS. Cilansetron is being evaluated in phase III trials, but up to now, only scarce information has been made available and most publications have appeared in abstract form only. In July 2001, it was reported that regulatory submissions were expected in 2003 [416185]. Also in July 2001, after discussion with the FDA, Solvay initiated a revised phase III program in diarrhea-predominant IBS and signed a five-year 'preferred-provider' clinical services agreement with Quintiles Transnational to conduct the trial. At this time, Solvay was also seeking marketing partners for cilansetron [416185]. By October 1999, Solvay was treating cilansetron as one of its main priorities, as it represented a novel class of compound [342434]. Solvay has predicted peak sales of euro 100 m to euro 1000 m [420654].
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PMID:Cilansetron. Solvay. 1189 Mar 60

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.
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PMID:Cilansetron: a new serotonergic agent for the irritable bowel syndrome with diarrhoea. 1575 94

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.
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PMID:Cilansetron: KC 9946. 1586 20

The aim of this article is to review the pathophysiology and clinical role of serotonin receptor modulators used in the treatment of irritable bowel syndrome. Serotonin is an important monoamine neurotransmitter that plays a key role in the initiation of peristaltic and secretory refl exes, and in modulation of visceral sensations. Several serotonin receptor subtypes have been characterized, of which 5HT3, 5HT4, and 5HT1b are the most important for GI function. 5HT4 agonists (eg, tegaserod) potentiate peristalsis initiated by 5HT1 receptor stimulation. 5HT4 agonists are therefore useful in constipation predominant form of IBS and in chronic constipation. 5HT3 antagonists (Alosetron and Cilansetron) prevent the activation of 5HT3 receptors on extrinsic afferent neurons and can decrease the visceral pain associated with IBS. These agents also retard small intestinal and colonic transit, and are therefore useful in diarrhea-predominant IBS. Tegaserod has been demonstrated in several randomized, placebo controlled trials to relieve global IBS symptoms as well as individual symptoms of abdominal discomfort, number of bowel movements and stool consistency. Several randomized, controlled trials have shown that alosetron relieves pain, improves bowel function, and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. However, ischemic colitis and severe complications of constipation have been major concerns leading to voluntary withdrawal of Alosetron from the market followed by remarketing with a comprehensive risk management program.
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PMID:Serotonin receptor modulators in the treatment of irritable bowel syndrome. 1872 19

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.
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PMID:Cilansetron in the treatment of diarrhea-predominant irritable bowel syndrome? 1907 30