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)

Drug development for functional gastrointestinal disorders is complex. These conditions involve central and peripheral physiological changes, together with psychological factors. Methodological problems have included a poor appreciation of the physiological and psychological correlates of patients' symptoms, a lack of animal models of proven relevance, and safety issues. Government, patient pressure groups and the Internet can also influence a drug's success. Most recent interest has focused on the serotonin (5-HT) modifying drugs. Cisapride has been withdrawn in some countries because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists, developed to modify visceral sensation, have caused constipation; alosetron, also withdrawn, caused ischaemic colitis. The 5-HT4 agonists induce peristalsis; tegaserod and prucalopride, both delayed in their development due to issues of safety and efficacy, benefit patients with 'constipation-predominant' irritable bowel syndrome or idiopathic constipation. 5-HT1 agonists improve impaired gastric accommodation and symptoms in patients with functional dyspepsia. Antidepressants also affect serotonin metabolism. Previous examples of success in this area involved drugs targeted at peripheral receptors mediating motor function or secretion. Modification of sensory function is a much more challenging objective. The experience with serotonin modifying drugs has been mixed, and some important lessons are there to be learnt.
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PMID:Review article: the complexity of drug development for irritable bowel syndrome. 1187 86

Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visccral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin. A, N-methyl-D-aspartate, alpha 2-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.
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PMID:Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds. 1218 41

The irritable bowel syndrome (IBS) remains a therapeutic challenge in part because of the limited understanding of the pathophysiology. The placebo response rate varies in randomized controlled trials from 20 to 70%, and can persist for up to at least 1 year. It is contentious whether dietary fibre and bulking agents relieve the symptoms of IBS; constipation probably improves. Anticholinergic and antispasmodic agents are of questionable benefit in IBS despite positive meta-analyses of poor quality trials. A meta-analysis concluded that the tricyclic antidepressants were superior to placebo in IBS, although the individual trial results were variable. Selective serotonin reuptake inhibitors are of uncertain benefit. Laxatives are used for constipation but probably poorly control the IBS symptom complex. Loperamide is superior to placebo in improvement of diarrhoea but not abdominal pain in IBS. Tegaserod is a well- tolerated aminoguanidine indole derivative of serotonin that is a partial 5HT4-receptor agonist with prokinetic properties; a therapeutic gain over placebo of 5% to 15% has been observed in constipation-predominant IBS in females. Alosetron is a 5HT3-receptor antagonist that is efficacious in females with diarrhoea-predominant IBS, with a 12% to 17% therapeutic gain; the risk of ischaemic colitis is 1 in 350, with very severe constipation occurring in about 1 in 1000. Optimizing study design remains a challenge in IBS. New visceral analgesic and motility modifying agents, as well as anti-inflammatory agents are in trials, and hopefully additional efficacious therapeutic options for patients with IBS will soon emerge.
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PMID:Evaluation of drug treatment in irritable bowel syndrome. 1296 80

Tegaserod is a new partial agonist of serotonin 5-HT4 receptors specifically developed for the treatment of nondiarrhoeal forms of irritable bowel syndrome (IBS). Among its various effects is the stimulation of the peristaltic reflex with its promotility action appearing to affect the whole length of the gastrointestinal tract. Tegaserod has been assessed in a number of international multicentre trials and its use leads to an improvement in abdominal pain and bowel dysfunction as well as global well-being, at the expense of remarkably few adverse effects. It is noteworthy that it also appears to improve bloating, a benefit that has not been previously reported for a medication used in IBS. The optimal dose is 6 mg twice daily and the advantage of tegaserod over placebo in different trials varies from 5-20% with the number needed to treat ranging from 5-15 depending on the time at which this effect is calculated during the course of a trial. Recent experience with other drugs acting on 5-HT receptors has focused attention on possible safety issues such as prolongation of the QTc interval on the electrocardiogram and ischaemic colitis. However, data from efficacy trials and studies specifically designed to address the safety of tegaserod have not revealed any evidence of cardiotoxicity or the potential for causing ischaemic colitis. Furthermore, investigation of possible interactions with other drugs such as warfarin or the oral contraceptive have not resulted in any prescribing restrictions. Inappropriate prescription of tegaserod to a subgroup of IBS patients for which the drug was not designed, does not appear to have any serious consequences. Most of the efficacy data on tegaserod has been accumulated in females, simply as a result of the failure to recruit adequate numbers of males or restriction of trials to females. There is therefore insufficient information to assess whether there might be any potential gender differences in responsiveness. For this reason, the drug is currently only licensed for use in females.
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PMID:Benefit-risk assessment of tegaserod in irritable bowel syndrome. 1500 35

This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT(4) receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation. Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems. Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy. Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not effect electrocardiographic parameters. Laboratory parameters are mostly unaffected by tegaserod, although several individuals have exhibited increased eosinophil counts. In summary, tegaserod exhibits a favourable safety and tolerability profile in IBS patients based on data from clinical trials. Diarrhoea is the most common adverse event associated with tegaserod use. Continued post-US marketing surveillance will further define the safety and tolerability profile of tegaserod.
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PMID:Safety profile of tegaserod, a 5-HT4 receptor agonist, for the treatment of irritable bowel syndrome. 1523 Jun 44

To assist the radiologist in differentiating the colitis in children, this review proposes a systematic US approach to the disease, presents the US aspect of the normal colon and describes three distinctive US patterns reflecting the intramural extension of the histopathological changes. Each pattern corresponds to one or several diseases producing alterations in the same layer(s). Stratified thickening suggests an inflammatory mucosal process resulting from infection (as in advanced appendicitis or in infectious colitis) or to inflammation (as in IBD). Nonstratified thickening with loss of the haustral folds reflects a marked submucosal infiltrate. Color Doppler is required to distinguish between an inflammatory disease (as advanced CD or neutropenic colitis) and an ischemic colitis (HUS in children). Nonstratified thickening with preservation of the length of the haustral folds is the sign of an intraluminal deposit due to PMC. Correlating the sonographic pattern and the anatomic distribution of the disease with the clinical and laboratory findings often permits to propose a specific diagnosis.
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PMID:Sonographic diagnosis of colitis in children. 1523 10

Gastrointestinal symptoms are the most common side-effects of tegaserod therapy. In data pooled from Phase III randomized controlled trials in patients with irritable bowel syndrome with constipation, diarrhoea was reported by 8.8% of patients treated with tegaserod 6 mg b.d. vs. 3.8% of patients treated with placebo. Similar rates were observed in international post-US marketing randomized controlled trials. In most patients, tegaserod-induced diarrhoea was mild and transient. In randomized controlled trials, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of irritable bowel syndrome patients discontinued tegaserod due to diarrhoea. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea and flatulence) was similar in tegaserod-treated and placebo-treated patients. Pooled analysis of Phase III and post-US marketing randomized controlled trials did not demonstrate significant differences between tegaserod-treated and placebo-treated patients in the incidence of abdominal/pelvic surgery. No episodes of ischaemic colitis were reported in tegaserod-using patients in any Phase III or post-marketing randomized controlled trials, and post-marketing surveillance indicated that the rate of ischaemic colitis in tegaserod-using patients was lower than that in non-tegaserod-using patients. Pooled analysis of Phase III randomized controlled trials demonstrated an increase in the incidence of headaches in tegaserod-treated (6 mg b.d.) vs. placebo-treated patients (15% vs. 12.3%, respectively; P < 0.05), although post-US marketing randomized controlled trials did not demonstrate this increase. Other extra-gastrointestinal adverse events occurred with similar frequency in tegaserod-treated and placebo-treated patients. Tegaserod-treated patients in randomized controlled trials did not demonstrate significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. In summary, tegaserod exhibits a favourable safety and tolerability profile in irritable bowel syndrome patients based on data from clinical trials.
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PMID:Review article: the safety profile of tegaserod. 1552 52

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

Tegaserod, a potent partial agonist of the serotonin 5-HT4 receptor, is used to treat women with constipation-predominant irritable bowel syndrome. Since the drug's approval, the manufacturer has received infrequent although serious reports of diarrhea and ischemic colitis in patients taking the drug. These instances have led to a recent warning letter to physicians and a change in the prescription labeling of tegaserod. We describe the development of ischemic colitis in a woman who was treated with tegaserod and review the relationship among ischemic colitis, tegaserod use, and irritable bowel syndrome. Potential mechanisms involved in the occurrence of ischemic colitis in patients receiving tegaserod are also discussed.
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PMID:Tegaserod-associated ischemic colitis. 1597 22

Functional diarrhea occurs as part of the irritable bowel syndrome (IBS) and as an isolated symptom as functional (painless) diarrhea. Progress has been made in defining these disorders and in identifying new mechanisms involved in symptom production. A strong link exists between intestinal infection and IBS, as is the role of 5-hydroxytryptamine (5-HT). The importance of persistent subclinical inflammation is also emerging as a potential etiologic factor, particularly in post-infectious IBS. Although changes in the bacterial flora and bacterial overgrowth have been put forward as additional new contributors to symptom production, the case is not strong. These developments in pathogenesis have facilitated the introduction of new therapies. 5-HT(3) antagonists reduce bowel frequency and pain in women with diarrhea-predominant IBS, but their use is limited because of ischemic colitis. Prednisolone lacks efficacy, and early results with probiotics and herbal remedies are encouraging but require confirmation by larger trials.
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PMID:Functional diarrhea. 1616 32


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