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)

Management of patients with irritable bowel syndrome (IBS) is based on the positive diagnosis of the symptom complex, limited exclusion of underlying organic disease and institution of a therapeutic trial. As a general approach, physician should establish an effective therapeutic relationship by providing clearly understood explanation to patients of the causes and implications of their symptoms, supported by reassurance and appropriate therapy. Treatment of IBS needs to be individualized, focusing on patients' predominant symptoms. In diarrhea- predominant IBS, loperamide and some antispasmodic agents are efficacious. In constipation-predominant IBS, fiber and bulk laxatives are used empirically, but their efficacy is variable and may aggravate bloating. The 5-HT4 receptor agonist, tegaserod is efficacious in female patients with IBS and constipation. In patients with IBS and abdominal pain, antispasmodics and antidepressants can be used but there is weak evidence of potential benefit. New novel pharmacological agents are being carefully appraised as potential drugs for the future.
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PMID:[Management of irritable bowel syndrome]. 1649 78

A growing body of evidence implicates abnormal serotonergic regulation of gastrointestinal function in the pathogenesis of the irritable bowel syndrome (IBS). Drugs targeting this system are therefore attractive concepts. The partial 5-HT4 receptor agonist tegaserod might be predicted to have positive therapeutic effects on a constipated and uncomfortable gut. However, IBS runs a chronic, benign course and carries no associated mortality, so it is imperative that the safety profile of new pharmacological agents made available to physicians is exemplary. The authors review the evidence for 5-HT in the aetiology of IBS and its symptoms, and the data available concerning the partial 5-HT4 receptor agonist tegaserod, in terms of rationale, efficacy and safety.
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PMID:The rationale, efficacy and safety evidence for tegaserod in the treatment of irritable bowel syndrome. 1650 51

In the gut, serotonin (5-hydroxytryptamine: 5-HT) exerts a variety of effects on intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells, which are related to the expression of multiple 5-HT receptor types and subtypes regulating motility, vascular tone, secretion and perception. Agonists and antagonists at 5-HT receptors have gained access to the market for the two major variants of the irritable bowel syndrome (IBS), a functional disorder characterized by abdominal pain associated with diarrhea and/or constipation in the absence of any organic abnormality. Indeed, the 5-HT3 receptor antagonist alosetron is available in the US market for the treatment of women with severe, diarrhea-predominant IBS (D-IBS) refractory to conventional therapy, whereas tegaserod, a partial 5-HT4 receptor agonist, has been approved by the FDA and other regulatory agencies for the treatment of women with constipation-predominant IBS (C-IBS) or functional constipation. This review is mainly intended to discuss the role of non-neuronal (paracrine) and neuronal 5-HT in the pathophysiology of functional gastrointestinal disorders (FGIDs), such as IBS and functional dyspepsia, and the mechanisms through which drugs acting on 5-HT receptors regulate visceral motility, perception and secretion in these two conditions.
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PMID:Drugs acting on serotonin receptors for the treatment of functional GI disorders. 1669 64

Previous studies demonstrated the efficacy of electro-acupuncture (EA) in relieving chronic visceral hypersensitivity (CVH) in IBS rats. However, ST25 which is a key acupoint for patients with IBS has not been reported in these experiments. Eight CVH rats were treated by EA at both ST25 and ST37 for 20 min, once daily for seven consecutive days, model rats (n = 8) and normal rats (n = 8) as controls. After the first EA treatment, the abdominal withdrawal reflex scores were investigated to evaluate the pain threshold. After seven EA treatments, the concentrations of 5-hydroxytryptamine (5-HT), 5-HT3 receptor (5-HT3R) and 5-HT4 receptor (5-HT4R) in colon tissue were assayed quantitatively by enzyme-linked immunosorbent assay. The results showed that EA improved the pain threshold of CVH rats, reduced the 5-HT concentration and increased the 5-HT4R concentration, but had no effect on the 5-HT3R concentration. Further studies are needed to optimize the choice of two-matching points for EA in the treatment of CVH rats.
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PMID:Acupuncture at both ST25 and ST37 improves the pain threshold of chronic visceral hypersensitivity rats. 1938 29

Tegaserod is a first-in class selective serotonin 4 receptor agonist approved for the treatment of irritable bowel syndrome. In March 2007, the US Food and Drug Administration (FDA) suspended its use citing increased cardiovascular (CV) events in clinical trials. However, there is no known mechanistic basis for an adverse CV effect. To reassess the CV safety of tegaserod, teagaserod-treated patients (pts) in the Intermountain Healthcare database were identified (n = 2603), matched 1:6 with untreated (n = 15,618) patients by age, sex, and date of tegaserod initiation, and followed for an average of 2.5 years. Age averaged 38.6 +/- 13.5 years, and 94% were female. Cardiovascular event rates were low and similar in patients treated with tegaserod and matched untreated patients. For the primary composite CV endpoint, 54 (0.35%) untreated and 12 (0.46%) treated pts had an event (treated OR = 1.27, 95% CI: 0.68-2.38, P =.46), with 7 and 0 events, respectively, occurring within 3 months. A total of 12 (0.1%) untreated and 1 (<0.1%) treated pts were hospitalized for a myocardial infarction (MI). 36 (0.2%) untreated and 10 (0.4%) treated pts for a cardiovascular accident, and 1 pt in each group for unstable angina. A total of 6 (<0.1%) untreated and no treated pts died from cardiac causes. Event rates were comparable to expected rates in this population of mostly premenopausal women. This large epidemiologic study failed to confirm a reported large event differential for tegaserod that was noted incidentally in a clinical trials database, suggesting that the prior observation may have been due to chance.
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PMID:Lack of association of tegaserod with adverse cardiovascular outcomes in a matched case-control study. 1960 72

New therapies are being developed for irritable bowel syndrome (IBS). These advances are based on understanding pathophysiology or the development of medications with greater selectivity in classes of agents with known efficacy. Prucalopride, the newest European Medicines Agency-approved 5-hydroxytryptamine receptor 4 (5-HT(4)) agonist, is effective in the treatment of chronic constipation with improved cardiovascular safety relative to older 5-HT(4) drugs; similarly, ramosetron, the 5-hydroxytryptamine receptor 3 (5-HT(3)) antagonist, appears efficacious in diarrhea-predominant IBS. Secretagogues with different mechanisms of action target apical domains in enterocytes that are involved in chloride secretion, such as chloride channels, the cystic fibrosis transmembrane regulator, and guanylate cyclase C. As a class, such secretagogues have high efficacy and safety for constipation. With more data obtained from phase 2 and 3 trials, we expect other classes of medications, including bile acid modulators, anti-inflammatory agents, visceral analgesics, and newer centrally acting agents to be efficacious and enter the armamentarium for the treatment of IBS in the future.
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PMID:Emerging pharmacologic therapies for irritable bowel syndrome. 2069 41

Irritable bowel syndrome is a common functional disorder of the gut. The cause is not known. Symptoms can be quite variable and include abdominal pain, bloating, and sometimes bouts of diarrhea and/or constipation. It causes a great deal of discomfort and distress, but it does not permanently harm the intestine and does not lead to a serious disease, such as cancer. There are numerous treatment options in functional gastrointestinal disorders acting peripherally by influencing motility and visceral sensitivity. However, older 5-HT4 receptor agonists had limited clinical success because they were associated with changes in the cardiac function. New generation 5-HT4 receptor agonists, 5-HT, antagonists or partial antagonists are promising approaches to treat gastrointestinal dysmotility, particularly colonic diseases. A further new approach is the activation of chloride cannels within the gastrointestinal wall by the prostaglandin E metabolite lubiprostone. In patients with chronic constipation, lubiprostone produced a bowel movement, with sustained improvement in frequency as well as other constipation symptoms. Ongoing clinical trials suggest that linaclotide, a first-in-class, 14-amino acid peptide guanylate cyclase C (GC-C) receptor agonist and intestinal secretagogue is also an effective treatment for chronic constipation. The pharmacological profile suggests that orally administered linaclotide may be capable of improving the abdominal symptoms and bowel habits of patients suffering from of constipation-predominant irritable bowel syndrome and chronic constipation. Data are emerging, but the efficacy and safety profile of these agents in the treatment irritable bowel disease appears encouraging. Further randomized controlled trials are warranted.
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PMID:[New therapeutical approaches for treatment of irritable bowel syndrome]. 2118 48

Chronic constipation is a very common functional gastrointestinal disorder which can be associated with significant impairments in quality of life for some people with the condition. Its management has, traditionally, been based on dietary and lifestyle changes and the use of a variety of laxative agents. The evidence base for the efficacy of the latter is, in many cases, slim. Not surprisingly, many patients remain dissatisfied with laxatives thus leading to the development of more pharmacological approaches. Among these approaches is the use of prokinetic agents; while prior molecules have been troubled by lack of selectivity and cardiac side effects, the new agent, prucalopride, appears to be highly selective for the serotonin 5-HT4 receptor and is, therefore, a potent stimulator of gut motility. In three large pivotal randomized controlled trials, prucalopride has been effective in relieving the cardinal symptoms of chronic constipation; these effects have been sustained in open-label follow up for as long as 18 months. The safety profile has been encouraging and, especially so, the absence of arrhythmogenic potential. Studies in men, in constipation-predominant irritable bowel syndrome and in other motor disorders are eagerly awaited.
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PMID:Prucalopride: safety, efficacy and potential applications. 2228 5

Serotonin (5-hydroxytryptamine, 5-HT) induces various effects in the central nervous system, cardiovascular system and gastrointestinal tract. The response depends primarily on the nature of the 5-HT receptors involved. In the light of the current knowledge about the anatomy and physiology of the serotonergic system and the distribution of the various 5-HT receptors in the gut, the established and potential therapeutic impact of 5-HT receptor ligands are discussed. In particular, selective 5-HT receptor ligands influencing intestinal motility and pain perception such as the 5-HT4 receptor agonist prucalopride appear promising for the treatment of irritable bowel syndrome.
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PMID:Physiological, pathophysiological and therapeutic impact of the enteric serotonergic system. 2243 71

5-HT4 receptor antagonists have been suggested to have clinical potential in treatment of atrial fibrillation, diarrhea-prone irritable bowel syndrome and urinary incontinence. Recently, the use of 5-HT4 antagonists has been suggested to have a therapeutic benefit in heart failure. Affinity for the hERG potassium ion channel and increased risk for prolonged QT intervals and arrhythmias has been observed for several 5-HT4 ligands. Serotonin may also have beneficial effects in the central nervous system (CNS) through stimulation of the 5-HT4 receptor, and reduced distribution of 5-HT4 antagonists to the CNS may therefore be an advantage. Replacing the amide and N-butyl side chain of the 5-HT4 receptor antagonist SB207266 with an ester and a benzyl dimethyl acetic acid group led to compound 9; a hydrophilic 5-HT4 antagonist with excellent receptor binding and low affinity for the hERG potassium ion channel. To increase oral bioavailability of carboxylic acid 9, two different prodrug approaches were applied. The tert-butyl prodrug 11 did not improve bioavailability, and LC-MS analysis revealed unmetabolized prodrug in the systemic circulation. The medoxomil ester prodrug 10 showed complete conversion and sufficient bioavailability of 9 to advance into further preclinical testing for treatment of heart failure.
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PMID:Synthesis and pharmacological properties of a new hydrophilic and orally bioavailable 5-HT4 antagonist. 2371 70


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