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)

Therapeutic use of 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists for diarrhoea-predominant irritable bowel syndrome may be accompanied by constipation. We hypothesized that ME3412, 5-chloro-2-(1,4-diazacycloheptan-1-yl)-7-methylbenzoxazole, a novel partial agonist of the 5-HT(3) receptor, would minimize constipation without reducing antidiarrhoeal activity. Receptor binding studies showed that ME3412 is highly selective for the human 5-HT(3) receptor (K(i) = 1.51 nmol L(-1)). A 5-HT(3) receptor agonist, 2-methyl-5-HT, caused contractile response in the isolated guinea-pig ileum and accelerated secretion in the guinea-pig colonic mucosal preparation. ME3412 and 5-HT(3) receptor antagonist, alosetron, antagonized the 2-methyl-5-HT-induced responses with similar potency in insurmountable and surmountable manner, respectively. ME3412 caused weak agonism in isolated ileum strips and also in the colonic mucosa with intrinsic activity of 0.09 and 0.59, respectively. In conscious dogs, alosetron (3 microg kg(-1) i.v.) suppressed the migrating motor complex (MMC), whereas a relatively high dose (300 microg kg(-1)) of ME3412 was required for inhibition of MMC. ME3412 and alosetron suppressed 5-HT induced-diarrhoea in mice. In contrast, ME3412 did not significantly affect colonic propulsion compared with alosetron. These results imply that the partial agonist may relieve diarrhoea with low risk of inducing constipation.
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PMID:Comparison between partial agonist (ME3412) and antagonist (alosetron) of 5-hydroxytryptamine 3 receptor on gastrointestinal function. 1578 49

The bowel exhibits reflexes in the absence of CNS input. To do so, epithelial sensory transducers, such as enterochromaffin (EC) cells, activate the mucosal processes of intrinsic (IPANs) and extrinsic primary afferent (sensory) neurons. EC cells secrete serotonin (5-HT) in response to mucosal stimuli. Submucosal IPANs, which secrete acetylcholine and calcitonin gene-related peptide, initiate peristaltic and secretory reflexes and are activated via "5-HT1P" receptors. Release of neurotransmitters is enhanced by 5-HT4 receptors, which are presynaptic and strengthen neurotransmission in prokinetic pathways. 5-HT3 receptors mediate signaling to the CNS and thus ameliorate cancer chemotherapy-associated nausea and the visceral hypersensitivity of diarrhea-predominant irritable bowel syndrome (IBS-D); however, because 5-HT3 receptors also mediate fast ENS neurotransmission and activate myenteric IPANs, they may be constipating. 5-HT4 agonists are prokinetic and relieve discomfort and constipation in IBS-C and chronic constipation. 5-HT4 agonists do not initiate peristaltic and secretory reflexes but strengthen pathways that are naturally activated. Serotonergic signaling in the mucosa and the ENS is terminated by a transmembrane 5-HT transporter, SERT. Mucosal SERT and tryptophan hydroxylase-1 expression are decreased in experimental inflammation, IBS-C, IBS-D, and ulcerative colitis. Potentiation of 5-HT due to the SERT decrease could account for the discomfort and diarrhea of IBS-D, while receptor desensitization may cause constipation. Similar symptoms are seen in transgenic mice that lack SERT. The loss of mucosal SERT may thus contribute to IBS pathogenesis.
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PMID:Nerves, reflexes, and the enteric nervous system: pathogenesis of the irritable bowel syndrome. 1579 84

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

Irritable bowel syndrome (IBS) has been associated with substantial time lost from work (absenteeism) and reduced productivity at work (presenteeism), which are the indirect costs of illness. This article presents a productivity model demonstrating the indirect costs associated with IBS and the reduction in those costs for a cohort of female employees hypothetically treated with tegaserod, a new selective serotonin (5-hydroxytryptamine [5-HT]) type 4 (5-HT4) receptor agonist, which is approved by the US Food and Drug Administration for treating women with IBS-C. The model is based on economic and epidemiologic published literature and clinical trial results. In this model, tegaserod treatment resulted in 1882 dollars in avoided lost productivity per treated female employee. Considering only the benefits of decreased work loss and the costs of medical therapy, the model predicts a benefit/cost ratio of 3.75 in the base case. From an employer's perspective, medical therapy for IBS with tegaserod is cost-effective under a series of assumptions for the treatment of women with IBS with constipation.
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PMID:Tegaserod treatment for IBS: a model of indirect costs. 1592 63

Irritable bowel syndrome (IBS) is a debilitating disease, which is characterised by recurrent abdominal cramping and pain, and is associated with either constipation and/or diarrhoea. It is approximately twice as prevalent in women as it is in men and is among the most common gastrointestinal (GI) disorders encountered in primary care. The aetiology of the disease is poorly understood but may include motility dysregulation, visceral sensitivity, inflammation, bacterial infection, dietary antigens, psychological stress, GI surgery or a gut-brain phenomenon. At present, there is no acceptable treatment for IBS, although recent advances indicate that some relief may be achieved by the administration of compounds that act on 5-HT (serotonin) receptors. This suggestion is the result of numerous studies which have shown that 5-HT may exert a number of diverse effects on human GI tissues. In addition, it has emerged that the levels of the 5-HT metabolite (5-HIAA) are raised in the plasma of IBS patients and that administration of 5-HT-like compounds may mimic the symptoms of IBS. It has therefore been proposed that therapy with compounds that act at 5-HT receptors will return the intestine to normal activity and alleviate the pain experienced by these patients. One compound (alosetron, a 5-HT3 receptor antagonist) has already been released onto the market but showed benefit in female patients only and only in those whose primary symptom was diarrhoea. In addition, the compound was recently withdrawn following concerns over its safety. The reasons why alosetron only appears to show efficacy in females, why these treatments are only effective in a subset of the population of IBS patients and why alosetron elicits its particular side effect profile have not been elucidated. One further serotonergic compound, tegaserod (Zelmac, a 5-HT4 receptor agonist), has shown promise for the treatment of patients with constipation-predominant IBS and is currently in pre-registration for this indication. It is clear, however, that further research will have to take place before the utility of serotonergic modulation in the treatment of IBS can be fully validated.
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PMID:Serotonergic modulation and irritable bowel syndrome. 1598 96

Correlations exist between the incidence of depression, irritable bowel syndrome (IBS) and overactive bladder [Masand, P.S., Kaplan, D.S., Gupta, S., Bhandary, A.N., Nasra, G.S., Kline, M.D., Margo, K.L., 1995. Major depression and irritable bowel syndrome: is there a relationship? J. Clin. Psychiatry 56, 363-367.; Cukier, J.M., Cortina-Borja, M., Brading, A.F., 1997. A case-control study to examine any association between idiopathic detrusor instability and gastrointestinal tract disorder, and between irritable bowel syndrome and urinary tract disorder. Br. J. Urol. 79, 865-878.; Monga, A.K., Marrero, J.M., Stanton, S.L., Lemieux, M.C., Maxwell, J.D., 1997. Is there an irritable bladder in the irritable bowel syndrome? Br. J. Obstet. Gynaecol. 104, 1409-1412.; Zorn, B.H., Montgomery, H., Pieper, K., Gray, M., Steers, W.D., 1999. Urinary incontinence and depression. J. Urol. 162, 82-84.]. Furthermore, alterations in serotonergic neurotransmission may play a common role in the etiology of these disorders. Serotonin reuptake transporter knockout mice (5-HTT(-/-)) display phenotypes consistent with clinical features of mood and bowel disorders including anxiety and abnormal gastrointestinal motility [Holmes, A., Murphy, D.L., Crawley, J.N., 2003. Abnormal behavioral phenotypes of serotonin transporter knockout mice: parallels with human anxiety and depression. Biol. Psychiatry 54, 953-959.]. In the present study, we evaluated bladder function in 5-HTT(-/-) mice. We have found that female 5-HTT(-/-) mice exhibit bladder dysfunction, characterized by significant increases in the frequency of spontaneous non-voiding bladder contractions and decreases in void volume compared to control female mice. These differences were not observed in male knockout mice. These studies provide significant supporting data for a mechanistic link between alterations in 5-HT, depression, IBS and overactive bladder in women.
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PMID:Female, but not male, serotonin reuptake transporter (5-HTT) knockout mice exhibit bladder instability. 1602 97

During our search for therapeutic agents to treat diarrhea-predominant IBS, we found that 2-substituted benzoxazole derivatives have a characteristic 5-HT(3) receptor partial agonist activity with high affinity. Some of these compounds showed high in vitro metabolical stability, and 6g showed marked antidiarrhetic activity with little side effect of constipation in in vivo tests. Our results indicate that 5-HT(3) receptor partial agonists might be superior as therapeutic agents to the drugs currently used for IBS treatment.
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PMID:Orally active benzoxazole derivative as 5-HT3 receptor partial agonist for treatment of diarrhea-predominant irritable bowel syndrome. 1625 Jun 67

Tegaserod is a novel selective serotonin receptor type-4 (5-HT(4)) partial agonist that stimulates gastrointestinal (GI) motility. Tegaserod has proven efficacy in irritable bowel syndrome with constipation in women and in men and women with chronic idiopathic constipation. The effects on gastric emptying, small bowel transit and colonic transit have not been studied in detail in male and female subjects. This study aimed therefore to assess the effect of gender on GI transit with and without tegaserod. A randomized, placebo-controlled, double-blind, crossover study was performed in 40 healthy subjects (23 males, 17 females). Each treatment period involved three and a half days of bid treatment with either 6 mg tegaserod or an identical placebo. Transit parameters were assessed by a scintigraphy. Tegaserod significantly accelerated gastric emptying, small bowel and colonic transit times (P<0.05-0.0001). The effect was more apparent in male subjects than in females (P=0.044 to P<0.0001). The most striking prokinetic effects were observed in the upper GI tract (stomach and small intestine). In both healthy male and female subjects, tegaserod markedly accelerated small intestinal transit, and induced a significant increase in gastric emptying time and colonic transit. The results imply that tegaserod is a potent prokinetic agent throughout the GI in both sexes.
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PMID:Effect of tegaserod on gut transit in male and female subjects. 1633 97

Tegaserod is a 5-HT(4) receptor partial agonist approved for the treatment of irritable bowel syndrome in women with constipation and in both men and women with chronic constipation. The efficacy of tegaserod is based on the importance of 5-HT(4) receptors regulating intestinal peristalsis and secretion, and possibly visceral sensory pathways. Our aim was to investigate the effect of tegaserod on colorectal sensitivity using models of normal and exaggerated responsiveness to colorectal distension (CRD). The visceromotor responses (VMR) to CRD at graded pressures (0-60 mmHg) were measured by the number of reflex abdominal contractions. Acute colorectal hypersensitivity was induced by intracolonic infusion of dilute acetic acid. Chronic hypersensitivity was observed in rats following spontaneous resolution of trinitrobenzenesulfonic acid-induced colitis. Rats with normosensitive colons served as controls. Tegaserod (0.1-10 mg kg(-1)) caused dose-dependent reduction of the VMR to CRD in control rats and in those with colonic hypersensitivity. 5-HT(4) antagonists reversed the effects of tegaserod in rats with normosensitive colons, and partially inhibited effects in rats with colonic hypersensitivity. Central administration of tegaserod had no inhibitory effect. These results support the assumption that colonic hypersensitivity could be normalized by tegaserod acting, at least in part, through peripheral 5-HT(4) receptors.
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PMID:Activation of peripheral 5-HT receptors attenuates colonic sensitivity to intraluminal distension. 1637 Oct 86

The association between migraine and functional gastrointestinal disorders has been confirmed by many clinical observations and epidemiological studies. In most patients during the attacks of migraine, apart from various neurological and vascular symptoms, gastrointestinal disturbances occur including nausea, vomiting, abdominal pain or diarrhea. Functional gastrointestinal disorders, such as irritable bowel syndrome (IBS), are reported in migraine patients in periods between the attacks as well. On the other hand 23-53% of IBS patients have frequent headaches. Migraine and IBS often coexist with fibromyalgia and other chronic pain syndromes and functional disorders. Migraine and IBS affect approximately 10-20% of the general population, usually young adults. Both diseases are more prevalent in women, perhaps due to the role of estrogen in their pathogenesis. Looking for the common pathogenetic mechanisms of IBS and migraine the role of the brain-gut axis, neuroimmune and neuroendocrine interactions are being considered. The influence of stress on symptom occurrence and severity seems to be associated with hyperactivity of the hypothalamic-pituitary-adrenal axis. The enteric nervous system as a source of numerous neurotransmitters and visceral reflexes is a plausible common pathogenic link between IBS and migraine. In particular serotonin being the main neurotransmitter of the gastrointestinal tract plays a relevant role in the pathogenesis of IBS as well as migraine. Nowadays, agonists and antagonists of serotoninergic receptors are the most efficacious drugs for IBS and migraine therapy. Some side effects of triptans, 5-HT(1B/D) agonists, used in migraine treatment may be connected with the influence of triptans on the gastrointestinal functions. A better understanding of the relationship between migraine and IBS may result in more effective treatment of both diseases.
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PMID:[Migraine and irritable bowel syndrome]. 1641 71


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