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)

Serotoninergic innervation may contribute to the control of colonic motility and to visceral sensation from the large bowel. Indeed, ondansetron hydrochloride, a selective 5-hydroxytryptamine type 3 receptor antagonist, has been shown to slow colonic transit in healthy volunteers. Thus, we wished to determine whether 5-hydroxytryptamine type 3 receptor blockade slows colonic and small bowel transit in patients with diarrhea-predominant irritable bowel syndrome (IBS) and whether symptoms would be ameliorated with drug therapy. Of 14 patients with well-established IBS who entered a randomized, double-blind, placebo-controlled crossover pilot trial of 4 weeks of treatment with ondansetron, 16 mg three times daily, 11 completed the study. A minimal "washout period" of 4 weeks (median, 7 weeks) separated the two phases of the trial because patients were required to have similar symptoms before both periods of the study. Colonic transit tended to be longer during drug therapy than during the placebo trial, but this difference was not significant. Small intestinal transit and orocecal transit were unchanged by the drug. The integrated and peak postprandial increases in neurotensin, peptide YY, and human pancreatic polypeptide in serum were not significantly different in the drug and placebo periods. After treatment with ondansetron, stool consistency improved significantly; however, stool frequency, stool weight, abdominal pain, and the symptom criteria for IBS were not significantly altered by the drug. The results of this pilot study suggest that the motor effects expected with 5-hydroxytryptamine type 3 receptor blockade (namely, slowed colonic transit) may be diminished in some patients with IBS. The subjective improvement in stool consistency may reflect changes in the perception of defecation.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Selective 5-hydroxytryptamine type 3 receptor antagonism with ondansetron as treatment for diarrhea-predominant irritable bowel syndrome: a pilot study. 143 22

Serotonin (5-hydroxytryptamine; 5-HT) is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function. A number of receptor or recognition sites have been identified in the gut, but recently most attention has focused on the 5-HT3 and 5-HT4 receptors. The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut. A number of selective 5-HT3 antagonists have been developed including ondansetron, granisetron, tropisetron renzapride and zacopride. While the substituted benzamide prokinetics (for example, metoclopramide, cisapride) also block 5-HT3 receptors in high concentrations, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptor. Some 5-HT3 antagonists have 5-HT4 agonist activity (for example, renzapride, zacopride) and others do not (for example, ondansetron, granisetron), while tropisetron in high concentrations is a 5-HT4 antagonist. Based on the pharmacological data, it has been suggested that specific 5-HT antagonists and agonists may prove to be beneficial in a number of gastrointestinal disorders including the irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, gastrooesophageal reflux and refractory nausea. In this review, the rationale for the use of these compounds is discussed, and the available experimental evidence is summarized.
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PMID:Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. 160 46

Ondansetron (GR 38032F), a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist, is a highly effective and safe drug for the prophylaxis and treatment of emesis induced by various chemotherapy regimens in cancer patients. Recent studies have shown that ondansetron is also effective in post-anaesthesia and radiation-induced nausea and vomiting. When compared with high-dose metoclopramide, ondansetron appeared to be superior. Furthermore, ondansetron has been shown to improve stool consistency and to reduce stool frequency in patients with diarrhoea-predominant irritable bowel syndrome.
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PMID:Closing remarks. Ondansetron: effects on gastrointestinal motility. 183 38

The irritable bowel syndrome (IBS) is an umbrella for the diagnosis of heterogeneous conditions that are awaiting better identification of specific manometric causes. This article focuses on the concept that future therapy for IBS will rely on identification of subgroups and in turn tailor the specific therapeutic approaches to an appreciation of the pathophysiology and symptom predominance of these subgroups. Future therapies will rely on the following principles: (1) prokinetic agents to coordinate upper gastrointestinal and colonic motility as well as improve the propulsive nature of colonic contractions; (2) gastrointestinal hormone agonists such as erythromycin and antagonists such as sandostatin and cholecystokinin antagonists; (3) spasmolytic therapy incorporating calcium channel blocking and anticholinergic agents; (4) inhibition of ovulatory cycle changes in circulating concentrations of gonadal hormones in women, who tend to dominate the IBS population; (5) incorporation of concepts relating to the role of subtypes of 5-hydroxytryptamine receptors in control of neural and myogenic function; (6) reassessment of food intolerance and sensitivity; and (7) incorporation of concepts relating to psychologic profiles and psychologic treatment approaches. IBS is a rich and fertile area for application of the exciting new pharmacologic advances relating to gastrointestinal smooth-muscle and neural innervation of the gut. Improvement in the understanding and treatment of IBS will be one of the major accomplishments of this decade.
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PMID:New directions in the irritable bowel syndrome. 206 57

Bowel dysfunction such as irritable bowel syndrome caused by stress is well described. Previous reports suggest that 5-hydroxytryptamine (5-HT) mediates alteration of bowel motility. In this study, the effects of water-immersion stress and the administration of 5-HT on the expression of a 60-kDa heat shock protein (HSP60) in rat colonic mucosa were investigated. The effect of YM-060, a 5-hydroxytryptamine 3 (5-HT3) receptor antagonist, on the expression of this protein was also studied. Water-immersion stress and the administration of 5-HT induced synthesis of HSP60 in rat colonic mucosa. The induction of HSP60 and the number of defecations were clearly inhibited by the oral administration of YM-060. Our results suggest that the induction of HSP60 in rat colonic mucosa by water-immersion stress may be associated with gastrointestinal motility mediated by 5-HT, especially via 5-HT3 receptors.
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PMID:Regulation of 60-kDa heat shock protein expression by systemic stress and 5-hydroxytryptamine in rat colonic mucosa. 787 66

In some patients with the irritable bowel syndrome, rectal urgency and discomfort are major clinical problems and, under experimental conditions, these symptoms are perceived at lesser volumes of rectal distension than they are in asymptomatic controls. Further, a 5-hydroxytryptamine type-3 receptor antagonist increased the threshold for rectal discomfort in irritable bowel syndrome. Our aims were, (a) to measure rectal sensation during isobaric distensions of the rectum, and (b) to test the effect of another selective 5HT3-antagonist, ondansetron 0.15 mg/kg, on rectal sensitivity, colonic tone, rectal tone and manometric responses. Ten healthy volunteers and five patients with diarrhoea-predominant irritable bowel syndrome were studied. A multilumen barostat-manometric assembly was placed in the descending colon, and a second barostat balloon was positioned in the rectum. Tone in the wall of the colon and rectum was measured by the barostat balloon volume during a constant pressure clamp, while intraluminal pressures were recorded by manometry; perceived sensations were also recorded before and after the intravenous administration of ondansetron or placebo in blinded fashion. Rectal resistance to stretch was greater and rectal urgency was induced by lower distending pressures in irritable bowel syndrome, however, basal tone in the rectum was similar in health and irritable bowel syndrome. Ondansetron did not change rectal sensitivity (first sensation or urgency) or tone. Rectal distension did not alter tone in the descending colon or colonic manometry; ondansetron did not influence any index of colonic function.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of a 5HT3-antagonist (ondansetron) on rectal sensitivity and compliance in health and the irritable bowel syndrome. 828 Aug 23

The effect of granisetron, a specific 5-hydroxytryptamine 3-receptor antagonist, on the anorectal responses to rectal distension and a 1000-calorie meal was assessed in 12 patients with irritable bowel syndrome. Each patient was studied on three occasions, receiving intravenously either 40 mcg/kg granisetron, 160 mcg/kg granisetron or normal saline. Granisetron caused a dose-dependent reduction in rectal sensitivity, manifested by an increase in the threshold volumes at which the sensations of gas, desire to defecate, urgency and discomfort were perceived. This reached significance for all sensations at the higher dose level (P < 0.01). No significant changes in anal pressures, rectal compliance or distension-induced motor activity occurred following drug administration. A dose-dependent reduction in post-prandial motility was observed following intravenous granisetron and this was highly significant at 160 mcg/kg (P = 0.005). These results suggest that the 5 hydroxytryptamine receptor antagonists may have a therapeutic role in patients with irritable bowel syndrome.
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PMID:Reduction of rectal sensitivity and post-prandial motility by granisetron, a 5 HT3-receptor antagonist, in patients with irritable bowel syndrome. 838 53

Postviral fatigue syndrome (PFS) occurs both in epidemics and sporadically. Many of the original epidemics were related to poliomyelitis outbreaks which either preceded or followed them. The core clinical symptoms are always the same: severe fatigue made worse by exercise, myalgia, night sweats, atypical depression and excessive sleep. The other common symptoms include dysequilibrium disorders and irritable bowel syndrome. We have detected enteroviral genome sequences in muscle biopsies from cases of PFS, using specific enteroviral oligonucleotide primers in the polymerase chain reaction (PCR). In addition, whole virus particles can be demonstrated in PCR-positive muscle, using solid-phase immuno-electron microscopy. An increase in the number and size of muscle mitochondria was found in 70% of PFS cases, suggesting an abnormality in metabolic function. Evidence of hypothalamic dysfunction was present, particularly involving 5-hydroxytryptamine metabolism. A putative model of PFS, based on persistent enteroviral infection in laboratory mice, revealed resolving inflammatory lesions in muscle with, however, a marked increase in the production of certain cytokines in the brain. This model may help to explain the pathogenesis of PFS.
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PMID:Enteroviruses and postviral fatigue syndrome. 838 8

A novel series of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives 4,5,6 and 7 was prepared and evaluated for activities as 5-hydroxytryptamine (5-HT3) receptor antagonists which may be useful for the treatment of irritable bowel syndrome (IBS) as well as nausea and vomiting associated with cancer chemotherapy. These compounds were designed by modifying the aromatic-carbonyl part of N-(2-methoxyphenyl)-4,5,6,7-tetrahydro-1H-5-benzimidazolylcarboxamide 3, leaving the imidazole moiety unchanged as the amine part. The indole derivatives 7d, g, h and indolizine derivatives 7k, l were found to be highly potent on the von Bezold-Jarisch (B.J.) reflex test with ID50 values of below 0.1 microgram/kg, and the indoline derivative 6c, indole derivatives 7a, d, g, benzofurane derivative 7j and indolizine derivative 7k were observed to be very potent on the colonic contraction with IC50 values of below 0.1 microM. In particular, 7l was the most potent on the B.J. reflex (ID50 = 0.018 microgram/kg), approximately 200 and 50 times more potent than ondansetron 1 and granisetron 2, and 7k was the most potent on the colonic contraction (IC50 = 0.011 microM), approximately 70 and 6 times more potent than 1 and 2, respectively.
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PMID:Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. II. Synthesis and structure-activity relationships of 4,5,6,7-tetrahydro-1H-benzimidazole derivatives. 868 15

We prepared a novel series of conformationally restricted fused imidazole derivatives 4b, 4c and 4d (possessing 4,5,6,7-tetrahydroimidazo[4,5-c] pyridine and substituted 4,5,6,7-tetrahydro-1H-benzimidazole for 4b, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine for 4c and 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine for 4d as a basic amine part and (2-methoxyphenyl)aminocarbonyl group as an aromatic-carbonyl part). Their activities were then evaluated as an 5-hydroxytryptamine (5-HT3) receptor antagonist which may be useful for the treatment of irritable bowel syndrome (IBS) as well as for nausea and vomiting associated with cancer chemotherapy. The most potent compound was N-(2-methoxyphenyl)-4,5,6, 7-tetrahydro-1H-benzimidazole-5-carboxamide 14 in this series with an ID50 value of 0.32 microgram/kg on the von Bezold-Jarisch reflex in rats and an IC50 value of 0.43 microM on the isolated colonic contraction in guinea pig, approximately ten and two times more potent than ondansetron 1, respectively. The structure activity relationships (SAR) study suggested that the high potency of 14 may be attributed to the suitable position and direction of the N-C-N centroid in the conformationally restricted imidazole ring against the planar (2-methoxyphenyl)aminocarbonyl part in the binding of 14 to the receptor.
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PMID:Novel 5-hydroxytryptamine (5-HT3) receptor antagonists. I. Synthesis and structure-activity relationships of conformationally restricted fused imidazole derivatives. 868 29


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