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)

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

We wished to determine if visceral perception in the rectum and stomach is altered in patients with irritable bowel syndrome and to evaluate the effects on visceral sensation of 5-HT3 receptor blockade. Twelve community patients with diarrhea-predominant irritable bowel syndrome and 10 healthy controls were studied in a double-blind, randomized, placebo-controlled study. Using two barostats, the stomach and rectum were distended, with pressure increments of 4 mm Hg, from 10 to 26 mm Hg; visceral perception was measured on an ordinal scale of 0-10. Personality traits were measured using standard psychological methods, and somatic pain was evaluated by immersion of the nondominant hand in cold water. The effect of 5-HT3 antagonism was tested with a single intravenous dose of ondansetron at 0.15 mg/kg. Gastric perception was higher in irritable bowel syndrome, but rectal distension was perceived similarly in irritable bowel syndrome and controls. Pain tolerance to cold water was also similar in irritable bowel syndrome and controls. Ondansetron induced rectal relaxation and increased rectal compliance but did not significantly alter gastric compliance or visceral perception. Psychological test scores were similar in patients and controls. We conclude that in this group of psychologically normal patients with irritable bowel syndrome, who were not chronic health-care seekers, visceral perception was normal. Ondansetron did not alter gut perception in health or in irritable bowel syndrome.
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PMID:Visceral perception in irritable bowel syndrome. Rectal and gastric responses to distension and serotonin type 3 antagonism. 772 Apr 76

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 function of serotonin (5-HT)3 receptors on colonic transit was investigated in unanesthetized rats. The colonic transit was accelerated by 5-HT (10 mg/kg, s.c.), 2-methyl-5-HT (30 mg/kg, s.c.), neostigmine (0.03-0.1 mg/kg, s.c.), corticotropin releasing factor (CRF; 1 microgram intracerebroventricular administration) and restraint stress (for 45 minutes). A potent and selective 5-HT3 receptor antagonist, azasetron (+/-)-N-(1-azabicyclo[2.2.2]oct-3-yl)-6-chloro- 4-methyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-8-carboxamide monohydrochloride ; 0.01-10 mg/kg, p.o. inhibited the 5-HT-, CRF- and stress-accelerated colonic transit in a dose-dependent manner. Ondansetron (10 mg/kg, p.o.) and granisetron (1 mg/kg, p.o) also inhibited the stress-accelerated colonic transit, but azasetron was more effective than these two drugs. Atropine methylbromide (0.1 mg/kg, s.c.) and tetrodotoxin (0.01 mg/kg, s.c.) inhibited the accelerated colonic transit under stress conditions, but methysergide (10 mg/kg, s.c.), SDZ205-557 (10 mg/kg, s.c.), domperidone (30 mg/kg, p.o.), trimebutine (300 mg/kg, p.o.), did not. Azasetron (10 micrograms) administered intracerebroventricularly did not inhibit the stress-induced acceleration. These results suggest that endogenous 5-HT which is released through stress accelerates the colonic transit via the 5-HT3 receptors and finally a cholinergic mechanism. It is considered that azasetron inhibits colonic transit particularly under stress conditions through the blockade of the peripheral 5-HT3 receptors. Azasetron may improve bowel function in stress-related colonic dysfunction like irritable bowel syndrome.
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PMID:The function of 5-HT3 receptors on colonic transit in rats. 865 66

The irritable bowel syndrome (IBS) is a consortium of symptoms including abdominal pain and alterations in the pattern of defaecation. There is no single pathophysiological marker of IBS although it is generally accepted that some patients do have abnormalities of intestinal motility and/or enhanced visceral sensitivity. There is also an increasing acceptance that the central nervous system, an important component of the brain-gut axis, also plays an important role in symptom production both in the response to stress and when there is an underlying affective disorder. During the past decade new therapeutic targets have been identified that have permitted the development of new drugs with therapeutic potential for IBS. Identification and characterization of 5-hydroxytryptamine (5-HT) receptors in the gastrointestinal tract particularly 5-HT3 and 5-HT4 receptors, which are involved not only in modulating gut motility but in visceral sensory pathways, has led to a number of studies of 5-HT3 (Alosetron, Granisetron and Ondansetron) and 5-HT4 (SB-207266A) antagonists. Both classes of drug appear to reduce visceral sensitivity and have inhibitory effects on motor activity in the distal intestine. Early clinical studies suggest that these agents may have a role in painful, diarrhoea-predominant IBS. 5-HT4 agonists (HTF919, Zelmac) may improve constipation-predominant IBS by normalizing bowel habit and thereby reducing abdominal pain. Alternative approaches to reducing visceral sensation include the use of the opioid kappa agonists, which have no central opioid effects although clinical trials have suggested that these agents are not highly effective in relieving IBS pain. There are in addition, new approaches to modify intestinal motility including the development of gut selective muscarinic M3 receptor antagonists such as zamifenacin and the 5-HT4 partial agonist, HTF919. Preliminary studies suggest that these agents may have therapeutic potential in IBS. Anti-depressants are increasingly used to treat affective disorder in IBS but in addition appear to have added value because of their ability to reduce visceral hypersensitivity and alter gut transit. Therapeutic effects are often obtained at doses below those normally used to treat depression. IBS continues to be a therapeutic challenge because of its diverse symptomatology and lack of a single pathophysiological target for drug intervention.
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PMID:Irritable bowel syndrome: new pharmaceutical approaches to treatment. 1058 Sep 22

Substance P (SP) is an important neurotransmitter that mediates various gut functions; however, its precise pathophysiological role remains unclear. In this study, we investigated the effect of SP on colonic function and the effect of TAK-637 [(aR,9R)-7-[3,5-bis(trifluoromethyl)benzyl]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]naphthyridine-6,13-dione] a new neurokinin-1 (NK1) receptor antagonist, on colonic responses to SP or stress in Mongolian gerbils. SP and the selective NK1 agonist [pGlu6]SP6-11 significantly increased fecal pellet output. TAK-637 reduced [pGlu6]SP6-11-induced defecation, but did not significantly affect neurokinin A-, 5-hydroxytryptamine- or carbachol-stimulated defecation. Oral TAK-637 decreased restraint stress-stimulated fecal pellet output with an ID50 value of 0.33 mg/kg. Ondansetron and atropine, but not the peripheral kappa-receptor agonist trimebutine, also reduced restraint stress-stimulated defecation. TAK-637 inhibited the increase in fecal pellet output stimulated by intracerebroventricular injection of corticotropin-releasing factor, but did not affect the stress-induced increase in plasma adrenocorticotropic hormone levels. Denervation of the sensory neurons with capsaicin did not affect stress-stimulated defecation. These results suggest that NK1 receptors in the enteric plexus play an important role in stress-induced changes in colonic function, and that TAK-637 may be useful in the treatment of functional bowel diseases such as irritable bowel syndrome.
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PMID:Effects of TAK-637, a novel neurokinin-1 receptor antagonist, on colonic function in vivo. 1145 17

The aim of this study was to develop colon-specific delivery systems of ondansetron using natural polymers such as guar gum and sodium alginate. For this purpose colon specific matrix tablets were prepared by a direct compression method. The physical properties of the tablets were tested and in vitro release studies were performed by a flow-through cell apparatus. The amount of polymers affected the in vitro drug release from the matrix tablets. A high amount of polymers provided slow drug release whereas the release of ondansetron from the tablets prepared with low amount of polymers was found to be fast. Ondansetron-alginate and/or guar gum matrix tablet formulations can deliver the drug to the small and large intestine thus these matrix may be a promising system for the reduction of visceral sensitivity and inhibition of motor activity in irritable bowel syndrome (IBS).
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PMID:Investigation of colon-specific dosage forms of ondansetron prepared with natural polymers. 1715 83

1. 5-Hydroxytryptamine (5-HT) has an important role in the pathogenesis of irritable bowel syndrome. To investigate the effects of 5-HT on the contractile activity of myocytes of the guinea-pig proximal colon, cell imaging before and after contraction was undertaken and images were analysed using image-analysis software. Ion currents and membrane potentials were measured. Cytoplasmic free Ca(2+) was recorded using a confocal microscope following loading of the cells with the fluorescent probe Fura-2AM. 2. 5-Hydroxytryptamine reduced cell length in a dose-dependent manner (EC(50) = 0.189 micromol/L). Under current clamp, 10 micromol/L 5-HT reduced action potential amplitude (measured as peak height) and decreased action potential duration, as well as depolarizing the resting potential from -68.4 +/- 3.6 to -22.96 +/- 4.65 mV. Iberiotoxin (1 micromol/L) blocked the effects of 5-HT in reducing the time to repolarization (T(90)) and nicardipine (5 micromol/L) blocked the effects of 5-HT in reducing action potential amplitude. 3. In the whole-cell mode, 5-HT enhanced L-type Ca(2+) currents, large conductance K(+) channel (BK(Ca)) currents and spontaneous transient outward currents (STOC). In addition, 5-HT increased intracellular Ca(2+) levels. Ondansetron (10 micromol/L) blocked the effects of 5-HT in enhancing L-type Ca(2+) currents, BK(Ca) currents and STOC. 4. In conclusion, 5-HT induces contraction of colonic myocytes, mostly as a result of Ca(2+) release from the sarcoplasmic reticulum (SR) following activation of 5-HT(3) receptors and the inositol 1,4,5-trisphosphate pathway. In addition, the effect of 5-HT in decreasing action potential amplitude is mediated by the release of Ca(2+) from the SR, as well as by enhanced L-type Ca(2+) current. 5-Hydroxytryptamine decreased action potential duration by enhancing BK(Ca) current.
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PMID:Mechanisms mediating serotonin-induced contraction of colonic myocytes. 1720 46

In an outbreak of waterborne giardiasis where 1300 subjects were diagnosed, with Giardia lamblia, 139 continued to have abdominal symptoms of whom two of three had negative stool culture and microscopy. These were considered to have a postinfectious functional gastrointestinal disorder. We investigated visceral hypersensitivity in patients with persisting abdominal symptoms after Giardia infection and assessed the effect of 5HT(3)-antagonist ondansetron. Twenty-two patients with Giardia negative stools and 19 controls were included. A subset of patients (n = 15) had both irritable bowel syndrome (IBS) and functional dyspepsia (FD). All subjects underwent a satiety test with a soup combined with three-dimensional ultrasound. Fifteen of 22 patients underwent double-blind, randomized, placebo-controlled study with the 5-HT(3) antagonist ondansetron given orally. Drinking capacity was lower in patients than in controls (P < 0.01) and gastric emptying was reduced (P < 0.05). Patients had more symptoms both fasting and postprandially (P < 0.001) compared to controls. Ondansetron had no effect on these parameters except from less nausea postprandially (P < 0.05). In conclusion, patients with Giardia-induced gastrointestinal symptoms developed both IBS and FD. They exhibited gastric hypersensitivity with lower drinking capacity and delayed gastric emptying. The 5-HT(3) antagonist ondansetron did not improve drinking capacity, gastric emptying or symptoms except nausea.
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PMID:Increased visceral sensitivity in Giardia-induced postinfectious irritable bowel syndrome and functional dyspepsia. Effect of the 5HT3-antagonist ondansetron. 1797 37

There is a clear unmet need for new treatments in irritable bowel syndrome with diarrhea (IBS-D). Ondansetron, an old 5-hydroxy-tryptamine3 antagonist, used for chemotherapy-induced nausea and vomiting and with favorable side effect profile, has shown promising results in previous trials. In this issue, efficacy with a novel bimodal release ondansetron formulation was presented in IBS-D. The bimodal release ondansetron improved stool consistency, presumably by slowing transit time, and tended to improve other IBS symptoms as well. The authors proposed C-reactive protein levels as a tool to select responders because a better response was seen in patients with slightly elevated C-reactive protein levels. Future large-scale studies will determine the role of bimodal release ondansetron in IBS-D with and without low-grade inflammation.
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PMID:Positive Effect of Bimodal Release Ondansetron in Irritable Bowel Syndrome With Diarrhea: Relevance of Low-Grade Inflammation? 3307 46


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