Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P46098 (5-HT3 receptor)
 2,290 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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 selective 5HT uptake inhibitor, litoxetine (SL 81.0385), currently under development as an antidepressant was shown to have antiemetic properties in the ferret. Litoxetine (at 1 and 10 mg/kg i.v.) dose dependently reduced the number of retches and vomiting as well as the number of emetic episodes induced by cisplatin (10 mg/kg i.v.) and delayed the onset of emesis. Fluoxetine (at 1 or 10 mg/kg i.v.) failed to inhibit cisplatin-induced emetic responses and, in contrast, significantly increased the number of retches and vomiting and accelerated the onset of emesis. The possibility that the antiemetic effects of litoxetine may be mediated through an interaction with 5HT3 receptors was studied using [3H]quipazine or [3H]BRL 43694 to label the 5HT3 receptor. Litoxetine has moderate affinity for cerebral 5HT3 receptors (Ki = 85 nM), while fluoxetine, similar to other 5HT uptake inhibitors, has only negligible affinity for this receptor (Ki = 6.5 microM). It is proposed that litoxetine inhibits cisplatin-induced emetic responses due to its moderate 5HT3 antagonist properties. The clinical use of the majority of serotonergic antidepressants (e.g. fluoxetine, fluvoxamine etc.) is associated with gastrointestinal discomfort (particularly nausea and vomiting) as a major side-effect. If nausea and vomiting associated with the use of 5 HT uptake inhibitors are due to stimulation of 5HT3 receptors, the concomitant 5HT3 antagonism of litoxetine may limit the gastrointestinal side-effects of this novel antidepressant and thus offer an important advantage.
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PMID:Litoxetine: a selective 5-HT uptake inhibitor with concomitant 5-HT3 receptor antagonist and antiemetic properties. 838 15

We have investigated the behavioral effect of the 5-hydroxytryptamine3 (5-HT3) receptor agonists 1-phenylbiguanide (PBG) and m-chlorophenylbiguanide (mCPBG) in rats after i.p. and i.c.v. injection. It was hoped that this approach may provide an alternative means of studying the role of 5-HT3 receptors on animal behavior, for the majority of related studies have used antagonists at this subtype. Both PBG (3-60 mg/kg, i.p.) and mCPBG (1-30 mg/kg i.p.) produced abdominal constrictions, writhing and salivation in some, but not all, rats. The most marked behaviors were seen after mCPBG (30 mg/kg, i.p.), where paw shakes and chin rubbing was also recorded. Almost certainly as a consequence of these behaviors, PBG (3-30 mg/kg, i.p.) and mCPBG (0.3-10 mg/kg, i.p.) produced a conditioned place aversion. Pretreatment with the 5-HT3 antagonists ondansetron (0.01-0.1 mg/kg, s.c.), ICS205-930 and quaternized ICS205-930 (both 0.1 mg/kg, i.p.) blocked the PBG (30 mg/kg, i.p.)-induced place aversion. PBG (30 mg/kg, i.p.) and mCPBG (10 mg/kg, i.p.) also produced a conditioned taste aversion. The central administration of PBG (1-30 micrograms, i.c.v.) and mCPBG (0.1-10 micrograms, i.c.v.) enhanced locomotor- and gnawing-related behavior, although the effects with PBG seemed more consistent. These PBG (10 micrograms, i.c.v.)-induced behaviors were completely blocked by haloperidol (0.01-0.1 mg/kg, s.c.). In contrast, ondansetron (0.0001-1 mg/kg, s.c.) and ICS205-930 (0.1 mg/kg, i.p.) produced only a mild and inconsistent attenuation of these responses. PBG (1-30 micrograms, i.c.v.) failed to produce any place conditioning (i.e., neither a preference nor aversion was found). It is concluded that activation of peripheral 5-HT3 receptors leads to aversive-type behaviors, which may be related to gastrointestinal discomfort or malaise. In contrast, central injection of PBG and mCPBG produced a range of dopamine-related behaviors; however, a 5-HT3 receptor involvement is unclear. Because both PBG and mCPBG have dopamine releasing properties, the use of 5-HT3 agonists lacking such effects and/or the use of more discrete microinjection studies are needed to more clearly elucidate the roles of 5-HT3 receptors in the central nervous system.
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PMID:Behavioral effects of the 5-hydroxytryptamine3 receptor agonists 1-phenylbiguanide and m-chlorophenylbiguanide in rats. 845 Apr 78

The possibility that 5-hydroxytryptamine (5-HT) acts as a key sensitising agent in the aetiology of irritable bowel syndrome (IBS) is reviewed. The strategic locations of 5-HT and its receptors are described, the most dominant being the 5-HT3 and 5-HT4 type. 5-HT, acting mostly at 5-HT3 or 5-HT3-like receptors, enhances the sensitivity of visceral neurones projecting between the gut and the central nervous systems. 5-HT, acting at 5-HT4 receptors promotes the sensitivity of enteric neurones that react to luminal stimuli. 5-HT4 and 5-HT3 receptors also mediate, respectively, sensitising and physiological actions of 5-HT on gastro-intestinal motor and secretory functions. This distribution implies that some 5-HT3 receptor antagonists might reduce certain symptoms of IBS, such as pain, by reducing the reactivity of the visceral afferent neurones linking the gut with the brain and spinal cord. However, such antagonists are not likely to find widespread clinical acceptance because they can also affect normal lower bowel function and promote constipation. 5-HT4 receptor antagonists, by contrast, reduce 5-HT-induced enteric nerve hypersensitivity without notably affecting the function of the normal bowel. Accordingly, these agents may reduce the symptoms of IBS directly, by reducing the incidence of defecation and diarrhoea and indirectly, by reducing both 'rebound' constipation and the post-prandial discomfort and pain associated with gastrointestinal hyper-reactivity.
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PMID:5-Hydroxytryptamine and functional bowel disorders. 895 36

Irritable bowel syndrome is characterized by recurrent abdominal pain and altered bowel function. In designing studies to evaluate new treatments for this disease, however, it is difficult to select appropriate endpoints to reflect improvement in the range of symptoms of the syndrome. In the present study we evaluated the parameter of adequate relief of abdominal pain and discomfort, as perceived by the patients, as a key endpoint for efficacy in the treatment of patients with irritable bowel syndrome. Abdominal pain and bowel function data were collected daily from 370 patients with the disease during treatment with placebo or a novel potent 5HT3 receptor antagonist. Once every 7 days adequate relief of pain and discomfort was assessed. Quality-of-life data were collected using self-administered questionnaires. The endpoint of adequate relief was significantly (P < 0.05) correlated with improvement in pain severity scores, percentage of pain-free days, percentage of days with urgency, improvement in stool frequency and consistency, and quality-of-life parameters. Adequate relief of pain and discomfort is significantly correlated with changes in multiple parameters associated with irritable bowel syndrome and can be used as an endpoint for assessing response to therapy in these patients.
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PMID:Adequate relief as an endpoint in clinical trials in irritable bowel syndrome. 960 85

Irritable bowel syndrome (IBS) represents one of the most common gastrointestinal-related diagnoses. Although the precise etiologic basis of IBS is not known, a common presenting symptom is abdominal pain or discomfort that is thought to develop, at least in part, from a heightened awareness of visceral nociceptive input. Agents capable of reducing this heightened visceral nociception would, therefore, have utility in the treatment of IBS. In this study we evaluated the effects of intravenous and intracerebroventricular administration of a 5-HT3 receptor antagonist, alosetron, on blood pressure changes associated with rectal distension in anesthetized and awake dogs. This vasoactive reflex serves as a model for visceral nociception. For intracerebroventricular studies, the cerebroventricular guides were placed over the lateral ventricle. In anesthetized studies, blood pressure was measured by femoral artery cannulation. In awake studies, blood pressure was monitored by noninvasive measurement. A rectal balloon was placed in the rectum of each dog and maintained throughout the experiments. Each dose of alosetron was given to the dogs as an intravenous or intracerebroventricular bolus, and every 30 min the rectal balloon was inflated and blood pressure responses observed. In both anesthetized and awake dogs alosetron produced a significant inhibition of the vasoactive reflex. In particular, alosetron showed high potency when administered intracerebroventricularly. Alosetron, administered either centrally or peripherally, appears to modulate the visceral nociceptive effect of rectal distension in dogs.
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PMID:Central modulation of rectal distension-induced blood pressure changes by alosetron, a 5-HT3 receptor antagonist. 995 18

Distension of the gastrointestinal tract elicits abdominal pain, as well as sensations such as discomfort or fullness. Many patients with irritable bowel syndrome have been reported to show a reduced threshold to the pain or discomfort due to experimental rectal distension. This hypersensitivity of the gut may be characteristics of the irritable bowel, as well as other functional gastrointestinal disorders. Intestinal distension in animals induces a range of responses which have been used as indexes of visceral nociception. This paper reviews a recently introduced canine model used to assess the antinociceptive properties of a novel 5-HT3 receptor antagonist, alosetron.
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PMID:Review article: evaluation of drugs in experimental gut distension models. 1042 41

Minimally invasive therapy aims to minimize the trauma of any interventional process but still achieve a satisfactory therapeutic result. The development of "critical pathways," rapid mobilization and early feeding have contributed towards the goal of shorter hospital stay. This concept has been extended to include laparoscopic cholecystectomy and hernia repair. Reports have been published confirming the safety of same day discharge for the majority of patients. However, we would caution against overenthusiastic ambulatory laparoscopic cholecystectomy on the rational but unproven assumption that early discharge will lead to occasional delays in diagnosis and management of postoperative complications. Intraoperative complications of laparoscopic surgery are mostly due to traumatic injuries sustained during blind trocar insertion and physiologic changes associated with patient positioning and pneumoperitoneum creation. General anesthesia and controlled ventilation comprise the accepted anesthetic technique to reduce the increase in PaCO2. Investigators have recently documented the cardiorespiratory compromise associated with upper abdominal laparoscopic surgery, and particular emphasis is placed on careful perioperative monitoring of ASA III-IV patients during insufflation. Setting limits on the inflationary pressure is advised in these patients. Anesthesiologists must maintain a high index of suspicion for complications such as gas embolism, extraperitoneal insufflation and surgical emphysema, pneumothorax and pneumomediastinum. Postoperative nausea and vomiting are among the most common and distressing symptoms after laparoscopic surgery. A highly potent and selective 5-HT3 receptor antagonist, ondansetron, has proven to be an effective oral and IV prophylaxis against postoperative emesis in preliminary studies. Opioids remain an important component of the anesthesia technique, although the introduction of newer potent NSAIDs may diminish their use. A preoperative multimodal analgesic regimen involving skin infiltration with local anesthesia. NSAIDs to attenuate peripheral pain and opioids for central pain may reduce postoperative discomfort and expedite patient recovery/discharge. There is no conclusive evidence to demonstrate clinically significant effects of nitrous oxide on surgical conditions during laparoscopic cholecystectomy or on the incidence of postoperative emesis. Laparoscopic cholecystectomy has proven to be a major advance in the treatment of patients with symptomatic gallbladder disease.
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PMID:Anesthetic implications of laparoscopic surgery. 1060 86

Alosetron is a potent and highly selective serotonin 5-HT3 receptor antagonist which has been evaluated for the management of irritable bowel syndrome (IBS). It blocked the fast 5HT3-mediated depolarisation of guinea-pig myenteric and submucosal neurons in vitro, with half-maximal inhibition at approximately 55 nmol/L. Alosetron attenuated the visceral nociceptive effect of rectal distension in conscious or anaesthetised dogs. It increased the compliance of the colon to distension in patients with IBS and delayed colonic transit in patients with IBS or carcinoid diarrhoea and in healthy volunteers. A single dose of alosetron 4 mg increased in vivo fluid absorption in normal human small intestine. In clinical trials in patients with IBS, alosetron 1 mg twice daily was effective in relieving abdominal pain and discomfort. Alosetron was most effective in female patients and particularly in those with diarrhoea-predominant IBS. In patients with IBS and healthy volunteers who received alosetron, the most common adverse event was constipation.
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PMID:Alosetron. 1077 33

Existing pharmacotherapeutic options for the treatment of patients with irritable bowel syndrome (IBS) are limited in treating the multiple symptoms associated with the disorder. There is much interest in the use of serotonin agents as new therapeutics. Acting primarily through 5-HT3 and 5-HT4 receptors, serotonin elicits changes in motor function and possibly visceral sensation. Two serotonin agents were developed specifically for IBS: tegaserod, a 5-HT4 receptor partial agonist, and alosetron, a 5-HT3 receptor antagonist (which is no longer available). Phase III clinical trial data show that during a 12-week treatment period with tegaserod, IBS patients with abdominal pain and discomfort, bloating, and constipation experienced significant global relief (i.e., improvement in overall well-being, abdominal pain, and bowel habit) compared with placebo. Improvement in bowel movement frequency and consistency was achieved and pain was relieved by 1 week. During 12 weeks of treatment, alosetron was shown to elicit significant relief of abdominal pain and discomfort compared with placebo or mebeverine in female IBS patients with diarrhea. Alosetron slowed colonic transit and treatment efficacy was apparent after a week of treatment. Another 5-HT4 receptor agonist, prucalopride, which is being developed for chronic constipation, accelerates colonic transit and increases stool frequency. Therefore, this agent may be of benefit in IBS patients with constipation.
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PMID:Drug therapy options for patients with irritable bowel syndrome. 1147 11


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