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

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.
 ...
PMID:5-Hydroxytryptamine and functional bowel disorders. 895 36

In 1983, Coates conducted a survey that ranked the side-effects perceived by patients receiving chemotherapy in the order of their severity. Vomiting and nausea were found to be the two most distressing side-effects. They have an impact on quality of life and compliance with treatment. The development of 5HT3 antagonists has been a major step forward in the prevention and treatment of chemotherapy-induced nausea and vomiting. Presently, these antiemetics are routinely used as concomitant therapy in emetogenic chemotherapy regimens. The purpose of this study was to evaluate the impact of 5HT3 antagonists on patient perceptions of the side-effects of chemotherapy. Coates' survey was replicated in patients who received 5HT3 antagonists for acute nausea and vomiting resulting from emetogenic chemotherapy. Patients received the survey to identify those physical and non-physical side-effects that they attributed to chemotherapy and were asked to rank the five most distressing side-effects. Of the 197 patients who consented to take part in the study, 181 were evaluable. Nausea, hair loss and vomiting were described as the three most distressing side-effects of chemotherapy. Eighty per cent of all the patients actually experienced nausea and 57% experienced vomiting. Hair loss appeared to be more distressing to women (P < 0.001) but, in other aspects, gender, age and marital status did not influence the ranking of the three most distressing side-effects. Constipation was ranked as 6th and was not identified as a distressing side-effect in 1983. Nausea and vomiting remain to be the first and third most distressing side-effects of chemotherapy, even though the incidence and severity of acute nausea and vomiting are now significantly reduced.
 ...
PMID:Patient perceptions of the side-effects of chemotherapy: the influence of 5HT3 antagonists. 937 66

A series of benzoxazoles with a nitrogen-containing heterocyclic substituent at the 2-position was prepared and evaluated for 5-HT3 partial agonist activity on isolated guinea pig ileum. The nature of the substituent at the 5-position of the benzoxazole ring affected the potency for the 5-HT3 receptor, and the 5-chloro derivatives showed increased potency and lowered intrinsic activity. 5-Chloro-7-methyl-2-(4-methyl-1-homopiperazinyl)benzoxazole (6v) exhibited a high binding affinity in the same range as that of the 5-HT3 antagonist granisetron, and its intrinsic activity was 12% of that of 5-HT. Compound 6v inhibited 5-HT-evoked diarrhea but did not prolong the transition time of glass beads in the normal distal colon even at a dose of 100 times the ED50 for diarrhea inhibition in mice. Compounds of this type are expected to be effective for the treatment of irritable bowel syndrome without the side effect of constipation.
 ...
PMID:Benzoxazole derivatives as novel 5-HT3 receptor partial agonists in the gut. 968 41

5-HT3 receptor antagonists are used to treat radiation-induced sickness. The purpose of this study was to define anti-emetic efficacy and potential for harm of these drugs in radiotherapy. A systematic search, critical appraisal and quantitative analysis of relevant data using the number-needed-to-treat or harm (NNT/H) were conducted. Acute (0 to 24h) and delayed (beyond 24 h) anti-emetic efficacy were analysed separately. Data from 1,404 patients were found in 40 trials published in 36 reports. Data from 197 patients receiving ondansetron or granisetron in five randomised trials were regarded as valid according to preset criteria. One placebo-controlled trial had 10 patients per group and in this ondansetron was not significantly different from placebo. In a larger (n = 105) placebo-controlled trial, ondansetron was significantly more efficacious than metoclopramide for complete control of acute vomiting (NNT 2.2, 95% confidence interval (CI) 1.7-3.3) and acute nausea (NNT 3.6, 95% CI 2.2-10.2). Three trials reported delayed outcomes with ondansetron or granisetron: there was no evidence of any difference compared with placebo or other anti-emetics. Two trials reported no acute or delayed but a 'worst day' outcome; in these ondansetron's antivomiting effect was significantly better than placebo (NNT 4.4, 95% CI 2.5-23) or prochlorperazine (NNT 3.8, 95% CI 2.4-10.3), but not its antinausea effect. Constipation and headache were associated significantly with 5-HT3 receptor antagonists compared with other anti-emetics or placebo (NNH 6.4 and 17.1, respectively). Only 14% of published data enabled valid estimation of the anti-emetic efficacy of 5-HT3 receptor antagonists in radiotherapy. There was some evidence that these drugs prevent acute vomiting: 40% of treated patients will benefit (NNT approximately 2.5). The evidence for nausea was less clear. There was no evidence that these drugs are of any benefit beyond 24 h. There was evidence that they produce specific adverse effects.
 ...
PMID:Efficacy of 5-HT3 receptor antagonists in radiotherapy-induced nausea and vomiting: a quantitative systematic review. 1002 3

Among the most distressing symptoms experienced by patients who have undergone high-dose chemotherapy and stem cell transplantation are nausea and vomiting. The chemotherapy regimens used in high-dose conditioning protocols are highly emetogenic. The 5HT3 receptor antagonists are very effective in the prevention and abolition of nausea and vomiting resulting from chemotherapeutic drugs. One of them, tropisetron, is a selective antagonist of serotonin 5HT3 receptors with proven efficacy against emesis. Dexamethasone is also known as an effective agent against nausea and vomiting. The addition of dexamethasone to a 5HT3 receptor antagonist is synergistic, as has been shown in many trials with highly emetogenic drugs. The aim of the present trial was to study the efficacy and safety profile of the combination of tropisetron and dexamethasone in controlling nausea and vomiting in patients receiving megatherapy prior to stem cell transplantation. We studied 31 patients. All of them were evaluable for response and toxicity. The majority of patients achieved complete or major protection against acute vomiting (71-83%), and 67-84% of the patients had no or mild nausea. The combination was tolerated well, and only a minority of patients reported side effects. Among them the most common were headache (in three patients) and constipation. No patient withdrew from the study because of toxicity. It has become evident from our data that the administration of 5 mg tropisetron daily in combination with 20 mg dexamethasone for 8 days can prevent the acute emesis otherwise experienced by patients receiving high-dose chemotherapy as conditioning in stem cell transplantation programmes.
 ...
PMID:The anti-emetic efficacy of tropisetron plus dexamethasone in patients treated with high-dose chemotherapy and stem cell transplantation. 1008 87

Although it is unclear to what extent irritable bowel syndrome (IBS) symptoms represent a normal perception of abnormal function or an abnormal perception of normal function, many believe that IBS constitutes the clinical expression of an underlying motility disorder, affecting primarily the mid- and lower gut. Indeed, transit and contractile abnormalities have been demonstrated with sophisticated techniques in a subset of patients with IBS. As a consequence, drugs affecting gastrointestinal (GI) motility have been widely employed with the aim of correcting the major IBS manifestations, ie, pain and altered bowel function. Unfortunately, no single drug has proven to be effective in treating IBS symptom complex. In addition, the use of some medications has often been associated with unpleasant side effects. Therefore, the search for a truly effective and safe drug to control motility disturbances in IBS continues. Several classes of drugs look promising and are under evaluation. Among the motor-inhibiting drugs, gut selective muscarinic antagonists (such as zamifenacin and darifenacin), neurokinin2 antagonists (such as MEN-10627 and MEN-11420), beta3-adrenoreceptor agonists (eg, SR-58611A) and GI-selective calcium channel blockers (eg, pinaverium bromide and octylonium) are able to decrease painful contractile activity in the gut (antispasmodic effect), without significantly affecting other body functions. Novel mechanisms to stimulate GI motility and transit include blockade of cholecystokinin (CCK)A receptors and stimulation of motilin receptors. Loxiglumide (and its dextroisomer, dexloxiglumide) is the only CCKA receptor antagonist that is being evaluated clinically. This drug accelerates gastric emptying and colonic transit, thereby increasing the number of bowel movements in patients with chronic constipation. It is also able to reduce visceral perception. Erythromycin and related 14-member macrolide compounds inhibit the binding of motilin to its receptors on GI smooth muscle and, therefore, act as motilin agonists. This antibiotic accelerates gastric emptying and shortens orocecal transit time. In the large bowel a significant decrease in transit is observed only in the right colon, which suggests a shift in fecal distribution. Several 'motilinomimetics' have been synthesized. Their development depends on the lack of antimicrobial activity and the absence of fading of the prokinetic effect during prolonged administration. 5-hydroxytryptamine (5-HT)4 agonists with significant pharmacological effects on the mid- and distal gut (such as prucalopride and tegaserod) are available for human use. These 'enterokinetic' compounds are useful for treating constipation-predominant IBS patients. 5-HT3 receptor antagonists also possess a number of interesting pharmacological properties that may make them suitable for treatment of IBS. Besides decreasing colonic sensitivity to distension, these drugs prolong intestinal transit and may be particularly useful in diarrhea-predominant IBS. Finally, when administered in small pulsed doses, octreotide, besides reducing the perception of rectal distension, accelerates intestinal transit, although other evidence disputes such an effect.
 ...
PMID:Management of irritable bowel syndrome: novel approaches to the pharmacology of gut motility. 1020 10

Binding properties of gastrointestinal prokinetic benzamides for both cloned human 5-hydroxytryptamine (5-HT)3 receptors and cloned human 5-HT4 receptors were examined and pharmacological properties of YM-53389{(+)-(S)-2-chloro-5-methoxy-4-[5-(2-piperidylmethyl)-1,2, 4-oxadiazol-3-yl]aniline monohydrochloride} were characterised in animals. Cisapride, renzapride and zacopride inhibited specific binding of [3H]ramosetron to cloned human 5-HT3 receptors, with Ki values of 684, 7.64 and 0.38 n m, respectively. YM-53389, however, slightly replaced that (Ki>10,000 n m). YM-53389, cisapride, renzapride and zacopride replaced specific binding of [3H]GR 113808 to cloned human 5-HT4 receptors, with Ki values of 54.6, 41.5, 115 and 373 n m, respectively. The potency for inhibitory effect of YM-53389 on 5-HT3 receptor-mediated contraction in the guinea-pig isolated colon was very low with pIC50 of 4.7. YM-53389 exerted 5-HT4 receptor-mediated relaxation in the carbachol-precontracted rat isolated oesophagus with pEC50 of 6.3. In mice, YM-53389 at 10 and 30 mg kg-1, s.c. significantly shortened whole gut transit time, in contrast to cisapride, renzapride and zacopride which were reported to delay that. YM-53389 had no significant effect on upper gastrointestinal propulsion at doses up to 30 mg kg-1, s.c. Based on these results, YM-53389 may surpass existing benzamides in facilitating lower intestinal propulsion and benefit patients with gastrointestinal disorders associated with impair of intestinal propulsion, such as constipation, based on the selective interaction with human 5-HT4 receptors vs human 5-HT3 receptors.
 ...
PMID:Pharmacological properties of a novel gastrointestinal prokinetic benzamide selective for human 5-HT4 receptor versus human 5-HT3 receptor. 1032 95

Irritable bowel syndrome (IBS) is one of the most common gastrointestinal-related conditions. In this review, the safety and efficacy of alosetron, a potent and selective 5-HT3 receptor antagonist, in the treatment of IBS are discussed. Alosetron has been shown to produce statistically significant improvements in abdominal pain, stool consistency, stool frequency and urgency in female IBS patients. By contrast, no consistent improvement has been seen in male IBS patients treated with alosetron. The only adverse event of note with alosetron was constipation, and this represents a class effect of 5-HT3 receptor antagonists. In conclusion, alosetron is a safe and effective treatment for female IBS patients.
 ...
PMID:Review article: the safety and efficacy of alosetron, a 5-HT3 receptor antagonist, in female irritable bowel syndrome patients. 1042 45

The paper is devoted to review literature data on intravenous and oral antiemetic effectivity of granisetron (GRAN) a selective 5HT3 antagonist and to determine the optimal dose for the prophylaxis of chemotherapy-induced acute emesis. The drug was put on the market in the injectable form in 1994 and in the oral form in 1995, so a sufficient number of reports have been published for the evaluation. According to the summarized data on 6095 patients treated with intravenous GRAN, on average 66% antiemetic complete response (CR) rate was reached (i.e. no vomiting in the first 24 hours of chemotherapy). Best results were observed with the dose of 40 microg/kg intravenous GRAN, on average 70% CR (range 47-93%) were achieved in 4182 of the 6095 patients with this dose. In 942 patients treated with the mostly applied oral dose of GRAN (1 mg twice daily), on average 61% CR (range 52-82%) were reported. Side effects were weak and transient, mostly headache and constipation were observed. Headache appeared in 13% with the use of 40 microg/kg intravenous dose GRAN and in 18% with 1 mg oral dose twice daily Constipation was observed in 5.3% and 17% with the injection and oral dose, respectively.
 ...
PMID:About the antiemetic effectivity of granisetron in chemotherapy-induced acute emesis: a comparison of results with intravenous and oral dosing. 1046 29

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.
 ...
PMID:Alosetron. 1077 33


<< Previous 1 2 3 4 5 6 7 Next >>