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)

Lotronex (alosetron hydrochloride) is a 5-HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP 2C9 and 3A4. Alprazolam is a short-acting benzodiazepine commonly prescribed for the treatment of anxiety disorders and a potential comedication in patients with IBS. Alprazolam is extensively metabolized by CYP3A4. This clinical study was conducted to assess the potential for a metabolic drug interaction between these two CYP3A4 substrates. This was an open-label, randomized, two-period, crossover study in 12 healthy female and male volunteers to determine the effect of concomitant administration of alosetron at the recommended dose of 1 mg p.o. bid on the pharmacokinetics of alprazolam following a single oral 1 mg dose. The results showed no effect of alosetron on the pharmacokinetics of alprazolam. Mean alprazolam AUC was 210 and 202 ng.h/mL in the absence and the presence of alosetron, respectively. Therefore, alprazolam may be safely coadministered with alosetron without the need for dosage adjustment.
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PMID:Effect of alosetron on the pharmacokinetics of alprazolam. 1130 2

Lotronex (alosetron hydrochloride) is a 5-HT3 receptor antagonist indicated for the treatment of irritable bowel syndrome (IBS) in females whose predominant bowel habit is diarrhea. Alosetron is extensively metabolized by multiple cytochrome P450 (CYP) enzymes, including CYP2C9 and CYP3A4. Fluoxetine is an antidepressant that is administered as a racemic mixture of equipotent R- and S-enantiomers. Fluoxetine metabolism involves CYP2D6 and CYP2C9 in the formation of its major metabolite, norfluoxetine. This metabolite is also present as two enantiomers, of which only the S-enantiomer exhibits comparable antidepressant activity. This study was conducted to assess the potential for an effect of alosetron on the pharmacokinetics of fluoxetine. This was an open-label, two-period, nonrandomized, crossover study in 12 healthy female and male volunteers. The pharmacokinetics for both enantiomers of fluoxetine and norfluoxetine were examined following single oral doses of 20 mg fluoxetine, given alone and in combination with alosetron 1 mg twice daily for 15 days. The results showed small delays in peak concentration but no clinically significant effect of alosetron on the pharmacokinetics of S- and R-fluoxetine or S- and R-norfluoxetine. Coadministration of alosetron and fluoxetine was well tolerated by all subjects.
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PMID:Effect of alosetron on the pharmacokinetics of fluoxetine. 1130 3

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

Irritable bowel syndrome (IBS) comprises a major proportion of gastrointestinal and primary care practice worldwide. The past several years have seen the rapid evolution of a new and comprehensive model of IBS based on alterations in brain-gut interactions. Alterations in the bidirectional communication between the enteric nervous system and the central nervous system are implicated in the pathogenesis of IBS. 5-Hydroxytryptamine (5-HT; serotonin), a major neurotransmitter in the gastrointestinal tract, and its receptors 5-HT3 and 5-HT4 are involved in the control of gastrointestinal function. A number of abnormal motor and sensory patterns have been reported in patients with IBS. However, it is not known whether these abnormalities are related to symptoms or have a role in establishing a diagnosis of functional gastrointestinal disorders. Visceral hyperalgesia in IBS patients can be secondary to altered receptor sensitivity at the viscus itself and altered central modulation of sensation involving psychological influences in the interpretation of these sensations. The development of diagnostic criteria for IBS helps to avoid unnecessary and costly investigations. A detailed history allows us to diagnose IBS and search for another cause if warning symptoms are present. The Rome criteria are presently used to define IBS and are currently the most widely applied criteria used in clinical diagnosis and research purposes. Abdominal pain or discomfort associated with chronic altered bowel habits are the mainstay in diagnosis, while the supportive criteria may be used to further classify IBS patients into diarrhea-predominant or constipation-predominant subgroups. Minimal diagnostic tests have been advocated in the initial diagnostic approach to patients with suspected IBS, depending on the predominant symptom. The therapeutic goals in IBS must focus on the overall well-being of the patient, including abdominal symptoms and the accompanying nonbowel symptoms and affective disorders. It is important to establish an effective physician-patient relationship and to reassure the patient once the diagnosis of IBS is made. Dietary modification may be of value in some patients with IBS. Dietary fiber is frequently recommended for patients with constipation-predominant IBS. Two novel serotonin agonists are currently under development for constipated IBS patients, tegaserod and prucalopride. Antidiarrheal agents, including loperamide and diphenoxylate, may help patients with diarrhea-predominant IBS. 5-HT3 receptor antagonists may play a role in the management of such patients in the future. Psychological treatment and antidepressants should be considered when IBS symptoms are severe or refractory or associated with psychological distress and impaired quality of life.
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PMID:Irritable bowel syndrome: update on pathogenesis and management. 1211 90

Anticholinergics and prokinetics are mainstays of therapy for Irritable Bowel Syndrome (IBS) patients despite their limited efficacy and troublesome side-effect profile. The clinical limitations of these drugs are a result of their relative broad and nonspecific pharmacologic interaction with various receptors. Recent advances in gut physiology have led to the identification of various receptor targets that may play a pivotal role in the pathogenesis of IBS. Medicinal chemists searching for safe and effective IBS therapies are now developing compounds targeting many of these specific receptors. The latest generation of anticholinergics, such as zamifenacin, darifenacin, and YM-905, provide selective antagonism of the muscarinic type-3 receptor. Tegaserod, a selective 5-HT4 partial agonist, tested in multiple clinical trials, is effective in reducing the symptoms of abdominal pain, bloating, and constipation. Ezlopitant and nepadudant, selective antagonists for neurokinin receptors type 1 and type 2, respectively, show promise in reducing gut motility and pain. Loperamide, a mu (mu) opioid receptor agonist, is safe and effective for IBS patients with diarrhea (IBS-D) as the predominant bowel syndrome. Fedotozine, a kappa (kappa) opioid receptor agonist, has been tried as a visccral analgesic in various clinical trials with conflicting results. Alosetron, a 5-HT3 receptor antagonist, has demonstrated efficacy in IBS-D patients but incidents of ischemic colitis seen in post-marketing follow-up resulted its removal from the market. Compounds that target cholecystokinin. A, N-methyl-D-aspartate, alpha 2-adrenergic, and corticotropin-releasing factor receptors are also examined in this review.
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PMID:Irritable bowel syndrome neuropharmacology. A review of approved and investigational compounds. 1218 41

The 5HT3 receptor antagonist alosetron has been tested in several trials on irritable bowel syndrome (IBS) patients. The aim of the present meta-analysis was to determine its effect on adequate relief of pain or global improvement of symptoms in IBS patients. Six large, multicentre, randomized, placebo-controlled trials fulfilled pre-set criteria for high quality and were included in the meta-analysis; 1762 patients were randomized to alosetron treatment and 1356 to placebo. Seventy-five per cent of the patients experienced diarrhoea-predominant IBS and 93% were females. The pooled odds ratio for adequate relief of pain or global symptoms improvement was 1.81 [95% confidence interval (CI) 1.57-2.10). The average number of patients needed to treat with alosetron for one patient to achieve improvement over placebo treatment was seven (95% CI 5.74-9.43). The present analysis shows that alosetron 1 mg b.i.d. positively impacts global symptoms, and pain and discomfort in non-constipated IBS female patients. One in four patients treated with alosetron may develop constipation. The efficacy of alosetron is unclear in male patients.
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PMID:Efficacy of alosetron in irritable bowel syndrome: a meta-analysis of randomized controlled trials. 1258 72

Through effects on gastrointestinal motor and secretory function as well as visceral sensation, serotonin (5-HT) plays a key role in the pathogenesis of irritable bowel syndrome (IBS). In particular, 5-HT3 and 5-HT4 receptors appear to be very important in IBS. This article critically appraises the evidence supporting the use of the 5-HT3 receptor antagonist alosetron in the treatment of women with diarrhea-predominant IBS. The safety profile and restricted-use program for alosetron is also reviewed. This discussion is followed by a comprehensive review of the efficacy and safety data in support of tegaserod for women with constipation-predominant IBS.
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PMID:Tegaserod and other serotonergic agents: what is the evidence? 1277 1

The irritable bowel syndrome (IBS) remains a therapeutic challenge in part because of the limited understanding of the pathophysiology. The placebo response rate varies in randomized controlled trials from 20 to 70%, and can persist for up to at least 1 year. It is contentious whether dietary fibre and bulking agents relieve the symptoms of IBS; constipation probably improves. Anticholinergic and antispasmodic agents are of questionable benefit in IBS despite positive meta-analyses of poor quality trials. A meta-analysis concluded that the tricyclic antidepressants were superior to placebo in IBS, although the individual trial results were variable. Selective serotonin reuptake inhibitors are of uncertain benefit. Laxatives are used for constipation but probably poorly control the IBS symptom complex. Loperamide is superior to placebo in improvement of diarrhoea but not abdominal pain in IBS. Tegaserod is a well- tolerated aminoguanidine indole derivative of serotonin that is a partial 5HT4-receptor agonist with prokinetic properties; a therapeutic gain over placebo of 5% to 15% has been observed in constipation-predominant IBS in females. Alosetron is a 5HT3-receptor antagonist that is efficacious in females with diarrhoea-predominant IBS, with a 12% to 17% therapeutic gain; the risk of ischaemic colitis is 1 in 350, with very severe constipation occurring in about 1 in 1000. Optimizing study design remains a challenge in IBS. New visceral analgesic and motility modifying agents, as well as anti-inflammatory agents are in trials, and hopefully additional efficacious therapeutic options for patients with IBS will soon emerge.
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PMID:Evaluation of drug treatment in irritable bowel syndrome. 1296 80

Irritable bowel syndrome (IBS) is the most common chronic gastrointestinal (GI) disorder, affecting about 20% of the world's population. Chronic abdominal pain or discomfort relieved by defecation and associated with altered bowel habits are the mainstay in diagnosis. The pathophysiology of IBS remains unknown. This biopsychosocial disorder involves dysregulation of the nervous system, altered intestinal motility, and increased visceral sensitivity. All of these result from dysregulation of the bidirectional communication between the gut with its enteric nervous system and the brain (the brain-gut axis), modulated by various psychosocial and environmental factors (e.g. infection, inflammation). Numerous neurotransmitters are found in the brain and gut that regulate GI activities, including 5-hydroxytryptamine (5-HT, serotonin) and its 5-HT3 and 5-HT4 receptors. The current approach to IBS patients is based on a positive diagnosis of the symptom complex, exclusion of underlying organic disease, and institution of a therapeutic trial. Traditional symptomatic treatment has included antidiarrheals, laxatives and bulking agents/fiber, low-dose tricyclic antidepressants, antispasmodics for pain, and "alternative" therapies (e.g. psychotherapy, hypnotherapy). The scientific evidence supporting this therapy is limited. Novel approaches include visceral analgesics and serotonin agonists and antagonists. In patients with severe diarrhea, 5-HT3 receptor antagonists (e.g. alosetron) and selective M3-type anticholinergics are indicated, in constipation 5-HT4 agonists (e.g. tegaserod), and in pain alfa2-adrenergics (e.g. clonidine), cholecystokinin antagonists, kappa-opioid agonists (e.g. fedotozine), and neurokinin antagonists; some of these agents are still being investigated. Understanding the brain-gut axis is crucial in the development of effective therapies for IBS.
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PMID:The brain-gut axis in irritable bowel syndrome--clinical aspects. 1517 82

The 5-HT3 receptor antagonist alosetron (Lotronex) is indicated for use in women with severe, chronic, diarrhea-predominant irritable bowel syndrome (IBS) who have failed conventional therapy. Oral contraceptives (OCs) and alosetron are potential co-medications in women of childbearing age. This study assessed the effect of alosetron co-administration on pharmacodynamic markers of contraceptive efficacy, on the pharmacokinetics of estrogen and progesterone OC components, and on the activity of biochemical markers for the risk of thrombosis. This was an open label, nonrandomized two-way crossover study in 18 healthy women stabilized for 3 months on a low-dose OC containing ethinyl estradiol (EE) and levonorgestrel (LN). Alosetron had no effect on serum concentrations of luteinizing hormone (LH) or follicle-stimulating hormone. Ovarian activity grades (assessing follicle size, progesterone, and 17beta-estradiol concentrations) were similar during OC use with and without alosetron. Steady-state (Day 21) AUC24, Cmax, and tmax of both LN and EE were similar during coadministration of alosetron with an OC. Concentrations and activity of biochemical markers of thrombosis risk were not different in the presence of alosetron. These results indicate that alosetron does not alter the pharmacokinetics or pharmacodynamic markers of efficacy for a low-dose combination OC. The results also suggest that thromboembolic risk is not increased when alosetron is co-administered with an OC.
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PMID:Pharmacodynamics and pharmacokinetics of oral contraceptives co-administered with alosetron (Lotronex). 1538 53


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