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)

Functional dyspepsia is a complex syndrome with a poorly defined pathophysiology, resulting in uncertainties in its therapeutic approach. Abnormalities in gastrointestinal motility and sensitivity alone or combined seem to play a role in a substantial subgroup of patients. Drugs capable of prokinetic effects, such as antidopaminergics (eg, metoclopramide, domperidone, levosulpiride) and serotonin 5-HT4 receptor agonists (eg, tegaserod) can be potentially used in the treatment of dyspeptic patients. Furthermore, 5-HT4 receptor agonists do not appear to increase the gastric fundus tone which may also contribute to improved symptoms in subsets of patients. Alosetron, a 5-HT3 receptor antagonist, has been investigated mainly in irritable bowel syndrome, and the few studies performed in functional dyspepsia have provided conflicting results. Erythromycin and related derivatives, the motilides, represent another class of prokinetic compounds able to accelerate gastric emptying and potentially indicated in functional dyspepsia. The stimulatory effect on fundic tone and the occurrence of tachyphilaxis hamper the efficacy of these drugs in the long-term treatment. kappa-opioid receptor agonists might be useful for functional digestive syndromes because of their antinociceptive effects, but there are few available results and most are inconclusive. Results are also needed to prove efficacy of antidepressants (tricyclic agents and 5-HT reuptake inhibitors). Future clinical trials should be performed so that the formal structure required by good clinical practice can be adapted to detect significant effects in subgroups of patients with functional dyspepsia. Therapy should be ideally targeted to the different pathophysiologic abnormalities of these subgroups. The identification of the mechanisms leading to symptom generation should facilitate the development of newer and more effective therapeutic strategies in functional dyspepsia.
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PMID:Delayed Gastric Emptying in Functional Dyspepsia. 1523

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

Several 5-HT3 receptor antagonists are available (tropisetron, ondansetron, granisetron, dolasetron, and palonsetron), and further compounds are in clinical development. These substances show only minor differences in the activity profile regarding their affinity for particular receptors. 5-HT3 receptor antagonists are primarily used and found effective in the prevention and treatment of chemotherapy-induced nausea and emesis, and in postoperative nausea and vomiting (PONV). Antagonism of the 5-HT3 receptors in the peripheral and central nervous system is a probable mechanism of action. The substances are suitable as first-line therapy (combined with a corticosteroid) for the prevention of acute nausea and vomiting in patients treated with moderately to severely emetogenic chemotherapeutic agents. This combination is also moderately effective in the prevention of delayed nausea and vomiting. 5-HT3 receptor antagonists are an important constituent in the prevention and treatment of emesis and nausea caused by radiation therapy, especially in patients receiving whole body or upper abdominal treatment. Alosetron was found clinically effective in diarrhoea-predominant irritable bowel syndrome, whereas tropisetron in fibromyalgia and related pain disorders. Further indications for such treatment include anxiety disorders, alcohol dependence, drug withdrawal, and psychosis related to treatment of Parkinson's disease. 5-HT3 receptor antagonists are well tolerated with the most frequently reported adverse effects being headache, constipation, dizziness, tiredness, and gastrointestinal disturbances such as abdominal pain or constipation. Intravenous administration of serotonin induces the Bezold-Jarisch reflex and causes small reversible changes in electrocardiogram (ECG) parameters.
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PMID:Spectrum of use and tolerability of 5-HT3 receptor antagonists. 1551 6

To evaluate therapies available for the treatment of irritable bowel syndrome, and provide consensus recommendations for their use, a total of 51 double-blind clinical trials using bulking agents, prokinetics, antispasmodics, alosetron, tegaserod and antidepressants were selected. The quality of studies was assessed using 5-point scale. Meta-analyses were performed on all studies, and on 'high-quality studies'. The efficacy of fibre in the global irritable bowel syndrome symptoms relief (OR: 1.9; 95% CI:1.5-2.4) was lost after exclusion of low-quality trials (OR: 1.4; 95% CI: 1.0-2.0, P = 0.06). When excluding the low-quality trials, an improvement of global irritable bowel syndrome symptoms with all antispasmodics (OR: 2.1; 95% CI:1.8-2.9) was maintained only for octylonium bromide, but on the basis of only two studies. Antidepressants were effective (OR: 2.6, 95% CI: 1.9-3.5), even after exclusion of low-quality studies (OR: 1.9, 95% CI: 1.3-2.7). Alosetron (OR: 2.2; 95% CI: 1.9-2.6) and tegaserod (OR: 1.4; 95% CI: 1.2-1.5) showed a significant effect in women. We recommend the use of tegaserod for women with irritable bowel syndrome with constipation and alosetron for women with severe irritable bowel syndrome with diarrhoea. Antidepressants can be beneficial for irritable bowel syndrome with diarrhoea patients with severe symptoms. Loperamide can be recommended in painless diarrhoea. Evidence is weak to recommend the use of bulking agents in the treatment of irritable bowel syndrome with constipation.
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PMID:Meta-analysis: The treatment of irritable bowel syndrome. 1586 77

Serotonin (5-HT) plays an important role in the pathophysiology of irritable bowel syndrome (IBS). Using alpha-[(11)C]methyl-L-tryptophan-positron emission tomography (PET), it was demonstrated that brain 5-HT synthesis is increased in patients with IBS, in a gender-specific manner. The aims of the study were to evaluate the effects of alosetron on brain 5-HT synthesis in patients with IBS. Six male and five female non-constipation-predominant IBS patients were enrolled. The subjects received alosetron or a placebo for 14 days, separated by a 2-week washout period. On day 14, rectal distensions commenced just prior to the PET scan (which was performed for 80 min), and continued for 20-min periods. The functional images were analysed with SPM99. Alosetron vs placebo treatments, in a randomized, double-blinded, crossover manner, were studied. 5-HT synthesis was greater in several regions in the males than in the females during the alosetron treatment, whereas there was no region in which the females had greater synthesis. There were significant gender-treatment interactions of synthesis in the cingulate gyrus, caudate nucleus, globus pallidus, and cerebellum. The gender differences in the effect of alosetron on brain 5-HT synthesis may be related to the gender differences in the efficacy of alosetron.
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PMID:The effects of the 5-HT3 antagonist, alosetron, on brain serotonin synthesis in patients with irritable bowel syndrome. 1578 42

Treatment of irritable bowel syndrome (IBS) remains challenging for patients and practitioners. Current therapeutic choices include antidepressants and psychotherapy, which are thought to target central nervous system triggers of symptoms. Data supporting these treatments are reviewed. Therapeutic agents targeted at receptors in the enteric nervous system have recently been developed to act locally in the gut. Alosetron, an antagonist for serotonin-3 receptors, reduces intestinal motility, secretion, and possibly sensitivity. It is effective for diarrhea predominant IBS, although there are some potentially serious side effects. Tegaserod, a serotonin-4 receptor agonist, is a prokinetic agent that speeds small bowel transit and right colon transit in IBS, reducing symptoms of constipation, pain, and bloating. IBS symptoms are improved with integration of old and new therapies, combined with reassurance, education, and lifestyle adjustments.
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PMID:Psychotherapeutics and serotonin agonists and antagonists. 1579 92

Based on current evidence, bulking agents are not more effective than placebo at improving global irritable bowel syndrome (IBS)symptoms, although they may increase stool frequency in large doses. Tricyclic antidepressants are more effective than placebo for patients with diarrhea-predominant IBS. Imodium is more effective than placebo at improving stool consistency and decreasing stool frequency in patients with IBS, and it may be an important component for treating diarrhea-predominant IBS. Antispasmodics agents available in the United States are not more effective than placebo for treating IBS, although the studies are small and poorly designed. There are no randomized controlled trials examining the efficacy of laxatives for managing IBS. Tegaserod is more effective than placebo at improving global IBS symptoms in women with nondiarrhea-predominant IBS. Alosetron is more effective than placebo in women with diarrhea-predominant IBS, although its use should be limited to patients who have failed conventional therapy because of its adverse event profile.
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PMID:Efficacy of current drug therapies in irritable bowel syndrome: what works and does not work. 1586 38

Alosetron hydrochloride (Lotronex, GlaxoSmithKline, Inc) is a safe and effective agent for selective patients with severe irritable bowel syndrome when prescribed as recommended. We describe the first reported case of acute liver injury in a 39-year-old white woman who developed symptomatic hepatitis 28 days after starting alosetron. All other competing causes of acute hepatitis were excluded by radiologic and laboratory studies and the liver injury resolved after drug discontinuation. Although the mechanism of alosetron hepatotoxicity is unknown, metabolic idiosyncrasy is suspected since the drug is known to be extensively metabolized by cytochrome-P450 enzymes. Clinicians prescribing alosetron should be aware of this potential side effect if unexplained abdominal pain, jaundice,or abnormal liver biochemistries are encountered in a treated patient.
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PMID:Acute hepatitis associated with alosetron (Lotronex). 1600 Sep 36

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that can present with a wide array of symptoms that make treatment difficult. Current therapies are directed at relieving symptoms of abdominal pain or discomfort, bloating, constipation, and diarrhea. Pharmacologic agents used to treat IBS-associated pain include myorelaxants, peppermint oil, and peripherally acting opiates. Dicyclomine and hyoscyamine, the two myorelaxants available in the United States, have not been proven effective in reducing abdominal pain in patients with IBS. The efficacy of peppermint oil is debated, but methodological problems with existing studies preclude definitive judgment. Loperamide is ineffective for relief of abdominal pain. For IBS patients with excessive abdominal bloating, a small number of studies suggest that bacterial eradication with gut-directed antibiotics and bacterial reconstitution with nonpathogenic probiotics may reduce flatulence. For constipation-predominant (C-IBS) symptoms, current treatment options include fiber supplementation, polyethylene glycol, and tegaserod. Soluble fibers (ispaghula, calcium polycarbophil, psyllium) are more effective than insoluble fibers (wheat bran, corn fiber) in alleviating global symptoms and relieving constipation, although fiber in general has marginal benefit in treatment of overall IBS symptoms. Polyethylene glycol increases bowel frequency in chronic constipation, but its overall efficacy against IBS is unclear. Tegaserod, a 5-HT(4) agonist, demonstrates superiority over placebo in improving bowel frequency and stool consistency and alleviating abdominal pain and bloating in women with C-IBS. Overall global symptoms are modestly improved with tegaserod when compared with placebo. Additional agents under investigation for C-IBS include the ClC(2) chloride channel opener lubiprostone, mu-opioid receptor antagonist alvimopan, and 5-HT(4) agonist renzapride. For diarrhea-predominant (D-IBS) symptoms, available therapies include loperamide, alosetron, and clonidine. Alosetron, a 5-HT(3) antagonist, is superior to placebo for reducing bowel frequency, improving stool consistency, and relieving abdominal pain in women with D-IBS. However, alosetron is available under a restricted license because of concerns for ischemic colitis and severe constipation necessitating colectomy. Clonidine may be helpful in alleviating global symptoms for D-IBS patients.
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PMID:Current gut-directed therapies for irritable bowel syndrome. 1683 50

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.
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PMID:[Antagonists of the type 3 serotonin receptor (5 -HT3) in IBS]. 1689 18


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