td-5108 and Irritable-Bowel-Syndrome

Multiple pharmacologic treatments are available for the management of irritable bowel syndrome (IBS), and a large body of evidence has been presented. However, the strength and credibility of the evidence have not been comprehensively evaluated. We aimed to review the systematic reviews and meta- analyses of pharmacologic treatments for IBS and evaluate the credibility of the findings.. We searched MEDLINE, Embase, and Cochrane library from inception to September 2019 for systematic reviews evaluating the effectiveness of pharmacologic treatments for IBS. We summarized relative ratios (RR), evaluated the credibility of the evidence and classified the evidence into convincing, highly suggestive, suggestive, and weak.. We included 11 systematic reviews with 40 meta-analyses (330 randomized controlled trials and 86,459 participants) assessing 10 treatment categories and 2 drugs. Most of the pharmacologic treatments were significantly superior over placebo as reported by the included meta-analyses. The evidence for 5-hydroxytryptamine (5-HT)3 antagonists (RR=1.56, 95%CI: 1.43-1.71), antispasmodics (RR=1.19, 95%CI: 1.02-1.39), and alosetron (RR=1.46, 95%CI: 1.26-1.71) were highly suggestive for relieving global IBS symptoms. 5-HT4 agonists (RR= 1.26, 95%CI: 1.19-1.34) and guanylate cyclase-C (GCC) agonists (RR=1.73, 95%CI: 1.54-1.95) were found to give convincing evidence for the improvement of the responder rate. 5-HT3 antagonists (RR=1.32, 95%CI: 1.26-1.38) offered convincing evidence for relieving abdominal pain.. Evidence for 5-HT3 antagonists, 5-HT4 agonists and GCC agonists, antispasmodics, and alosetron were suggestive for the treatment of IBS. However, owing to the risk of bias in randomization methods, the results for GCC should be interpreted with caution.

Topics: Carbolines; Gastrointestinal Agents; Guanylyl Cyclase C Agonists; Humans; Irritable Bowel Syndrome; Parasympatholytics; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome

Irritable bowel syndrome (IBS) is a chronic, recurrent bowel disorder with an unknown etiology, which is most likely multifactorial. Increased mucosal permeability, visceral hypersensitivity and activation status of intestinal mucosal immune cells cause changes in gastrointestinal (GI) motility, secretion and sensation observed in the course of IBS. Permanent, cumbersome symptoms, such as diarrhea, constipation and abdominal pain greatly lower the quality of life of IBS patients. On this basis, according to the Rome IV criteria, different forms of IBS can be distinguished.. This article focuses on the role of serotonin system in the pathophysiology of IBS as a potential therapeutic target. We shortly describe several molecules, associated with serotonin receptors, mainly 5-HT3 receptor antagonists and 5-HT4 receptor agonists, that are used in the treatment of motility disorders and visceral pain in IBS patients. We summarize the findings obtained in the clinical trials and elaborate on the safety of the serotonin ligands. Although the majority of serotonin receptor ligands relieve global symptoms, there are also some adverse effects, which can be dangerous for patients.. We postulate that currently, among all serotonin-targeting compounds, ramosetron is the best treatment option for IBS-D patients, due to its exceptional efficacy in both genders as well as good tolerability. Whereas, tegaserod is highly recommended for IBS-C sufferers. Nevertheless, numerous studies on the new serotonin receptor ligands are conducted to ensure the delivery of novel compounds with improved efficacy and safety profiles.

Topics: Clinical Trials as Topic; Humans; Indoles; Irritable Bowel Syndrome; Lactones; Ligands; Quality of Life; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Sesquiterpenes

Irritable bowel syndrome (IBS) affects about 15 % of the US population and results in significant morbidity and health care costs. There remains a significant unmet need for effective treatments particularly for the pain component of IBS and other functional gastrointestinal disorders (FGIDs). Progress made in our understanding of pathophysiological mechanisms such as the role of altered bile acid metabolism, neurohormonal regulation, immune dysfunction, the epithelial barrier and secretory properties of the gut has led to advancements in therapeutic armamentarium for IBS. This review discusses the new drugs for constipation and diarrhea-predominant IBS subtypes that have been tested or have been under investigation over the last 3-4 years. Overall, there is a promising pipeline of investigational drugs for the future treatment of IBS and related FGIDs.

Topics: Constipation; Diarrhea; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Receptors, Atrial Natriuretic Factor; Serotonin 5-HT4 Receptor Agonists

The diagnosis of irritable bowel syndrome (IBS) remains a diagnosis of exclusion, whereby an extensive investigation is performed to exclude other organic diseases that may explain the symptoms of patients. Attempts to have a positive diagnosis based on symptom assessments failed to achieve widely use in clinical practice. Abnormalities in the gastrointestinal endocrine cells in IBS patients have been reported recently, providing evidence that IBS is an organic disorder, and opening the door to the use of these abnormalities as markers for a positive diagnosis of IBS. New and promising drugs for the treatment of IBS with constipation as the predominant symptom are currently on the market, and the treatment results have been satisfactory thus far.

Topics: Benzofurans; Biomarkers; Constipation; Humans; Irritable Bowel Syndrome; Peptides; Serotonin 5-HT4 Receptor Agonists

Ischaemic colitis (IC) is the most common form of ischaemic injury to the gastrointestinal (GI) tract. IC typically presents with the sudden onset of lower abdominal pain, cramping and rectal bleeding, and is usually self-limited with low morbidity, although it may cause gangrenous or fulminant colitis, especially when the right colon is involved. Multiple medical conditions, as well as several pharmacological agents, are associated with IC, including irritable bowel syndrome (IBS) and drugs used for its treatment that act on gut serotonin 5-HT receptors. These include the selective 5-HT(3) receptor antagonist alosetron, currently approved for the treatment of severe diarrhoea-predominant IBS in women who fail to respond to conventional treatment, and cilansetron, another 5-HT(3) receptor antagonist that is no longer in clinical development. In addition, the 5-HT(4) receptor partial agonist tegaserod, which was approved for the treatment of constipation-predominant IBS in women, was associated with IC in the postmarketing setting, as was renzapride, a 5-HT(4) agonist/5-HT(3) antagonist. Although several hypotheses have been proposed, the pathophysiological basis for development of IC with 5-HT(3) receptor antagonists or 5-HT(4) receptor agonists remains unknown. Of interest, several population-based studies demonstrated that a diagnosis of IBS (independent of serotonergic therapies) increases the risk of developing IC 2- to 4-fold. As a result, IBS patients with the acute onset of abdominal pain, tenderness, diarrhoea or lower intestinal bleeding, especially those with predisposing conditions or medications, should be evaluated promptly for IC. The management of IC remains supportive; most cases of non-gangrenous IC, as seen in the alosetron and tegaserod databases, have been transient and have resolved spontaneously without complications or death. Despite the small number of deaths associated with alosetron in patients with complications of constipation and because of the ongoing requirement to prescribe alosetron under a risk management plan, misconceptions persist regarding the definition, incidence, severity and outcome of IC in clinical trials and the postmarketing setting. In this article, the frequency and clinical characteristics of IC associated with the use of alosetron and other serotonergic agents are examined, evidence of an association between IC and IBS is reviewed, and a scoring system to aid in the diagnosis of IC in any clinical situatio

Topics: Animals; Carbolines; Colitis, Ischemic; Female; Humans; Indoles; Irritable Bowel Syndrome; Male; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists

Chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (C-IBS) are commonly reported gastrointestinal (GI) disorders that have a major impact on health and quality of life. Patients experience a range of symptoms of which infrequency of bowel movement is but one and report that straining, the production of hard stools, and unproductive urges are more bothersome than stool infrequency. Additionally, in C-IBS, patients report abdominal pain and bloating as particularly troubling. Traditional treatments, such as laxatives, are often ineffective, especially in more severe constipation over the long term. In a population-based survey of constipation sufferers, half were not satisfied with their current treatment, due predominantly to poor efficacy. 5-Hydroxytryptamine receptor 4 (5-HT4) agonists stimulate GI motility and intestinal secretion, and tegaserod has demonstrated efficacy in improving bowel habit. Tegaserod also improves constipation-associated symptoms including bloating, abdominal discomfort, stool consistency, and straining in patients with both CIC and C-IBS. However, tegaserod has been withdrawn due to an association with serious adverse cardiovascular effects. Further 5-HT(4) receptor agonists, including prucalopride and TD-5108 are in development and show exciting results in clinical studies in CIC patients, suggesting further product approvals are likely. Headache and diarrhea are the most commonly reported adverse event with this class of agent. Recently a novel prosecretory agent has been approved for the treatment of both CIC and C-IBS. Lubiprostone stimulates chloride secretion through activation of type-2 chloride channels, increasing intestinal secretion and transit, and its use has been associated with improvements in bowel habit and symptoms of constipation. Nausea, diarrhea, and headache are the most commonly reported adverse events. Linaclotide also stimulates intestinal chloride secretion, but this molecule achieves this indirectly, through the activation of guanylate cyclase C. Data are emerging, but the efficacy and safety profile of this agent in the treatment of CIC and C-IBS appears encouraging.

Topics: Alprostadil; Azabicyclo Compounds; Benzofurans; Chloride Channels; Chronic Disease; Constipation; Gastrointestinal Agents; Gastrointestinal Motility; Guanylate Cyclase; Humans; Indoles; Irritable Bowel Syndrome; Laxatives; Lubiprostone; Peptides; Safety; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome

Constipation is a common gastrointestinal disease affecting 2-27% of the population in Western hemisphere. Approximately in half of patients the diagnosis of functional constipation is made after having ruled out secondary causes. Treatment of chronic functional constipation primarily addresses education on toilet habits, dietary advice, and patient reassurance. Further therapies are guided according to functional subtype slow-transit constipation, dyssynergic defecation, and constipation-predominant irritable bowel syndrome (IBS-C). Traditionally, the pharmacologic treatment of constipation uses primarily bulking agents and/or laxatives (osmotic or secretory). However, often these therapies do not provide the desired improvement, have a short-lived efficacy and/or are accompanied by side-effects such as bloating and abdominal cramps. Thus, there is a clinical need for new, more potent drugs particularly for patients who are not satisfactorily treated by conventional therapies. This review discusses recent developments in the pharmacologic treatment of chronic constipation including recently FDA-approved lubiprostone, emerging 5-HT receptors modifiers, investigational substances, and probiotics.

Topics: Alprostadil; Animals; Chronic Disease; Constipation; Drug Therapy; Drugs, Investigational; Humans; Irritable Bowel Syndrome; Lubiprostone; Probiotics; Serotonin 5-HT4 Receptor Agonists

Tegaserod, a selective and partial agonist at the 5-hydroxytryptamine (5-HT [serotonin]) receptor subtype 4 (5-HT4), is the only United States Food and Drug Administration-approved drug for the treatment of constipation-predominant irritable bowel syndrome (IBS) in women. The drug's stimulation of 5-HT4 receptors on intestinal enterocytes increases peristaltic activity and fluid secretion into the gut lumen, facilitating stool passage. In addition, affinity of tegaserod for 5-HT4 receptors modulates visceral sensitivity, which helps alleviate abdominal pain associated with constipation-predominant IBS. The drug's pharmacokinetic and pharmacodynamic parameters do not differ significantly with age or sex. Tegaserod safely and effectively relieves overall gastrointestinal symptoms and abdominal discomfort and normalizes bowel habits in patients with constipation-predominant IBS. It is associated with few drug interactions. In clinical studies, tegaserod was well tolerated, and its adverse-effect profile was similar to that of placebo. Severe diarrhea, as well as abdominal pain, flatulence, headache, and nausea, were the most commonly reported events. Patients who experience severe diarrhea should discontinue the drug. With the data available, tegaserod remains an option for patients with constipation-predominant IBS.

Topics: Constipation; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Treatment Outcome

Over the past 30 years, the main treatment of irritable bowel syndrome has aimed to normalize gastrointestinal transit using either laxatives or antidiarrheal agents, with or without the concurrent use of spasmolytics. The recent introduction of serotonin-related drugs has stimulated investigations into the pathophysiology of irritable bowel syndrome, including an evaluation of visceral sensitivity. At the same time, more information has been acquired on the status of the local immune system as a possible cause for sensitization of nerve terminals. Such investigations have stimulated the emergence of new concepts and original candidate drugs for the treatment of this functional disorder. Particular attention is devoted to the correction of visceral hyperalgesia.

Topics: Animals; Corticotropin-Releasing Hormone; Humans; Irritable Bowel Syndrome; Nerve Growth Factor; Neurokinin-1 Receptor Antagonists; Psychotherapy; Receptor, Cholecystokinin A; Receptor, PAR-2; Receptors, Neurokinin-3; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins

This article reviews the safety and tolerability profile of tegaserod, a novel selective partial agonist of the serotonin 5-HT(4) receptor. Tegaserod was recently approved for the treatment of women with irritable bowel syndrome (IBS) with constipation. Tegaserod exhibits rapid absorption from the small intestine, and is excreted unchanged in the faeces and as metabolites in the urine. Meal ingestion decreases its bioavailability. There is little effect of age or gender on pharmacokinetics, although plasma levels may be slightly higher in the elderly. Tegaserod has no effect on plasma levels of other drugs metabolised by cytochrome P450 enzyme systems. Gastrointestinal symptoms are the most common adverse effects of tegaserod therapy. In data pooled from phase III randomised controlled trials (RCTs) in IBS with constipation patients, diarrhoea was reported by 8.8% of patients treated with tegaserod 6mg twice daily versus 3.8% of patients receiving placebo. Similar rates have been observed in international post-US marketing RCTs. In most patients, tegaserod-induced diarrhoea was mild and transient. In RCTs, it did not elicit fluid or electrolyte disturbances, and fewer than 3% of IBS patients discontinued tegaserod due to diarrhoea. Since its release, rare cases of more severe diarrhoea and ischaemic colitis have been reported. The incidence of other gastrointestinal symptoms (e.g. abdominal pain, nausea, and flatulence) has been similar among tegaserod-treated patients and placebo-treated patients. Pooled analysis of phase III RCTs and post-US marketing RCTs have not demonstrated significant differences between tegaserod-treated patients and placebo-treated patients in the incidence of abdominal-pelvic surgery. There is no convincing evidence that rebound gastrointestinal symptoms occur upon termination of tegaserod therapy. Pooled analysis of phase III RCTs demonstrated an increase in the incidence of headaches among tegaserod-treated patients (6mg twice daily) compared with placebo-treated patients (15% vs 12.3%, respectively, p < 0.05), although post-US marketing RCTs have not observed this increase. Other extra-gastrointestinal adverse events occur with similar frequency among tegaserod-treated patients and placebo-treated patients. Tegaserod-treated patients in RCTs have not demonstrated significant prolongation of the QTc interval or cardiac arrhythmias compared with placebo-treated patients. Supra-therapeutic doses in healthy volunteers did not eff

Topics: Drug Interactions; Humans; Indoles; Irritable Bowel Syndrome; Product Surveillance, Postmarketing; Randomized Controlled Trials as Topic; Serotonin 5-HT4 Receptor Agonists

Activation of serotonin 5-HT(4) receptors has been proposed as treatment for irritable bowel syndrome, a common, complex and distressing gastrointestinal disorder. Abnormal intestinal motility and sensitivity in irritable bowel syndrome patients can result in diarrhea, constipation, abdominal pain, bloating, headache and fatigue; these and other symptoms can lead to exacerbation of psychological stress, which may in turn induce further physiological abnormalities and patient discomfort. The serotonin agonist tegaserod binds with high affinity to 5-HT(4) receptors and has demonstrated potent pharmacological effects on the mid- and distal gut. Tegaserod has been safely employed in clinical trials where it has demonstrated efficacy in normalizing intestinal function, thereby improving irritable bowel syndrome symptoms.

Topics: Constipation; Humans; Indoles; Irritable Bowel Syndrome; Randomized Controlled Trials as Topic; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists

Topics: Antidepressive Agents, Tricyclic; Antidiarrheals; Dietary Fiber; Female; Humans; Irritable Bowel Syndrome; Loperamide; Male; Parasympatholytics; Psychotherapy; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Agents; Serotonin Antagonists

Functional gastrointestinal disorders are characterised by central and peripheral physiological changes, associated with psychological factors. Successful drug development has been hindered by lack of adequate characterisation of the nature of symptoms and their physiological and psychological correlates. Animal models of chronic stress are lacking. High levels of drug safety are now demanded for treating non-life threatening conditions. Once close to market, patient pressure groups, health care providers and insurers, government, and the internet can all influence a drug's success. Serotonin-modifying drugs have been the main recent focus of development, with mixed results. Cisapride has been withdrawn because of concerns related to QT prolongation and cardiac arrhythmias. The 5-HT3 antagonists have been developed on the questionable assumption that they modify visceral sensation in patients. Problems have arisen with alosetron being associated with ischaemic colitis and a high incidence of constipation. The 5-HT4 agonists have their major effect on inducing peristalsis, and may modify gut secretion and sensory function. Tegaserod and prucalopride show promise in patients with constipation and related symptoms. 5-HT1 agonists may play a role in treating functional dyspepsia, partly by improving impaired gastric accommodation to a meal. Antidepressants, often found to be clinically beneficial in these disorders, also affect serotonin metabolism. Past successes, such as loperamide or the somatostatin analogue octreotide, involved targeting end organ receptors influencing motor function or secretion. Modifying sensory function is much more challenging. Future research with novel compounds need to keep these recent lessons in mind.

Topics: Antidepressive Agents; Benzofurans; Carbolines; Cisapride; Constipation; Drug Industry; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Administration, Oral; Adult; Anti-Bacterial Agents; Arrhythmias, Cardiac; Asian People; Benzamides; Case-Control Studies; Cisapride; Cross-Over Studies; Double-Blind Method; Electrocardiography; Female; Humans; Indoles; Irritable Bowel Syndrome; Long QT Syndrome; Male; Morpholines; Moxifloxacin; Piperidines; Placebos; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Agonists of 5-hydroxytryptamine 4 receptor are potential agents for irritable bowel syndrome with predominant constipation (IBS-C). However, only tegaserod has been approved for a very limited population in the US.. To evaluate the efficacy and safety of minesapride in patients with Rome IV defined IBS-C.. A double-blind, placebo-controlled, dose-finding study was performed. Overall, 411 patients were randomised to receive minesapride at 10, 20 or 40 mg/d, or placebo for 12 weeks. The primary endpoint was Food and Drug Administration (FDA) composite endpoint (responder: a patient who reported an increase in one or more complete spontaneous bowel movements from baseline and improvement of ≥30% from baseline in weekly average of worst abdominal pain score, both in the same week for ≥6/12 weeks).. The FDA composite responder rate was 13.6% (14/103) in the placebo group, 13.6% (14/103) in the 10 mg group, 19.2% (20/104) in the 20 mg group and 14.9% (15/101) in the 40 mg group, and no dose-response relationship was found. A greater percentage of minesapride 40 mg-treated patients than placebo-treated patients met both responder requirements for ≥9/12 weeks as the stricter composite evaluation (P < 0.05). Furthermore, minesapride 40 mg significantly increased SBM frequency compared with placebo (adjusted P < 0.001 at Week 12). The most common adverse event was mild diarrhoea.. Minesapride was safe and well-tolerated. Although the primary endpoint was negative, minesapride 40 mg is likely to improve the stricter composite endpoint and SBM frequency. Japan Pharmaceutical Information Center Number: Japic CTI-163459.

Topics: Abdominal Pain; Adult; Constipation; Diarrhea; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Morpholines; Piperidines; Serotonin 5-HT4 Receptor Agonists; Treatment Outcome; Young Adult

The 5-HT(4) receptor agonist, mosapride citrate, accelerates gastric emptying. However, the effect of mosapride on colonic function has not been well investigated. We examined whether mosapride changes rectosigmoid motility and perception in patients with irritable bowel syndrome (IBS).. Thirty-seven patients with IBS and 18 healthy subjects were studied. All subjects underwent a rectosigmoid barostat test to measure pain perception to intraluminal distention and resting smooth muscle motility for 20 min in the fasting state. Irritable bowel syndrome patients were then randomly assigned to receive either mosapride 15 mg (n=19) or placebo (n=18) orally with 200 mL water. Rectosigmoid motility and perception were measured again for 60 min following dosing. Rectosigmoid tone and contractility were evaluated in each 10-min period.. The pain threshold in the patients was significantly lower than that in controls (P<0.01). There were no differences between mosapride and placebo groups in pain threshold, barostat bag volume, or number of contractions at baseline. Mosapride significantly decreased the mean bag volume (P<0.01; group × period interaction by two-way anova) and increased the mean number of contractions (P<0.05) compared with placebo, but did not affect the perception. In IBS patients with constipation (i.e., excluding diarrhea-predominant subjects), mosapride (n=13) increased rectosigmoid tone (P<0.01) and contractions (P<0.05) more than placebo (n=14).. Mosapride stimulates colonic motility without any adverse effect. These findings suggest that mosapride may have the potential to treat IBS patients with constipation and/or functional constipation. Further clinical trials are warranted to confirm the efficacy of this agent.

Topics: Adult; Animals; Benzamides; Colon, Sigmoid; Female; Gastrointestinal Motility; Humans; Irritable Bowel Syndrome; Male; Manometry; Morpholines; Pain Perception; Receptors, Serotonin, 5-HT4; Rectum; Serotonin 5-HT4 Receptor Agonists; Serotonin Plasma Membrane Transport Proteins; Young Adult

This was an exploratory study of renzapride in 168 male and female patients with non-D, non-C irritable bowel syndrome (IBS). Patients were randomized to placebo or renzapride (1, 2, or 4 mg/day) for 8 weeks. The primary efficacy variable was patient-reported satisfactory relief of IBS symptoms. Secondary variables included relief of abdominal pain/discomfort. The proportion of patients reporting satisfactory relief of their IBS symptoms for at least 50% of the time did not differ significantly from those on placebo. However, post hoc analysis in women showed differences in responder rate on renzapride versus placebo of 18.2% (95% CI -5% to 42%; P = 0.066) during weeks 1-4 and 6% (95% CI -21% to 33%; P = 0.339) during weeks 5-8. Renzapride was well tolerated and most adverse events were mild to moderate in intensity. Further studies are warranted to determine whether renzapride is beneficial in this patient population.

Topics: Adult; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Defecation; Dose-Response Relationship, Drug; Double-Blind Method; Electrocardiography; Female; Humans; Irritable Bowel Syndrome; Male; Middle Aged; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Treatment Outcome

Opioid neurons exhibit tonic restraint on intestinal motility; opioid antagonists stimulate peristalsis and increase transit. In vitro, 5-hydroxytryptamine (5-HT4) agonists combined with selective opioid antagonists significantly increased colonic propulsion relative to a 5-HT4 agonist alone. We hypothesized that the combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit more than either treatment alone in female constipation-predominant irritable bowel syndrome (C-IBS) patients. Our aim was to examine the effect of tegaserod 6 mg b.i.d. alone and combined with naltrexone 50 mg on intestinal transit and stool characteristics in females with C-IBS. Forty-eight patients were randomized to tegaserod alone, naltrexone alone or in combination with tegaserod or placebo for 6 days. Small bowel, ascending colon half-life (in pharmacokinetics) (t1/2), and colonic geometric centre (8, 24, 48 h) were assessed by scintigraphy. Tegaserod increased small bowel (P < 0.01) and colon transit (P < 0.01). Naltrexone did not accelerate colonic transit relative to placebo. Combination treatment did not significantly accelerate transit relative to tegaserod alone. Tegaserod and tegaserod with naltrexone resulted in looser stool form (P < 0.01). In female C-IBS patients, tegaserod accelerates small bowel and colon transit and contributed to looser stool consistency. Use of naltrexone, 50 mg, does not support the hypothesis that combination of 5-HT4 agonist and non-selective opioid antagonist enhances intestinal transit.

Topics: Adult; Constipation; Double-Blind Method; Drug Therapy, Combination; Female; Gastrointestinal Motility; Humans; Indoles; Irritable Bowel Syndrome; Male; Middle Aged; Naltrexone; Narcotic Antagonists; Radionuclide Imaging; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Topics: Algorithms; Benzofurans; Canada; Chronic Disease; Constipation; Dietary Fiber; Dietary Supplements; Disease Management; Gastroenterologists; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Laxatives; Needs Assessment; Peptides; Practice Guidelines as Topic; Practice Patterns, Physicians'; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Receptors, Peptide; Serotonin 5-HT4 Receptor Agonists; Surveys and Questionnaires

Traditional symptom-based therapies of irritable bowel syndrome (IBS) are directed at the relief of individual IBS symptoms, but they are often of limited efficacy in addressing the entire symptom complex. Combinations of drugs to target bothersome symptoms are suggested as the first-line pharmacologic treatment. Increasing knowledge of the pathophysiology and molecular mechanisms of IBS has resulted in the development of several new therapeutic approaches. Thirteen consensus statements for the treatment of IBS were developed using the modified Delphi approach. Exclusion diets have modest efficacy in improving symptoms in some IBS patients. Symptom-based therapies with dietary fiber, bulking agents, laxatives, antispasmodics and laxatives are effective in the improvement of some individual symptoms, e.g. dietary fiber and bulking agents for constipation, laxatives for constipation, antispasmodics for abdominal pain and discomfort, antidiarrheals for diarrhea. 5HT3 receptor antagonists and 5HT((4)) receptor agonists are effective in the relief of global IBS symptoms and individual symptoms such as abdominal pain and abnormal bowel habits. A short term course of nonabsorbable antibiotics may improve global IBS symptoms, particularly in patients with diarrhea- predominant IBS. Some probiotics appear to have the potential benefit in improving global IBS symptoms. Selective C-2 chloride channel activator is more effective than placebo at relieving global IBS symptoms in patients with constipation-predominant IBS. Both tricyclic antidepressants and selective serotonin reuptake inhibitors are equally effective in relieving global IBS symptoms, and have some benefits in treating abdominal pain. Certain types of psychologic therapy may be effective in improving global symptoms in some IBS patients. Further studies are strongly needed to develop better treatment strategies for Korean patients with IBS.

Topics: Anti-Infective Agents; Antidepressive Agents; Antidiarrheals; Dietary Fiber; Humans; Irritable Bowel Syndrome; Laxatives; Parasympatholytics; Probiotics; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists

Tegaserod is a first-in class selective serotonin 4 receptor agonist approved for the treatment of irritable bowel syndrome. In March 2007, the US Food and Drug Administration (FDA) suspended its use citing increased cardiovascular (CV) events in clinical trials. However, there is no known mechanistic basis for an adverse CV effect. To reassess the CV safety of tegaserod, teagaserod-treated patients (pts) in the Intermountain Healthcare database were identified (n = 2603), matched 1:6 with untreated (n = 15,618) patients by age, sex, and date of tegaserod initiation, and followed for an average of 2.5 years. Age averaged 38.6 +/- 13.5 years, and 94% were female. Cardiovascular event rates were low and similar in patients treated with tegaserod and matched untreated patients. For the primary composite CV endpoint, 54 (0.35%) untreated and 12 (0.46%) treated pts had an event (treated OR = 1.27, 95% CI: 0.68-2.38, P =.46), with 7 and 0 events, respectively, occurring within 3 months. A total of 12 (0.1%) untreated and 1 (<0.1%) treated pts were hospitalized for a myocardial infarction (MI). 36 (0.2%) untreated and 10 (0.4%) treated pts for a cardiovascular accident, and 1 pt in each group for unstable angina. A total of 6 (<0.1%) untreated and no treated pts died from cardiac causes. Event rates were comparable to expected rates in this population of mostly premenopausal women. This large epidemiologic study failed to confirm a reported large event differential for tegaserod that was noted incidentally in a clinical trials database, suggesting that the prior observation may have been due to chance.

Topics: Adult; Cardiovascular Diseases; Case-Control Studies; Databases as Topic; Female; Gastrointestinal Agents; Humans; Indoles; Irritable Bowel Syndrome; Logistic Models; Male; Middle Aged; Odds Ratio; Prospective Studies; Risk Assessment; Risk Factors; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists; Time Factors

Topics: Drug Approval; Drug Industry; Humans; Indoles; Irritable Bowel Syndrome; Risk Assessment; Serotonin 5-HT4 Receptor Agonists; United States; United States Food and Drug Administration

Irritable bowel syndrome is a functional gastrointestinal disorder characterized by abnormal sensation and motility in the lower gastrointestinal tract. In constipation-type irritable bowel syndrome, decreased bowel motility causes stagnation of feces and gas, resulting in enhanced pain sensation of the bowel. Mosapride citrate is a selective serotonin 5- HT4 receptor agonist and enhances propulsive activity throughout the gastrointestinal tract. Mosapride citrate was orally administered to 11 patients with constipation-type irritable bowel syndrome to investigate its effect on this disease. The result showed that mosapride citrate alleviated abdominal pain and abdominal distension, loosened stools, shortened bowel transit time, and decreased flatus in the bowel. The results suggest that mosapride citrate is useful for the treatment of irritable bowel syndrome.

Topics: Benzamides; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Morpholines; Serotonin 5-HT4 Receptor Agonists

Tegaserod, a potent partial agonist of the serotonin 5-HT4 receptor, is used to treat women with constipation-predominant irritable bowel syndrome. Since the drug's approval, the manufacturer has received infrequent although serious reports of diarrhea and ischemic colitis in patients taking the drug. These instances have led to a recent warning letter to physicians and a change in the prescription labeling of tegaserod. We describe the development of ischemic colitis in a woman who was treated with tegaserod and review the relationship among ischemic colitis, tegaserod use, and irritable bowel syndrome. Potential mechanisms involved in the occurrence of ischemic colitis in patients receiving tegaserod are also discussed.

Topics: Adult; Colitis, Ischemic; Female; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT4 Receptor Agonists; Serotonin Receptor Agonists

Topics: Antidepressive Agents; Cisapride; Female; Humans; Indoles; Irritable Bowel Syndrome; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists

Topics: Carbolines; Humans; Indoles; Irritable Bowel Syndrome; Polypharmacy; Serotonin 5-HT3 Receptor Antagonists; Serotonin 5-HT4 Receptor Agonists; Serotonin Antagonists; Serotonin Receptor Agonists