benzofurans and Irritable-Bowel-Syndrome

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

A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat.. This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat.. The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced.

Topics: Benzofurans; Chronic Disease; Constipation; Dipeptides; Humans; Irritable Bowel Syndrome; Laxatives; Natriuretic Peptides; Peptides; Thiazepines

Topics: Algorithms; Anti-Infective Agents; Benzofurans; Diagnosis, Differential; Diet, Carbohydrate-Restricted; Evidence-Based Medicine; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Practice Guidelines as Topic; Randomized Controlled Trials as Topic; Rifamycins; Rifaximin

Patients with functional gastrointestinal disorders constitute the majority of patients seeking healthcare for gastrointestinal symptoms in primary and secondary care. Of these disorders irritable bowel syndrome (IBS) is one of the most common and affects 10-20% in the Western world. IBS is a functional bowel disorder characterized by chronic abdominal pain, discomfort, bloating, and alteration of bowel habits in the absence of any detectable organic cause. Sex and gender aspects are important in understanding differences between men and women in their risk and experience of IBS. Relative to men, women are diagnosed more frequently with IBS. Female patients are more likely to be constipated, complain of abdominal distension and of certain extracolonic symptoms. Given the variability of IBS, the most successful treatment will be comprehensive, involving multiple strategies. Efficacy, safety and tolerability are important in the evaluation of IBS therapies, as patients are likely to require long-term treatment. Laxatives, antidiarrheals or antispasmodics are common in the treatment of IBS but the majority of patients receive antispasmodics followed by prokinetic agents. In treatment of IBS there appears to be a greater clinical response to serotonergic agents developed for IBS in women compared to men. There is an absence of drugs licensed specifically for the treatment of IBS. Further studies with novel agents are needed, to evaluate new approaches to IBS management including gender specific behavioral therapies and better characterization of patient subgroups with regard to drug therapy so that personalized therapy can be tested.

Topics: Antidepressive Agents; Antidiarrheals; Benzofurans; Female; Gonadal Steroid Hormones; Humans; Irritable Bowel Syndrome; Laxatives; Male; Parasympatholytics; Probiotics; Sex Characteristics

This review introduces new therapeutic options in the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. Therefore, prucalopride and lubiprostone are discussed including their mechanisms and side effects. In addition, other substances that are currently under evaluation such as renzapride and linaclotide are described, since recent results showed a significant effect in patients with constipation. Thus, after the withdrawal of tegaserod due to cardiac side effects, new potent drugs are now available for the treatment of constipation.

Topics: Alprostadil; Benzamides; Benzofurans; Bridged Bicyclo Compounds, Heterocyclic; Cathartics; Chloride Channel Agonists; Constipation; Humans; Irritable Bowel Syndrome; Lubiprostone; Peptides; Randomized Controlled Trials as Topic; Receptors, Guanylate Cyclase-Coupled; Receptors, Serotonin, 5-HT4

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

The estimated prevalence of irritable bowel syndrome (IBS) in Western countries is 7-15%, with a female:male ratio of 2-2.5:1 in IBS patients who seek healthcare services; however, the female predominance is lower in the general population. IBS has a significant impact on health-related quality of life and is associated with a significant healthcare and economic burden. Management of IBS is comprised of general measures and pharmacologic and nonpharmacologic treatment. However, there are ongoing efforts to find more effective therapeutic approaches. As advancements in the understanding of the pathophysiology of IBS continue to grow, new and effective treatments with novel mechanisms of action that have the potential to improve relief of IBS symptoms over current treatments are likely to be developed. This article provides an overview of current and emerging therapies for IBS and also highlights sex and gender differences in clinical trials and treatment response.

Topics: Benzofurans; Complementary Therapies; Diet Therapy; Female; Fibrinolytic Agents; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Randomized Controlled Trials as Topic; Sex Distribution

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

Patients with functional bowel disorders develop gas retention and symptoms in response to intestinal gas loads that are well tolerated by healthy subjects. Stimulation of 5HT-4 receptors in the gut has both prokinetic and antinociceptive effects. The aim of this study is to determine the effect of prucalopride, a highly selective 5HT-4 agonist, on gas transit and tolerance in women with functional bowel disorders complaining of constipation.. Twenty-four women with functional bowel disorders complaining of constipation were included in the study. Patients were studied twice on separate days in a cross-over design. On each study day, an intestinal gas challenge test was performed. During the five previous days, prucalopride (2 mg/day) or placebo was administered. Abdominal symptoms, stool frequency, and stool consistency were recorded during the treatment period on daily questionnaires.. During the gas challenge test, prucalopride did not decrease the volume of gas retained in the subset of patients who had significant gas retention (≥ 200 mL) while on placebo. However, in those patients who had increased symptoms during the gas test (≥ 3 on a 0 to 6 scale) when on placebo, prucalopride did significantly reduce the perception of symptoms (2.3 ± 0.5 mean score vs 3.5 ± 0.3 on placebo; P = 0.045). During the treatment period with prucalopride, patients exhibited an increase in the total number of bowel movements and decreased stool consistency compared with placebo.. Prucalopride reduces abdominal symptoms without modifying gas retention when patients with functional bowel disorders are challenged with the gas transit and tolerance test. European Clinical Trials Database (EudraCT2011-006354-86).

Topics: Benzofurans; Constipation; Cross-Over Studies; Double-Blind Method; Female; Gases; Gastrointestinal Transit; Humans; Irritable Bowel Syndrome; Serotonin Receptor Agonists; Treatment Outcome

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

Topics: Animals; Benzimidazoles; Benzofurans; Bile Acids and Salts; Carbolines; Colesevelam Hydrochloride; Colestipol; Disease Models, Animal; Enteric Nervous System; Female; Humans; Imidazoles; Indoles; Irritable Bowel Syndrome; Loperamide; Lubiprostone; Male; Mice; Natriuretic Peptides; Peptides; Phenylalanine; Receptors, Serotonin, 5-HT3; Receptors, Serotonin, 5-HT4; Rifamycins; Rifaximin; Serotonin; Serotonin Antagonists; Serotonin Receptor Agonists; Visceral Pain