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)

Familial Mediterranean fever (FMF) is a hereditary episodic febrile syndrome that is expressed by acute spells of fever, painful manifestations in the abdomen, chest and joints, and slow development of nephropathic amyloidosis. Despite the recent cloning of the FMF gene (MEFV) and the identification of about 40 disease-related mutations, the diagnosis is still clinically dependent, and the pathogenesis and most of the clinical heterogeneity remain to be explained. Because episodic abdominal pain affects 95% of FMF patients, most of them are seen by gastroenterologists and undergo complete or partial abdominal imaging before the diagnosis is made. Focusing on recent advances in FMF, this article reviews both common and infrequent manifestations that a gastroenterologist may encounter during workups of FMF patients. These include episodic abdominal pain, paralytic or mechanical ileus, constipation, diarrhea, ascites, malabsorption, bowel infarction, and bleeding, arising directly from FMF or secondary to FMF common associations such as amyloidosis, vasculitides, inflammatory bowel disease, irritable bowel syndrome, or colchicine side effects. This article will help the gastroenterologist to cope with most clinical situations related to the abdominal and alimentary tract in patients with FMF.
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PMID:Abdominal and digestive system associations of familial Mediterranean fever. 1468 3

Kappa (kappa)-opioid receptor agonists are particularly effective analgesics in experimental models of visceral pain. Their analgesic effects are mediated in the periphery. The molecular targets involved include peripherally located kappa-receptors and possibly, at least for some nonpeptidic kappa-agonists, additional nonopioid molecular targets such as sodium channels located on primary sensory afferents. Overall, these properties are expected to be of therapeutic interest in various visceral pain conditions, including abdominal surgery associated with postoperative pain and ileus, pancreatitis pain, dysmenorrhea, labor pain and functional disorders such as irritable bowel syndrome or dyspepsia. The first kappa-agonists to be developed were brain-penetrating organic small molecules. Their development was eventually discontinued due to central side effects such as sedation and dysphoria attributed to kappa-receptors located behind the blood-brain barrier. New drug discovery programs are now geared towards the design of peripherally-selective kappa-agonists. So far, most of the organic molecule-based peripheral kappa-agonists have achieved limited peripheral selectivity and a practically insufficient therapeutic window to justify full development. These compounds have been used in a small number of clinical pilot studies involving visceral pain. Although encouraging, the clinical data available so far with this class of compounds are too limited and fragmented to fully validate the therapeutic utility of kappa-agonists in visceral pain. Additional clinical studies with safer kappa-agonists (i.e. with higher peripheral selectivity) are still required. The most suitable tools to address this question in the future appear to be the newly discovered class of tetrapeptide-based kappa-agonists, which have shown unprecedented levels of peripheral selectivity.
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PMID:Peripheral kappa-opioid agonists for visceral pain. 1505 26

Lubiprostone [RU 0211, SPI 0211] is a bicyclic fatty acid that acts as a chloride channel opener, increasing intestinal water secretion. Lubiprostone, an orally-administered formulation, is one of a series of functional fatty acid compounds discovered by Dr Ryuji Ueno, and is currently undergoing development for the treatment of constipation, constipation-predominant irritable bowel syndrome (IBS-C) and postoperative ileus with Sucampo Pharmaceutical's. Lubiprostone activates a specific chloride channel (CLC2) on cells lining the gut, thereby naturally increasing intestinal fluid secretion. The increased fluid level softens the stool, promotes spontaneous bowel movements, and reduces abdominal discomfort/pain and bloating. The chloride channel is a protein that controls cell membrane transport of chloride ion. Lubiprostone acts on the ClC-2 chloride channel, which is located in the apical intestinal membrane. In November 2004, Takeda Pharmaceuticals entered into a collaboration and licensing agreement for Lubiprostone with Sucampo Pharmaceuticals for the treatment of chronic constipation and constipation-predominant Irritable Bowel Syndrome (c-IBS). Under the terms of the agreement, Takeda received the right to market the product in the US and Canada, while Sucampo reserved the co-promotion rights for these countries. Takeda's wholly-owned US subsidiary, Takeda Pharmaceuticals North America Inc., will sell lubiprostone once the product is approved by the US FDA. Takeda will also receive an option for marketing rights in other territories, including Japan and Europe. Takeda and Sucampo agreed on the exclusive manufacturing and supply of Lubiprostone by R-Tech Ueno, Ltd, a member of the Sucampo Group. Sucampo has the potential to receive up to dollar US 210 million in initial and milestone payments, some of which are contingent upon the successful achievement of several milestones. Takeda will fund a major part of development costs not only for chronic constipation and c-IBS, but also for other indications in the gastroenterology field. Takeda will make royalty payments to Sucampo after the product is launched. In May 2005, Sucampo received dollar US 20 million from Takeda Pharmaceutical as payment for achieving a development milestone of initiating a phase III clinical trial of lubiprostone to treat patients with constipation-predominant irritable bowel syndrome. Sucampo Pharmaceuticals submitted a new drug application (NDA) for lubiprostone to the FDA on 31 March 2005 for approval in the treatment of chronic idiopathic constipation (CIC) and associated symptoms in adults. Sucampo completed three long-term, open-label safety studies, which will support the NDA for lubiprostone, in treating constipation. Results from its second open-label safety study with lubiprostone were announced in February 2004, with the first two studies demonstrating long-term safety and sustained effectiveness in constipated subjects. In the US, the final phase III study for chronic constipation was completed in the fourth quarter of 2004. In November 2004, Sucampo announced completing a phase II safety and efficacy study of lubiprostone for the treatment of IBS-C. This study, which was initiated in April 2003, randomised 195 patients with documented IBS into four treatment groups (three doses of SPI 0211 and placebo) from 19 locations throughout the US.
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PMID:Lubiprostone: RU 0211, SPI 0211. 1599 86

Recent research has provided new information about drugs that could be used to treat functional motility disorders. Promotility drugs accelerate gastric emptying or colonic transit and these properties may contribute to their efficacy in treating symptoms associated with gastroparesis, functional dyspepsia or constipation. 5-Hydroxytryptamine4 receptors are targets for drugs (tegaserod, renzapride) that treat symptoms in constipated irritable bowel syndrome patients and in gastroparesis. Drugs acting at motilin (erythromycin) and cholecystokinin-1 (dexloxiglumide) receptors accelerate gastric emptying. Dexloxiglumide might be useful in the treatment of functional dyspepsia particularly that associated with lipid intake. Alvimopan is a mu-opioid receptor antagonist that does not cross the blood brain barrier. Alvimopan is effective in treating postsurgical ileus and perhaps opiate-induced bowel dysfunction. Successes and failures of recent efforts to develop promotility agents revealed opportunities and challenges for developing new promotility drugs. The pharmacological properties of partial agonists might be exploited to develop effective promotility drugs. However, opposing actions of promotility agents on motility (increased contraction vs decreased accommodation) limit the clinical efficacy of drugs with these opposing actions. Selection of appropriate patient populations for evaluation of new drugs is also critical.
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PMID:Basic and clinical pharmacology of new motility promoting agents. 1618 2

Opioids have been used medicinally and recreationally for thousands of years. The clinical use of opioids for gastrointestinal conditions has been limited by central nervous system side effects. A new generation of peripheral opioid receptor ligands free of central nervous system side effects is being developed. Clinical trials with the peripherally acting mu opioid receptor antagonists' alvimopan and N-methylnaltrexone show promise for improving postoperative ileus- and opioid-induced constipation. Likewise, preliminary studies with the peripherally acting kappa opioid agonist fedotozine showed promise in the treatment of irritable bowel syndrome (IBS) and functional dyspepsia. Further studies are on hold presumably due to lack of efficacy in subsequent studies. However, clinical studies are underway for newer kappa opioid agonists such as asimadoline and ADL 10-0101.
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PMID:Peripheral opioids for functional GI disease: a reappraisal. 1669 67

In the past decade, the results of many studies on gastrointestinal motility and perception have been published that may be relevant to the clinician. A new classification of oesophageal motor disorders has been proposed in which "ineffective oesophageal motility" largely replaces the former "non-specific oesophageal motor disorders". Recent studies have shown that the incidence of transient lower oesophageal sphincter relaxations can be reduced pharmacologically, and this may open doors to a new therapeutic approach in gastro-oesophageal reflux disease. The mechanisms through which hiatus hernia promotes reflux have become clearer. The recently developed technique of intraluminal impedance monitoring has made it possible to study oesophageal transit, non-acid reflux and its role in the generation of reflux symptoms, as well as the characteristics of belching. Measurement of gastric emptying by means of a non-radioactive isotope and breath-testing has become widely available but, unfortunately, this development has not yet been accompanied by the advent of new therapeutic options for gastroparesis. The term "enteric dysmotility" has been coined for the condition in which upper abdominal symptoms are associated with distinct small intestinal bowel motility disorders in the absence of ileus-like episodes. The role of high-amplitude propagated contractions in the pathogenesis of constipation has been further defined. In cases of suspected sphincter of Oddi dysfunction, manometry of both sphincters (IBD and pancreatic) is now felt to be advisable.
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PMID:Recent developments in gastrointestinal motility. 1678 19

The gastrointestinal tract is innervated by extrinsic noradrenergic nerves which regulate various digestive functions, including mucosal secretions, bowel propulsion and gut sensations, via activation of alpha2-adrenoceptors. These receptors are mostly involved in the prejunctional modulation of enteric neurotransmission, but they act also at extra-neural postjunctional sites. Alpha2-adrenoceptor population consists of distinct subtypes, designated as alpha2A, alpha2B and alpha2C, endowed with different physiological and pharmacological properties, and the attempts to classify alpha2-adrenoceptors at gastrointestinal level have indicated a large predominance of alpha2A subtypes. Studies in humans have shown a favourable influence of alpha2-adrenoceptor activation on colonic tone and sensation, and there is clinical evidence indicating that alpha2-agonists can improve intestinal functions and induce a satisfactory relief of symptoms in patients with irritable bowel syndrome. In addition, genetic investigations have highlighted significant associations of alpha2-adrenoceptor gene polymorphisms with constipation and somatic symptoms in functional disorders of lower digestive tract. Post-operative ileus is a common surgical complication characterized by severe alteration of gut motility, resulting mainly from neurogenic and inflammatory mechanisms. Experiments in models of post-operative ileus have demonstrated an intense expression of alpha2-adrenoceptors in monocytes recruited into the intestinal muscularis, and provided consistent evidence that these receptors promote post-operative gut dysfunctions by hampering enteric neurotransmission and contributing to local inflammatory reaction. Changes in the enteric nervous system are being increasingly recognized also as major determinants of digestive symptoms associated with bowel inflammation. In this regard, studies based on functional and molecular approaches concur in suggesting that the expression of enteric alpha2-adrenoceptors is up-regulated in the presence of intestinal inflammation, and that alpha2-mediated mechanisms are responsible for gut motor alterations occurring at both inflamed and non-inflamed sites. The present review discusses pathophysiological implications of enteric alpha2-adrenoceptors, in the attempt to highlight potential therapeutic applications for drugs targeted on these receptors.
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PMID:Enteric alpha-2 adrenoceptors: pathophysiological implications in functional and inflammatory bowel disorders. 1761 14

Although the concept of purinergic signalling arose from experiments designed to find the identity of the non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmitter in the gut, it has taken many years for the more general importance of the various roles of ATP as a physiological messenger in the gut to be recognized. Firstly, vasoactive intestitial polypeptide (VIP) and later nitric oxide (NO) were considered the NANC transmitter and it was only later, after the concept of cotransmission was established, that ATP, NO and VIP were recognized as cotransmitters in NANC nerves, although the proportions vary in different gut regions. Recently, many purinoceptor subtypes have been identified on myenteric, submucosal motor, sensory and interneurons involved in synaptic neurotransmission and neuromodulation and reflex activity of several kinds, including ascending excitatory and descending inhibitory reflex pathways. Nucleotide receptors have been shown to be expressed on enteric glial cells and interstitial cells of Cajal. Purinergic mechanosensory transduction, involving release of ATP from mucosal epithelial cells during distension to stimulate subepithelial nerve endings of intrinsic and extrinsic sensory nerves to modulate peristalsis and initiate nociception respectively, is attracting current attention. Exciting new areas of interest about purinergic signalling in the gut include: involvement of purines in development, ageing and regeneration, including the role of stem cells; studies of the involvement of nucleotides in the activity of the gut of invertebrates and lower vertebrates; and the pathophysiology of enteric purinergic signalling in diseases including irritable bowel syndrome, postoperative ileus, oesophageal reflux, constipation, diarrhoea, diabetes, Chaga's and Hirschprung's disease.
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PMID:The journey to establish purinergic signalling in the gut. 1840 38

Daikenchuto (TU-100) is a traditional Japanese (Kampo) medicine used to treat postoperative ileus. TU-100 dose dependently increases gastrointestinal (GI) motility by modulating cholinergic and serotonergic mechanisms in animal studies. The aim of this study was to evaluate the effects of orally administered TU-100 on GI and colonic transit and bowel function in healthy humans. In a randomized, parallel-group, double-blind, placebo-controlled, dose-response study, 60 healthy subjects were randomly assigned to placebo or TU-100 2.5 g or 5 g tid ingested immediately before meals for 5 consecutive days. We measured GI and colonic transit by validated scintigraphy and stool frequency and consistency by daily diaries of bowel function. There were overall treatment effects on colonic filling at 6 h without any significant differences between each dose of TU-100 and placebo. There tended to be overall treatment effects on ascending colon (AC) emptying half-time; the TU-100 (7.5 g/day) treatment significantly accelerated AC emptying compared with placebo. There were numerically higher values of GC24 (which reflect overall colonic transit) with both doses of TU-100, but these changes were not statistically significant. There were no significant overall treatment effects on gastric emptying or stool frequency and consistency. One subject, who received 7.5 g/day of TU-100, had elevated creatine phosphokinase following the study. TU-100 (7.5 g/day) significantly accelerated AC emptying. Further randomized controlled trials in patients with functional constipation or irritable bowel syndrome with constipation are warranted to evaluate the clinical efficacy of TU-100 in these disorders.
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PMID:Effect of daikenchuto (TU-100) on gastrointestinal and colonic transit in humans. 2037 29

Opioids are well known to exert potent central analgesic actions. In recent years, the numerous studies have unfolded the critical role of opioids in the pathophysiology of various diseases as well as in biological phenomenon of therapeutic interest. The endogenous ligands of opioid receptors are derived from three independent genes and their appropriate processing yields the major representative opioid peptides beta-endorphin, met-enkephalin, leu-enkephalin and dynorphin, respectively. These peptides and their derivatives exhibit different affinity and selectivity for the mu-, delta- and kappa-receptors located on the central and the peripheral neurons, neuroendocrine, immune, and mucosal cells and on many other organ systems. The present review article highlights the role of these peptides in central nervous system disorders such as depression, anxiety, epilepsy, and stress; gastrointestinal disorders such as diarrhea, postoperative ileus, ulceration, and irritable bowel syndrome; immune system and related inflammatory disorders such as osteoarthritis and rheumatoid arthritis; and others including respiratory, alcoholism and obesity/binge eating. Furthermore, the key role of opioids in different forms of pre- and post-conditioning including ischemic and pharmacological along with in remote preconditioning has also been described.
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PMID:Extending pharmacological spectrum of opioids beyond analgesia: multifunctional aspects in different pathophysiological states. 2120 57


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