Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1291077 (bloating)
 1,674 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tegaserod is a selective partial agonist acting on serotonergic type 4 receptors (5-HT(4)). Pharmacodynamic studies indicate that tegaserod is able to stimulate gut propulsion and secretion with a net prokinetic effect. In contrast to other 5-HT(4) agonists endowed with a complex pharmacological profile, tegaserod has a reliable prokinetic activity in the colon. Clinical trials show that tegaserod is effective and safe in the treatment of patients with irritable bowel syndrome. In particular, tegaserod relieves symptoms of abdominal pain, discomfort, abdominal bloating and constipation.
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PMID:Tegaserod: a new 5-HT(4) agonist in the treatment of irritable bowel syndrome. 1215 Jun 98

The diagnosis of irritable bowel syndrome (IBS) is arbitrary, being based on criteria defined by consensus rather than specific biologic markers. IBS is merely a consortium of symptoms and as presently defined is no more a disease than dyspnea or fatigue are diseases. In this context, it is therefore not surprising that defining the nature of pain has proven elusive. It is often etiologically assumed that the origins of the pain seen in IBS patients are mechanistically distinct from those of some of the other symptoms of IBS such as diarrhea and constipation. In addition pain is assumed to be part of a continuum ranging from complete absence of any pain to varying degrees of discomfort to severe pain. Both of these assumptions should be challenged: there are no data to support the notion that discomfort and pain experienced in IBS are mediated through different pathways than symptoms such as bloating or that they are not merely the consequence of the physiological perturbations associated with altered bowel function. Similarly one can easily argue that visceral pain may actually be the cause rather than the effect of the altered gut function seen in IBS. Abdominal discomfort could then be the consequence of the latter and be only indirectly related to pain. It is likely that central (such as stress) and peripheral factors (such as intestinal infection) will produce similar symptoms but via markedly different pathways. It may be time to deconstruct IBS as a concept and to approach the clinical picture from a mechanistic rather than a phenomenological perspective, particularly if we are interested in understanding the basis of the symptoms and develop effective therapeutic modalities. Our patients deserve no less.
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PMID:The nature of pain in irritable bowel syndrome. 1218 36

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

Irritable bowel syndrome (IBS) is a multi-factorial gastrointestinal condition affecting 8-22 % of the population with a higher prevalence in women and accounting for 20-50 % of referrals to gastroenterology clinics. It is characterised by abdominal pain, excessive flatus, variable bowel habit and abdominal bloating for which there is no evidence of detectable organic disease. Suggested aetiologies include gut motility and psychological disorders, psychophysiological phenomena and colonic malfermentation. The faecal microflora in IBS has been shown to be abnormal with higher numbers of facultative organisms and low numbers of lactobacilli and bifidobacteria. Although there is no evidence of food allergy in IBS, food intolerance has been identified and exclusion diets are beneficial to many IBS patients. Food intolerance may be due to abnormal fermentation of food residues in the colon, as a result of disruption of the normal flora. The role of probiotics in IBS has not been clearly defined. Some studies have shown improvements in pain and flatulence in response to probiotic administration, whilst others have shown no symptomatic improvement. It is possible that the future role of probiotics in IBS will lie in prevention, rather than cure.
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PMID:A review of the role of the gut microflora in irritable bowel syndrome and the effects of probiotics. 1221 82

Bloating is a frequently reported symptom in functional bowel disorders. It usually occurs in combination with other symptoms, but may also occur in isolation. The severity of bloating tends to worsen during the course of the day and improves overnight. Although frequently considered to be a subjective phenomenon, recent studies have shown that bloating is associated with a measurable increase in abdominal girth. The pathophysiology of bloating remains elusive, but the evidence supports a sensorimotor dysfunction of the bowel. The possible mechanisms include abnormal gas trapping, fluid retention, food intolerance and altered gut microbial flora. Further studies are needed to define the sensorimotor abnormalities associated with bloating, which might be segmental and transient rather than generalized and persistent. The lack of understanding of this symptom is paralleled by a limited availability of therapeutic options. Conventional medications used in functional bowel disorders are not helpful and may indeed worsen the symptoms. In future, new drugs with activity against serotonin and kappa receptors, or novel approaches such as the use of exclusion diets, probiotics and hypnotherapy, may prove to be useful.
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PMID:Review article: bloating in functional bowel disorders. 1239 95

Opioid treatment for postoperative or chronic pain is frequently associated with adverse effects, the most common being dose-limiting and debilitating bowel dysfunction. Postoperative ileus, although attributable to surgical procedures, is often exacerbated by opioid use during and following surgery. Postoperative ileus is marked by increased inhibitory neural input, heightened inflammatory responses, decreased propulsive movements and increased fluid absorption in the gastrointestinal tract. The use of opioids for chronic pain is characterised by a constellation of symptoms including hard dry stools, straining, incomplete evacuation, bloating, abdominal distension and increased gastroesophageal reflux. The current management of opioid-induced bowel dysfunction among patients receiving opioid analgesics consists primarily of nonspecific ameliorative measures. Intensive investigations into the mode of action of opioids have characterised three opioid receptor classes -mu, delta and kappa- that mediate the myriad of peripheral and central actions of opioids. Activation of mu-opioid receptors in the gastrointestinal tract is responsible for inhibition of gut motility, whereas receptors in the central nervous system mediate the analgesic actions of opioids. Blocking peripheral opioid receptors in the gut is therefore a logical therapeutic target for managing opioid-induced bowel dysfunction. Available opioid antagonists such as naloxone are of limited use because they are readily absorbed, cross the blood-brain barrier, and act at central opioid receptors to reverse analgesia and elicit opioid withdrawal. Methylnaltrexone and alvimopan are recently developed opioid antagonists with activity that is restricted to peripheral receptors. Both have recently shown the ability to reverse opioid-induced bowel dysfunction without reversing analgesia or precipitating central nervous system withdrawal signs in non-surgical patients receiving opioids for chronic pain. In addition, recent clinical studies with alvimopan suggest that it may normalise bowel function without blocking opioid analgesia in abdominal laparotomy patients with opioid-related postoperative ileus.
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PMID:Opioid-induced bowel dysfunction: pathophysiology and potential new therapies. 1265 45

Diabetic gastroparesis is a common and debilitating condition affecting millions of patients with diabetes mellitus worldwide. Although gastroparesis in diabetes has been known clinically for more than 50 years, treatment options remain very limited. Until recently, the scientific literature has offered few clues regarding the precise aetiology of gastric dysfunction in diabetes.Up to 50% of patients with diabetes may experience postprandial abdominal pain, nausea, vomiting and bloating secondary to gastric dysfunction. There is no clear association between length of disease and the onset of delayed gastric emptying. Gastroparesis affects both type 1 (insulin dependent) and type 2 (non- insulin dependent) forms of diabetes. Diagnosis requires identifying the proper symptom complex, while excluding other entities (peptic ulcer disease, rheumatological diseases, medication effects). The diagnosis of gastroparesis may be confirmed by demonstrating gastric emptying delay during a 4-hour scintigraphic study. Treatment options are limited and rely on dietary modifications, judicious use of available pharmacological agents, and occasionally surgical or endoscopic placement of gastrostomies or jejunostomies. Gastric pacing offers promise for patients with medically refractory gastroparesis but awaits further investigation. Current pharmacological agents for treating gastroparesis include metoclopramide, erythromycin, cisapride (only available via a company-sponsored programme) and domperidone (not US FDA approved). All of these drugs act as promotility agents that increase the number or the intensity of gastric contractions. These medications are not uniformly effective and all have adverse effects that limit their use. Cisapride has been removed from the open market as a result of over 200 reported cases of cardiac toxicity attributed to its use. Unfortunately, there is a paucity of clinical studies that clearly define the efficacy of these agents in diabetic gastroparesis and there are no studies that compare these drugs to each other. The molecular pathophysiology of diabetic gastroparesis is unknown, limiting the development of rational therapies. New studies, primarily in animals, point to a defect in the enteric nervous system as a major molecular cause of abnormal gastric motility in diabetes. This defect is characterised by a loss of nitric oxide signals from nerves to muscles in the gut resulting in delayed gastric emptying. Novel therapies designed to augment nitric oxide signalling are being studied.
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PMID:Current concepts in diabetic gastroparesis. 1282 60

Cholecystokinin (CCK) is a brain-gut peptide; it functions both as a neuropeptide and as a gut hormone. Although the pancreas and the gallbladder were long thought to be the principal peripheral targets of CCK, CCK receptors are found throughout the gut. It is likely that CCK has a physiological role not only in the stimulation of pancreatic and biliary secretions but also in the regulation of gastrointestinal motility. The motor effects of CCK include postprandial inhibition of gastric emptying and inhibition of colonic transit. It is now evident that at least two different receptors, CCK(1) and CCK(2) (formerly CCK-A and CCK-B, respectively), mediate the actions of CCK. Both localization and functional studies suggest that the motor effects of CCK are mediated by CCK(1) receptors in humans. Since CCK is involved in sensory and motor responses to distension in the intestinal tract, it may contribute to the symptoms of constipation, bloating and abdominal pain that are often characteristic of functional gastrointestinal disorders in general and irritable bowel syndrome (IBS), in particular. CCK(1) receptor antagonists are therefore currently under development for the treatment of constipation-predominant IBS. Clinical studies suggest that CCK(1) receptor antagonists are effective facilitators of gastric emptying and inhibitors of gallbladder contraction and can accelerate colonic transit time in healthy volunteers and patients with IBS. These drugs are therefore potentially of great value in the treatment of motility disorders such as constipation and constipation-predominant IBS.
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PMID:Involvement of endogenous CCK and CCK1 receptors in colonic motor function. 1510 Jan 63

The irritable bowel syndrome (IBS) is part of the spectrum of functional bowel disorders characterised by a diverse consortium of abdominal symptoms including abdominal pain, altered bowel function (bowel frequency and/or constipation), bloating, abdominal distension, the sensation of incomplete evacuation and the increased passage of mucus. It is not surprising therefore that no single, unifying mechanism has as yet been put forward to explain symptom production in IBS. The currently favoured model includes both central and end-organ components which may be combined to create an integrated hypothesis incorporating psychological factors (stress, distress, affective disorder) with end-organ dysfunction (motility disorder, visceral hypersensitivity) possibly aggravated by sub-clinical inflammation as a residuum of an intestinal infection. There is currently no universally effective therapy for IBS. Standard therapy generally involves a symptom-directed approach; anti-diarrhoeal agents for bowel frequency, soluble fibre or laxatives for constipation and smooth muscle relaxants and anti-spasmodics for pain. New drug development has focused predominantly on agents that modify the effects of 5-hydroxytryptamine (5-HT) in the gut, principally the 5-HT(3) receptor antagonists for painful diarrhoea predominant IBS and 5-HT(4) agonists for constipation predominant IBS. More speculative new therapeutic approaches include anti-inflammatory agents, antibiotics, probiotics, antagonists of CCK1 receptors, tachykinins and other novel neuronal receptors.
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PMID:Treatment options in irritable bowel syndrome. 1532 13

Irritable bowel syndrome (IBS) is a functional, multifactorial disease characterized by abdominal pain and erratic bowel habit. Changes in gastrointestinal motor function, enhanced perception of stimuli arising from the gut wall and psychosocial factors are thought to be major contributors for symptom generation. In recent years, several additional factors have been identified and postulated to interact with these classical mechanisms. Reduced ability to expel intestinal gas with consequent gas trapping and bowel distension may contribute to abdominal discomfort/pain and bloating. Abnormal activation of certain brain regions following painful stimulation of the rectum suggests altered processing of afferent signals. An acute gastrointestinal infection is now a recognized aetiological factor for symptom development in a subset of IBS patients (i.e. post-infectious IBS), who are probably unable to down-regulate the initial inflammatory stimulus efficiently. Furthermore, low-grade inflammatory infiltration and activation of mast cells in proximity to nerves in the colonic mucosa may also participate in the frequency and severity of perceived abdominal pain in post-infectious and non-specific IBS. Initial evidence suggests the existence of changes in gut microflora, serotonin metabolism and a genetic contribution in IBS pathophysiology. These novel mechanisms may aid a better understanding of the complex pathophysiology of IBS and to develop new therapies.
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PMID:New pathophysiological mechanisms in irritable bowel syndrome. 1533 8


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