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)

Among the significant current topics in gastroenterology, the endoscopic capsule, virtual colonography, and ischaemic colitis deserve special considerations. Main indications of the endoscopic capsule are the diagnosis of small intestinal (bleeding) angiodysplasias, Crohn's lesions and tumours. The main drawbacks are gastrointestinal blockage of the capsule due to stenosis and flat batteries before the capsule reaches the distal small intestine. Future advantages may stem from a wider pre-use of an auto-digestible capsule capable of pre-cautionary excluding stenotic gastrointestinal segments ant the pill-cam for the evaluation of the oesophagus. Virtual colonography is a promising and attractive non-invasive alternative for the detection of tumoral colonic lesions (polyps and cancers). Its specific role as a screening procedure or investigation of symptomatic patients has to be better established. In a near future development of patients-friendly bowel preparation, high standard level of the evaluators and advances in computed software should likely allow a better definition of its overall potential. Ischaemic colitis is still a very difficult proposition for gastroenterologists and surgeons from any point of view. Its prompt recognition is a very significant advantage for the therapy. In addition to the advances in diagnostics and therapy, recent data have been reported as far as the pathogenesis of ischaemic colitis is concerned. Useful information has paradoxically come from the side effects of the 5-HT3 antagonists and 5-HT4 agonists used in treatment of irritable bowel syndrome patients.
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PMID:[Gastroenterology: recent advances and perspectives]. 1725 32

The 5-HT3 receptor is a pentameric ligand-gated cation channel which is found in the central and peripheral nervous system and on extraneuronal locations like lymphocytes, monocytes and fetal tissue. Five monomer subtypes, the 5-HT(3A-E) subunits, have been identified which show differences in the amino-terminal and the transmembrane region. The functional relevance of different receptor compositions is not yet clarified. 5-HT3 receptors are located predominantly in CNS regions that are involved in the integration of the vomiting reflex, pain processing, the reward system and anxiety control. The preferential localization on nerve endings is consistent with a physiological role of 5-HT3 receptors in the control of neurotransmitter release such as dopamine, cholecystokinin, glutamate, acetylcholine, GABA, substance P, or serotonin itself. 5-HT3-receptor agonists cause unpleasant effects like nausea and anxiety, and no clinical use has been considered. In contrast, the introduction of 5-HT3-receptor antagonists for chemotherapy-induced vomiting was extremely successful. After development of other gastrointestinal indications like postoperative vomiting and diarrhea-predominant irritable bowel syndrome recent research focuses on rheumatological indications such as fibromyalgia, rheumatoid arthritis and tendinopathies. Positive effects have also been observed for pain syndromes such as chronic neuropathic pain and migraine. These effects seem to be related to substance P-mediated inflammation and hyperalgesia. Furthermore, antiinflammatory and immunomodulatory properties have been observed for 5-HT3-receptor antagonists which might explain promising findings in systemic sclerosis and other immunological conditions. For all of these innovative indications the optimal dosing schedule is a crucial issue, since a bell-shaped dose-response curve has been observed repeatedly for 5-HT3-receptor antagonists, particularly in CNS effects.
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PMID:The neuronal 5-HT3 receptor network after 20 years of research--evolving concepts in management of pain and inflammation. 1731 6

The 5-HT3 receptor is a neurotransmitter-gated ion channel. It is a member of the Cys-loop family of receptors, which also includes nicotinic acetylcholine, glycine and GABAA receptors. Each member of the family consists of an arrangement of five subunits surrounding a central ion-conducting pore. The 5-HT3 receptor binding site is composed of six loops from two adjacent subunits, and the critical ligand binding residues within these loops are well documented. There are a range of 5-HT3 receptor agonists and competitive antagonists, but it is the antagonists that dominate their clinical use. Studies have proposed a range of disease symptoms that might be amenable to 5-HT3 receptor selective compounds; however, so far only the treatment of emesis and irritable bowel syndrome have been fully realised. In this review, the authors look at the structure, function and distribution of 5-HT3 receptors and how this may influence their role in disease. The authors also describe the existing clinical applications of 5-HT3 antagonists and the future potential of these drugs.
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PMID:The 5-HT3 receptor as a therapeutic target. 1737 82

In the gut, 5-HT acts as a paracrine signalling molecule released by enterochromaffin cells and as a transmitter released by some descending serotonergic interneurons. It has a prominent role in the regulation of motility, vascular tone, secretion and perception both in normal and under certain pathophysiological conditions, such as the carcinoid syndrome and the irritable bowel syndrome (IBS). Serotonin is known to markedly influence bowel function by activating at least five receptor types (5-HT(1,2,3,4,7)). Among all 5-HT receptors, those belonging to the 5-HT3 (a ionotropic receptor) and 5-HT4 (a metabotropic receptor) type are the most extensively studied in gastroenterology, resulting in commercially available (although not worldwide) serotonergic agents for the treatment of IBS and functional dyspepsia. Recently, 5-HT7 receptors have been found to participate in the accommodation process of the circular muscle during the preparatory phase of ileal peristalsis. Since an exaggerated accommodation of the gut wall may contribute to abdominal distension and bloating, 5-HT7 receptor ligands may offer innovative opportunities for the pharmacological treatment of functional bowel disorders.
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PMID:[Recent insights into the pathogenesis of abdominal symptoms in functional bowel disorders]. 1743 64

Relieving abdominal pain is the principal treatment objective for patients with irritable bowel syndrome. No single drug stands out in the treatment strategy for this illness. Antispasmodics, magnesium aluminum silicates, and alverine citrate drugs all remain initial options for treatment, although their prescription is impeded by the fact that an increasing number are no longer approved for reimbursement. Increased dietary fibers often have a harmful effect on symptoms. Some patients are probably intolerant to some foods but there is no satisfactory proof on which to base a restrictive diet. Improved knowledge of the pathophysiology of irritable bowel syndrome has made it possible to diversify treatments that act first on one of the key pathophysiologic elements, visceral hypersensitivity. Antidepressants (especially tricyclics) can be used at low doses. Among the serotonergic drugs, serotonin 5-HT4 receptors agonists (tegaserod) may be available soon, but the development of 5-HT3 antagonists (alosetron, cilansetron) has been stopped for safety reasons (ischemic colitis and severe constipation). Non-drug options such as hypnosis, psychotherapy, relaxation, or yoga, may also be proposed to some patients. Probiotics are a possible treatment in the future.
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PMID:[Irritable bowel syndrome: current treatment options]. 1749 Aug 49

Dynogen Pharmaceuticals Inc, under license from Mitsubishi Pharma Corp, is developing pumosetrag (MKC-733, DDP-733), an orally available gastroprokinetic agent and locally acting 5-HT3 partial agonist, for the potential treatment of irritable bowel syndrome (IBS) with constipation and nocturnal gastroesophageal reflux disease (GERD). In September 2005, Dynogen commenced a phase II proof-of-concept trial of pumosetrag in IBS with constipation; positive results were reported in February 2007 and a phase IIb trial was to start in the fourth quarter of 2007. In September 2006, the company had initiated a phase Ib trial in nocturnal GERD.
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PMID:Drug evaluation: Pumosetrag for the treatment of irritable bowel syndrome and gastroesophageal reflux disease. 1752 Aug 71

5-HT(3) receptor antagonists are clinically available for treating patients with irritable bowel syndrome (IBS) but their use is restricted because of a link with some episodes of ischaemic colitis. However, the role of 5-HT3 receptors in regulating colonic blood flow has not been systematically investigated. Thus, we examined acute and chronic treatment with alosetron, a potent and selective antagonist of the 5-HT3 receptor, on baseline colonic blood flow and haemodynamic responses during occlusion and reactive hyperaemia in the pentobarbitone-anaesthetized rat. Colonic haemodynamics were assessed using ultrasonic recordings of superior mesenteric blood flow (MBF) and laser Doppler recordings of colonic vascular perfusion (VP). Blood pressure (BP) was also monitored and in some experiments tissue oxygen was detected polarographically. Alosetron (10, 30, 100 microg kg(-1), i.v.) had no effect on baseline haemodynamics nor responses to nitric oxide synthase inhibition with N(omega)-nitro-l-arginine methyl ester (l-NAME) (16 mg kg(-1)). Arterial occlusion (5 min) reduced MBF (-98.6 +/- 0.6%) and VP (-70.7 +/- 5.4%) followed by a post-occlusion reactive hyperaemia (MBF = +94.5 +/- 19.1%; VP = +60.0 +/- 22.3%) the magnitude of which was unchanged following acute (30 microg kg(-1)) or chronic alosetron administration (0.5 mg kg(-1) twice daily, 5 days). Alosetron did not significantly alter baseline colonic blood flow in the anaesthetized rat; nor did it interfere with vascular control mechanisms activated during occlusion and reactive hyperaemia.
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PMID:Impact of 5-HT3 receptor blockade on colonic haemodynamic responses to ischaemia and reperfusion in the rat. 1759 42

Serotonin (5-HT) plays a critical role in the regulation of gastrointestinal motility, secretion and sensation. Serotonin is secreted by enterochromaffin (EC) cells and acts on receptors located on smooth muscles, enterocytes and nerves (5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT7). Enterocytes express the serotonin reuptake transporter (SERT), which terminate the action of 5-HT. There are lines of evidence that functional gastrointestinal disorders, as irritable bowel syndrome (IBS), are associated with defective enteric serotonergic signaling. Plasma level and mucosal cells containing EC are increased in diarrhea predominant IBS. Serotonin reuptake transporter expression in colonic mucosa is significantly reduced in IBS. Moreover, 5-HT receptor agonists and antagonists seem to be effective in the treatment of symptoms of IBS. 5-HT3 receptor antagonists--alosetrone, granisetrone, ondansetrone--modulate visceral sensitivity and slow intestinal transit. They have proved to be effective in diarrhea predominant IBS. 5-HT4 agonists--tegaserode, prucalopride--relieve abdominal pain and bloating and improve intestinal transit in constipation predominant IBS. 5-HT4 antagonist--piboserode--is being investigated for a diarrhea predominant IBS.
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PMID:[Role of serotonin in the pathophysiology of the irritable bowel syndrome]. 1817 58

The 5-hydroxytryptamine 3 (5-HT3) receptor is expressed widely in the central and peripheral nervous systems, where it mediates or modulates a wide range of physiological processes. The receptor is targeted by drugs administered for nausea and/or emesis and irritable bowel syndrome and has been proposed as a potential drug target in various psychiatric disorders. The 5-HT3 receptor is a pentameric ligand-gated ion channel and belongs to the Cys-loop receptor family. In contrast to the immense heterogeneity characterizing other Cysloop receptors, native 5-HT3 receptors historically have been considered a much more homogenous receptor population. However, the recent discovery of additional 5-HT3 subunits and the dawning realization that central and peripheral 5-HT3 receptor populations might comprise several subtypes characterized by distinct functional properties has emphasized the complexity of human 5-HT3 receptor signaling. In this review potential implications of these findings and of the entirely new layer of interindividual diversity introduced to the 5-HT3 receptor system by genetic variations will be outlined.
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PMID:3B but which 3B and that's just one of the questions: the heterogeneity of human 5-HT3 receptors. 1859 59

Researching the functions of serotonin, or 5-hydroxytryptamine (5-HT), in the gut has helped define new 5-HT receptors, increased the understanding of the side effects of numerous drugs and, via development of drugs, brought relief to millions of people suffering from disorders such as gastroparesis, dyspepsia, constipation, diarrhoea, irritable bowel syndrome and cancer. However, safety issues associated with alosetron and tegaserod (key drugs that modulate 5-HT function) have brought 5-HT and gastrointestinal research to a crossroad--is it now too hard to develop drugs in this area or is there a way forward? In this review, I describe the background to 5-HT in gastrointestinal physiology and disease, and the actions of drugs that interact with 5-HT3 and 5-HT4 receptors. Future research directions include modulating 5-HT availability by inhibition of tryptophan hydroxylase, understanding the functions of receptors such as 5-HT2B, 5-HT7 and the recently described 5-HT3-receptor subunits, and investigating how receptors activated by other products of tryptophan catabolism interact with gastrointestinal functions of 5-HT.
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PMID:5-hydroxytryptamine and the gastrointestinal tract: where next? 1908 55


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