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)

Serotonin (5-hydroxytryptamine; 5-HT) is found in the enteric nervous system where it has been implicated in controlling gastrointestinal motor function. A number of receptor or recognition sites have been identified in the gut, but recently most attention has focused on the 5-HT3 and 5-HT4 receptors. The functional role of the 5-HT3 receptor remains incompletely understood, but it is probably involved in the modulation of colonic motility and visceral pain in the gut. A number of selective 5-HT3 antagonists have been developed including ondansetron, granisetron, tropisetron renzapride and zacopride. While the substituted benzamide prokinetics (for example, metoclopramide, cisapride) also block 5-HT3 receptors in high concentrations, their prokinetic action is believed to be on the basis of their agonist effects on the putative 5-HT4 receptor. Some 5-HT3 antagonists have 5-HT4 agonist activity (for example, renzapride, zacopride) and others do not (for example, ondansetron, granisetron), while tropisetron in high concentrations is a 5-HT4 antagonist. Based on the pharmacological data, it has been suggested that specific 5-HT antagonists and agonists may prove to be beneficial in a number of gastrointestinal disorders including the irritable bowel syndrome, functional dyspepsia, non-cardiac chest pain, gastrooesophageal reflux and refractory nausea. In this review, the rationale for the use of these compounds is discussed, and the available experimental evidence is summarized.
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PMID:Review article: 5-hydroxytryptamine agonists and antagonists in the modulation of gastrointestinal motility and sensation: clinical implications. 160 46

5-Hydroxytryptamine (5-HT) is an important neurotransmitter and hormone/paracrine agent mediating various enteric functions. Its precise physiological and pathophysiological role remains unclear. This study investigated the effects of 5-HT on colonic function and the effects of the newly developed 5-HT3 and 5-HT4 receptor antagonist, FK1052, on colonic responses to 5-HT or stress stimulus in vivo. In conscious rats, both 5-HT and 5-methoxytryptamine significantly increased fecal pellet output and accelerated colonic transit. In contrast, the effect of 2-methyl-5-HT was slight. Although ondansetron and granisetron slightly reduced 5-HT (1 mg/kg s.c.) stimulated colonic transit, FK1052 [(+)-8,9-dihydro-10-methyl-7-[(5-methyl-4-imidazolyl)methyl]pyrido- [1,2-a]-indole-6(7H)-one hydrochloride], at 0.1 mg/kg p.o., inhibited completely the increases in the colonic transit. Furthermore, FK1052, ondansetron and granisetron significantly depressed the increase in fecal pellet output caused by wrap-restraint stress, with ED50 values of 0.21, 3.0 and 1.1 mg/kg p.o., respectively. Intraperitoneal administration of 5-HT and 5-methoxytryptamine, but not 2-methyl-5-HT, produced a dose-related increase in the incidence of diarrhea in fasted mice. 5-HT (0.32 mg/kg i.p.)-induced diarrhea was also inhibited by FK1052, ondansetron and granisetron, with ED50 values of 0.09, 2.3 and 0.88 mg/kg p.o., respectively. These findings suggest that 5-HT3 and 5-HT4 receptors may have an important role in colonic function and FK1052 may have therapeutic potential in the treatment of gastrointestinal dysfunction such as irritable bowel syndrome.
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PMID:Effect of FK1052, a potent 5-hydroxytryptamine3 and 5-hydroxytryptamine4 receptor dual antagonist, on colonic function in vivo. 833 76

The 5-HT4 receptor is a member of the seven transmembrane spanning G-protein-coupled family of receptors. The receptor is positively coupled to adenylate cyclase and exists in two isoforms (5-HT4S and 5-HT4L) that differ in the length and sequence of their carboxy termini. The 5-HT4 receptor is pharmacologically defined by selective agonists such as SC 53116 and RS 67506, and selective antagonists such as GR 113808, SB 204070, and RS 39604. The receptor is widely distributed in the central nervous system and peripheral tissues. In the periphery, the receptor plays an important role in the function of several organ responses including the alimentary tract, urinary bladder, heart and adrenal gland. In the alimentary tract, stimulation of 5-HT4 receptors has a pronounced effect on smooth muscle tone, mucosal electrolyte secretion, and the peristaltic reflex. In the urinary bladder, activation of 5-HT4 receptors modulates cholinergic/purinergic transmission. In the heart, stimulation of atrial 5-HT4 receptors produces positive inotropy and tachycardia that can precipitate arrhythmias. In the adrenal gland, agonism of 5-HT4 receptors stimulates release of cortisol, corticosterone, and aldosterone. Since its discovery in 1988, significant advances have been made in our understanding of the physiology and pharmacology of the 5-HT4 receptor. These advances have led to the development of several selective 5-HT4 receptor agonists and antagonists that may have therapeutic utility in the treatment of peripheral disorders such as irritable bowel syndrome, gastroparesis, urinary incontinence and cardiac arrhythmias.
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PMID:Peripheral 5-HT4 receptors. 890 10

The possibility that 5-hydroxytryptamine (5-HT) acts as a key sensitising agent in the aetiology of irritable bowel syndrome (IBS) is reviewed. The strategic locations of 5-HT and its receptors are described, the most dominant being the 5-HT3 and 5-HT4 type. 5-HT, acting mostly at 5-HT3 or 5-HT3-like receptors, enhances the sensitivity of visceral neurones projecting between the gut and the central nervous systems. 5-HT, acting at 5-HT4 receptors promotes the sensitivity of enteric neurones that react to luminal stimuli. 5-HT4 and 5-HT3 receptors also mediate, respectively, sensitising and physiological actions of 5-HT on gastro-intestinal motor and secretory functions. This distribution implies that some 5-HT3 receptor antagonists might reduce certain symptoms of IBS, such as pain, by reducing the reactivity of the visceral afferent neurones linking the gut with the brain and spinal cord. However, such antagonists are not likely to find widespread clinical acceptance because they can also affect normal lower bowel function and promote constipation. 5-HT4 receptor antagonists, by contrast, reduce 5-HT-induced enteric nerve hypersensitivity without notably affecting the function of the normal bowel. Accordingly, these agents may reduce the symptoms of IBS directly, by reducing the incidence of defecation and diarrhoea and indirectly, by reducing both 'rebound' constipation and the post-prandial discomfort and pain associated with gastrointestinal hyper-reactivity.
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PMID:5-Hydroxytryptamine and functional bowel disorders. 895 36

Irritable bowel syndrome (IBS) continues to provide a major therapeutic challenge to clinicians and those involved in drug development. It seems unlikely from the data before us that this multisymptom syndrome with peripheral and central components is likely to respond reliably in all patients to the same single agent. There is still a lack of well designed, appropriately powered, randomised clinical trials and the problems of dealing with the high placebo response rate in this group of patients remains a dilemma for trial designers. There are, however, some new ideas, particularly those relating to the role of hyperalgesia in IBS. For many patients, abdominal pain and bloating are the most distressing symptoms of this disease and the new drugs targeted at pain control, such as kappa agonists and serotonin antagonists (5-HT3) and possibly 5-HT4), may eventually find a place in the clinical management of this syndrome. Other candidates include somatostatin analogues and antidepressants, the latter predominantly for their effects on increasing pain threshold. More speculative new drugs for IBS include cholecystokinin antagonists such as loxiglumide and the gonadotrophin-releasing hormone analogue, leuprorelin (leuprolide). The results of on-going randomised clinical trials are still awaited for some of these newer agents. The irritable bowel syndrome (IBS) is the most common gastrointestinal condition encountered by general practitioners and is reported to account for up to 50% of the work of gastroenterologists in secondary care. However, most people with the symptoms of IBS (60 to 75%) do not consult a doctor. Its cause is unknown, its development is poorly understand and, perhaps not surprisingly, no universally agreed approach to treatment exists.
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PMID:New drugs in the management of the irritable bowel syndrome. 966 95

Tegaserod is a serotonin (5-hydroxytryptamine; 5-HT) receptor partial agonist which has been investigated for the treatment of irritable bowel syndrome (IBS). Specifically, it binds with high affinity to human 5-HT4 receptors, thereby stimulating the release of neurotransmitters and the peristaltic reflex in vitro. Small bowel transit (increased colonic filling over 6 hours) was accelerated in patients with constipation-predominant irritable bowel syndrome (IBS) receiving oral tegaserod 2mg twice daily for 1 week compared with those receiving placebo. In addition, there was a mean 20% increase of proximal colonic emptying in these patients. Oral tegaserod 2 (p < 0.05) or 6mg twice daily improved symptoms of abdominal discomfort, bloating and constipation (assessed using a Subjects' Global Assessment Scale) compared with placebo in patients with constipation-predominant IBS in a double-blind, dose-ranging study. The most frequent adverse events in patients with constipation-predominant IBS receiving oral tegaserod were transient diarrhoea and flatulence. No clinically relevant changes in blood pressure, pulse rate, QRS or QTc interval were reported with tegaserod doses of 25 to 100mg.
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PMID:Tegaserod. 1049 76

The irritable bowel syndrome (IBS) is a consortium of symptoms including abdominal pain and alterations in the pattern of defaecation. There is no single pathophysiological marker of IBS although it is generally accepted that some patients do have abnormalities of intestinal motility and/or enhanced visceral sensitivity. There is also an increasing acceptance that the central nervous system, an important component of the brain-gut axis, also plays an important role in symptom production both in the response to stress and when there is an underlying affective disorder. During the past decade new therapeutic targets have been identified that have permitted the development of new drugs with therapeutic potential for IBS. Identification and characterization of 5-hydroxytryptamine (5-HT) receptors in the gastrointestinal tract particularly 5-HT3 and 5-HT4 receptors, which are involved not only in modulating gut motility but in visceral sensory pathways, has led to a number of studies of 5-HT3 (Alosetron, Granisetron and Ondansetron) and 5-HT4 (SB-207266A) antagonists. Both classes of drug appear to reduce visceral sensitivity and have inhibitory effects on motor activity in the distal intestine. Early clinical studies suggest that these agents may have a role in painful, diarrhoea-predominant IBS. 5-HT4 agonists (HTF919, Zelmac) may improve constipation-predominant IBS by normalizing bowel habit and thereby reducing abdominal pain. Alternative approaches to reducing visceral sensation include the use of the opioid kappa agonists, which have no central opioid effects although clinical trials have suggested that these agents are not highly effective in relieving IBS pain. There are in addition, new approaches to modify intestinal motility including the development of gut selective muscarinic M3 receptor antagonists such as zamifenacin and the 5-HT4 partial agonist, HTF919. Preliminary studies suggest that these agents may have therapeutic potential in IBS. Anti-depressants are increasingly used to treat affective disorder in IBS but in addition appear to have added value because of their ability to reduce visceral hypersensitivity and alter gut transit. Therapeutic effects are often obtained at doses below those normally used to treat depression. IBS continues to be a therapeutic challenge because of its diverse symptomatology and lack of a single pathophysiological target for drug intervention.
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PMID:Irritable bowel syndrome: new pharmaceutical approaches to treatment. 1058 Sep 22

This article reviews briefly the evidence to support current therapies in irritable bowel syndrome (IBS) and the novel therapeutic approaches on the threshold of clinical application. Fiber is indicated at a dose of at least 12 grams per day in patients with constipation-predominant IBS. Loperamide (and probably other opioid agonists) are of proven benefit in diarrhea-predominant IBS; loperamide may also aid continence by enhancing resting anal tone, but there is no evidence that it results in pain relief. In general, smooth muscle relaxants are best used sparingly, on an as-needed basis, because their overall efficacy is unclear. The 5-HT3 antagonist, alosetron, results in adequate relief of pain and improvements in bowel function in female nonconstipated patients with IBS. Psychotropic agents are important in relieving depression and are of proven benefit for pain and diarrhea in patients with depression associated with IBS. Further trials with selective serotonin reuptake inhibitors are awaited. Psychological treatments including hypnotherapy are less widely available but may play an important role in the relief of pain. In summary, current therapies targeted on the predominant symptoms in IBS are moderately successful. As the bowel sensorimotor and limbic system disturbances of IBS are more clearly understood, we should anticipate other pharmacologic approaches in the near future, including alpha-adrenergic agonists and 5-HT4 agonists. New therapies directed at treatment of the syndrome, rather than relief of symptoms, are needed.
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PMID:Therapeutic approach to the patient with irritable bowel syndrome. 1058 70

Although the past few years have seen an exponential growth of compounds of potential interest for the treatment of functional gastrointestinal (GI) tract disorders, the gap that still exists between basic and clinical research is easily noticed if one considers the relative paucity of drugs that have received marketing authorisation for the treatment of irritable bowel syndrome (IBS). Traditional efficacy outcomes in drug development for IBS include the ability of the compound to affect GI tract motility (i.e. to exert a prokinetic or an antispasmodic effect), which is thought to be of importance if a motor disorder is the underlying pathophysiological mechanism. More recently, altered visceral sensitivity to a distending stimulus has been suggested to be a key pathophysiological feature, at least in some patients, and has become a target for therapeutic interventions. However, there is now growing consensus that the primary outcome measure in the treatment of functional disorders are those that reflect overall control of the patient's symptoms (pain, diarrhoea, constipation) in everyday situations such as the clinical global improvement scales. Although, in general, guidelines on the design of treatment trials for functional GI tract disorders advise against subcategorisation of patients according to the main symptom (because of symptom instability), subcategorisation indeed makes sense especially in IBS (constipation- or diarrhoea-predominant). Compounds with a specific indication for each subpopulation of patients are now emerging. The rationale for investigations on serotonin (5-hydroxytryptamine; 5-HT) receptor ligands in IBS rests mainly on the fact that serotonin, which may be released by enterochromaffin-like cells in the GI tract as well as from other sources, has a number of well documented motor effects on the GI tract and can produce hyperalgesia in several experimental models. Serotonin receptors belonging to the 5-HT3 and 5-HT4 subtype are the most extensively studied in gastroenterology, although hitherto 'orphan' receptor subtypes, such as the 5-HT7 and the 5-HT(1B/D) receptors, are now emerging. Among 5-HT3 receptor antagonists, alosetron was recently approved for the treatment of diarrhoea-predominant IBS and is an example of a compound that, at least theoretically, may act at multiple levels: by inhibiting visceral sensitivity, by increasing compliance, and by inhibiting excitatory 5-HT3 receptors located on both ascending and descending neuronal pathways involved in peristalsis. For this reason, 5-HT3 receptor antagonists may slow transit, hence the specific indication of alosetron in diarrhoea-predominant IBS. However, alosetron has been recently withdrawn by the manufacturer because of safety concerns. Hypomotility remains an attractive therapeutic target in IBS and the new generation of prokinetics includes several partial agonists at the 5-HT4 receptor, such as tegaserod (HTF-919) and prucalopride (R0-93877). In addition, preliminary evidence suggests that 5-HT4 receptors may also be involved in the modulation of visceral sensitivity. Second-generation 5-HT4 receptor agonists seem to be devoid of the QT-prolonging effects observed in some clinical circumstances with cisapride and may be more active at the colonic level. Piboserod (SB-207266A) is a 5-HT4 receptor antagonist under development for the treatment of diarrhoea-predominant IBS. Finally, interest in 5-HT7 and 5-HT(1B/D) receptor subtypes stems from the observation that the former receptors mediate smooth muscle relaxation (at least in the human colon), whereas sumatriptan (a 5-HT(1B/D) receptor agonist) can affect GI tract motility and visceral sensitivity.
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PMID:Irritable bowel syndrome: new agents targeting serotonin receptor subtypes. 1129 43

Coordinated activities of the central, autonomic, and enteric nervous systems modulate intestinal motor, sensory, and secretory activities that may contribute to the triad of dysfunction (altered motility, altered sensation, and psychosocial distress) observed in patients with irritable bowel syndrome (IBS). Autonomic modulation of gastrointestinal (GI) function occurs via the actions of neurotransmitters and neuromodulators such as serotonin (5-hydroxytryptamine, or 5-HT), norepinephrine, and dopamine. Of those modulators, serotonin has received the most attention with respect to disorders of GI function. Serotonin exerts its effects via neurocrine, paracrine, and endocrine pathways. Recent studies have demonstrated that serotonin, acting primarily through 5-HT3 and 5-HT4 receptors, is intricately involved in initiating the peristaltic reflex and facilitating intraluminal secretions. Serotonin receptors mediate reflex control of GI motility and secretion and may influence the perception of bowel function and pain under some circumstances. GI motor activity and sensory dysfunction in patients with IBS may be a result of alterations in serotonin levels or associated 5-HT receptors. Serotonin agonists and antagonists such as tegaserod, a 5-HT4 agonist, may offer new treatments that normalize GI motor and sensory functions in patients with disorders of GI function.
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PMID:The role of serotonin in the pathophysiology of irritable bowel syndrome. 1147 10


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