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)

A growing body of evidence implicates abnormal serotonergic regulation of gastrointestinal function in the pathogenesis of the irritable bowel syndrome (IBS). Drugs targeting this system are therefore attractive concepts. The partial 5-HT4 receptor agonist tegaserod might be predicted to have positive therapeutic effects on a constipated and uncomfortable gut. However, IBS runs a chronic, benign course and carries no associated mortality, so it is imperative that the safety profile of new pharmacological agents made available to physicians is exemplary. The authors review the evidence for 5-HT in the aetiology of IBS and its symptoms, and the data available concerning the partial 5-HT4 receptor agonist tegaserod, in terms of rationale, efficacy and safety.
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PMID:The rationale, efficacy and safety evidence for tegaserod in the treatment of irritable bowel syndrome. 1650 51

Acupuncture has long been used for patients with irritable bowel syndrome. However, it has remained unclear. The aim of this study was to testify the effect of electro-acupuncture(EA) on (1) visceral hypersensitivity induced by the mechanical colorectal irritation during postnatal development of rats, and (2) stress-induced colonic motility changes on rats with chronic visceral hypersensitivity. The abdominal withdrawal reflex (pain threshold and score) for visceral hypersensitivity and fecal pellet output for motor dysfunction were selected as two indexes for measurement. In addition, the effect of EA on 5-HT(4a) receptor and serotonin transporter (SERT) expression in the colon mucosa was analyzed semi-quantitatively through immunohistochemistry and 5-HT concentration in the colon tissue was observed through spectro-photo-fluorimeter detection, respectively. Our results showed that EA significantly elevated pain threshold, decreased the scores and also decreased fecal pellet output during water avoid stress. Furthermore, EA decreased 5-HT concentration in colon in rats with CVH and CVH rats with water avoidance stress, and increased the 5-HT(4a) and SERT expression in rats with CVH. Thus, it can be concluded that EA attenuates behavioral hyperalgesia and stress-induced colonic motor dysfunction in CVH rats via serotonergic pathway.
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PMID:Electro-acupuncture attenuates stress-induced defecation in rats with chronic visceral hypersensitivity via serotonergic pathway. 1665 Mar 87

In the gut, serotonin (5-hydroxytryptamine: 5-HT) exerts a variety of effects on intrinsic enteric neurons, extrinsic afferents, enterocytes and smooth muscle cells, which are related to the expression of multiple 5-HT receptor types and subtypes regulating motility, vascular tone, secretion and perception. Agonists and antagonists at 5-HT receptors have gained access to the market for the two major variants of the irritable bowel syndrome (IBS), a functional disorder characterized by abdominal pain associated with diarrhea and/or constipation in the absence of any organic abnormality. Indeed, the 5-HT3 receptor antagonist alosetron is available in the US market for the treatment of women with severe, diarrhea-predominant IBS (D-IBS) refractory to conventional therapy, whereas tegaserod, a partial 5-HT4 receptor agonist, has been approved by the FDA and other regulatory agencies for the treatment of women with constipation-predominant IBS (C-IBS) or functional constipation. This review is mainly intended to discuss the role of non-neuronal (paracrine) and neuronal 5-HT in the pathophysiology of functional gastrointestinal disorders (FGIDs), such as IBS and functional dyspepsia, and the mechanisms through which drugs acting on 5-HT receptors regulate visceral motility, perception and secretion in these two conditions.
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PMID:Drugs acting on serotonin receptors for the treatment of functional GI disorders. 1669 64

Serotonin-selective reuptake transporter (SERT) expression is decreased in animal models of intestinal inflammation and in individuals with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS), and it is possible that resultant changes in intestinal serotonin signalling contribute to the manifestation of clinical features associated with these disorders. The objective of this investigation was to determine whether inhibition of SERT function leads to changes in gut motility and sensitivity. Mice underwent a 14-day treatment with the SERT inhibitor, paroxetine (20 mg kg(-1)), or vehicle (saline/propylene glycol). Gastrointestinal (GI) transit following charcoal gavage, colonic motility, stool frequency and visceromotor responses to colorectal distension were evaluated. In mice treated with paroxetine, stool output was decreased, upper GI transit was delayed, and colonic sensitivity to a nociceptive stimulus was attenuated. These results demonstrate that reduced SERT function (via pharmacological blockade) significantly alters GI motility and sensitivity in mice, and support the concept that altered SERT expression and function could contribute to symptoms associated with IBS and IBD.
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PMID:Effects of serotonin transporter inhibition on gastrointestinal motility and colonic sensitivity in the mouse. 1670 Jul 26

Irritable bowel syndrome (IBS) is a functional gastrointestinal disorder that can present with a wide array of symptoms that make treatment difficult. Current therapies are directed at relieving symptoms of abdominal pain or discomfort, bloating, constipation, and diarrhea. Pharmacologic agents used to treat IBS-associated pain include myorelaxants, peppermint oil, and peripherally acting opiates. Dicyclomine and hyoscyamine, the two myorelaxants available in the United States, have not been proven effective in reducing abdominal pain in patients with IBS. The efficacy of peppermint oil is debated, but methodological problems with existing studies preclude definitive judgment. Loperamide is ineffective for relief of abdominal pain. For IBS patients with excessive abdominal bloating, a small number of studies suggest that bacterial eradication with gut-directed antibiotics and bacterial reconstitution with nonpathogenic probiotics may reduce flatulence. For constipation-predominant (C-IBS) symptoms, current treatment options include fiber supplementation, polyethylene glycol, and tegaserod. Soluble fibers (ispaghula, calcium polycarbophil, psyllium) are more effective than insoluble fibers (wheat bran, corn fiber) in alleviating global symptoms and relieving constipation, although fiber in general has marginal benefit in treatment of overall IBS symptoms. Polyethylene glycol increases bowel frequency in chronic constipation, but its overall efficacy against IBS is unclear. Tegaserod, a 5-HT(4) agonist, demonstrates superiority over placebo in improving bowel frequency and stool consistency and alleviating abdominal pain and bloating in women with C-IBS. Overall global symptoms are modestly improved with tegaserod when compared with placebo. Additional agents under investigation for C-IBS include the ClC(2) chloride channel opener lubiprostone, mu-opioid receptor antagonist alvimopan, and 5-HT(4) agonist renzapride. For diarrhea-predominant (D-IBS) symptoms, available therapies include loperamide, alosetron, and clonidine. Alosetron, a 5-HT(3) antagonist, is superior to placebo for reducing bowel frequency, improving stool consistency, and relieving abdominal pain in women with D-IBS. However, alosetron is available under a restricted license because of concerns for ischemic colitis and severe constipation necessitating colectomy. Clonidine may be helpful in alleviating global symptoms for D-IBS patients.
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PMID:Current gut-directed therapies for irritable bowel syndrome. 1683 50

Irritable bowel syndrome (IBS) is a common chronic gastrointestinal (GI) disorder, but its pathophysiology remains unknown. 5-hydroxytryptamine (5-HT, serotonin) is an important neurotransmitter involved in the brain-gut connection. Alosetron, a 5-HT3 receptor antagonist, has been demonstrated in randomized, placebo-controlled trials (RCT) to be effective in diarrhea-predominant IBS(IBS-D). Constipation is the most common adverse event. Alosetron improved abdominal pain and discomfort and stool consistency in both female and male patients, but it did not improve other symptoms (sense of urgency, stool frequency and bloating) in male patients. Although less is known about the gender differences in therapeutic benefit, a new 5-HT3 antagonist, cilansetron, has demonstrated effectiveness in male and female IBS-D patients and is currently under clinical trials.
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PMID:[Antagonists of the type 3 serotonin receptor (5 -HT3) in IBS]. 1689 18

Clinical studies with the fixed herbal combination product STW 5 (Iberogast) have indicated an efficacy comparable to metoclopramide (5-HT(3) antagonist) and cisapride (5-HT(4) agonist) in functional gastro-intestinal diseases like functional dyspepsia (FD) and irritable bowel syndrome (IBS). Since serotonin (5-HT(3) and 5-HT(4)) and muscarinic M(3) receptors are known to play a central role in the etiology of FD and IBS, the extracts contained in STW 5 and several of their phytochemical components were studied in vitro for binding affinities to these receptors of the intestine. STW 5 inhibited the binding of (3)H-GR113808 and (3)H-4-DAMP to 5-HT(4) and M(3) receptors, respectively, about 10 times more potently than the binding of (3)H-GR65630 to 5-HT(3) receptors. IC(50) values for STW 5 did correspond to extract dilutions of 1:1000 (M(3) binding) and 1:2000 (5-HT(4) binding). In addition, STW 5 also potently inhibited the binding to opioid receptors with an IC(50) value of 1:2000. Of the nine herbal extracts contained in STW 5, the fresh plant extract of bitter candy tuft (Iberis amara) selectively inhibited binding to M(3) receptors, while ethanolic extracts of celandine herb and chamomile flower were selective to 5-HT(4), and liquorice root to 5-HT(3) receptors. Binding affinities to human recombinant 5-HT(3), 5-HT(4) and M(3) receptors were qualitatively similar to those of the corresponding intestinal receptors. The benzylisoquinoline alkaloid berberine had significant inhibitory action on 5-HT(4) and M(3) binding, showing IC(50) values of 40 ng/ml (100 nM) and 200 ng/ml (500 nM), respectively, but is present in the extract of celandine herb only in traces, so that also for the celandine extract a cooperative effect of several phytochemical constituents can be assumed. These in vitro data indicate that 5-HT(4) (to a lesser degree 5-HT(3)), muscarinic M(3), and opioid receptors represent target sites for the treatment of FD and IBS with STW 5 (Iberogast).
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PMID:Binding of STW 5 (Iberogast) and its components to intestinal 5-HT, muscarinic M3, and opioid receptors. 1697 40

Alone among organs of the body, the gut is able to mediate reflexes in the absence of input from the brain or spinal cord. This ability appears to be caused by the secretion of serotonin (5-HT) by enterochromaffin (EC) cells of the mucosal epithelium. This 5-HT is secreted into the wall of the gut, where it stimulates the mucosal processes of intrinsic and extrinsic primary afferent neurons. The intrinsic primary afferents, which are activated by 5-HT1P/4 receptors, initiate peristaltic and secretory reflexes. The extrinsic primary afferent neurons send distress and other signals to the central nervous system. Extrinsic nerves are activated by 5-HT(3) receptors. The 5-HT that is involved in mucosal signaling is inactivated by uptake into mucosal epithelial cells, which are mediated by an integral membrane protein called the serotonin reuptake transporter (SERT). The epithelial SERT is the same molecule as that which transports 5-HT in the central and enteric nervous systems. Increasing evidence suggests that abnormal enteric release or inactivation of 5-HT is involved in the pathogenesis of irritable bowel syndrome (IBS). Spread of 5-HT to inappropriate sites in IBS may activate 5-HT(3) receptors on extrinsic afferent fibers and motor neurons, giving rise to visceral hypersensitivity and abnormal motility, respectively. A potent 5-HT(3) antagonist, such as alosetron, can prevent both of these effects and is therefore useful in treating IBS. 5-HT also appears to function as a growth factor in the development of enteric neurons. The developmental effects of 5-HT are mediated by the 5-HT(2B) receptor, which is developmentally regulated. The importance of serotonergic mechanisms in enteric physiology probably accounts for the gastrointestinal "side effects" of compounds that inhibit SERT. The newly discovered role of 5-HT in enteric neuronal development suggests that drugs that interfere with the action or inactivation of 5-HT should be used in pregnancy only with extreme caution, if at all.
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PMID:5-HT (serotonin) physiology and related drugs. 1702 28

Intestinal motility, secretion, and blood flow are controlled and integrated by the enteric nervous system (ENS). The ENS is like a "brain-in-the-gut," with many of the neurophysiologic properties of the central nervous system. Serotonin is a neurotransmitter at synapses in the microcircuits of the ENS. Serotonin is also released from enterochromaffin cells and inflammatory/immune cells to act at serotonergic receptors on neurons of the ENS. Four important actions are (1) fast and (2) slow excitation of enteric neurons, (3) presynaptic inhibition of neurotransmitter release at synapses in ENS microcircuits, and (4) excitation of intestinal sensory afferent fibers. Fast excitation and stimulation of sensory afferents are mediated by 5-HT(3) serotonergic receptors and slow excitation by 5-HT(1P) receptors. Presynaptic inhibitory receptors are not conclusively defined. The efficacy of a new 5-HT(3) receptor blocking drug in the treatment of the diarrhea-predominant form of the irritable bowel syndrome in women suggests the importance of this receptor subtype in the mediation of neurogenic secretory diarrhea, motility abnormality, and abdominal pain and discomfort.
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PMID:Enteric nervous system, serotonin, and the irritable bowel syndrome. 1703 Nov 57

Early life stress has been implicated as a risk factor for irritable bowel syndrome (IBS). We studied the effect of neonatal maternal separation on the visceromotor response and the expression of c-fos, 5-HT, and its receptors/transporters along the brain-gut axis in an animal model of IBS. Male neonatal Sprague-Dawley rats were randomly assigned to a 3-h daily maternal separation (MS) or nonhandling (NH) on postnatal days 2-21. Colorectal balloon distention (CRD) was performed for assessment of abdominal withdrawal reflex as a surrogate marker of visceral pain. Tissues from dorsal raphe nucleus in midbrain, lumbar-sacral cord, and distal colon were harvested for semiquantitative analysis of c-fos and 5-HT. The expression of 5-HT expression, 5-HT3 receptors, and 5-HT transporter were analyzed by RT-PCR. Pain threshold was significantly lower in MS than NH rats. The abdominal withdrawal reflex score in response to CRD in MS rats was significantly higher with distension pressures of 40, 60, and 80 mmHg. In MS rats, the number of c-fos-like immunoreactive nuclei at dorsal horn of lumbar-sacral spinal cord increased significantly after CRD. 5-HT content in the spinal cord of MS rats was significant higher. In the colon, both 5-HT-positive cell number and 5-HT content were comparable between MS and NH groups before CRD. Post-CRD only MS rats had significant increase in 5-HT content. Protein and mRNA expression levels of 5-HT3 receptors and 5-HT transporter were similar in MS and NH rats. Neonatal maternal separation stress predisposes rats to exaggerated neurochemical responses and visceral hyperalgesia in colon mimicking IBS.
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PMID:Effects of neonatal maternal separation on neurochemical and sensory response to colonic distension in a rat model of irritable bowel syndrome. 1711 May 21


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