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 rise in intracellular calcium is the predominant signal that leads to the activation of the contractile machinery in gastrointestinal smooth muscle. The primary sources of activating calcium are illustrated in Fig. 2. Voltage- and peptide-mediated release of intracellular calcium contribute to activation of some gastrointestinal smooth muscles. However, the primary source of activating calcium appears to be an influx of calcium across the plasma membrane. The degree of modulation of electrical activity by peptides varies depending upon the region of the gastrointestinal tract studied. Second messenger systems are undoubtly involved in the transduction pathway for receptor-mediated changes in ion channel activity in gastrointestinal smooth muscle. However, in comparison to other excitable cell types, little is known about the coupling mechanisms whereby peptide-receptor binding alters ion channel activity in gastrointestinal smooth muscle. This represents one of the challenging areas to be studied in the field of gastrointestinal smooth muscle. One disease in which a better appreciation of the regulation of ion channel activity could lead to therapeutic benefit is irritable bowel syndrome. A coupling of smooth muscle electrical activity to hypermotility in irritable bowel syndrome has been reported. CCK increases the level of spike activity which triggers hypermotility [40]. It would follow that inhibition of calcium influx should reduce spiking and, therefore, hypermotility. In fact, the calcium channel blockers nifedipine and nicardipine have been shown to decrease colonic motility in irritable bowel syndrome patients [62-64]. As our understanding of gastrointestinal smooth muscle ion channels expands, development of a gastrointestinal selective calcium channel blocker may be possible. This class of agents would be effective in the treatment of irritable bowel syndrome and potentially other peptide-related spastic smooth muscle disorders.
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PMID:Modulation of electrical activity in gastrointestinal smooth muscle by peptides. 128 67

In irritable bowel syndrome (IBS), motility disturbances occur from the upper gastrointestinal tract to the distal colon, where regulatory peptides have a wide-spread distribution. Studies on basal and postprandial plasma levels of different gut hormones show that VIP, CCK, and motilin may be closely related to the symptoms including abdominal pain, diarrhea and constipation. In addition, peptide YY and NPY have effects on absorption in the intestine, and some opioid peptides exert actions on colonic motility in IBS patients. Recent studies revealed that gall bladder in IBS has an abnormal sensitivity to CCK-8, indicating that IBS patients has an generalized abnormality of the smooth muscle of the digestive tract. Gut hormones, which act as hormones, neurotransmitters and neuromodulators depending on their releasing site, may therefore play an important role in IBS patients.
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PMID:[Role of gut hormones in irritable bowel syndrome]. 128 45

Clues to the pathogenesis of functional pain syndromes may be derived from the study of stimuli that precipitate or aggravate symptoms. In this study, cholecystokinin octapeptide (CCK-8, 0.06 microgram/kg) and placebo were given by intravenous infusion (5 min) in random order to control subjects and four groups of patients with unexplained abdominal pain. Induction of pain and nausea were assessed by linear analogue scales while sympathoadrenomedullary responses were assessed by serial changes in plasma concentrations of noradrenaline, adrenaline and dopamine. Scores for pain and nausea were low after infusion of placebo. After infusion of CCK-8, pain scores were significantly higher in patients with spontaneous pain than in control subjects, but significant increases in nausea were restricted to patients with irritable bowel syndrome and a subgroup of patients with pain after cholecystectomy. Although some groups showed increases in plasma concentrations of catecholamines after the infusion of CCK-8, the size of these increases was neither consistent among patients within each group nor predictive of scores of pain and nausea in individual subjects. Pain during the infusion of CCK-8 was a feature common to patients with diverse functional pain syndromes, and did not appear to be attributable to activation of the sympathetic nervous system.
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PMID:Responses to cholecystokinin octapeptide in patients with functional abdominal pain syndromes. 161 Oct 17

We have described previously that the gallbladder responds abnormally to infusions of cholecystokinin octapeptide (CCK-8) in patients with irritable bowel syndrome (IBS). To confirm these results and to examine the possible mechanisms, patients with IBS and predominant symptoms of diarrhea or constipation were compared with matched controls. During infusions of CCK-8 at one of three doses, the response of the gallbladder was measured ultrasonographically. The levels of CCK-8 reached in the peripheral circulation and degradation of the peptide in vitro and in vivo were used to evaluate metabolism of cholecystokinin. We confirmed that the gallbladders of patients with IBS responded abnormally to CCK-8; however, the differences were not due to any prereceptor event. Instead, this abnormality in IBS must be explained by an atypical response at the level of the target tissues.
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PMID:Abnormal gallbladder motility in irritable bowel syndrome: evidence for target-organ defect. 153 72

Specific abnormalities of colonic and small bowel motility are identifiable and associated with symptoms in IBS. Characteristic abnormalities in colonic motility include a prolonged increase in 3-cycles/min colonic motor activity after a meal, an exaggerated increase in 3-cycles/min motor activity in response to stressors and CCK, and increased visceral sensitivity and motor activity in response to balloon distention. Symptoms in patients with IBS correlate in some cases with the abnormal gastrocolonic response and with pain induced by distention at various sites in the colon. Small bowel motility abnormalities identified reproducibly in IBS include an increase in daytime jejunal DCCs, an increase in daytime ileal PPCs, and more frequent cycling of daytime MMCs (in diarrhea-predominant IBS only). DCCs and PPCs are strongly associated with symptoms in IBS, and PPCs associated with altered ileocecal transit may be an important mechanism of symptoms in some patients with IBS. Esophageal and gastroduodenal motility abnormalities are inconsistently identified in IBS, and most symptoms in IBS appear to be secondary to small bowel or colonic dysfunction. Because of the paroxysmal nature of these motor abnormalities in IBS, prolonged motility recordings are required to better understand the pathophysiology of this syndrome. Patients with IBS may have altered visceral sensation and changes in afferent reflex mechanisms that modulate GI motility. These patients do not have a generalized increase in pain perception, but may have a distinct sensitivity to visceral afferent stimulation in both gastrointestinal and other viscera. Whether the altered "setpoint" to visceral afferent stimulation in IBS is intrinsic to the smooth muscle of viscera or secondary to CNS and ANS modulation is not known. Many of the symptoms and abnormalities of small bowel and colonic motility in IBS probably result from these changes in afferent sensation and reflex mechanisms. These findings support the concept that IBS is an abnormality of intestinal motility in conjunction with a "sensitive" gut.
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PMID:Motility disorders in the irritable bowel syndrome. 206 53

Gastrointestinal (GI) motility is centrally controlled through the sympathetic and parasympathetic nerves, sympathetic effects being partly mediated by beta adrenoceptors. Although beta adrenoceptor agonists and antagonists are widely used for different disorders, little is known about the influence of these agents on GI motility. The present study was initiated to investigate whether there is a physiological, beta adrenergic influence on human GI motility and to describe the effects of selective beta adrenoceptor stimulation on motility in the proximal and distal parts of the GI tract. Esophageal peristalsis was measured in healthy subjects using electronic catheters. Distal colonic motility was measured with an open-tipped, water-perfused catheter in the sigmoid colon and from an air-filled balloon in the rectum in healthy subjects and in patients with the irritable bowel syndrome (IBS). In one study, colonic motility was stimulated with continuous infusion of the octapeptide of cholecystokinin (CCK-OP). Esophagus: Peristaltic amplitude was increased in the distal smooth muscle part of the esophageal body after infusion of both the nonselective beta blocker propranolol and the beta-1 selective blocker metoprolol. After infusion of the beta-1 agonist prenalterol and the beta-2 selective agonist terbutaline, a profound decrease in esophageal peristaltic amplitude was seen. Pretreatment with metoprolol selectively blocked the response to a moderate dose of prenalterol but did not block the response to terbutaline. The latter response was blocked by propranolol. Peristaltic velocity in the proximal part of the esophagus was decreased by beta-1 stimulation and in the distal part by beta-2 stimulation. Distal colon: In healthy subjects the sigmoid motility index showed a dose-dependent increase after metoprolol and propranolol, respectively. The increase was more marked after propranolol infusion. Terbutaline decreased the sigmoid motility index both in healthy subjects and in patients with the IBS. Furthermore, the rectal motility index was decreased in the group of healthy subjects. The effects of prenalterol on rectal and sigmoid motility did not differ from those of placebo. The IBS patient group showed larger intraindividual variations in sigmoid motility from day to day and also lower rectal motility indices than the healthy subjects. Infusion of CCK-OP increased the sigmoid motility index compared to non-stimulated conditions. No effects on CCK-OP stimulated motility were seen after either terbutaline, prenalterol or placebo.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Beta adrenergic influence on esophageal and colonic motility in man. 286 39

Though the pathophysiology of the irritable bowel syndrome (IBS) is commonly attributed to dysfunction of the large intestine, evidence exists to incriminate the small bowel. In order to further explore the role of the small bowel in IBS several stimuli were applied, in an attempt to unmask the dysmotility of the jejunum and ileum. These included infusions of cholecystokinin-octapeptide (CCK-OP), a high fat meal, neostigmine and balloon distension of the ileum. Three groups (n = 8) each of age and sex matched healthy volunteers were studied; patients with IBS complained of predominant constipation (n = 8) or diarrhoea (n = 8). Patients with IBS responded excessively to stimulation by CCK-OP, fatty meal, and ileal distension. In general patients with diarrhoea were more sensitive to stimuli than those with constipation. The ileum responded more to stimulation than the jejunum. As in the large bowel, stimuli appear to unmask intestinal dysmotility in patients with IBS. Motor abnormalities were often accompanied by abdominal symptoms, raising the possibility that dysfunction of the small bowel contributes to the symptoms of IBS.
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PMID:Dysmotility of the small intestine in irritable bowel syndrome. 319 98

We compared responses of the gallbladder to graded intravenous infusions of cholecystokinin octapeptide (CCK-OP) in normal controls (n = 8) and patients with irritable bowel syndrome (IBS) with predominant constipation (n = 8) or diarrhea (n = 8). The doses of CCK-OP ranged from subphysiological (negligible contraction of the gallbladder) to supraphysiological (90% contraction of gallbladder and abdominal side effects) amounts. All gallbladders contracted progressively in response to CCK-OP, and a Weibull model (power exponential function) described precisely the gallbladder's response to CCK-OP. Patients with IBS responded differently from normal patients; those with constipation contracted their gallbladders more and those with diarrhea contracted less in response to the peptide. Gallbladders were also stimulated with a high-fat, liquid meal; all patients' gallbladders contracted, but clear differences between groups could not be demonstrated postprandially. The results suggest that the smooth muscle of the gallbladder in IBS has an abnormal sensitivity to CCK-OP, and the results support the concept that IBS can be a generalized abnormality of the smooth muscle of the digestive tract.
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PMID:Altered sensitivity of the gallbladder to cholecystokinin octapeptide in irritable bowel syndrome. 331 95

Dexloxiglumide, the (R)-isomer of loxiglumide, is a selective and highly potent CCK1 receptor antagonist. It is twice as potent as the racemic compound. because the anti-CCK activity is specific to the (R)-form, whereas the (S)-isomer is almost ineffective. It has been developed by Rotta Research Lab SpA for the treatment of diseases in which CCK1 receptor activity is potentially involved, including gastrointestinal motility, food intake and pancreatic disorders [218696]. Its receptor-mediated actions have been described in multiple in vitro and in vivo pharmacological systems. Results from both preclinical and clinical studies indicate that it is an effective inhibitor of gallbladder contraction, improves lower esophegal sphincter (LES) function, accelerates gastric emptying, accelerates colonic transit and significantly decreases symptoms in IBS and functional dyspepsia patients, and therefore has potential as an effective treatment for constipation-predominant IBS. functional dyspesia, constipation, LES function, gastric emptying disorders and biliary colics. Forest Laboratories has entered into an agreement with Rotta for the development and marketing of dexloxiglumide for the treatment of constipation-predominant IBS and phase III studies are currently ongoing in the US. In August 2000, Merrill Lynch expected that dexloxiglumide would not be launched until 2004 [379892], and in June 2001, predicted a US filing date in 2003 [413928].
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PMID:Dexloxiglumide Rotta Research Lab. 1209 Jul 34

In recent years there has been an increasing appreciation of the complexity of functional gastrointestinal disorders. These represent a spectrum of conditions which may affect any part of the gastrointestinal tract in which there appears to be dysregulation of visceral function and afferent sensation and a strong association with emotional factors and stress. There is a clear psychological dimension, with up to 60% of irritable bowel syndrome (IBS) patients reported to have psychological co-morbidities and altered pain perception is also common in comparison with control populations. The role of the enteric nervous system, the sensory pathways and the brain as well as the influence of the latter on sympathetic and parasympathetic outflow have likewise attracted increasing interest and have led to exciting new methods to study their complex interactions. The concept of low-grade inflammation, such as might occur after infection, acting as a trigger for neuromuscular dysfunction has also led to the broad integrative hypotheses that help to explain the biopsychosocial dimensions seen in functional gastrointestinal disease. The multi-component model places a major emphasis on neurogastroenterology and enteric and neuro-immune interactions where new approaches to pharmacotherapy lie. Drugs may affect motility, visceral sensation and other aspects of gut function such as secretion or absorption. More particularly, however, has been the search for and attempts to influence important mediators of these primary gut functions. Such targets include serotonin and selected 5-HT receptors, which are involved in gut motility, visceral sensation and other aspects of gut function, CCK receptors which are involved in the mediation of pain in the gut and nociception in the CNS, opioid receptors involved in pain in the brain, spinal cord and periphery, muscarinic M3-receptors, substance P and neurokinin A and B receptors which are involved in motor adaptation and pain transmission in association with inflammation, gabba receptors involved in nociception and cannabinoid receptors which are involved in the control of acetyl choline release in the gut. With a better understanding of the structures and pathways involved in visceral perception and hyperalgesia, in the CNS, spinal cord and the gut and new pharmacological tools we will be better able to elucidate the neuropharmacology of visceral perception and its relationship to gut dysfunction. It is likely that there will be multiple therapeutic options based on the spectrum of abnormalities capable of causing the spectrum of symptoms of functional gastrointestinal disorders in any individual patient.
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PMID:Evolving concepts in functional gastrointestinal disorders: promising directions for novel pharmaceutical treatments. 1247 96


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