The role of serotonin in the pathophysiology of irritable bowel syndrome.
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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. (+info)
Drug therapy options for patients with irritable bowel syndrome.
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Existing pharmacotherapeutic options for the treatment of patients with irritable bowel syndrome (IBS) are limited in treating the multiple symptoms associated with the disorder. There is much interest in the use of serotonin agents as new therapeutics. Acting primarily through 5-HT3 and 5-HT4 receptors, serotonin elicits changes in motor function and possibly visceral sensation. Two serotonin agents were developed specifically for IBS: tegaserod, a 5-HT4 receptor partial agonist, and alosetron, a 5-HT3 receptor antagonist (which is no longer available). Phase III clinical trial data show that during a 12-week treatment period with tegaserod, IBS patients with abdominal pain and discomfort, bloating, and constipation experienced significant global relief (i.e., improvement in overall well-being, abdominal pain, and bowel habit) compared with placebo. Improvement in bowel movement frequency and consistency was achieved and pain was relieved by 1 week. During 12 weeks of treatment, alosetron was shown to elicit significant relief of abdominal pain and discomfort compared with placebo or mebeverine in female IBS patients with diarrhea. Alosetron slowed colonic transit and treatment efficacy was apparent after a week of treatment. Another 5-HT4 receptor agonist, prucalopride, which is being developed for chronic constipation, accelerates colonic transit and increases stool frequency. Therefore, this agent may be of benefit in IBS patients with constipation. (+info)
Irritable bowel syndrome: toward a cost-effective management approach.
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OBJECTIVE: To examine the economic implications of current irritable bowel syndrome (IBS) management practices and formulate recommendations based on these implications. METHODS: Relevant English-language research publications in which the direct and indirect costs of IBS were examined, identified using a search of records contained in Medline. RESULTS: Review of the identified publications indicates that in Western nations, IBS management is associated with high direct costs (particularly for diagnostic testing, office visits, pharmacotherapy, and emergency department visits). Indirect costs, associated with lost wages and decreased productivity, account for the largest proportion of the IBS economic burden. Moreover, rapid projected growth in IBS disease-related costs indicates a need for more focused attention toward improved treatment of IBS. More cost-effective management might be achieved by diagnosing and instituting nonpharmacologic and pharmacologic management earlier in the disease process. Under such an approach, patients are classified based on symptoms and a therapeutic trial is begun. More extensive, expensive diagnostic testing is reserved for patients refractory to treatment or for whom serious disease must be ruled out. CONCLUSION: IBS is a condition with high direct and indirect costs. Management strategies should be evaluated both on their clinical efficacy and on their cost effectiveness. As new, IBS-specific pharmacotherapies become available, the ability to diagnose and manage the condition in a cost-effective manner can be improved. (+info)
Effects of YM905, a novel muscarinic M3-receptor antagonist, on experimental models of bowel dysfunction in vivo.
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We investigated the effects of YM905 [(+)-(1S,3'R)-quinuclidin-3'-yl 1-phenyl-1,2,3,4-tetrahydroisoquinoline-2-carboxylate monosuccinate], a new orally active muscarinic M3-receptor antagonist, on bowel dysfunction in vivo using experimental models that reproduce the symptoms present in irritable bowel syndrome (IBS). YM905 potently inhibited restraint stress-induced fecal pellet output in fed rats (ED50: 4.0 mg/kg) and diarrhea in fasted rats (ED50: 1.7 mg/kg), with similar potencies to the inhibition of bethanechol-, neostigmine- and nicotine-induced fecal pellet output in rats (ED50: 3.3, 7.9 and 4.5 mg/kg, respectively). YM905 also inhibited 5-hydroxytryptamine (5-HT)-, prostaglandin E2- and castor oil-induced secretory diarrhea in mice (ED50: 5.5, 14 and 6.3 mg/kg, respectively), but showed no significant effect on cholera toxin-induced intestinal secretion in mice. In addition, YM905 (3, 10 mg/kg) reversed morphine-decreased postprandial defecation in ferrets, a model of spastic constipation, whereas remosetron, a 5-HT3-receptor antagonist, was not effective. The mode of YM905 action was similar to that of darifenacin, a selective M3-receptor antagonist, with equivalent potencies. By contrast, propantheline, an antimuscarinic drug that has been used for IBS, was much less potent. These results show that YM905 ameliorates a wide spectrum of bowel dysfunctions through the blockade of M3 receptors, suggesting its therapeutic potential for treating IBS. (+info)
Effects of alosetron on spontaneous migrating motor complexes in murine small and large bowel in vitro.
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Alosetron (Lotronex) is a serotonin subtype 3 (5-HT3) receptor antagonist that alleviates symptoms of irritable bowel syndrome (IBS) in female patients. Alosetron may act centrally, involve the alteration of ascending pain sensation, or modulate peristaltic, secretory, or sensory function. To investigate further the mechanisms underlying its action and gender selectivity we recorded the effect of increasing concentrations of alosetron or ondansetron on spontaneous migrating motor complexes (MMCs) from isolated terminal ileum or colon from C57BL/6 mice. Both antagonists inhibited MMC frequency before affects on duration or amplitude. The threshold of inhibition for alosetron was 100-fold less in small intestine from females (20 nM) than from males. The opposite effect of gender was observed with ondansetron in the colon. All MMCs were abolished by either drug at 10 microM. Our results demonstrate that alosetron selectively inhibits MMC frequency in isolated preparations of murine bowel. Because contractile events in the ileum correlate with symptoms of IBS in humans, the gender selectivity of alosetron may be caused by a direct action within the small intestine. (+info)
Tegaserod, a 5-HT(4) receptor partial agonist, relieves symptoms in irritable bowel syndrome patients with abdominal pain, bloating and constipation.
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AIM: To investigate the efficacy and safety of tegaserod, a novel 5-HT(4) receptor partial agonist, in a randomized, double-blind, placebo-controlled, 12-week treatment, multicentre study. METHODS: Eight hundred and eighty-one patients with irritable bowel syndrome, characterized by abdominal pain, bloating and constipation, received tegaserod, 2 mg b.d. or 6 mg b.d., or placebo for 12 weeks. RESULTS: Tegaserod, 2 mg b.d. and 6 mg b.d., showed a statistically significant relief of overall irritable bowel syndrome symptoms, measured by a weekly, self-administered questionnaire. At end-point, treatment differences from placebo were 12.7% and 11.8% for 2 mg b.d. and 6 mg b.d., respectively. The effect of tegaserod was noted as early as week 1, and was sustained over the 12-week treatment period. Individual irritable bowel syndrome symptoms assessed daily also showed a statistically significant improvement of abdominal discomfort/pain, number of bowel movements and stool consistency, and a favourable trend for reducing days with significant bloating. Adverse events were similar in all groups, with transient diarrhoea being the only adverse event seen more frequently with tegaserod than placebo. CONCLUSIONS: Based upon the results of this study, tegaserod offers rapid and sustained relief of the abdominal pain and constipation associated with irritable bowel syndrome. Tegaserod is also well tolerated. (+info)
Critical role for tumor necrosis factor alpha in controlling the number of lumenal pathogenic bacteria and immunopathology in infectious colitis.
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Infection of mice with the intestinal bacterial pathogen Citrobacter rodentium results in colonic mucosal hyperplasia and a local Th1 inflammatory response similar to that seen in mouse models of inflammatory bowel disease. In these latter models, and in patients with Crohn's disease, neutralization of tumor necrosis factor alpha (TNF-alpha) is of therapeutic benefit. Since there is no information on the role of TNF-alpha in either immunity to noninvasive bacterial pathogens or on the role of TNF-alpha in the immunopathology of infectious colitis, we investigated C. rodentium infection in TNFRp55(-/-) mice. In TNFRp55(-/-) mice, there were higher colonic bacterial burdens, but the organisms were cleared at the same rate as C57BL/6 mice, showing that TNF-alpha is not needed for protective antibacterial immunity. The most striking feature of infection in TNFRp55(-/-) mice, however, was the markedly enhanced pathology, with increased mucosal weight and thickness, increased T-cell infiltrate, and a markedly greater mucosal Th1 response. Interleukin-12 p40 transcripts were markedly elevated in C. rodentium-infected TNFRp55(-/-) mice, and this was associated with enhanced mucosal STAT4 phosphorylation. TNF-alpha is not obligatory for protective immunity to C. rodentium in mice; however, it appears to play some role in downregulating mucosal pathology and Th1 immune responses. (+info)
Do published guidelines for evaluation of irritable bowel syndrome reflect practice?
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BACKGROUND: The only US guidelines listed in the National Guideline Warehouse for the diagnosis of Irritable Bowel Syndrome (IBS) are the expert opinion guidelines published by The American Gastroenterology Association. Although the listed target audience of these guidelines includes family physicians and general internists, the care recommended in the guidelines has not been compared to actual primary care practice. This study was designed to compare expert opinion guidelines with the actual primary care provided and to assess outcomes in the 3 years following the IBS diagnosis. METHODS: This is a retrospective medical record review study using a random sample of incident IBS cases from all Olmsted County, Minnesota providers diagnosed between January 1, 1993 and December 31, 1995. Data was collected on all care and testing provided to the subjects as well as 3-year outcomes related to the IBS diagnosis. RESULTS: Of the 149 IBS patients, 99 were women and the mean age was 47.6 years. No patient had all of the diagnostic tests recommended in the guidelines. 42% had the basic blood tests of CBC and a chemistry panel. Sedimentation rate (2%) and serum thyroxine level (3%) were uncommon. Colon imaging studies were done in 41% including 74% of those over the age of 50. In the 3 years following the diagnosis, only one person had a change in diagnosis and no diagnoses of gastro-intestinal malignancies were made in the cohort. CONCLUSIONS: Primary care practice based diagnostic evaluations for IBS differ significantly from the specialty expert opinion-based guidelines. Implementation of the specialty guidelines in primary care practice would increase utilization with apparent limited improvement in diagnostic outcomes. (+info)