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This Article Full Text Full Text (PDF) Supplemental Appendix All Versions of this Article: 296/6/G1299    most recent 00011.2009v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Sweetser, S. Articles by Zinsmeister, A. R. PubMed PubMed Citation Articles by Sweetser, S. Articles by Zinsmeister, A. R.

NEUROREGULATION AND MOTILITY

Do corticotropin releasing factor-1 receptors influence colonic transit and bowel function in women with irritable bowel syndrome?

¹Clinical Enteric Neuroscience Translational and Epidemiological Research (C.E.N.T.E.R.) and ³Department of Health Sciences Research, Division of Biostatistics, College of Medicine, Mayo Clinic, Rochester, Minnesota; and ²Discovery Medicine and Clinical Pharmacology Neurosciences, Bristol-Myers Squibb, Princeton, New Jersey

Submitted 18 January 2009 ; accepted in final form 27 March 2009

Corticotropin releasing factor (CRF), a mediator of stress response, alters gastrointestinal (GI) functions. Stress-related changes in colonic motility are blocked by selective CRF₁ receptor antagonists. Our aim was to assess whether modulation of central and peripheral CRF₁ receptors affects colonic transit and bowel function in female patients with diarrhea-predominant irritable bowel syndrome (D-IBS). This randomized, double-blind, placebo-controlled, 2-wk study evaluated the effects of oral pexacerfont (BMS-562086), a selective CRF₁ receptor antagonist, 25 and 100 mg qd, on GI and colonic transit of solids [by validated scintigraphy with primary end point colonic geometric center (GC) at 24 h] and bowel function (by validated daily diaries) in 39 women with D-IBS. The 100-mg dose was comparable to a dose that inhibited colonic motility in stressed rats. Treatment effects were compared by analysis of covariance with baseline colonic transit as covariate. The study had 80% power ( = 0.05) to detect clinically meaningful (26%) differences in colonic transit. Thirty-nine of 55 patients fulfilled eligibility criteria (9 screen failures, 5 baseline GC24 outside prespecified range). At baseline, three treatment groups had comparable age, body mass index, and GC 24 h. Significant effects of pexacerfont relative to placebo were not detected on colonic GC24 (P = 0.53), gastric emptying, orocecal transit, ascending colon emptying half-time, and stool frequency, consistency, and ease of passage. No safety issues were identified. We conclude that in women with D-IBS, pexacerfont, 25 or 100 mg qd, does not significantly alter colonic or other regional transit or bowel function. The role of central and peripheral CRF₁ receptors in bowel function in D-IBS requires further study.

corticotropin releasing factor; pexacerfont; diarrhea-predominant irritable bowel syndrome; gastrointestinal transit; randomized trial