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

Seth Sweetser, Michael Camilleri, Sara J. Linker Nord, Duane D. Burton, Lorna Castenada, Robert Croop, Gary Tong, Randy Dockens, Alan R. Zinsmeister

Research output: Contribution to journalArticlepeer-review

99 Scopus citations

Abstract

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 (α = 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.

Original languageEnglish (US)
Pages (from-to)G1299-G1306
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume296
Issue number6
DOIs
StatePublished - Jun 2009

Keywords

  • Corticotropin releasing factor
  • Diarrhea-predominant irritable bowel syndrome
  • Gastrointestinal transit
  • Pexacerfont
  • Randomized trial

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

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