Effect of a glucagon-like peptide 1 analog, ROSE-010, on GI motor functions in female patients with constipation-predominant irritable bowel syndrome

Am J Physiol Gastrointest Liver Physiol. 2012 Jul;303(1):G120-8. doi: 10.1152/ajpgi.00076.2012. Epub 2012 Apr 19.

Abstract

The glucagon-like peptide 1 (GLP-1) analog ROSE-010 reduced pain during acute exacerbations of irritable bowel syndrome (IBS). Our objective was to assess effects of ROSE-010 on several gastrointestinal (GI) motor and bowel functions in constipation-predominant IBS (IBS-C). In a single-center, randomized, parallel-group, double-blind, placebo-controlled, dose-response study, we evaluated safety, pharmacodynamics, and pharmacokinetics in female patients with IBS-C. ROSE-010 (30, 100, or 300 μg sc) or matching placebo was administered once daily for 3 consecutive days and on 1 day 2-10 days later. We measured GI and colonic transit by validated scintigraphy and gastric volumes by single-photon emission computed tomography. The primary end points were half time of gastric emptying of solids, colonic transit geometric center at 24 h, and gastric accommodation volume. Analysis included intent-to-treat principle, analysis of covariance (with body mass index as covariate), and Dunnett-Hsu test for multiple comparisons. Exposure to ROSE-010 was approximately dose-proportional across the dose range tested. Demographic data in four treatment groups of female IBS-C patients (total 46) were not different. Gastric emptying was significantly retarded by 100 and 300 μg of ROSE-010. There were no significant effects of ROSE-010 on gastric volumes, small bowel or colonic transit at 24 h, or bowel functions. The 30- and 100-μg doses accelerated colonic transit at 48 h. Adverse effects were nausea (P < 0.001 vs. placebo) and vomiting (P = 0.008 vs. placebo). Laboratory safety results were not clinically significant. In IBS-C, ROSE-010 delayed gastric emptying of solids but did not retard colonic transit or alter gastric accommodation; the accelerated colonic transit at 48 h with 30 and 100 μg of ROSE-010 suggests potential for relief of constipation in IBS-C.

Publication types

  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Area Under Curve
  • Constipation / diagnostic imaging
  • Constipation / drug therapy*
  • Constipation / etiology
  • Defecation / drug effects
  • Dose-Response Relationship, Drug
  • Double-Blind Method
  • Endpoint Determination
  • Female
  • Gastric Emptying / drug effects
  • Gastrointestinal Agents / pharmacokinetics
  • Gastrointestinal Agents / pharmacology*
  • Gastrointestinal Agents / therapeutic use*
  • Gastrointestinal Motility / drug effects*
  • Gastrointestinal Transit / drug effects
  • Glucagon-Like Peptide 1 / adverse effects
  • Glucagon-Like Peptide 1 / analogs & derivatives*
  • Glucagon-Like Peptide 1 / pharmacokinetics
  • Glucagon-Like Peptide 1 / pharmacology*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Irritable Bowel Syndrome / complications
  • Irritable Bowel Syndrome / diagnostic imaging
  • Irritable Bowel Syndrome / drug therapy*
  • Middle Aged
  • Pain Measurement
  • Peptide Fragments / adverse effects
  • Peptide Fragments / pharmacokinetics
  • Peptide Fragments / pharmacology*
  • Radiopharmaceuticals
  • Receptors, Glucagon / drug effects
  • Sodium Pertechnetate Tc 99m
  • Stomach / anatomy & histology
  • Stomach / diagnostic imaging
  • Tomography, Emission-Computed, Single-Photon
  • Young Adult

Substances

  • GLP1R protein, human
  • Gastrointestinal Agents
  • Glucagon-Like Peptide-1 Receptor
  • Peptide Fragments
  • Radiopharmaceuticals
  • Receptors, Glucagon
  • glucagon-like peptide (7-37), valyl(10)-
  • Glucagon-Like Peptide 1
  • Sodium Pertechnetate Tc 99m