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

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.

• Authors: Michael Camilleri, Maria Vazquez-Roque, Johanna Iturrino, Amy Boldingh, Duane Burton, Sanna McKinzie, Banny S Wong, Archana S Rao, Enda Kenny, Maria Månsson, Alan R Zinsmeister
• Journal: American journal of physiology. Gastrointestinal and liver physiology (Am J Physiol Gastrointest Liver Physiol) Vol. 303 Issue 1 Pg. G120-8 (Jul 2012) ISSN: 1522-1547 [Electronic] United States
• PMID: 22517769 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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