title: 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.affiliation: Mayo Clinic, 200 First St. SW, Rochester, MN 55905, USA. camilleri.michael@mayo.edu
authors.forename: Michael
authors.initials: M
authors.lastname: Camilleri
authors.forename: Maria
authors.initials: M
authors.lastname: Vazquez-Roque
authors.forename: Johanna
authors.initials: J
authors.lastname: Iturrino
authors.forename: Amy
authors.initials: A
authors.lastname: Boldingh
authors.forename: Duane
authors.initials: D
authors.lastname: Burton
authors.forename: Sanna
authors.initials: S
authors.lastname: McKinzie
authors.forename: Banny S
authors.initials: BS
authors.lastname: Wong
authors.forename: Archana S
authors.initials: AS
authors.lastname: Rao
authors.forename: Enda
authors.initials: E
authors.lastname: Kenny
authors.forename: Maria
authors.initials: M
authors.lastname: Månsson
authors.forename: Alan R
authors.initials: AR
authors.lastname: Zinsmeister
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D003248:Constipation / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology; D003672:Defecation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D023381:Endpoint Determination; D005260:Female; D005746:Gastric Emptying / Q000187:drug effects; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D005769:Gastrointestinal Motility / Q000187:drug effects*; D005772:Gastrointestinal Transit / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D043183:Irritable Bowel Syndrome / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008875:Middle Aged; D010147:Pain Measurement; D010446:Peptide Fragments / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon / Q000187:drug effects; D013670:Sodium Pertechnetate Tc 99m; D013270:Stomach / Q000033:anatomy & histology / Q000000981:diagnostic imaging; D015899:Tomography, Emission-Computed, Single-Photon; D055815:Young Adult
chemical_list: C000593833:GLP1R protein, human; D005765:Gastrointestinal Agents; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D019275:Radiopharmaceuticals; D018027:Receptors, Glucagon; C574776:glucagon-like peptide (7-37), valyl(10)-; D052216:Glucagon-Like Peptide 1; D013670:Sodium Pertechnetate Tc 99m