title: Receptor-mediated inhibition of small bowel migrating complex by GLP-1 analog ROSE-010 delivered via pulmonary and systemic routes in the conscious rat.
abstract: BACKGROUND
  ROSE-010, a Glucagon-Like Peptide-1 (GLP-1) analog, reduces gastrointestinal motility and relieves acute pain in patients with irritable bowel syndrome (IBS). The rat small bowel migrating myoelectric complex (MMC) is a reliable model of pharmacological effects on gastrointestinal motility. Accordingly, we investigated whether ROSE-010 works through GLP-1 receptors in gut musculature and its effectiveness when administered by pulmonary inhalation.
  
  
  METHODS
  Rats were implanted with bipolar electrodes at 5, 15 and 25 cm distal to pylorus and myoelectric activity was recorded. First, intravenous or subcutaneous injections of ROSE-010 or GLP-1 (1, 10, 100 μg/kg) with or without the GLP-1 receptor blocker exendin(9-39)amide (300 μg/kg·h), were studied. Second, ROSE-010 (100, 200 μg/kg) Technosphere® powder was studied by inhalation.
  
  
  RESULTS
  The baseline MMC cycle length was 17.5±0.8 min. GLP-1 and ROSE-010, administered intravenously or subcutaneously, significantly inhibited myoelectric activity and prolonged MMC cycling; 100 μg/kg completely inhibited spiking activity for 49.1±4.2 and 73.3±7.7 min, while the MMC cycle length increased to 131.1±11.4 and 149.3±15.5 min, respectively. Effects of both drugs were inhibited by exendin(9-39)amide. Insufflation of ROSE-010 (100, 200 μg/kg) powder formulation totally inhibited myoelectric spiking for 52.6±5.8 and 70.1±5.4 min, and increased MMC cycle length to 102.6±18.3 and 105.9±9.5 min, respectively.
  
  
  CONCLUSIONS
  Pulmonary delivery of ROSE-010 inhibits gut motility through the GLP-1R similar to natural GLP-1. ROSE-010 causes receptor-mediated inhibition of MMC comparable to that of intravenous or subcutaneous administration. This suggests that ROSE-010 administered as a Technosphere® inhalation powder has potential in IBS pain management and treatment.
authors.affiliation: Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Per.Hellstrom@medsci.uu.se
authors.forename: P M
authors.initials: PM
authors.lastname: Hellström
authors.forename: A
authors.initials: A
authors.lastname: Smithson
authors.forename: G
authors.initials: G
authors.lastname: Stowell
authors.forename: S
authors.initials: S
authors.lastname: Greene
authors.forename: E
authors.initials: E
authors.lastname: Kenny
authors.forename: C
authors.initials: C
authors.lastname: Damico
authors.forename: A
authors.initials: A
authors.lastname: Leone-Bay
authors.forename: R
authors.initials: R
authors.lastname: Baughman
authors.forename: M
authors.initials: M
authors.lastname: Grant
authors.forename: P
authors.initials: P
authors.lastname: Richardson
mesh_terms: D000280:Administration, Inhalation; D061605:Administration, Intravenous; D000818:Animals; D003243:Consciousness; D004353:Drug Evaluation, Preclinical; D004567:Electrodes, Implanted; D005769:Gastrointestinal Motility / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D007279:Injections, Subcutaneous; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D043183:Irritable Bowel Syndrome / Q000378:metabolism; D008297:Male; D016065:Myoelectric Complex, Migrating / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; C574776:glucagon-like peptide (7-37), valyl(10)-; C083773:exendin (9-39); D052216:Glucagon-Like Peptide 1