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. MATERIALS AND 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.
Subject(s)
Glucagon-Like Peptide 1/analogs & derivatives , Myoelectric Complex, Migrating/drug effects , Peptide Fragments/administration & dosage , Peptide Fragments/pharmacology , Receptors, Glucagon/antagonists & inhibitors , Administration, Inhalation , Administration, Intravenous , Animals , Consciousness , Drug Evaluation, Preclinical , Electrodes, Implanted , Gastrointestinal Motility/drug effects , Glucagon-Like Peptide 1/administration & dosage , Glucagon-Like Peptide 1/pharmacology , Glucagon-Like Peptide-1 Receptor , Injections, Subcutaneous , Intestine, Small/drug effects , Intestine, Small/metabolism , Irritable Bowel Syndrome/metabolism , Male , Rats , Rats, Sprague-Dawley , Receptors, Glucagon/metabolism , Statistics, Nonparametric , Time FactorsABSTRACT
AIM: The feasibility of administering native glucagon-like peptide 1 (GLP-1) as GLP-1 Technosphere Inhalation Powder for diabetes therapy has been demonstrated in a rat model. METHODS: GLP-1 Technosphere Inhalation Powders containing 5, 10 and 15% GLP-1 were prepared and administered to healthy female Sprague-Dawley rats and to male Zucker diabetic obese rats. Rats received a single dose of GLP-1 Technosphere Powder by pulmonary insufflation. GLP-1 pharmacokinetic and pharmacodynamic responses were measured. RESULTS: Maximum circulating GLP-1 concentrations were achieved at approximately 10 min after dosing with detectable levels at 40 min. In a food consumption study, Sprague-Dawley rats receiving GLP-1 Technosphere Powder once-daily consumed less food than control rats for up to 24 h after dosing. Cumulative food consumption was decreased approximately 10% after 78 h. In an intraperitoneal glucose tolerance test, Zucker diabetic fatty rats receiving 2 mg GLP-1 Technosphere Powder (0.3 mg GLP-1) by pulmonary insufflation exhibited lower glucose concentrations and higher insulin concentrations than control rats. Pancreatic evaluations showed no differences in apoptotic index or cell proliferation of beta-cells. In addition, a dose-related increase in insulin expression within the pancreas was observed. CONCLUSIONS: These data demonstrate the feasibility of administering native GLP-1 as GLP-1 Technosphere Inhalation Powder for diabetes therapy.
