The effects of a novel metabotropic glutamate receptor 5 antagonist (AZD2066) on transient lower oesophageal sphincter relaxations and reflux episodes in healthy volunteers

• Published in: Alimentary pharmacology & therapeutics 2012-05, Vol.35 (10), p.1231-1242
• Main Authors: Rohof, W. O., Lei, A., Hirsch, D. P., Ny, L., Astrand, M., Hansen, M. B., Boeckxstaens, G. E.
• Format: Article
• Language: English
• Subjects: Adult; Analysis of Variance; Biological and medical sciences; Cross-Over Studies; Digestive system; Dose-Response Relationship, Drug; Double-Blind Method; Esophageal Sphincter, Lower - drug effects; Gastroenterology. Liver. Pancreas. Abdomen; Gastroesophageal Reflux - drug therapy; Gastrointestinal Agents - administration & dosage; Gastrointestinal Agents - pharmacokinetics; Gastrointestinal Agents - pharmacology; Humans; Hydrogen-Ion Concentration; Isoxazoles - administration & dosage; Isoxazoles - pharmacokinetics; Isoxazoles - pharmacology; Male; Medical sciences; Pharmacology. Drug treatments; Postprandial Period - drug effects; Receptor, Metabotropic Glutamate 5; Receptors, Metabotropic Glutamate - administration & dosage; Receptors, Metabotropic Glutamate - antagonists & inhibitors; Triazoles - administration & dosage; Triazoles - pharmacokinetics; Triazoles - pharmacology; Young Adult
• ISSN: 0269-2813; 1365-2036
• DOI: 10.1111/j.1365-2036.2012.05081.x

Summary Background Selective metabotropic glutamate receptor 5 (mGluR5) antagonists inhibit transient lower oesophageal sphincter relaxations (TLESRs) in animals and acid reflux in humans. Aim To assess the effect of single doses of the mGluR5 antagonist AZD2066 on TLESRs and reflux in humans. Methods Healthy male volunteers received AZD2066 13 mg and placebo (part A), or AZD2066 2 mg and AZD2066 6 mg and placebo (part B), in a randomised crossover study. Postprandial manometry/pH‐impedance measurements were taken after each dose. Results A total of 13 individuals completed part A of the study and 19 individuals completed part B. There was a significant reduction in the geometric mean number of TLESRs (27%; P = 0.02) and the geometric mean number of reflux episodes (51%; P = 0.01) in subjects receiving AZD2066 13 mg compared with placebo. Adverse events in participants receiving AZD2066 13 mg were mostly related to the nervous system [dizziness (3/13); disturbance in attention (3/13)]. Adverse events were reversible and of mild intensity. There were no serious adverse events. The effects of AZD2066 appeared dose‐dependent, with smaller reductions in TLESRs and reflux episodes (relative to placebo) and fewer adverse events observed for AZD2066 2 mg and AZD2066 6 mg compared with AZD2066 13 mg. Conclusion The mGluR5‐mediated inhibition of TLESRs may be a useful approach for inhibiting gastro‐oesophageal reflux.