Document Detail

The GABA(B) receptor agonist AZD9343 inhibits transient lower oesophageal sphincter relaxations and acid reflux in healthy volunteers: a phase I study.
MedLine Citation:
PMID:  19650825     Owner:  NLM     Status:  In-Process    
BACKGROUND: Transient lower oesophageal sphincter relaxations (TLESRs) represent an interesting target for the treatment of gastro-oesophageal reflux. Baclofen reduces TLESRs and reflux episodes, but is not optimal for clinical application because of its central side effects. Therefore, new agents are required. AIM: To study the effect of AZD9343, a new selective GABA(B) receptor agonist, in healthy volunteers. METHODS: A total of 27 subjects participated in a placebo-controlled, randomized, two-centre phase I study. Subjects underwent oesophageal manometry and pH-metry for 3 h postprandially. Before meal ingestion, a single oral dose of placebo, 60 and 320 mg AZD9343 or 40 mg baclofen was given on four separate days. RESULTS: Somnolence was reported after 320 mg AZD9343 and baclofen. Reversible short-lasting paraesthesia was reported after AZD9343. AZD9343 320 mg and baclofen significantly reduced the number of TLESRs with 32% and 40% respectively. Acid reflux was significantly decreased by AZD9343 and baclofen. Like baclofen, AZD9343 increased LES pressure before meal intake. AZD9343 320 mg and baclofen significantly reduced the swallowing rate. CONCLUSIONS: Like baclofen, AZD9343 dose-dependently decreases the number of TLESRs and acid reflux episodes, increases LES pressure and reduces swallowing, extending the concept that GABA(B) agonists are potent reflux inhibitors. However, discovery of analogues with an improved side effect profile is warranted.
H Beaumont; A Smout; M Aanen; H Rydholm; A Lei; A Lehmann; M Ruth; G Boeckxstaens
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2009-07-24
Journal Detail:
Title:  Alimentary pharmacology & therapeutics     Volume:  30     ISSN:  1365-2036     ISO Abbreviation:  Aliment. Pharmacol. Ther.     Publication Date:  2009 Nov 
Date Detail:
Created Date:  2009-10-07     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8707234     Medline TA:  Aliment Pharmacol Ther     Country:  England    
Other Details:
Languages:  eng     Pagination:  937-46     Citation Subset:  IM    
Academic Medical Centre, Amsterdam, The Netherlands.
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