The GABA(B) receptor agonist AZD9343 inhibits transient lower oesophageal sphincter relaxations and acid reflux in healthy volunteers: a phase I study.
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.


OBJECTIVE
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.
Beaumont
H
H
Academic Medical Centre, Amsterdam, The Netherlands.
Smout
A
A
Aanen
M
M
Rydholm
H
H
Lei
A
A
Lehmann
A
A
Ruth
M
M
Boeckxstaens
G
G
D000328:Adult; D001418:Baclofen / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D049630:Esophageal Sphincter, Lower / Q000187:drug effects*; D058786:GABA-B Receptor Agonists; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009125:Muscle Relaxants, Central / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
D058786:GABA-B Receptor Agonists; D009125:Muscle Relaxants, Central; D001418:Baclofen