Effect of lesogaberan, a novel GABA(B)-receptor agonist, on transient lower oesophageal sphincter relaxations in male subjects.
BACKGROUND
Transient lower oesophageal sphincter relaxations (TLESRs) are a major mechanism behind gastro-oesophageal reflux disease (GERD).


OBJECTIVE
To assess the effect of lesogaberan (AZD3355) - a novel peripherally active GABA(B) receptor agonist - on TLESRs.


METHODS
Twenty-four healthy men were enrolled in this single-blind, placebo-controlled, randomized, single-centre, three-period crossover phase 1 study. Subjects were randomized to receive single oral doses of lesogaberan (0.8 mg/kg), baclofen (40 mg) and placebo, separated by washout periods of < or = 7 days. Subjects finished a meal 1 h after the dose. Oesophageal manometry and pH-metry measurements were taken during the 3 h after the meal.


RESULTS
Twenty-one subjects completed the study. Compared with placebo, lesogaberan 0.8 mg/kg significantly reduced the number of TLESRs by 36% [geometric mean ratio (GMR): 0.64; 95% confidence interval (CI): 0.51-0.82] and significantly reduced the number of acid reflux episodes (mean reduction: 1.6; 95% CI: 0.34-2.9). Lesogaberan also significantly increased lower oesophageal sphincter (LES) pressure by 39% compared with placebo (GMR: 1.39; 95% CI: 1.18-1.64). Comparable results were observed with baclofen. Similar numbers of adverse events were reported by subjects taking lesogaberan and placebo.


CONCLUSIONS
Compared with placebo, lesogaberan significantly reduced TLESRs and acid reflux episodes and increased LES pressure.
Boeckxstaens
G E
GE
Academic Medical Center, Amsterdam, the Netherlands. guy.boeckxstaens@med.kuleuven.be <guy.boeckxstaens@med.kuleuven.be>
Rydholm
H
H
Lei
A
A
Adler
J
J
Ruth
M
M
D000293:Adolescent; D000328:Adult; D001418:Baclofen / Q000008:administration & dosage*; D018592:Cross-Over Studies; D049630:Esophageal Sphincter, Lower / Q000187:drug effects*; D018755:GABA Agonists / Q000008:administration & dosage / Q000493:pharmacokinetics; D005764:Gastroesophageal Reflux / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008365:Manometry; D008875:Middle Aged; D009126:Muscle Relaxation / Q000187:drug effects*; D010721:Phosphinic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics; D011437:Propylamines / Q000008:administration & dosage* / Q000493:pharmacokinetics; D055815:Young Adult
D018755:GABA Agonists; D010721:Phosphinic Acids; D011437:Propylamines; C545087:lesogaberan; D001418:Baclofen