Efficacy of a motilin receptor agonist (ABT-229) for the treatment of gastro-oesophageal reflux disease.

BACKGROUND: ABT-229 is a potent motilin agonist without significant antibiotic activity. It has been shown to improve gastric emptying in humans and to increase lower oesophageal sphincter pressure in cats. AIM: To assess the efficacy of four different doses of ABT-229 (1.25 mg, 2.5 mg, 5 mg, 10 mg b.d.) compared to placebo in the treatment of gastro-oesophageal reflux disease, and to determine its safety in patients with gastro-oesophageal reflux disease. METHODS: In a double-blind, multicentre study, 324 patients with heartburn were randomized to receive four different doses of ABT-229 or placebo for 8 weeks. The efficacy was evaluated by Patient Symptom Questionnaire, daily diary, endoscopy and global evaluation of efficacy. RESULTS: There were no statistically significant improvement scores for any of the ABT-229 treatment groups vs. the placebo group in any of the efficacy parameters. Reflux symptom scores were significantly worse after treatment in the dyspeptic group. ABT-229 appeared to be well tolerated and safe in total daily doses up to 20 mg. CONCLUSION: ABT-229 appears to have limited, if any, clinical utility in the treatment of gastro-oesophageal reflux disease.

Effect of novel motilide ABT-229 versus erythromycin and cisapride on gastric emptying in dogs.

ABT-229 (8,9-anhydro-4"-deoxy-3'-N-desmethyl-3'-N-ethylerythromycin B-6,9-hemiacetal), a synthetic derivative of erythromycin (ERY) with no antibiotic activity, has been shown to bind to motilin receptors and stimulate contractile activity of the antrum and small intestine. The objective of this study was to determine the effect of ABT-229 on canine gastric emptying (GE) and contractile activity of the antrum and duodenum in response to a solid meal. Six beagles were used to determine GE of a solid meal and contractile activity in response to either vehicle, ABT-229 (0.17, 0.83, 2.5, or 5.0 microg/kg/min), ERY (33.3 microg/kg/min), or cisapride (CIS) (10 microg/kg/min). Lag (t(lag)), half-emptying (t(1/2)), and complete emptying (t(full)) times were determined. Contractile data were analyzed for motility index and gastroduodenal coordination. Compared with vehicle, ABT-229 dose dependently accelerated GE, t(lag) was decreased at the two highest doses, t(1/2) was decreased compared with vehicle at the three highest doses, and t(full) was decreased at all doses compared with vehicle. ERY also decreased t(1/2) and t(full), whereas CIS decreased all GE parameters. The slopes of the linear phase of GE curves for all drugs and doses were greater than those for vehicle. ABT-229 dose dependently increased the motility index as well as gastroduodenal coordination. ABT-229 (two highest doses) and CIS accelerated GE of a solid meal by decreasing the lag phase and increasing the rate of GE, whereas ERY only increased the rate of GE. The data suggest that ABT-229 is 7- to 40-fold more potent than ERY in accelerating GE.