268 A NOVEL APPROACH TO TREAT OVERACTIVE BLADDER BY POSITIVE MODULATION OF THE GABA-B RECEPTOR (GABA-BR) WITH ADX71441

Abstract

INTRODUCTION AND OBJECTIVES: GABA is important for micturition control. The GABA-BR agonist baclofen reduces urethral resistance and detrusor overactivity in patients with spasticity. However, baclofen’s side effects limit its use in overactive bladder (OAB). Anti-muscarinics are standard treatment for OAB, but these have use-limiting anticholinergic effects. ADX71441 is a novel, orally active GABA-BR positive allosteric modulator with potentially improved safety and pharmacokinetics over baclofen and no anticholinergic side effect profile. ADX71441 was studied in a diuretic stress-induced preclinical model of OAB and its efficacy compared to the muscarinic oxybutynin. METHODS: Male C57BL/6 mice, food-restricted pre-experiment, were left untreated or given vehicle, ADX71441 1, 3, 10 mg/kg or oxybutynin 100 mg/kg p.o. (n 8/group). Treated mice received water 1ml s.c. 55 min later, followed by furosemide. First micturition event latency, micturition frequency, total and average micturition volumes were assessed for 90 min post diuretic. RESULTS: Administration of ADX71441 dose-dependently prolonged micturition latency, reduced micturition frequency, and volumes. Efficacy was statistically significant for ADX71441 (10 mg/kg) which returned most parameters to untreated control levels and was similar to oxybutynin. CONCLUSIONS: In the diuretic stress-induced OAB model, ADX71441 showed clinically relevant improvements on urinary parameters, comparable to oxybutinin at the 10 mg/kg dose. GABA-BR positive modulation by ADX71441 has potential as a novel approach to OAB treatment.