MINIMAL CARDIAC ELECTROPHYSIOLOGICAL ACTIVITY OF ALPRENOXIME, A SITE-ACTIVATED OCULAR BETA-BLOCKER, IN DOGS

A closed chest catheter technique was used in dogs to examine the potential cardiac effects of alprenoxime, a potent new ocular anithypertensive agent. Alprenoxime was designed to undergo metabolic activation to the beta-blocker, alprenolol, specifically with the eye using hydrolase and reductase enzymes that reside in the iris-ciliary body. Previous studies in rabbits confirmed that intraocular pressure (IOP) significantly decreased after topically instilling opthalmic drops of alprenoxime, while heart rates remained essentially unchanged after intravenous dosing. To further explore the safety and ocular specificity of this potential antiglaucoma drug, several cardiac electrophysiologic parameters were monitored during alprenoxime infusion in anesthetized dogs. In contrast to the pharmacologically significant increases (33-144%) measured after alprenolol or other previously tested beta antagonist infusion, the identical dose of alprenoxime had no effect on sinus cycle length (SCL), conduction times through the bundle of His and atrium (H and AH), or any other monitored cardiac electrophysiologic parameter. No changes greater than 6% from baseline were detected with alprenoxime infusion. Similarly, no beta-antagonist cardiac activity could be detected in isoporterenol simulated dogs after alprenoxime. The results demonstrate that alprenoxime has no significant cardiac activity at doses much greater than potential therapeutic levels. The study provides further support than the new agent could be safely used in treating glaucoma.