Effects of Rho kinase inhibitors on intraocular pressure (IOP) and aqueous humor dynamics in rabbits and monkeys.

Abstract

Abstract: : Purpose:To determine the effect on IOP of two Rho kinase inhibitors (HMN–1152 and Y–27632) in rabbits and monkeys and the effect on aqueous humor dynamics of Y–27632 in monkeys. Methods: At least 3 months prior to drug treatment, one eye of every monkey was treated with laser burns to the trabecular meshwork to elevate IOP. In efficacy studies (New Zealand albino rabbits, NZA; conscious cynomolgus monkeys, CYNO; ketamine–sedated rhesus monkeys, RHESUS), IOP was measured at baseline and at intervals for 6 hours after dosing (9 a.m.) with either drug or vehicle. IOP was compared with baseline (time=0) measurement (NZA, CYNO) or to a vehicle diurnal curve at comparable time points (RHESUS). In mechanism studies (sedated CYNO), IOP, aqueous flow, fluorophotometric outflow facility and uveoscleral outflow were determined on baseline day and after treating both eyes with Y–27632 at 5 p.m. the day before and at 9 a.m. on the treatment day. Baseline data were compared to treatment data with paired t–tests. Results: Efficacy: Within 3 hours of dosing in NZA eyes (n=5), Y–27632 (2%) lowered IOP by 29% (p<0.05) and HMN–1152 (2%) by 32% (p<0.05). Within 3 hours of dosing in lasered CYNO eyes, Y–27632 (2%) lowered IOP by 35% (p<0.05). HMN–1152 (1%) lowered IOP in CYNO (n=8 or 9) and RHESUS (n=12) lasered eyes (42% and 39%, respectively; p<0.05) and normal eyes (35% and 28%, respectively; p<0.05). Mechanism: In Y–27632–treated hypertensive CYNO eyes (n=12) compared with baseline, IOP was reduced by 28% (p=0.05) at 2.5 hours after the second dose, and increases were found in aqueous flow (56%; p=0.01), uveoscleral outflow (154%; p=0.01) and outflow facility (88%; p=0.01). In normotensive eyes of the same animals, aqueous flow was increased by 20% (p=0.04). Conclusions: Rho kinase inhibitors effectively lower IOP in animal models for at least 6 hours after dosing. The IOP reduction after Y–27632 is caused by an increase in both outflow facility and uveoscleral outflow. The outflow effect more than compensates for the increase in aqueous formation so that IOP decreases. Rho kinase inhibitors may lower IOP while increasing nutritive support to the eye.

Keywords: intraocular pressure • pharmacology