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Purpose. To evaluate the ocular hypotensive effect of topical CS-088, an angiotensin AT1 receptor antagonist, and the effect of CS-088 on aqueous humor dynamics. Methods. The effects of CS-088 on intraocular pressure (IOP) were studied in 2 models of rabbit ocular hypertension. Experimental ocular hypertension was induced in albino rabbits by injecting α-chymotrypsin into the anterior chamber (α-chymotrypsin rabbit). The effects of the single application of CS-088 were examined. Additionally, CS-088 was repeatedly administered over a period of 3 weeks to hereditary ocular hypertensive rabbits (buphthalmic rabbits, JWHR bu/bu) and the IOPs were monitored throughout the experiment. The effects of CS-088 on aqueous humor dynamics were also examined in normal rabbits. In this study, the methods of IOP recovery rate, two-level constant pressure perfusion and fluorescein-dextran perfusion were used respectively to determine the aqueous inflow, outflow facility and uveoscleral outflow (USF). Results. CS-088 at 1% and 2% significantly lowered the IOP in the α-chymotrypsin rabbits with a maximum IOP reduction of 10.1 mmHg. The maximum effect obtained with 2% CS-088 was no greater than that with 1% CS-088. In the buphthalmic rabbits, 2% CS-088 also lowered IOP significantly. Timolol was effective in both models. In the study on aqueous humor dynamics, a slight increase in USF (17%) was seen after a topical application of CS-088 whereas changes in aqueous inflow or outflow facility were not observed. Conclusions. Topical CS-088 can decrease IOP in rabbits. Despite the USF change, the ocular hypotensive mechanism by CS-088 was not fully determined. [ABSTRACT FROM AUTHOR]

Abstract: To evaluate the effect of CS-088, an angiotensin AT1 receptor antagonist, on intraocular pressure (IOP) in monkey eyes with unilateral laser-induced glaucoma. A multiple-dose study was performed in 8 glaucomatous monkey eyes. One 50µl drop of CS-088, 2% or 4%, was topically applied to the glaucomatous eye at 9:30 a.m. and 3:30 p.m. for 5 consecutive days. IOP was measured hourly for 6 hours beginning at 9:30 a.m. for one baseline day, one vehicle-treated day, and daily for 5 days of treatment with CS-088. The washout period between the two drug concentrations was at least 2 weeks. Twice daily administration of 2 % CS-088 for 5 days did not reduce the IOP until the third dose on day 2 of the treatment regimen. A significant (p<0.02) reduction in IOP began 1 hour after the third dose, and lasted for 3 hours. The maximum reduction in IOP was 5.3± 0.8 (mean±SEM) mmHg (15%) (p<0.001), with the longest duration of IOP reduction of at least 6 hours after dosing on day 5. The 4% dose of CS-088 reduced (p<0.05) IOP from 1 to 5 hours after the first dose. The maximum reduction in IOP was 6.9±1.0 mmHg (20%), with the longest duration of IOP reduction of at least 18 hours after administration on day 5. Both 2% and 4% CS-088 showed enhancement of the ocular hypotensive effect with repeated dosing. 4% CS-088 produced greater (p<0.05) IOP reduction with longer duration of action than 2%. Topically applied CS-088, a new antagonist drug at the angiotensin AT1 receptor, reduced IOP in glaucomatous monkey eyes in a dose-dependent manner. [Copyright &y& Elsevier]