BVT.28949 as a Potential Ocular Hypotensive Agent in Monkeys

Abstract

Abstract: : Purpose: To determined the effect of two different topical doses of BVT.28949, a selective 5–HT2A antagonist, on intraocular pressure (IOP) in ocular normotensive cynomolgus monkeys. Methods: Before drug administration, baseline IOP was measured by Goldmann applanation tonometry in eight ocular normotensive cynomolgus monkeys, and a slit lamp examination (SLE) was performed under ketamine anesthesia. The animals were randomly divided in to two groups of four. BVT.28949, dissolved in phosphate buffer at pH 6.0 in concentrations of 10mM (dose 1) and 50mM (dose 2), was administered to the right eyes of group 1 and the left eyes of group 2. Single doses of 10µl were administered once daily to the respective eyes and phosphate buffer at pH 6.0 (vehicle) was similarly administered to the contralateral eyes. There was a 1–week washout period between the last treatment with dose 1 and the first treatment with dose 2. On days 1 and 5, prior to the 1^st and 5^th dose, SLE was performed and a daily baseline IOP (BL) was measured. Following these doses, IOP was measured at 0.5, 1, 1.5, 2, 3, 4, 5 and 6 hours. SLEs were done at 3 and 6 hours. Results: On day 1, eyes treated with BVT.28949 showed an IOP decrease that was generally maintained for the duration of the 6 hour observation period; at 0.5 and 1.5 hours post treatment IOP significantly decreased from BL by 1.94±0.43 and 1.81±0.58 mmHg [mean±s.e.m.] (p<0.005 and p<0.02, respectively). Eyes treated with vehicle had no significant change in IOP. Following the 5^th dose of BVT.28949, IOP decreased significantly, between 1.25 and 2.25 mmHg, at 1.5, 3, 4, 5 and 6 hours (p<0.05) compared to BL. There were no significant post–treatment IOP changes in the vehicle–treated eyes. After 1 administration of BVT.28949 at dose 2, IOP decreased significantly by 1.31 to 2.06 mmHg when corrected for BL (p<0.05), at 1.5, 2, 3, 4 and 6 hours, while vehicle–treated eyes showed no significant change. By day 5, BVT.28949–treated eyes showed significant changes of 1.63 to 2.88 mmHg, at 1, 1.5, 2, 3, 4 and 5 hours post–treatment (p<0.05), while IOP in vehicle–treated eyes showed no significant change. Conclusions: BVT.28949 treatments consistently produced a 1–3 mmHg reduction in mean IOP from BL pressures after 1 and 5 treatments at 10mM and 50mM doses. The two doses did not produce significantly different results, but dose 2 appears to have a more consistent and earlier effect.

Keywords: intraocular pressure