Effect of SPP 301, an Endothelin Antagonist, on Intraocular Pressure in Glaucomatous Monkey Eyes

Abstract

Purpose: To evaluate the effect of topical application of avosentan (SPP 301), endothelin receptor type A antagonist, on intraocular pressure (IOP) in monkey eyes with laser-induced unilateral glaucoma.

Materials and Methods: A multiple-dose study was performed in eight glaucomatous monkey eyes that were topically treated with SPP 301 by applying a 50 µl drop (25 µl × 2) at 9:30 a.m. and 3:30 p.m. for 5 consecutive days at three concentrations (0.003%, 0.03%, or 0.3%). IOP was measured hourly for 6 hrs on each day of the study beginning at 9:30 a.m. for one baseline day, one vehicle-treated day, and treatment days 1, 3, and 5.

Results: Twice daily administration of each of the three concentrations of SPP 301 for 5 days significantly (p < 0.05) reduced IOP. The maximum reduction in IOP occurred 2 or 3 hrs after morning dosing and was 1.8 ± 0.8 (mean ± SEM) mmHg (6%) for 0.003% SPP 301, 4.1 ± 0.7 mmHg (13%) for 0.03% SPP 301, and 7.1 ± 1.3 mmHg (21%) for 0.3% SPP 301. The longest duration of IOP reduction was for 2 hrs with 0.003% SPP 301, and was for at least 6 hrs with 0.03% and 0.3% concentrations. Compared to 0.03% or 0.003% concentrations, 0.3% SPP 301 produced a greater (p < 0.05) IOP reduction. IOP was reduced in fellow untreated normal eyes 2 hr after morning dosing with 0.3% SPP 301, maximum reduction in IOP (11%) occurred on day 1. Of the eyes treated with 0.3% SPP 301, one eye demonstrated mild conjunctival discharge and one eye was closed for 5 min after dosing.

Conclusion: Topically applied SPP 301, an endothelin antagonist, reduced IOP in glaucomatous monkey eyes in a dose-dependent manner. Endothelin antagonists, a novel class of compound, may have potential for the treatment of glaucoma.

KEYWORDS::

• Avosentan (SPP 301)
• Endothelin Antagonist
• Glaucoma monkey
• Intraocular pressure

ACKNOWLEDGMENTS

The authors wish to acknowledge support by an unrestricted grant from Research to Prevent Blindness, Inc., New York, NY and Speedel Experimenta Ltd., Basel, Switzerland.

Declaration of interest: Drs. Wang, Podos, and Serle have no proprietary interest in the drug evaluated in this article. Dr. Baltatu was an employee of Speedel Experimenta, Ltd. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.