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N. Kim, C. Crosson, C. Supuran, T. McCauley, G. Southan, R. Baumgartner, W. McVicar; INO-8875, An Adenosine A1 Agonist, in Development for Open-Angle Glaucoma Reduces IOP in Three Rabbit Models. Invest. Ophthalmol. Vis. Sci. 2009;50(13):4061.
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INO-8875, an adenosine A1 receptor agonist, is under development for treatment of primary open-angle glaucoma. INO-8875 was evaluated for its pharmacology, efficacy and safety profile in animal models.
In vitro receptor binding assays were used to characterize receptor selectivity of INO-8875. To evaluate in vivo efficacy, IOP responses and systemic blood levels were determined following topical administration of INO-8875 to Dutch-Belted (D-B) rabbits, and ocular normotensive and hypertensive New Zealand White (NZW) rabbits. To induce ocular hypertension, carbopol polymer (50 µL of 0.025%) was injected into the anterior chamber two weeks prior to drug administration. IOP was measured using a calibrated pneumotonometer. The preclinical safety profile of INO-8875 was determined in rabbits and dogs following once daily ocular dosing for 14 days.
Adenosine receptor-binding assays demonstrated that INO-8875 was highly selective to A1 receptors (Ki = 0.97 nM). In normotensive eyes of D-B and NZW rabbits, topical administration of INO-8875 (20 and 165 µg, respectively) produced significant lowering in IOP with a maximum reduction of 20 to 25% for approximately 6 hours. In ocular hypertensive eyes, administration of INO-8875 at a dose of 25 µg significantly lowered IOP by 20 to 30% from the baseline level at 1-hour, and sustained this effect throughout the 4-hour measurement time. Preclinical safety studies demonstrated that once daily ocular instillation for 14 days with INO-8875 (up to 2 mg/eye) was well-tolerated with no treatment-related ophthalmology and histopathology findings. Following ocular administration of INO-8875, systemic levels of INO-8875 were extremely low, suggesting that INO-8875 has the potential for a good therapeutic profile.
INO-8875, a selective adenosine A1 agonist, is effective in lowering IOP and has a favorable safety profile in relevant nonclinical models.
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