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N. Kim, C. Crosson, T. Lam, B. Christian, C. Busse, G. Cantone, R. Baumgartner, T. McCauley, W. McVicar; INO-8875, an Adenosine A1 Agonist, Lowers Intraocular Pressure Through the Conventional Outflow Pathway. Invest. Ophthalmol. Vis. Sci. 2010;51(13):3238.
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INO-8875, a highly selective adenosine A1 agonist, is under development for treatment of ocular hypertension and primary open-angle glaucoma. The mechanism of action by which INO-8875 lowers IOP was evaluated in vitro and ex vivo.
INO-8875 was studied in ocular normotensive Dutch-Belted rabbits and Cynomolgus monkeys. INO-8875 was delivered topically (40-50 µL) at 3-1000 µg in monkeys and at 1.5-150 µg in rabbits. IOP was measured using a tonometer. The signaling pathway and the site of action of INO-8875 was investigated in human trabecular meshwork cells by measuring extracellular signal-regulated kinases 1/2 (ERK 1/2) and matrix metallopeptidases-2 (MMP-2) via Western blot. The conventional outflow facility was measured in isolated perfused porcine anterior segments (corneo-scleral shells). An A1 antagonist (cyclopentyltheophylline; CPT) and a MAP-kinase inhibitor (1,4-diamino-2,3-dicyano-1,4-bis(2-aminophenylthio)butadiene; U0126) were used to confirm the activity of INO-8875.
A single topical INO-8875 dose of ≥5 and ≥10 µg significantly reduced IOP in rabbits and monkeys, respectively. The maximum IOP reduction in both species was 20-25% of baseline and occurred at 1-2 hours post-dose. IOP returned to baseline levels between 2-6 hrs post-dose. A large reservoir of drug was present in the trabecular meshwork region. The addition of INO-8875 to cultured human trabecular meshwork cells produced a rapid activation of ERK 1/2 within 10 minutes and the subsequent stimulation of MMP-2 by 2 hours. Both increases in ERK1/2 activation and MMP-2 secretion were blocked by the addition of CPT and U0126. In isolated perfused porcine anterior segments, the outflow facility was significantly increased following INO-8875 (10-7 M) compared to the vehicle treatment.
These experiments demonstrate that INO-8875, a novel selective adenosine A1 agonist, reduces IOP by increasing the conventional outflow facility. INO-8875 is currently in clinical development.
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