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W. M. Peterson, J. Lampe, T. Navratil, Y. Paran, K. Zvi, E. A. Hennes, B. T. Gabelt, B. Geiger, P. L. Kaufman, J. L. Vittitow; Topical Administration of a Novel and Potent Rho Kinase (ROK) Inhibitor INS117548 Alters the Actin Cytoskeleton, Effectively Lowers IOP, and Is Well Tolerated on the Ocular Surface. Invest. Ophthalmol. Vis. Sci. 2008;49(13):3816.
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To evaluate the effects of INS117548 on cytoskeletal integrity, IOP, and ocular surface tolerability in cell-based and in vivo assays.
The potency of INS117548 in inhibiting ROKβ/ROCK-I and ROKα/ROCK-II enzymatic activity was evaluated with a standard, commercially available IMAP assay. Reporter HeLaJW cells expressing YFP-tagged paxillin were treated with the compound and stained with phalloidin to evaluate effects on focal adhesions and actin. Non-glaucomatous cynomolgus monkeys with baseline IOPs of ~20 mmHg were instilled with INS117548 at ~9am on days 1-5 and ~5pm on days 1-4, and IOP measurements were made before the 9am instillation on days 1, 2 and 5, and every hour for 6 hours after the 9am instillation on days 2 and 5. The effects of acute ocular instillations of formulated INS117548 on the ocular surface were evaluated in albino rabbits.
The Ki’s for INS117548 against ROCK-I and ROCK-II were 14.4 ± 2.0 nM (n=5) and 5.8 ± 0.2 nM (n=8), respectively. INS117548 (0.83 µM - 200 µM) induced a dose-dependent decrease in the number of stress fibers, and focal adhesion size and numbers, but had no apparent effect on microtubules. INS117548 significantly lowered IOP at all three doses administered (30µl; 1, 3 and 10mM) with maximum IOP lowering of 20-25% relative to baseline at 1-3 hr following instillation. Prolonged, acute exposure of formulated INS117548 produced no observable effects on the ocular surface at ~3-fold of the minimally effective IOP-lowering dose. Exposure to higher doses resulted in mild, reversible and dose-dependent increases in conjunctival hyperemia, hemorrhage, and chemosis.
INS117548 is an efficacious and well-tolerated IOP-lowering agent in animal models and shows promise as a candidate for further clinical investigations in ocular hypertensive and glaucoma patients.
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