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M. Inatani, H. Tokushige, S. Nemoto, T. Tajika, M. Uehata, H. Tanihara; Intraocular Pressure–Lowering Effects of Topical Administration of Y–39983, a Novel Selective Rho–Associated Protein Kinase Inhibitor . Invest. Ophthalmol. Vis. Sci. 2005;46(13):3787.
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Purpose:To elucidate the intraocular pressure (IOP)–lowering effects of Y–39983, a selective Rho–associated protein kinase (ROCK) inhibitor derived from Y–27632, and the associated characteristics in animal eyes. Methods:The IOP, outflow facility, and safety were examined after the topical administration of Y–39983 in eyes of rabbits and monkeys. Additionally, pharmacokinetics was evaluated with topical administration of the radiolabeled compound. Blood flow at the optic nerve head was also measured by laser speckle method. Results:In rabbit and monkey eyes, administration of 0.01% to 0.1% Y–39983 induced a significant decrease in IOP in a dose–dependent manner. In monkey eyes, at 3 hours after the topical administration of 0.05% Y–39983, IOP resulted in maximal reduction by an average of 2.5 mmHg. The outflow facility was 1.66 times increased in Y–39983–treated rabbit eyes. Phrmacokinetic analysis showed the peak concentrations at 2 hours in aqueous humor, and at 4 hours in choroid/retina and iris/ciliary body. Autoradiogram demonstrated high radioactivities in eyelid, conjunctiva, cornea and iris/ciliary body. Increased blood flow at optic nerve head was observed during first 5 hours after the administration. Although no significant toxic changes in corneal surface, anterior chamber, lens, vitreous and retina were observed, slight conjunctival injection and hemorrhage were observed in Y–39983–treated eyes after 4 times of topical administration. Conclusions:We conclude that Y–39983 causes a remarkable reduction in IOP and a significant increase in outflow facility, and may be a useful therapeutic drug for the treatment of glaucoma.
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