Effects of topical administration of Y-39983, a selective Rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys
Effects of topical administration of Y-39983, a selective Rho-associated protein kinase inhibitor, on ocular tissues in rabbits and monkeys
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DOI：
10.1167/iovs.05-1617
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发表时间：
2007-07-01
影响因子：
4.4
通讯作者：
Tanihara, Hidenobu
中科院分区：
文献类型：
--
作者：
Tokushige, Hideki;Inatani, Masaru;Tanihara, Hidenobu
目的.目的：探讨Y-39983（一种来源于Y- 27632的选择性Rho相关卷曲螺旋形成蛋白激酶（ROCK）抑制剂）的降眼压作用及其相关特性。通过生化测定比较Y- 39983与Y- 27632对ROCK抑制的选择性。在局部给予Y-39983的白化病兔和食蟹猴中，通过气压计监测IOP。在白化病兔局部给药Y- 39983后2 h，分别采用两水平恒压灌注和异硫氰酸荧光素-葡聚糖灌注技术测量总流出设施和葡萄膜巩膜流出量。在白化病兔和食蟹猴中观察了Y- 39983局部给药的眼部毒理学效应。生化测定表明Y- 39983比Y-27632更有效地抑制ROCK。在家兔中，Y- 39983局部给药使常规流出量显著增加65.5%，随后IOP呈剂量依赖性显著降低。兔中0.1% Y-39983的最大IOP降低为13.2 +/- 0.6 mm Hg（平均值+/- SE）。在猴中，0.05% Y-39983局部给药后3小时，IOP的最大降低为2.5 +/- 0.8 mm Hg。在兔或猴中，除每天4次（间隔2小时）长期局部给药Y- 39983期间出现偶发点状结膜下出血外，未观察到眼组织中的严重副作用。然而，每日两次（间隔6小时）或每日三次（间隔5小时）给药未观察到点状结膜下出血。Y-39983导致流出道灵活性增加，随后IOP降低。Y-39983滴眼液可能是降低IOP的候选药物，因为它增加了常规流出量，且产生的副作用相对较少。
PURPOSE. To elucidate the intraocular pressure (IOP)-lowering effects and associated characteristics of Y-39983, a selective Rho-associated coiled coil-forming protein kinase (ROCK) inhibitor derived from Y- 27632, in animal eyes.METHODS. Y- 39983 was compared with Y- 27632 for selectivity of ROCK inhibition by biochemical assay. The IOP was monitored by pneumatonometer in albino rabbits and cynomolgus monkeys that were given topically administered Y-39983. The total outflow facility and uveoscleral outflow were measured by two-level constant-pressure perfusion and perfusion technique using fluorescein isothiocyanate-dextran, respectively, at 2 hours after topical administration of Y- 39983 in albino rabbits. The ocular toxicologic effects of topical administration of Y- 39983 were observed in albino rabbits and cynomolgus monkeys.RESULTS. A biochemical assay showed that Y- 39983 inhibited ROCK more potently than Y-27632. In rabbits, topical administration of Y- 39983 significantly increased conventional outflow by 65.5%, followed by significant, dose-dependent reduction in IOP. Maximum IOP reduction was 13.2 +/- 0.6 mm Hg ( mean +/- SE) at 0.1% Y-39983 in rabbits. In monkeys, at 3 hours after topical administration of 0.05% Y-39983, maximum reduction of IOP was 2.5 +/- 0.8 mm Hg. No serious side effects were observed in ocular tissues except sporadic punctate subconjunctival hemorrhage during long-term topical administration of Y- 39983 four times a day (at 2-hour intervals) in rabbits or monkeys. However, punctate subconjunctival hemorrhage was not observed with administration twice daily (at a 6-hour interval) or three times a day (at 5-hour intervals).CONCLUSIONS. Y-39983 causes increased outflow facility followed by IOP reduction. Y-39983 ophthalmic solution may be a candidate drug for lowering of IOP, since it increases conventional outflow and produces relatively few side effects.