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.

译文

目的:为了阐明动物眼中Y-39983(一种选自R-27632的选择性Rho相关的卷曲螺旋形成蛋白激酶(ROCK)抑制剂)Y-39983的降低眼内压(IOP)的作用和相关特征。
方法:通过生化分析比较Y-39983和Y-27632对ROCK的选择性。通过肺气量计在局部给予Y-39983的白化兔和食蟹猴中监测IOP。在白化兔中局部施用Y-39983后2小时,分别通过两级恒压灌注和灌注技术使用异硫氰酸荧光素-右旋糖酐测量总流出设施和葡萄膜巩膜流出。在白化病兔和食蟹猴中观察到局部施用Y-39983的眼部毒理作用。
结果:生化分析表明,Y-39983比ROCK-Y-27632对ROCK的抑制作用更强。在兔子中,局部施用Y-39983可将常规流出量显着增加65.5%,然后是IOP的剂量依赖性显着降低。在0.1%的Y-39983中,兔子的最大IOP降低为13.2 /-0.6毫米汞柱(平均/-SE)。在猴子中,局部给药0.05%Y-39983后3小时,IOP的最大降低为2.5±0.8 mm Hg。在兔子或猴子中,一天四次(以2小时为间隔)每天四次Y-39983长期局部给药期间,偶发性点状结膜下出血除外,在眼组织中未观察到严重的副作用。但是,每日两次(每隔6小时)或每天三次(每隔5小时)给药未观察到点状结膜下出血。
结论:Y-39983引起流出设施增加,随后IOP降低。 Y-39983眼用溶液剂可能是降低IOP的候选药物,因为它增加了常规流出量并且产生了相对较少的副作用。

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