Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension.
Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension.
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DOI：
10.1016/j.ophtha.2018.04.040
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发表时间：
2018-11
期刊：
影响因子：
13.7
通讯作者：
Johnson M
中科院分区：
文献类型：
--
作者：
Tanna AP;Johnson M
在一个优雅的实验室到床边研究的例子中，在20世纪90年代提出了一个假设，即流出通路中的细胞主动调节传统的流出阻力，并系统地进行了研究，揭示了IOP调节的新细胞和分子机制。药理学操作流出途径细胞的细胞骨架降低流出阻力的关键发现将聚光灯放在已知调节细胞骨架的Rho激酶途径上。最终，对Rho激酶抑制剂的研究发现了几种具有治疗意义的分子，今天给我们留下了两种新的眼科消肿剂，它们分别是日本的ripasudil和美国的netarsudil。这些代表了自1996年美国FDA批准拉坦前列素以来第一类新的临床有用的眼部消肿剂的成员。Rho激酶抑制剂作为一类降低青光眼和高眼压患者眼内压的药物的开发代表了转化研究的胜利。Rho激酶抑制剂单独使用或与其他已知的眼部消肿药物联合使用时有效。它们还提供了神经保护活性的可能性，对眼部血流的有利影响，甚至可以证明在传统青光眼手术中有用的抗纤维化作用。然而，局部不良反应，包括结膜充血、结膜下水肿和角膜轮状变性是常见的。靶向外流途径和视网膜细胞的Rho激酶抑制剂的开发可能使这些药物具有更大的临床影响。本综述的目的是描述Rho激酶抑制剂作为降低眼内压的治疗方法的基础科学，并总结迄今为止报道的临床研究结果。Rho激酶抑制剂的神经保护和血管活性特性以及这些药物的抗纤维化特性的背景下，他们可能在青光眼的药物和手术治疗的作用进行审查。
In an elegant example of bench to bedside research, a hypothesis that cells in the outflow pathway actively regulate conventional outflow resistance was proposed in the 1990s and systematically pursued, exposing novel cellular and molecular mechanisms of IOP regulation. The critical discovery that pharmacological manipulation of the cytoskeleton of outflow pathway cells decreased outflow resistance placed a spotlight on the Rho kinase pathway that was known to regulate the cytoskeleton. Ultimately, a search for Rho kinase inhibitors led to the discovery of several molecules of therapeutic interest, leaving us today with two new ocular hypotensive agents approved for clinical use – ripasudil in Japan and netarsudil in the US. These represent members of the first new class of clinically useful ocular hypotensive agents since the US FDA approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower intraocular pressure in patients with glaucoma and ocular hypertension represents a triumph in translational research. Rho kinase inhibitors are effective alone or when combined with other known ocular hypotensive medications. They also offer the possibility of neuroprotective activity, a favorable impact on ocular blood flow and even an anti-fibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower intraocular pressure and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors as well as the antifibrotic properties of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.
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影响因子：
4.2
作者：
Gedde, Steven J.;Herndon, Leon W.;Brandt, James D.;Budenz, Donald L.;Feuer, William J.;Schiffman, Joyce C.
通讯作者：
Schiffman, Joyce C.
影响因子：
2.9
作者：
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通讯作者：
Kaibuchi, Kozo
影响因子：
3.4
作者：
BILL, A;PHILLIPS, CI
通讯作者：
PHILLIPS, CI
影响因子：
4.4
作者：
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通讯作者：
Yuan, Fan
影响因子：
--
作者：
ALM, A;VILLUMSEN, J
通讯作者：
VILLUMSEN, J