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Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and Ocular Hypertension
Ophthalmology ( IF 13.1 ) Pub Date : 2018-07-12 , DOI: 10.1016/j.ophtha.2018.04.040
Angelo P Tanna 1 , Mark Johnson 2
Affiliation  

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 intraocular pressure (IOP) regulation. The critical discovery that pharmacologic 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 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP 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 antifibrotic 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 IOP 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.



中文翻译:


Rho 激酶抑制剂作为青光眼和高眼压的新型治疗方法



在从实验室到临床研究的一个典型例子中,流出通路中的细胞主动调节传统流出阻力的假设在 20 世纪 90 年代被提出并进行了系统的研究,揭示了眼内压 (IOP) 调节的新细胞和分子机制。对流出途径细胞的细胞骨架进行药理学操作可降低流出阻力这一重要发现使人们关注已知调节细胞骨架的 Rho 激酶途径。最终,对 Rho 激酶抑制剂的研究导致了几种具有治疗意义的分子的发现,今天我们有了两种批准用于临床的新型降眼压药物:日本的瑞帕舒地尔和美国的奈塔舒地尔。这些代表了自 1996 年美国食品和药物管理局批准拉坦前列素以来第一类临床上有用的新型降眼压药物的成员。Rho 激酶抑制剂作为一类用于降低青光眼和高眼压患者眼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降眼压药物联合使用均有效。它们还提供神经保护活性的可能性,对眼部血流的有利影响,甚至可能在传统青光眼手术中证明有用的抗纤维化作用。然而,局部不良反应很常见,包括结膜充血、结膜下出血和角膜轮转。针对流出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产生更大的临床影响。 本综述的目的是描述 Rho 激酶抑制剂作为降低眼压疗法的开发基础科学,并总结迄今为止报告的临床研究结果。 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在它们在青光眼的内科和外科治疗中可能发挥的作用的背景下进行了综述。

更新日期:2018-07-12
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