Rho Kinase Inhibitors as a Novel Treatment for Glaucoma and OcularHypertension

摘要

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 mayprove useful in conventional glaucoma surgery. Local adverse effects, however,including conjunctival hyperemia, subconjunctival hemorrhages and corneaverticillata, are common. Development of Rho kinase inhibitors targeted to thecells of the outflow pathway and the retina may allow these agents to have evengreater clinical impact.The objectives of this review are to describe the basic scienceunderlying the development of Rho kinase inhibitors as a therapy to lowerintraocular pressure and to summarize the results of the clinical studiesreported to date. The neuroprotective and vasoactive properties of Rho kinaseinhibitors as well as the antifibrotic properties of these agents are reviewedin the context of their possible role in the medical and surgical treatment ofglaucoma.