Abstract
Ripasudil hydrochloride hydrate (K-115), a specific Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, is developed for the treatment of glaucoma and ocular hypertension. Topical administration of ripasudil decreases intraocular pressure (IOP) by increasing conventional outflow through the trabeculae to Schlemm's canal, which is different from existing agents that suppress aqueous humor production or promote uveoscleral outflow. In this study, we demonstrated that ripasudil significantly lowered IOP in combined regimens with other glaucoma therapeutic agents in rabbits and monkeys. Ripasudil showed additional effects on maximum IOP lowering or prolonged the duration of IOP-lowering effects with combined administration of timolol, nipradilol, brimonidine, brinzolamide, latanoprost, latanoprost/timolol fixed combination, and dorzolamide/timolol fixed combination. These results indicate that facilitation of conventional outflow by ripasudil provides additive IOP-lowering effect with other classes of antiglaucoma agents. Ripasudil is expected to have substantial utility in combined regimens with existing agents for glaucoma treatment.
Highlights
Rho-kinase (Rho-associated coiled-coil containing protein kinase; ROCK), a member of the serine-threonine protein kinases, is an effector protein of low-molecular-weight Gprotein, Rho [1]
We demonstrated that topical instillation of ripasudil ophthalmic solution with other glaucoma therapeutic agents, such as β-blocker, αβ-blocker, α2-agonist, carbonic anhydrase inhibitors (CAI), and PG analogs, further reduced intraocular pressure (IOP) and for a longer duration
Combined treatment of ripasudil and timolol significantly lowered IOP at 0.5, 1, 2, 3, 4, and 5 h after instillation compared with vehicle and at 0.5, 3, and 4 h after instillation compared with ripasudil
Summary
Rho-kinase (Rho-associated coiled-coil containing protein kinase; ROCK), a member of the serine-threonine protein kinases, is an effector protein of low-molecular-weight Gprotein, Rho [1]. Aberrant regulation of ROCK levels in the eyes has been shown to be involved in the pathogenesis of diabetic retinopathy, age-related macular edema, cataract, corneal dysfunction, retinal disorders, and glaucoma [9,10,11,12,13,14,15,16,17,18,19,20]. Primary open-angle glaucoma (POAG), the commonest form of glaucoma, often observed chronic elevation of intraocular pressure (IOP). These were developed as a result of pathologically increased resistance to the drainage of the aqueous humor through outflow pathways [21]. IOP reduction is currently the only reliable and evidence-based management approach for the treatment of glaucoma [22]. There is a great clinical need for a novel class of agents, which possesses potent IOP-lowering effects, and can be used with other agents for combination therapy
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