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      Comparison of intraocular pressure-lowering effects of ripasudil hydrochloride hydrate for inflammatory and corticosteroid-induced ocular hypertension

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          Abstract

          Ocular hypertension (OHT) caused by inflammation or corticosteroid treatment is a common complication of uveitis. Ripasudil hydrochloride hydrate (K-115) is reportedly efficacious for lowering intraocular pressure (IOP). We retrospectively compared the IOP-lowering effect of K-115 for inflammatory and corticosteroid-induced OHT associated with uveitis. Thirty-six consecutive eyes of 27 patients with uveitis-associated OHT (20 and 16 eyes with inflammation- and corticosteroid-induced OHT, respectively) were treated with K-115 with or without other anti-glaucoma agents. In the inflammation-induced OHT, mean IOP and aqueous flare significantly decreased (P < 0.001 and P = 0.035, respectively), changing from 26.4 ± 7.5 mmHg and 28.1 ± 15.0 photon counts per millisecond (pc/ms) at the initial assessment to 17.9 ± 5.4 mmHg and 17.1 ± 10.7 pc/ms at the last visit, respectively. In the corticosteroid-induced OHT, mean IOP significantly decreased (P = 0.0005), changing from 26.7 ± 7.8 mmHg and 18.7 ± 11.2 pc/ms to 18.6 ± 8.8 mmHg and 22.6 ± 15.3 pc/ms, respectively; conversely, aqueous flare remained unchanged. In the inflammation-induced OHT, K-115 was more efficacious in the eyes with higher IOP. Neither remarkable adverse effects nor exacerbation of uveitis were observed in the eyes of either group during the observation period. K-115 decreased IOP in both inflammation- and corticosteroid-induced OHT associated with uveitis and played a synergistic role in reducing ocular inflammation in uveitis treatment.

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          Most cited references23

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          Rho kinase (ROCK) inhibitors.

          The Rho kinase (ROCK) isoforms, ROCK1 and ROCK2, were initially discovered as downstream targets of the small GTP-binding protein Rho. Because ROCKs mediate various important cellular functions such as cell shape, motility, secretion, proliferation, and gene expression, it is likely that this pathway will intersect with other signaling pathways known to contribute to cardiovascular disease. Indeed, ROCKs have already been implicated in the regulation of vascular tone, proliferation, inflammation, and oxidative stress. However, it is not entirely clear how ROCKs are regulated, what some of their downstream targets are, and whether ROCK1 and ROCK2 mediate different cellular functions. Clinically, inhibition of ROCK pathway is believed to contribute to some of the cardiovascular benefits of statin therapy that are independent of lipid lowering (ie, pleiotropic effects). To what extent ROCK activity is inhibited in patients on statin therapy is not known, but it may have important clinical implications. Indeed, several pharmaceutical companies are already actively engaged in the development of ROCK inhibitors as the next generation of therapeutic agents for cardiovascular disease because evidence from animal studies suggests the potential involvement of ROCK in hypertension and atherosclerosis.
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            Ripasudil: first global approval.

            Ripasudil hydrochloride hydrate (Glanatec® ophthalmic solution 0.4 %; hereafter referred to as ripasudil) is a small-molecule, Rho-associated kinase inhibitor developed by Kowa Company, Ltd. for the treatment of glaucoma and ocular hypertension. This compound, which was originally discovered by D. Western Therapeutics Institute, Inc., reduces intraocular pressure (IOP) by directly acting on the trabecular meshwork, thereby increasing conventional outflow through the Schlemm's canal. As a result of this mechanism of action, ripasudil may offer additive effects in the treatment of glaucoma and ocular hypertension when used in combination with agents such as prostaglandin analogues (which increase uveoscleral outflow) and β blockers (which reduce aqueous production). The eye drop product has been approved in Japan for the twice-daily treatment of glaucoma and ocular hypertension, when other therapeutic agents are not effective or cannot be administered. Phase II study is underway for the treatment of diabetic retinopathy. This article summarises the milestones in the development of ripasudil leading to the first approval for glaucoma and ocular hypertension.
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              International Uveitis Study Group (IUSG): clinical classification of uveitis.

              A simplified clinical classification system of uveitis has been proposed by the International Uveitis Study Group. Its aim is to assist in the diagnosis and evaluation of patients with uveitis. Used in conjunction with other recognized classification systems it will also enable enrollment of patients for clinical trials, and contribute to clinical guidelines.
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                Author and article information

                Contributors
                Role: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: Writing – review & editing
                Role: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                2 October 2017
                2017
                : 12
                : 10
                : e0185305
                Affiliations
                [001]Department of Ophthalmology, National Defense Medical College, Tokorozawa, Japan
                Massachusetts Eye & Ear Infirmary, Harvard Medical School, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-4913-7089
                Article
                PONE-D-17-21885
                10.1371/journal.pone.0185305
                5624590
                28968412
                e0b8631c-199b-4ace-9b35-e432d7ef19ff
                © 2017 Yasuda et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 8 June 2017
                : 11 September 2017
                Page count
                Figures: 3, Tables: 2, Pages: 11
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: Grant-in-Aid for Young Scientists B 17K16964
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/501100001691, Japan Society for the Promotion of Science;
                Award ID: Grants-in-Aid for Scientific Research C 16K11337
                Award Recipient :
                The study was supported by grants from the Grants-in-Aid for Scientific Research C (M. Takeuchi, 16K11337) and Grant-in-Aid for Young Scientists B (K. Takayama, 17K16964) from the Japan Society for the Promotion of Science. There are no conflicts of interest to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Immunology
                Immune Response
                Inflammation
                Medicine and Health Sciences
                Diagnostic Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Signs and Symptoms
                Inflammation
                Medicine and Health Sciences
                Ophthalmology
                Uveitis
                Biology and Life Sciences
                Anatomy
                Head
                Eyes
                Medicine and Health Sciences
                Anatomy
                Head
                Eyes
                Biology and Life Sciences
                Anatomy
                Ocular System
                Eyes
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Eyes
                Medicine and Health Sciences
                Ophthalmology
                Medicine and Health Sciences
                Vascular Medicine
                Blood Pressure
                Hypertension
                Biology and Life Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Trabecular Meshwork
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Ocular Anatomy
                Trabecular Meshwork
                Biology and Life Sciences
                Anatomy
                Ocular System
                Intraocular Pressure
                Medicine and Health Sciences
                Anatomy
                Ocular System
                Intraocular Pressure
                Medicine and Health Sciences
                Ophthalmology
                Eye Diseases
                Custom metadata
                All relevant data are within the paper and its Supporting Information files.

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