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Intraocular Pressure-Lowering Effect of Ripasudil Hydrochloride Hydrate

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Intraocular Pressure-Lowering Effect of Ripasudil Hydrochloride Hydrate ISSN: 2378-346X Kawara et al. Int J Ophthalmol Clin Res 2018, 5:083 DOI: 10.23937/2378-346X/1410083 Volume 5 | Issue 1 International Journal of Open Access Ophthalmology and Clinical Research RESEARCH ARTICLE Intraocular Pressure-Lowering Effect of Ripasudil Hydrochloride Hy- drate and Reasons for Discontinuation of Use in Clinical Practice Kana Kawara, Akiyasu Kanamori, Sotaro Mori, Yukako Inoue, Takuji Kurimoto, Sentaro Kusuhara, Yuko Yamada and Makoto Nakamura* Check for Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, Japan updates *Corresponding author: Makoto Nakamura, Division of Ophthalmology, Department of Surgery, Kobe University Graduate School of Medicine, 7-5-2 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan, E-mail: [email protected] that are commonly used include prostaglandin ana- Abstract log, which enhances uveoscleral outflow, adrenergic Background: To evaluate the intraocular pressure (IOP)-low- β-blocker and carbonic anhydrase inhibitor (CAI), which ering effect of ripasudil hydrochloride hydrate and the reasons for the discontinuation of its use in glaucomatous eyes with at reduce aqueous humor production, or adrenergic α2 least 2 ocular hypotensive medications. stimulant, which performs both mechanisms. The clin- Design: Retrospective case series. ical application of drugs that modify the conventional outflow pathway through trabecular meshwork and the Methods: We reviewed the medical records of 116 consec- utive patients with primary open angle, secondary, or de- Schlemm canal has been limited, except for pilocarpine velopmental glaucoma. The pre- and post-application IOP for pupillary block release, because of its insufficient up to 6 months after the initiation of ripasudil application IOP-lowering ability. As the Ocular Hypertension Treat- was compared after adjusted by the last observation carried ment Study revealed, more than 2 agents with different forward method. Multivariate analyses were used to identi- IOP-lowering mechanisms are often required for many fy factors that could account for the IOP-lowering effect of ripasudil. The reasons for discontinuation were evaluated. patients with glaucoma to achieve their target IOP [2]. However, it has been practically impossible thus far to Results: The median pre- and post-application IOP at 1, 3, and 6 months was 19.0, 17.5, 17.0, and 16.0 mmHg, respec- combine medications of enhanced conventional out- tively. IOP was significantly reduced after ripasudil application flow with other anti-glaucoma eyedrops that enhance at all time points (P < 0.00001, the mixed effect model). The the conventional outflow for long-term IOP control be- pre-application IOP and glaucoma type were associated with cause of the lack of an appropriate agent. the IOP-lowering effect of ripasudil. Twenty-seven and 8 pa- tients discontinued the application because of unsatisfactory Ripasudil hydrochloride hydrate, the newly devel- IOP reduction and intolerable side effects, respectively. oped rho-associated coiled-coil forming kinase (ROCK) Conclusion: Ripasudil reduced IOP in some patients with inhibitor, has been available in Japan since December multiple ocular hypotensives but was discontinued in a frac- 2014, and it reduces IOP by enhancing conventional tion of patients due to unsatisfactory IOP reduction and in- aqueous humor outflow via changes in the morphology tolerable side effects. of trabecular meshwork cells, inhibition of extracellular matrix production, and increased juxta-Schlemm canal Introduction permeability [3-6]. Clinical trials demonstrated that ri- Reduction of intraocular pressure (IOP) is the sole- pasudil eyedrops at 0.4% concentration significantly ly established, interventional treatment modality for lowered IOP in normal subjects [7] and in patients with glaucoma and is often medically manipulated irrespec- primary open angle glaucoma (POAG) and ocular hyper- tive of glaucoma type [1]. Ocular hypotensive eyedrops tension [8-10]. However, the clinical trials evaluated the Citation: Kawara K, Kanamori A, Mori S, Inoue Y, Kurimoto T, et al. (2018) Intraocular Pressure-Low- ering Effect of Ripasudil Hydrochloride Hydrate and Reasons for Discontinuation of Use in Clinical Practice. Int J Ophthalmol Clin Res 5:083. doi.org/10.23937/2378-346X/1410083 Received: November 21, 2017: Accepted: January 24, 2018: Published: January 26, 2018 Copyright: © 2018 Kawara K, 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. Kawara et al. Int J Ophthalmol Clin Res 2018, 5:083 • Page 1 of 8 • DOI: 10.23937/2378-346X/1410083 ISSN: 2378-346X additive effect of ripasudil only in patients with latano- intraocular inflammation, and local or systemic steroid prost or 0.5% timolol [11] and did not test the efficacy of administration. However, patients who had changed ripasudil in patients with secondary and developmental the regimen or content, if any, of the steroid therapy glaucoma. Furthermore, given the relatively short-term between 3 months prior to and 6 months after the ini- reaction time of ripasudil, the clinical trials measured tiation of ripasudil medication were excluded from the IOP twice per visit, that is, peak IOP measured 2 hours study entry, because such changes may have influenced after instillation and trough IOP measured just before the IOP control. The presence of glaucomatous optic instillation, which were analyzed separately [7-11]. nerve changes was not used as a criterion in this group. However, it is not practical to measure IOP twice a day Inclusion criterion for analysis was an eye with high- or schedule the interval between ripasudil instillation er IOP in patients who bilaterally received ripasudil or and IOP measurement for many patients in actual clini- in the right eye in patients whose IOP was the same cal practice. There are few studies evaluating the over- in both eyes. In other words, 1 eye per patient was in- all IOP-lowering effect of ripasudil eyedrops in such a cluded in the analysis. Exclusion criteria were eyes that situation. (1) underwent laser or intraocular surgeries within 6 The purpose of this study was to evaluate the ad- months before the start of ripasudil treatment and (2) ditive or switching effect of ripasudil in terms of over- could not have IOP measured by the Goldmann appla- all IOP reduction in Japanese patients with a variety of nation tonometer. glaucoma types and previously receiving at least 2 un- Full ophthalmic examinations were conducted in all specified anti-glaucoma medications, as well as the -rea 116 patients within 3 months before the initiation of sons for discontinuation in such patients [12]. ripasudil, which included best-corrected decimal visual Patients and Methods acuity, slit-lamp biomicroscopy, anterior chamber angle examination, stereo-fundoscopy under pupillary dila- Subjects tion, and central corneal thickness measurement using This is a retrospective case series. The study proto- a specular microscope (Noncon Robo SP-8000; Konan col was approved by the institutional review board of Medical, Tokyo, Japan). The average IOP calculated Kobe University (No. 270023; UMIN000025466), and from 2 measurements immediately before initiation of adhered to the tenets of the Declaration of Helsinki. We ripasudil medication was defined as the premedication obtained oral consent from all patients, or from legal IOP, whereas the single IOP measurement per visit at 1, guardians for patients under 20 years of age, after the 3, and 6 months was the post-medication IOP at each study purpose and design were fully explained and not- visit. The premedication prescription score was calcu- ed on the medical records. lated as 1 for any anti-glaucoma eyedrops and 2 for oral CAI. We reviewed the medical records of 116 consecutive glaucoma patients who were not under their own target Data analysis IOP, despite using at least 2 preexisting anti-glaucoma medications, met the inclusion and exclusion criteria Continuous variables were expressed as means ± SDs described below, and received ripasudil for the first if they followed the Gaussian distribution or medians time during December 2014, when ripasudil was on the (interquartile ranges) if they did not. market, and November 2015 in the outpatient clinic Pre-medication IOP and IOP measured at 1, 3, and 6 section of the Kobe University hospital. There was no months after initiation of ripasudil per patient were com- restriction based on patient age, glaucoma type, num- pared using the mixed effect model in two ways. First, the ber of anti-glaucoma medications, or intervals between comparisons were made among IOP data collected from ripasudil instillation and IOP measurement, in the initia- patients who completed follow up until 6 months after ini- tion of the ripasudil medication. tiation of ripasudil application. Second, the comparisons Patients with normal tension glaucoma were includ- were made among IOP data adjusted by the last observa- ed into those with POAG. Patients were defined as hav- tion carried forward (LOCF) method [13]. In other words, ing developmental glaucoma if they had the onset of missing data from patients who discontinued the ripasudil disease under 18 years of age, a history of elevated IOP medication by 6 months after ripasudil application were imputed with the LOCF method. exceeding 21 mmHg, if necessary, under general anes- thesia, abnormal corneal signs such as opacity, enlarge- Intergroup comparisons for continuous variables ment of diameter, and the presence of Haab’s striae in were made using an unpaired t-test or one-way analysis the case of children under 3 years, or glaucomatous op- of variance (ANOVA), followed by the Tukey-Kramer test tic nerve and visual field changes similar to POAG in the as a post hoc test, if they followed the Gaussian distri- case of older children. Patients were defined as having bution, and by Mann-Whitney U-test or Kruskal-Wallis secondary glaucoma if they had elevated IOP exceeding test if they did not follow the Gaussian distribution.
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