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Satoshi Iraha,1–5 Yasuhiko Hirami,1,2 Sachiko Ota,1,2 Genshiro A Sunagawa,3 Michiko Mandai,1–3 Hidenobu Tanihara,5 Masayo Takahashi,1–4 Yasuo Kurimoto1,2 1Department of Ophthalmology, Institute of Biomedical Research and Innovation Hospital, 2Department of Ophthalmology, Kobe City Medical Center General Hospital, 3Laboratory for Retinal Regeneration, RIKEN Center for Developmental Biology, Kobe, 4Application Biology and Regenerative Medicine, Graduate School of Medicine, Kyoto University, Kyoto, 5Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan Purpose: The purpose of this study was to examine the efficacy and safety of valproic acid (VPA) use in patients with retinitis pigmentosa (RP).Patients and methods: This was a prospective, interventional, noncomparative case study. In total, 29 eyes from 29 patients with RP whose best-corrected visual acuities (BCVAs) in logarithm of the minimum angle of resolution (logMAR) ranged from 1.0 to 0.16 with visual fields (VFs) of ≤10° (measured using Goldmann perimeter with I4) were recruited. The patients received oral supplementation with 400 mg of VPA daily for 6 months and were followed for an additional 6 months. BCVAs, VFs (measured with the Humphrey field analyzer central 10-2 program), and subjective questionnaires were examined before, during, and after the cessation of VPA supplementation.Results: The changes in BCVA and VF showed statistically significant differences during the internal use of VPA, compared with after cessation (P=0.001). With VPA intake, BCVA in logMAR significantly improved from baseline to 6 months (P=0.006). The mean deviation value of the VF significantly improved from baseline to 1 month (P=0.001), 3 months (P=0.004), and 6 months (P=0.004). These efficacies, however, were reversed to the baseline levels after the cessation of VPA intake. There were no significant relations between the mean blood VPA concentrations of each patient and the changes in BCVA and VF. During the internal use of VPA, 15 of 29 patients answered “easier to see”, whereas blurred vision was registered in 21 of 29 patients on cessation. No systemic drug-related adverse events were observed.Conclusion: While in use, oral intake of VPA indicated a short-term benefit to patients with RP. It is necessary to examine the effect of a longer VPA supplementation in a controlled study design. Keywords: retinitis pigmentosa, valproic acid, clinical trial, retina

Takahiro Kawaji,1,2 Tomoki Sato,2 Hidenobu Tanihara11Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Chuo-ku, 2Sato Eye & Internal Medicine Clinic, Kumamoto, JapanPurpose: To report the results of sutureless scleral fixation of a posterior chamber intraocular lens (IOL) by using our developed simple technique.Methods: We retrospectively reviewed the medical records of 48 eyes of 47 patients who underwent sutureless intrascleral IOL fixation by using our modified technique. A 25-gauge microvitreoretinal knife was used to perform sclerotomies and create limbus-parallel scleral tunnels with lamellar dissection in which the haptics were fixed.Results: The IOLs were fixed and centered well. The mean follow-up period was 26.7 months. Postoperative complications included smooth vitreous hemorrhage in four eyes (8.3%), cystoid macular edema in two eyes (4.2%), and iris capture of the IOL in two eyes (4.2%). No other complications, such as breakage of the IOL, spontaneous IOL dislocation, or retinal detachment, were detected during the follow-up period.Conclusion: The lamellar dissection of the limbus-parallel scleral tunnel can simplify the forceps-assisted introduction of the haptics into the scleral tunnel, and this technique seemed to be safe.Keywords: intraocular lenses, ophthalmologic surgical procedures, intrascleral fixation, sutureless fixation

Utako Kuroda, Toshihiro Inoue, Nanako Awai-Kasaoka, Kohei Shobayashi, Sachi Kojima, Hidenobu TaniharaDepartment of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, JapanPurpose: To compare the surgical outcomes of limbal-based and fornix-based trabeculectomy in eyes with a history of ocular incisional surgery.Methods: Twenty-six eyes underwent limbal-based trabeculectomy (group LB), and were condition matched with 26 eyes that received fornix-based trabeculectomy (group FB). Surgical failure was recorded retrospectively if the intraocular pressure value was either ≥21, ≥18, and ≥15 mmHg (conditions A, B, and C, respectively) or

Sachi Kojima, Toshihiro Inoue, Takahiro Kawaji, Hidenobu TaniharaDepartment of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Chuo-ku, Kumamoto, JapanPurpose: To determine the clinical features of tear fluid signs associated with filtration blebs via three-dimensional anterior segment optical coherence tomography (3D AS-OCT).Methods: In total, 152 eyes (130 patients) with glaucoma that underwent trabeculectomy with mitomycin C were evaluated retrospectively. We investigated tear fluid signs associated with filtration blebs, using 3D AS-OCT with custom software, and compared the findings of lower tear meniscus. We also analyzed postoperative intraocular pressure and the bleb parameters of filtration blebs between eyes with and without tear fluid signs.Results: We found tear fluid signs associated with filtration blebs in 45 (30%) of 152 eyes. The mean postoperative intraocular pressure of the eyes with the tear fluid sign in a filtration bleb was significantly lower than that in eyes without the tear fluid sign (P

Akira Haga,1 Masaru Inatani,1,2 Kohei Shobayashi,1 Sachi Kojima,1 Toshihiro Inoue,1 Hidenobu Tanihara11Department of Ophthalmology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan; 2Department of Ophthalmology, Faculty of Medical Science, University of Fukui, Fukui, JapanPurpose: To evaluate the risk factors for choroidal detachment after trabeculectomy with mitomycin C (MMC).Materials and methods: We retrospectively evaluated 420 patients (420 eyes) with glaucoma who underwent trabeculectomy with MMC between June 1, 2005 and December 31, 2010 at Kumamoto University Hospital, Japan. Choroidal detachment after trabeculectomy was defined as a solid-appearing elevation of the retina and choroid. Logistic multivariable analysis was applied to determine the risk factors for choroidal detachment. The following factors were assessed: gender, age, subtypes of glaucoma, eye laterality, history of previous cataract surgery, preoperative intraocular pressure (IOP; mean of three Goldmann applanation readings recorded on different days), postoperative IOP (mean of seven Goldmann applanation readings recorded on 7 consecutive days after trabeculectomy), and postoperative laser suture lysis.Results: Of the 420 patients, 79 (18.8%) revealed choroidal detachments. The mean period between trabeculectomy and choroidal detachment was 6.1 ± 3.6 days. The mean IOP at the time of the choroidal detachment was 5.5 ± 3.6 mmHg. Age (odds ratio [OR] = 1.028/year, P = 0.0068) and postoperative IOP (OR = 0.887/mmHg, P < 0.0001) were risk factors for choroidal detachment after trabeculectomy. The subgroup analysis for eyes with open angle glaucoma (201 patients) revealed that age (OR = 1.060/year, P = 0.0040) and postoperative IOP (OR = 0.898/mmHg, P = 0.0110) were significant risk factors for choroidal detachment after trabeculectomy with MMC.Conclusion: Among glaucoma patients, older age and lower postoperative IOP are risk factors for choroidal detachment after trabeculectomy with MMC. In eyes with open angle glaucoma, older age and lower postoperative IOP are risk factors for choroidal detachment after trabeculectomy with MMC.Keywords: choroidal detachment, intraocular pressure, mitomycin C, trabeculectomy

Aims: The aim of this study was to investigate the association between normal tension glaucoma and the candidate disease locus glaucoma 1, open angle, B (GLC1B) on chromosome 2. There are many reports describing the results of association or linkage studies for primary open angle glaucoma (POAG), with GLC1B as one of the loci associated with normal or moderately elevated intraocular pressure. However, there are few reports about the association of genes or defined genomic regions with normal tension glaucoma, which is the leading type of glaucoma in Japan. The GLC1B locus is hypothesized to be a causative region for normal tension glaucoma. Methods: Genomic DNA was extracted from whole blood of normal tension glaucoma (n = 143) and healthy controls (n = 103) of Japanese origin. Results: Fifteen microsatellite markers within and/or near to the GLC1 B locus were genotyped, and their association with normal tension glaucoma was analysed. Two markers D2S2264 and D2S176 had significant positive associations. Conclusion: The D2S176 marker had the strongest significant association and it is located 24 kb from the nearest gene NCK2, which now becomes an important new candidate gene for future studies of its association with normal tension glaucoma. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the long-term efficacy and safety of ripasudil-brimonidine fixed-dose combination (RBFC), a new intraocular pressure (IOP)-lowering medication for glaucoma and ocular hypertension (OHT)., Methods: This prospective, multicentre (23 sites in Japan), open-label study enrolled patients with primary open-angle glaucoma (POAG), OHT or exfoliative glaucoma and assigned them to one of four combination therapy cohorts, based on previous treatment(s) received: prostaglandin (PG) analogue (Cohort 1); PG analogue and beta-adrenoceptor blocker (β-blocker) (Cohort 2); PG analogue, β-blocker and carbonic anhydrase inhibitor (Cohort 3); or other/no treatment (Cohort 4). After a ≥ 4-week screening period, eligible patients received twice-daily RBFC for 52 weeks in addition to the treatments they were already receiving. Efficacy was assessed by change in IOP from baseline through week 52. Adverse events and adverse drug reactions (ADRs) were monitored throughout., Results: In total, 179 patients from Cohort 1 (n = 48), Cohort 2 (n = 44), Cohort 3 (n = 41) and Cohort 4 (n = 46) entered the RBFC treatment period. For all cohorts, mean IOP was significantly reduced at 11:00 (2 h after instillation of RBFC) through week 52 with the changes from baseline at week 52 of - 2.7 to - 4.1 mmHg across cohorts; all p < 0.001. Common ADRs were conjunctival hyperaemia (58%), allergic conjunctivitis (18%) and blepharitis (17%), most of which were mild in severity., Conclusion: These data demonstrated the long-term efficacy and safety of RBFC, both alone and in combination with other anti-glaucoma agents. RBFC may offer a new treatment option for the long-term management of glaucoma and OHT., Trial Registration: Japan Registry of Clinical Trials Identifier: jRCT2080225063., Date of Registration: 17 February 2020., (© 2024. The Author(s).)

Introduction: Multidrug regimens for glaucoma treatment often result in adherence issues due to inconvenience; these issues may be improved with fixed-dose combination drugs. The ophthalmic solution of ripasudil-brimonidine fixed-dose combination (RBFC; K-232) is the first treatment combining a Rho kinase inhibitor and an α 2 -adrenoceptor agonist, and has demonstrated ability to lower intraocular pressure (IOP) and have various effects on conjunctival hyperemia and corneal endothelial cell morphology. This study evaluates the pharmacologic effects of RBFC treatment versus its separate components-ripasudil or brimonidine., Methods: This single-center, prospective, randomized, open-label, blinded endpoint study with 3 × 3 crossover design randomly assigned healthy adult men to three groups (1:1:1) to undergo consecutive 8-day administration phases (with drug-free intervals of at least 5 days). Subjects received twice-daily instillation of RBFC → ripasudil → brimonidine (group A), ripasudil → brimonidine → RBFC (group B), or brimonidine → RBFC → ripasudil (group C). Endpoints included change in IOP, severity of conjunctival hyperemia, corneal endothelial cell morphology, pupil diameter, and pharmacokinetics., Results: Eighteen subjects were assigned in total (six to each group). RBFC significantly reduced IOP from baseline at 1 h post-instillation on days 1 and 8 (12.7 vs. 9.1 and 9.0 mmHg, respectively; both P < 0.001), and provided significantly greater IOP reductions than ripasudil or brimonidine at several time points. The most common adverse drug reaction with all three treatments was mild conjunctival hyperemia, which transiently increased in severity with RBFC or ripasudil, peaking at 15 min post-instillation. In post hoc analyses, conjunctival hyperemia scores were lower with RBFC than with ripasudil at several time points. Transient morphologic changes in corneal endothelial cells occurred for up to several hours with RBFC or ripasudil, but not with brimonidine. Pupil diameter did not change with RBFC., Conclusion: RBFC significantly reduced IOP compared with each agent alone. A combination of each agent's pharmacologic profile was observed in that of RBFC., Trial Registration: Japan Registry of Clinical Trials; Registration No. jRCT2080225220., (© 2023. The Author(s).)

Purpose: To confirm the superiority of the intraocular pressure (IOP)-lowering effect of the ripasudil-brimonidine fixed-dose combination (RBFC, K-232) to ripasudil 0.4% or brimonidine 0.1% ophthalmic solution., Design: Two prospective multicenter, randomized, double- or single-masked, active-controlled, phase 3 trials., Methods: Patients with primary open-angle glaucoma or ocular hypertension whose IOP level was ≥18 mm Hg during treatment with ripasudil or brimonidine alone were randomized to 2 groups (RBFC and ripasudil) in a 1:1 ratio in the ripasudil-controlled trial and to 3 groups (RBFC, brimonidine, and ripasudil-brimonidine combination) in a 2:2:1 ratio in the brimonidine-controlled trial. The allocated study drugs were instilled twice daily for 8 weeks. The primary efficacy endpoint was the change in IOP 2 hours after instillation (11 AM) from the baseline to weeks 4, 6, and 8., Results: There were 206 patients randomized in the ripasudil-controlled trial. Changes in IOP were -2.6 and -1.2 mm Hg in the RBFC and ripasudil groups, respectively, with a difference of -1.4 mm Hg (95% CI = -1.8 to -1.0 mm Hg; P < .001). There were 282 randomized patients in the brimonidine-controlled trial. Changes in IOP were -3.4 and -1.5 mm Hg in the RBFC and brimonidine groups, respectively, with a difference of -1.8 mm Hg (95% CI = -2.3 to -1.4 mm Hg; P < .001). The most frequent adverse event was conjunctival hyperemia., Conclusions: The IOP-lowering effect of RBFC was superior to that of ripasudil or brimonidine., (Copyright © 2022. Published by Elsevier Inc.)

We investigated the aqueous humor levels of vascular endothelial growth factor (VEGF), soluble VEGF receptor (sVEGFR)1, and sVEGFR2 in glaucoma patients and the correlations among them. Aqueous humor was collected from the anterior chamber at the start of glaucoma or cataract surgery. The levels of VEGF and its receptors, sVEGFR1 and sVEGFR2, were measured using multiplex bead-based immunoassays. Aqueous humor samples were obtained from 79 participants: 21 with primary open angle glaucoma (POAG), 22 with uveitic glaucoma (UG), 19 with neovascular glaucoma (NVG), and 17 with cataracts as controls. sVEGFR1 levels were significantly higher in NVG than in the other cases (NVG, 2839.8 pg/mL, P < 0.001). The sVEGFR2 levels of glaucoma patients were significantly higher than those of the controls (POAG, 699.0 pg/mL; UG, 866.2 pg/mL; NVG, 1198.1 pg/mL; P < 0.001). In the aqueous humor of glaucoma patients, sVEGFR1 and sVEGFR2 levels were positively correlated (POAG, P = 0.0196; UG, P = 0.0047; NVG, P = 0.0050). VEGF levels were negatively correlated with both sVEGFR1 (P = 0.0197) and sVEGFR2 (P = 0.0015) in POAG patients. In UG patients, the correlation between VEGF and sVEGFR1 levels was negative (P = 0.0144). sVEGFR2 levels were increased in various glaucomatous eyes. sVEGFR levels were negatively correlated with VEGF levels in some glaucoma types, implying that sVEGFRs may modulate the effects of aqueous VEGF in glaucoma pathogenesis., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: Glaucoma is a leading cause of irreversible blindness and ripasudil was the first Rho kinase inhibitor approved as antiglaucoma medication. Here we present the final analysis of the ROCK-J study, a large-scale post-marketing surveillance study to evaluate the long-term safety and effectiveness of ripasudil in Japanese patients with glaucoma or ocular hypertension in a real-word clinical setting., Methods: ROCK-J was a 24-month, prospective, open-label, observational study that included ripasudil-naïve patients with glaucoma or ocular hypertension who were initiating treatment with ripasudil according to the Japanese approved indication between June 1, 2015 and April 30, 2017. The primary safety endpoint was the incidence of adverse drug reactions (ADRs) (including blepharitis, plus assessment of its background factors); the primary efficacy endpoint was change in intraocular pressure (IOP) from baseline to 24 months., Results: A total of 3374 Japanese patients with glaucoma or ocular hypertension were evaluated for safety and 3178 for effectiveness of ripasudil over a mean 524.5-day observational period. Overall, 853 (25.3%) patients experienced adverse drug reactions; the most common were blepharitis (8.6%), conjunctival hyperemia (8.5%), and conjunctivitis (6.3%). Multivariate analyses demonstrated that patients were more likely to experience the ADR blepharitis with ripasudil treatment if they were female (hazard ratio [HR] 1.307; p = 0.040), had comorbid or a previous history of blepharitis (HR 2.178; p = 0.001), or had a history of allergy to pollen (HR 1.645; p = 0.003) or medication (HR 2.276; p < 0.001). IOP decreased significantly from baseline with ripasudil; the least-squares mean ± standard error change in IOP from baseline to 24 months was - 2.6 ± 0.1 mmHg (p < 0.001). Significant IOP changes were seen in four types of glaucoma, namely primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, and secondary glaucoma, and ocular hypertension., Conclusion: Ripasudil was safe and effective as an antiglaucoma medication with no new safety signals identified and significant reductions in IOP maintained over 24 months of treatment., (© 2022. The Author(s).)

To identify the factors associated with the surgical outcomes of Baerveldt glaucoma implant (BGI) for open-angle glaucoma (OAG), the medical records of 51 consecutive OAG patients (age, 43-91 years) who underwent BGI were retrospectively reviewed (median follow-up, 21.7 months). Surgical success was defined as the following postoperative intraocular pressures (IOPs, mmHg): (A) 6 ≤ IOP ≤ 21; (B) 6 ≤ IOP ≤ 18; and (C) 6 ≤ IOP ≤ 15 without loss of light perception or additional glaucoma surgery. Univariate analysis showed that age (all criteria), glaucoma type (criterion C), and preoperative IOP (criteria A and B) were the candidate factors (P < 0.20). When the patients were divided into two groups according to median age (72 years), the success probability was higher in the older group for criteria B (P = 0.047) and C (P = 0.02), and the postoperative IOP was lower in the older group 1-year post-surgery (P = 0.002). Furthermore, the multivariate Cox proportional hazards model revealed that older age was independently associated with surgical success for criteria B (relative risk [RR], 0.94; P = 0.02) and C (RR, 0.94; P = 0.01). In conclusion, older age is a factor associated with the surgical success of BGI for OAG., (© 2022. The Author(s).)