glanatec and Ocular-Hypertension

Ripasudil (K-115) is a novel Rho-associated protein kinase (ROCK) inhibitor. The Rho-ROCK pathway regulates key downstream effectors involved in many cellular functions, in particular in the actin cytoskeleton activity. The clinical effects of ripasudil expected on the eye include an intraocular pressure-lowering effect and a wound-healing activity on corneal endothelial cells, but many other functions are currently under investigation. To date, ripasudil has been approved in Japan (2014) for the treatment of glaucoma and ocular hypertension, and several clinical trials are currently investigating its role in the treatment of Fuchs' corneal dystrophy. In this review, we will discuss its pharmacokinetics, pharmacodynamics and clinical efficacy, focusing also on its safety and tolerability profile.

Topics: Clinical Trials as Topic; Endothelial Cells; Glaucoma; Humans; Isoquinolines; Japan; Ocular Hypertension; rho-Associated Kinases; Sulfonamides

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 intraocular pressure (IOP) regulation. The critical discovery that pharmacologic 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 2 new ocular hypotensive agents approved for clinical use: ripasudil in Japan and netarsudil in the United States. These represent members of the first new class of clinically useful ocular hypotensive agents since the US Food and Drug Administration approval of latanoprost in 1996. The development of Rho kinase inhibitors as a class of medications to lower IOP 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 antifibrotic effect that may prove useful in conventional glaucoma surgery. Local adverse effects, however, including conjunctival hyperemia, subconjunctival hemorrhages, and cornea verticillata, are common. Development of Rho kinase inhibitors targeted to the cells of the outflow pathway and the retina may allow these agents to have even greater clinical impact. The objectives of this review are to describe the basic science underlying the development of Rho kinase inhibitors as a therapy to lower IOP and to summarize the results of the clinical studies reported to date. The neuroprotective and vasoactive properties of Rho kinase inhibitors, as well as the antifibrotic properties, of these agents are reviewed in the context of their possible role in the medical and surgical treatment of glaucoma.

Topics: Antihypertensive Agents; Aqueous Humor; Benzoates; beta-Alanine; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Ocular Hypertension; rho-Associated Kinases; Sulfonamides; Translational Research, Biomedical

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.. Two prospective multicenter, randomized, double- or single-masked, active-controlled, phase 3 trials.. 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.. 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.. The IOP-lowering effect of RBFC was superior to that of ripasudil or brimonidine.

Topics: Antihypertensive Agents; Brimonidine Tartrate; Double-Blind Method; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Ocular Hypertension; Prospective Studies; Quinoxalines; Randomized Controlled Trials as Topic; Treatment Outcome

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. 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.. 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.. RBFC significantly reduced IOP compared with each agent alone. A combination of each agent's pharmacologic profile was observed in that of RBFC.. Japan Registry of Clinical Trials; Registration No. jRCT2080225220.

Topics: Adult; Antihypertensive Agents; Brimonidine Tartrate; Endothelial Cells; Glaucoma, Open-Angle; Humans; Hyperemia; Intraocular Pressure; Male; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; Quinoxalines

A clinical trial evaluated ocular hypotensive efficacy and safety of netarsudil 0.02% once daily (QD) relative to ripasudil 0.4% twice daily (BID).. This was a single-masked, randomized, phase 3, superiority study. Japanese patients were randomized to either the netarsudil 0.02% group or the ripasudil 0.4% group in a 1:1 ratio and treated for 4 weeks. The primary efficacy variable was mean diurnal intraocular pressure (IOP) (average of diurnal time points at 09:00, 11:00, and 16:00) at Week 4.. A total of 245 patients were included in the primary analysis. At Week 4, least squares (LS) mean of diurnal IOP adjusted for baseline was 15.96 and 17.71 mmHg in the netarsudil 0.02% and ripasudil 0.4% groups, respectively, demonstrating the superiority of netarsudil 0.02% QD over ripasudil 0.4% BID by a margin of - 1.74 mmHg (p < 0.0001). Mean reduction from baseline in mean diurnal IOP at Week 4 was 4.65 and 2.98 mmHg, respectively. Adverse events (AEs) occurred less frequently in netarsudil 0.02% than in ripasudil 0.4%, with the incidence of ocular AEs being 59.8% and 66.7%, respectively. The most frequently reported AE was conjunctival hyperemia in both groups, with an incidence of 54.9% and 62.6%, respectively. No serious eye-related AEs were reported.. Netarsudil ophthalmic solution 0.02% dosed QD (p.m.) was well tolerated and more effective in reducing IOP than ripasudil ophthalmic solution 0.4% dosed BID. Netarsudil 0.02% QD may become an important option for the treatment of Japanese patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).. ClinicalTrials.gov identifier, NCT04620135.

Topics: Glaucoma, Open-Angle; Humans; Intraocular Pressure; Japan; Ocular Hypertension; rho-Associated Kinases

Glaucoma leads to irreversible blindness. Numerous anti-glaucoma eye drops have been developed. Unfortunately, many patients with glaucoma still suffer from progressive visual disorders. Recently, ripasudil hydrochloride hydrate, a selective Rho-associated protein kinase inhibitor, was launched for the treatment of glaucoma. However, adverse events, such as conjunctival hyperemia, are often noted in clinical trials using healthy subjects. Therefore, we investigated the onset, offset, and kinetic changes of conjunctival hyperemia induced by ripasudil ophthalmic solution in patients with open-angle glaucoma or ocular hypertension who had already been treated with anti-glaucoma eye drops other than ripasudil. Conjunctival hyperemia was evaluated by both clinical grading by 3 ophthalmic physicians and pixel coverage of conjunctival blood vessels determined by conjunctival hyperemia-analyzing software. Conjunctival hyperemia appeared within 10 min post-instillation in most of the participants. Clinical grade and pixel coverage increased significantly 10 min post-instillation and then decreased. In most of the participants, hyperemia resolved within 2 h. Median conjunctival hyperemia offset was 90 min. A tendency of monotonic increase was observed between clinical grade and pixel coverage. Taken altogether, hyperemia induced by ripasudil was transient in glaucoma patients who had already been treated with anti-glaucoma eye drops other than ripasudil.

Topics: Adult; Aged; Aged, 80 and over; Case-Control Studies; Conjunctival Diseases; Female; Glaucoma, Open-Angle; Humans; Hyperemia; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; Sulfonamides; Young Adult

To investigate the intra-ocular pressure (IOP)-lowering effects and safety of 0.4% ripasudil (K-115), a Rho kinase inhibitor, twice daily for 52 weeks, in patients with open-angle glaucoma or ocular hypertension (OHT).. In this multicentre, prospective, open-label study, 388 patients with primary open-angle glaucoma, OHT or exfoliation glaucoma were enrolled and 354 of them were subdivided into four cohorts (monotherapy, 173; additive therapy to prostaglandin analogs, 62; β-blockers, 60; or fixed combination drugs, 59). The IOP reduction at trough and peak from baseline and adverse events was investigated.. Ripasudil showed IOP-lowering effects over 52 weeks in all the analyses of monotherapy, additive therapy and both subgroups (baseline IOP ≥21 mmHg and <21 mmHg) of monotherapy. The mean IOP reductions at trough and peak at week 52 were -2.6 and -3.7 mmHg for monotherapy, and -1.4 and -2.4, -2.2 and -3.0, and -1.7 and -1.7 mmHg, respectively, for additive therapy described above. The most frequently observed adverse events were conjunctival hyperaemia (n = 264, 74.6%), blepharitis (n = 73, 20.6%) and allergic conjunctivitis (n = 61, 17.2%). Most of the conjunctival hyperaemia findings were mild (97.0%), transient and resolved spontaneously (78.0%). Although 51 patients discontinued from the study due to blepharitis and/or allergic conjunctivitis (blepharitis, 28; allergic conjunctivitis, 17; both, 6), all the events resolved with or without treatment after the discontinuation of ripasudil administration.. Fifty-two week administration of 0.4% ripasudil revealed IOP-lowering effects and an acceptable safety profile when administered as monotherapy or as additive therapy, in patients with open-angle glaucoma or OHT.

Topics: Adrenergic beta-Antagonists; Aged; Antihypertensive Agents; Drug Combinations; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; rho-Associated Kinases; Sulfonamides; Tonometry, Ocular

To investigate the intra-ocular pressure (IOP)-lowering effects of a selective Rho kinase inhibitor, ripasudil (K-115), over 24 hr in patients with primary open-angle glaucoma (POAG) or ocular hypertension (OHT).. In this multicenter, prospective, randomized, open-label, 3-period, Latin-square crossover clinical study, 28 patients with POAG or OHT whose IOP level was 21 mmHg or higher were subdivided into three groups. Each patient was treated with placebo and ripasudil in concentrations of 0.2 and 0.4%, at 9:00 and 21:00 on day 1 through a total of 3 periods separated by washout periods. IOP was measured at 9:00, 10:00, 11:00, 13:00, 16:00, 19:00, 21:00, 22:00 and 23:00 on day 1, and 1:00, 4:00, 7:00 and 9:00 on day 2 in sitting position using Goldmann applanation tonometer. Main outcome measure was the IOP reduction of placebo and ripasudil from baseline.. The mean IOP reduction was -5.2 mmHg for 0.2%, -6.4 mmHg for 0.4% and -2.0 mmHg for placebo at 2 hr after the first instillation. Also, the corresponding values were -6.8 mmHg for 0.2%, -7.3 mmHg for 0.4% and -4.1 mmHg for placebo at 2 hr after the second instillation. Statistically significant IOP reduction, compared with placebo, was found for both 0.2 and 0.4% from 1 through 7 hr after each instillation. In safety, conjunctival hyperaemia was observed in 22 patients (79%) for 0.2%, 27 patients (96%) for 0.4% and three patients (11%) for placebo.. Ripasudil is a promising new topical medication to lower IOP for at least 7 hr after instillations in patients with POAG or OHT.

Topics: Adult; Circadian Rhythm; Cross-Over Studies; Enzyme Inhibitors; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Prospective Studies; rho-Associated Kinases; Sulfonamides; Tonometry, Ocular

Ripasudil hydrochloride hydrate (K-115), a novel rho kinase inhibitor, provides statistically significant intraocular pressure (IOP)-lowering effects and has a tolerable safety profile. However, no studies have evaluated ripasudil combined with β-blockers and prostaglandin analogues.. To evaluate the additive IOP-lowering effects and the safety of ripasudil, 0.4%, combined with timolol, 0.5%, or latanoprost, 0.005%, in patients with primary open-angle glaucoma or ocular hypertension.. We conducted 2, multicenter, randomized, double-masked, parallel group comparison studies of ripasudil-timolol and ripasudil-latanoprost in 29 and 36 Japanese clinical centers, respectively. Analyses were performed on an intention-treat-treat basis. After appropriate run-in periods with timolol or latanoprost, 208 and 205 patients whose IOP levels were 18 mm Hg or higher were enrolled in the ripasudil-timolol and ripasudil-latanoprost groups, respectively. Enrollment began December 1, 2011, and follow-up was completed on September 7, 2012, in the ripasudil-timolol study. Enrollment began December 1, 2011, and follow-up was completed on September 27, 2012, in the ripasudil-latanoprost study.. Patients were subdivided into 2 groups in each study and were treated with ripasudil or placebo twice daily for 8 weeks.. The IOP reductions in the ripasudil and placebo groups were analyzed with a repeated-measures analysis of variance model at weeks 4, 6, and 8, at trough (before instillation [9 am]) and peak (2 hours after instillation [11 am]) levels.. In the ripasudil-timolol study, the mean IOP reductions from baseline in the ripasudil and placebo groups were -2.4 and -1.5 mm Hg at 9 am for a difference of 0.9 mm Hg (95% CI, 0.4-1.3 mm Hg; P < .001) and -2.9 and -1.3 mm Hg at 11 am for a difference of 1.6 mm Hg (95% CI, 1.1-2.1 mm Hg; P < .001), respectively. In the ripasudil-latanoprost study, those IOP reductions were -2.2 and -1.8 mm Hg at 9 am for a difference of 0.4 mm Hg (95% CI, -0.0 to 0.9 mm Hg; P = .06) and -3.2 and -1.8 mm Hg at 11 am for a difference of 1.4 mm Hg (95% CI, 0.9-1.9 mm Hg; P < .001), respectively. The most frequently reported adverse event was conjunctival hyperemia, which was mild and in most cases resolved without treatment before the next instillation.. These clinical trials found additive IOP-lowering effects of ripasudil from placebo at trough and peak levels in combination with timolol and at peak level in combination with latanoprost. However, a definitive difference in the addition of placebo to latanoprost was not identified in the trough level.. clinicaltrials.jp Identifiers: JAPIC111700 and JAPIC111701.

Topics: Aged; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glaucoma, Open-Angle; Humans; Isoquinolines; Japan; Latanoprost; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Prostaglandins F, Synthetic; rho-Associated Kinases; Severity of Illness Index; Sulfonamides; Time Factors; Timolol; Tonometry, Ocular; Treatment Outcome

To identify the optimal dose of a novel Rho kinase inhibitor, K-115, by assessing dose dependency of the intraocular pressure (IOP)-lowering effects and the safety in patients with primary open-angle glaucoma or ocular hypertension.. Multicenter, prospective, randomized, placebo-controlled, double-masked, parallel group comparison clinical study.. After appropriate washout periods, 210 patients with primary open-angle glaucoma or ocular hypertension were subdivided into 4 groups and were treated with K-115 in concentrations of 0.1%, 0.2%, and 0.4% or placebo twice daily for 8 weeks. The dose response of IOP reduction and the incidence of adverse events by K-115 or placebo were investigated.. The mean baseline IOP was between 23.0 and 23.4 mm Hg. The mean IOP reductions of the last visit from baseline were -2.2 mm Hg, -3.4 mm Hg, -3.2 mm Hg, and -3.5 mm Hg, respectively, in the placebo, 0.1%, 0.2%, and 0.4% groups at before instillation (9:00); -2.5 mm Hg, -3.7 mm Hg, -4.2 mm Hg, and -4.5 mm Hg at 2 hours after instillation (11:00); and -1.9 mm Hg, -3.2 mm Hg, -2.7 mm Hg, and -3.1 mm Hg at 8 hours after instillation (17:00). The dose-dependent IOP-lowering effect of K-115 was statistically significant at all time points. Also, conjunctival hyperemia was found in 7 (13.0%) of 54 patients for placebo, 23 (43.4%) of 53 patients for the 0.1% group, 31 (57.4%) of 54 patients for the 0.2% group, and 32 (65.3%) of 49 patients for the 0.4% group.. On the basis of this dose-response study, K-115 0.4% has been selected to be the optimal dose and has the potential to be a promising new agent for glaucoma to control 24-hour IOP by twice-daily dosing.

Topics: Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Inhibitors; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Prospective Studies; rho-Associated Kinases; Sulfonamides; Tonometry, Ocular

Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a new group of NO-donating ripasudil derivatives

Topics: Animals; Glaucoma; Humans; Intraocular Pressure; Isoquinolines; Mice; Nitric Oxide; Ocular Hypertension; Retinal Ganglion Cells; rho-Associated Kinases; Sulfonamides

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.. 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.. 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.. 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.

Topics: Antihypertensive Agents; Blepharitis; Drug-Related Side Effects and Adverse Reactions; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Ocular Hypertension; Ophthalmic Solutions; Prospective Studies; rho-Associated Kinases; Sulfonamides; Treatment Outcome

The purpose of this study was to develop a preclinical compound, ITRI-E-(S)4046, a dual synergistic inhibitor of myosin light chain kinase 4 (MYLK4) and Rho-related protein kinase (ROCK), for reducing intraocular pressure (IOP).. ITRI-E-(S)4046 is an amino-pyrazole derivative with physical and chemical properties suitable for ophthalmic formulation. In vitro kinase inhibition was evaluated using the Kinase-Glo Luminescent Kinase Assays. A comprehensive kinase selectivity analysis of ITRI-E-(S)4046 was performed using the KINOMEscan assay from DiscoverRx. The IOP reduction and tolerability of ITRI-E-(S)4046 were assessed in ocular normotensive rabbits, ocular normotensive non-human primates, and ocular hypertensive rabbits. In vivo studies were conducted to assess drug concentrations in ocular tissue. The adverse ocular effects of rabbit eyes were evaluated following the OECD405 guidelines.. ITRI-E-(S)4046 showed highly selective kinase inhibitory activity against ROCK1/2, MYLK4, and mitogen-activated protein kinase kinase kinase 19 (MAP3K19), with high specificity against protein kinase A, G, and C families. In ocular normotensive rabbits and non-human primates, the mean IOP reductions of 0.1% ITRI-E-(S)4046 eye drops were 29.8% and 28.5%, respectively. In hypertonic saline-induced and magnetic beads-induced ocular hypertensive rabbits, the mean IOP reductions of ITRI-E-(S)4046 0.1% eye drops were 46.9% and 22.0%, respectively. ITRI-E-(S)4046 was well tolerated with only temporary and minor signs of hyperemia.. ITRI-E-(S)4046 is a novel type of highly specific ROCK1/2 and MYLK4 inhibitor that can reduce IOP in normotensive and hypertensive animal models. It has the potential to become an effective and well-tolerated treatment for glaucoma.

Topics: Animals; Benzoates; beta-Alanine; Calcium-Binding Proteins; Disease Models, Animal; Humans; Intraocular Pressure; Isoquinolines; Macaca; Male; Myosin-Light-Chain Kinase; Ocular Hypertension; Rabbits; rho-Associated Kinases; Sulfonamides; Tonometry, Ocular

To investigate the time-dependent change of corneal endothelial cell (CEC) morphology and density (CECD) in patients with glaucoma post instillation of rho-associated protein kinase inhibitor ripasudil (Rip) 0.4% eye drops.. This observational study involved 163 eyes of 163 patients with glaucoma in whom CEC morphological change was evaluated by CECD calculated via non-contact specular microscopy (NCSM) before and at 1 or 3 months post-Rip instillation. The change of CECD was plotted along with elapsed time from last instillation of Rip. The patients were divided into the following three groups based on the elapsed time post-Rip instillation: Early Group (<2 hours), Middle Group (≥2 hours, yet <6 hours) and Late Group (≥6 hours). The rate of CECD change was then analysed and compared among the three groups. An additional eight eyes of four patients with glaucoma were enrolled for a time-dependent study, with NCSM images evaluated before and at 1, 2, 3, 4 and 6 hours post-Rip instillation.. Morphological changes in the CECs appeared within 1 hour and recovered to normal within 6 hours post instillation. In the Early, Middle and Late Group, the median rate of CECD change as calculated by the NCSM automated software was -5.68%, -4.95% and -0.07%, respectively. The CEC images showed the same morphological changes with observational study in all four cases.. Due to transient morphological changes, the NCSM software produced misleading data for determining CECD within 1 hour post-Rip instillation, yet revealed that CEC morphology gradually recovered to normal within 6 hours.

Topics: Administration, Ophthalmic; Aged; Aged, 80 and over; Cell Count; Endothelium, Corneal; Enzyme Inhibitors; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Recovery of Function; Retrospective Studies; rho-Associated Kinases; Sulfonamides; Time Factors

Ripasudil is approved in Japan for glaucoma or ocular hypertension (OH) when other treatments are ineffective or cannot be administered. Its long-term safety and efficacy are being examined in a post-marketing surveillance study; 12-month data are described here.. This prospective, open-label, observational study enrolled patients with glaucoma or OH who started ripasudil during routine care. The key safety outcome was the incidence of adverse drug reactions (ADRs), focusing on allergy and/or inflammation-related ADRs such as blepharitis (including allergic) or conjunctivitis (including allergic). The primary efficacy endpoint was least squares mean (LSM) ± standard error (SE) change in intraocular pressure (IOP) from baseline to 12 months in all patients and in diagnostic groups. Secondary endpoints were change in IOP in groups stratified by treatment initiation pattern, number of concomitant drugs, and baseline IOP.. Overall, 3359 patients (48% male, mean age ± standard deviation [SD] 69.1 ± 12.7 years) were evaluated for safety and 3323 for efficacy. Diagnoses were primary open-angle glaucoma (43.9%), normal-tension glaucoma (36.6%), secondary glaucoma (8.7%), OH (4.2%), and primary closed-angle glaucoma (2.4%). Mean ± SD observation period was 300.1 ± 122.4 days; 1010 patients (30.1%) discontinued ripasudil by 12 months. ADRs occurred in 626 patients (18.6%); the most common were conjunctival hyperemia and blepharitis. Allergy and/or inflammation-related ADRs occurred in 388 patients (11.6%), most commonly blepharitis (5.6%) and conjunctivitis (4.2%). IOP decreased significantly from a mean ± SD 18.1 ± 6.1 mmHg at baseline; the LSM ± SE IOP change throughout 12 months of ripasudil treatment was - 2.6 ± 0.1 mmHg (- 14.0 ± 0.4%; p < 0.001). A significant decrease in IOP at 12 months was seen in all categories of baseline IOP (p < 0.001), and all types of glaucoma (p < 0.001), except neovascular glaucoma. Ripasudil was associated with a significant reduction in IOP at 12 months whether initiated as monotherapy or in combination with ≤4 concomitant glaucoma therapies (p < 0.001).. Ripasudil was safe and effective in patients with glaucoma or OH during routine care. No new safety signals were identified, and significant reductions in IOP were maintained over 12 months.

Topics: Antihypertensive Agents; Female; Glaucoma; Humans; Intraocular Pressure; Isoquinolines; Japan; Male; Ocular Hypertension; Ophthalmic Solutions; Product Surveillance, Postmarketing; Prospective Studies; rho-Associated Kinases; Sulfonamides; Treatment Outcome

Topics: Benzoates; beta-Alanine; Glaucoma; Humans; Intraocular Pressure; Isoquinolines; Ocular Hypertension; Patents as Topic; Protein Kinase Inhibitors; rho-Associated Kinases; Sulfonamides

To examine the use of ripasudil as a trabeculotomy outcome marker in patients with primary open-angle glaucoma (POAG).. Between May 2015 and December 2018, 35 eyes underwent trabeculotomy and were postoperatively followed for over 3 months. Ripasudil was defined as effective if drug administration resulted in a greater than 10% reduction in intraocular pressure (IOP). Patients were divided into effective (effective group) or non-effective (non-effective group) ripasudil administration groups. The need for additional glaucoma surgery or an IOP ≥ 21 mmHg indicated surgical failure. In both groups, a Kaplan-Meier survival-analysis was used to evaluate success probabilities related to postoperative IOP levels.. Effective IOP reduction occurred in 14 of 35 eyes after ripasudil administration, which was shown by a decrease of more than 10%. Postoperatively, both groups exhibited significant reductions of IOP and antiglaucoma medication use for up to 24 months. At 12 and 24 months after trabeculotomy, probabilities of success in the effective vs. non-effective group were 100% vs. 94.7 and 100% vs. 75.4%, respectively (P = 0.14).. Trabeculotomy is effective for achieving an IOP < 21 mmHg in ripasudil effective POAG eyes. Examination of ripasudil's IOP-lowering effects may be useful in predicting surgical outcomes after trabeculotomy.

Topics: Adult; Aged; Enzyme Inhibitors; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Kaplan-Meier Estimate; Middle Aged; Ocular Hypertension; Retrospective Studies; rho-Associated Kinases; Sulfonamides; Trabeculectomy

To evaluate the safety and intraocular pressure (IOP)-lowering effects of a ripasudil 0.4% ophthalmic solution in Japanese patients with glaucoma and ocular hypertension (OH) as a post-marketing surveillance.. This was a 2-year prospective observational study in patients with glaucoma or OH who had not previously received ripasudil. Patients registered in the study using a central internet-based system from June 1, 2015 to April 30, 2017. Data on adverse drug reactions (ADRs) and IOP were collected and analysed from the first 3 months of ripasudil treatment.. Of the 3058 patients in the safety analysis set, 3016 had IOP data and were included in the efficacy analysis. ADRs were seen in 244 (8.0%) of the 3058 patients. IOP decreased significantly in patients with primary open-angle glaucoma (- 2.9 ± 4.2 mmHg; p < 0.001), normal tension glaucoma (- 1.7 ± 2.4 mmHg; p < 0.001), primary angle-closure glaucoma (- 3.9 ± 5.3 mmHg; p < 0.001), and OH (- 3.8 ± 5.8 mmHg; p < 0.001). Significant IOP reduction was also noted in exfoliation glaucoma (- 3.0 ± 5.5 mmHg; p < 0.001), uveitis-associated glaucoma (- 4.7 ± 7.2 mmHg; p < 0.001) and steroid glaucoma (- 5.5 ± 6.0 mmHg; p < 0.001), but not for neovascular glaucoma (- 2.8 ± 12.1 mmHg; p = 0.669).. Ripasudil was safe and effective in the treatment of glaucoma and OH in Japanese patients, with a low incidence of ADRs or treatment discontinuation, and reduced IOP after 3 months of treatment.. Kowa Company, Ltd., Tokyo, Japan.

Topics: Aged; Dose-Response Relationship, Drug; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Incidence; Intraocular Pressure; Isoquinolines; Japan; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Product Surveillance, Postmarketing; Prospective Studies; Sulfonamides; Tonometry, Ocular; Treatment Outcome

The current study aimed to address whether ripasudil, a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor developed to treat glaucoma and ocular hypertension (OH), improves diabetic macular edema (DME) since it is known that ROCK upregulates vascular endothelial growth factor. We retrospectively investigated the foveal thickness (FT) measured by spectral-domain optical coherence tomography, visual acuity (VA), and intraocular pressure (IOP) in 12 eyes with DME that received ripasudil treatment for primary open-angle glaucoma or OH and compared them with 14 eyes that received no treatment. One month after ripasudil therapy, the mean FT decreased significantly from 439 ± 72 µm to 395 ± 62 µm (P = 0.003); this change was significantly different from that in the controls, in which the mean FT increased by 1 ± 39 µm (P = 0.01). Ripasudil also caused a significant decrease in IOP from 17.3 ± 5.2 mmHg to 14.6 ± 4.0 mmHg (P = 0.02); this change was significantly greater than that in the controls, in which IOP changed by 0.0 ± 1.6 mmHg (P < 0.008). There was no significant difference in the VA changes between groups. Our results suggested that ripasudil may have positive effects on both IOP and DME.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Diabetes Complications; Diabetes Mellitus; Diabetic Retinopathy; Female; Glaucoma; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Macular Edema; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Retrospective Studies; rho-Associated Kinases; Sulfonamides; Tomography, Optical Coherence; Visual Acuity

To assess the responses of the superficial peripapillary retinal vessel density (VD) and prelaminar flow index (PLFI) to topical Rho-assisted coiled-coil forming protein kinase (ROCK) inhibitor ripasudil and alpha-2 agonist brimonidine using optical coherence tomography angiography.. This is a prospective, non-randomized, comparative cohort study. We studied the response of optical coherence tomography angiography (OCTA) parameters to drugs in 24 eyes treated with ripasudil and 23 eyes treated with brimonidine at the Sensho-kai Eye Institute. After division by the signal strength (SS), we compared the responses of peripapillary VD/SS and PLFI/unit area (UA)/SS to topical eye drops in eyes with primary open-angle glaucoma (POAG) and ocular hypertension (OH).. In the superficial peripapillary retina, VD/SS increased significantly in the ripasudil-treated eyes (12.5 ± 21.7%, P = 0.018), but not in the brimonidine-treated eyes (- 2.0 ± 13.8%, P = 0.484). In the deeper area of the optic disc, the changes in the PLFI/UA/SS in the brimonidine-treated eyes (+ 0.9 ± 8.9%, P = 1.00) and ripasudil-treated eyes (- 1.3 ± 8.5%, P = 0.241) were not significant. Multivariate discriminant analysis showed that the change in the peripapillary VD/SS was the most important parameter (P = 0.0186) for differentiating ripasudil- and brimonidine-treated eyes.. The topical ROCK inhibitor ripasudil enhanced the peripapillary VD in POAG and OH, whereas the alpha-2 agonist brimonidine did not. The PLFI did not respond to either drug.

Topics: Adrenergic alpha-2 Receptor Agonists; Aged; Brimonidine Tartrate; Dose-Response Relationship, Drug; Female; Fluorescein Angiography; Follow-Up Studies; Fundus Oculi; Glaucoma, Open-Angle; Humans; Instillation, Drug; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Optic Disk; Prospective Studies; Retinal Vessels; rho-Associated Kinases; Sulfonamides; Tomography, Optical Coherence

Ripasudil accelerates aqueous humour drainage along the trabecular meshwork-Schlemm's canal route and has been approved for clinical use in Japan. We retrospectively investigated the efficacy and safety of adding ripasudil to existing treatment regimens to reduce intraocular pressure (IOP) in patients with glaucoma.. A total of 119 eyes from 119 subjects (61 men, 58 women) with primary open-angle glaucoma or ocular hypertension who had ripasudil added to their treatment regimens between December 2014 and June 2015 were included. An average of 3.8 ± 1.0 anti-glaucoma medications was in use before adding ripasudil. Subjects were divided into four groups based on the number of medications included in the original treatment regimen: ≤2, 3, 4, or ≥5 medications. The IOP was compared before and after 1 and 3 months of treatment with ripasudil for all subjects and between groups. Patients for whom ripasudil use was discontinued within 3 months were also examined.. The IOP was significantly lower in all patients after 1 month (17.5 ± 4.5 mmHg) and 3 months (16.8 ± 4.2 mmHg) of treatment than it was before (19.8 ± 5.3 mmHg, p < 0.0001). All groups were equivalent in the rate and magnitude of IOP change. Ripasudil administration was discontinued in five patients (4.2%) prior to the end of the study: three were lost to follow-up and two underwent glaucoma surgery.. Adding ripasudil to existing glaucoma treatment regimens is effective and safe in reducing IOP, regardless of the number of medications in use.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Drug Therapy, Combination; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Retrospective Studies; Sulfonamides

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.

Topics: Adrenal Cortex Hormones; Adult; Aged; Female; Humans; Inflammation; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Retrospective Studies; Sulfonamides; Visual Acuity

The purpose of the study was to evaluate the intraocular pressure (IOP)-lowering effect and tolerability of ripasudil, a rho-kinase inhibitor, in patients with glaucoma inadequately controlled with maximum medical therapy.. This prospective, noncomparative, interventional case series study included 35 patients with primary open angle glaucoma, in whom the glaucoma was poorly controlled with maximum medical therapy before starting the treatment with ripasudil. Ripasudil was instilled twice a day as adjunctive therapy to the ongoing glaucoma treatment. The primary end point was the degree of IOP reduction after 3 months of treatment, whereas the secondary end points were the percentage of patients reaching the predefined target IOP and the incidence of adverse events.. We examined 35 eyes of 35 patients with primary open angle glaucoma. The IOP reduction (relative percentage IOP reduction) from baseline was -2.8 mm Hg (-15.5%; 95% confidence interval, -1.6 to -3.9 mm Hg; P<0.001) after 3 months of treatment. The predefined target IOP was achieved in 48.5% (17/35) of the patients. The adverse events were conjunctival hyperemia (all patients), allergic conjunctivitis (2 patients), and ophthalmalgia (1 patient).. The addition of ripasudil was effective in lowering the IOP in patients with glaucoma poorly controlled with maximal medical therapy; moreover, the drug was well tolerated. In 48.5% of the patients in whom the predefined target IOP was achieved, this adjunctive therapy helped avoid glaucoma surgery at least in the short term.

Topics: Aged; Antihypertensive Agents; Drug Therapy, Combination; Enzyme Inhibitors; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Isoquinolines; Male; Maximum Tolerated Dose; Middle Aged; Ocular Hypertension; Ocular Hypotension; Prospective Studies; rho-Associated Kinases; Sulfonamides; Tonometry, Ocular

Recent clinical and experimental studies have reported favorable results when using Rho-associated kinase (ROCK) inhibitors for ocular disease, and in cell culture. Disruption of the human, nonpigmented ciliary epithelial cells (HNPCECs) that comprise the blood-aqueous barrier (BAB) induces anterior uveitis; these cells therefore provide a useful cell model of ocular disease. In this study, we examined the effects of ROCK inhibitors in anterior uveitis and in HNPCECs.. Aqueous flare values and intraocular pressures (IOPs) were determined in patients with anterior uveitis, 2 weeks after administration of ripasudil hydrochloride hydrate, a commercial ROCK inhibitor used to treat glaucoma or ocular hypertension. We also investigated the effects of Y-27632, a second ROCK inhibitor, in HNPCECs following exposure to matrix metalloproteinases (MMPs) and human tumor necrosis factor-alpha (TNF-α).. Patients with anterior uveitis, glaucoma, or ocular hypertension, referred to the Aichi Medical University from February to July 2015, were enrolled. Thirty eyes from 25 outpatients were studied. Aqueous flare values and IOPs were significantly decreased 2 weeks after ripasudil hydrochloride hydrate treatment, with no adverse events. In a cultured HNPCEC monolayer, permeability was markedly increased following exposure to MMPs-1, 3, 9, and TNF-α, with these effects attenuated by exposure to Y-27632. In cultured HNPCECs, Y-27632 provoked a marked alteration in cytoskeletal morphology without a significant change in expression levels of claudin-1 and occludin.. ROCK inhibitors may confer favorable effects in anterior uveitis, possibly due to a reorganized BAB, although the relevant mechanisms remain unclear.

Topics: Adult; Aged; Aqueous Humor; Betamethasone; Cell Culture Techniques; Cell Membrane Permeability; Cells, Cultured; Female; Glaucoma; Humans; Isoquinolines; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Protein Kinase Inhibitors; Retrospective Studies; rho-Associated Kinases; Sulfonamides; Uveitis, Anterior

Ripasudil hydrochloride hydrate (K-115), a specific Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor, was the first ophthalmic solution developed for the treatment of glaucoma and ocular hypertension in Japan. Topical administration of K-115 decreased intraocular pressure (IOP) and increased outflow facility in rabbits. This study evaluated the effect of K-115 on monkey trabecular meshwork (TM) cells and Schlemm's canal endothelial (SCE) cells. K-115 induced retraction and rounding of cell bodies as well as disruption of actin bundles in TM cells. In SCE-cell monolayer permeability studies, K-115 significantly decreased transendothelial electrical resistance (TEER) and increased the transendothelial flux of FITC-dextran. Further, K-115 disrupted cellular localization of ZO-1 expression in SCE-cell monolayers. These results indicate that K-115 decreases IOP by increasing outflow facility in association with the modulation of TM cell behavior and SCE cell permeability in association with disruption of tight junction.

Topics: Actins; Animals; Cells, Cultured; Endothelial Cells; Glaucoma; Haplorhini; Intraocular Pressure; Isoquinolines; Japan; Male; Ocular Hypertension; Ophthalmic Solutions; Rabbits; rho-Associated Kinases; Sulfonamides; Tight Junctions; Trabecular Meshwork; Zonula Occludens-1 Protein