Search

To evaluate the intraocular pressure (IOP)-reducing efficacy and safety of Rho-kinase inhibitor (RKI). Published studies in PubMed and EMBASE were searched on March 20, 2021. Study selection and data extraction were performed according to PRISMA. Meta-analysis of the IOP-lowering effect was performed with the bivariate random-effects model, with studies categorized into 2 classes: RKI versus placebo and RKI versus another medication. The main outcome was the difference in IOP reduction between RKI and non-RKI groups. Subgroup analysis of adjunctive RKI efficacy and additional review of its major ocular adverse events (AE) were also performed. Ten (2.6%) out of 391 studies were retrieved. In the RKI versus placebo class, RKI showed greater IOP reduction after 4–8 weeks (mean difference = − 1.69 mmHg [− 2.22, − 1.16], P

Medical management remains the cornerstone of glaucoma management despite advances in the surgical or laser procedures. After a leap of almost two decades of the advent of prostaglandin analogues, recently a new class of drug, Rho kinase (ROCK) inhibitors, has come to limelight because of their varied therapeutic potential in different clinical conditions of eye, especially glaucoma. Their efficacy of lowering intraocular pressure (IOP) by virtue of an entirely different mechanism of decreasing outflow resistance has ignited a series of clinical trials evaluating their potential as monotherapy or as adjunct to existing antiglaucoma medications, and three of them ripasudil, netarsudil and roclatan have even been approved for clinical use in the recent past. There are evidences suggesting their beneficial effects in glaucoma patients even via non-IOP-dependent mechanisms like neuroprotection by improving blood flow to the optic nerve and increasing ganglion cell survival. They can even act as antifibrotic agents and reduce bleb scarring after glaucoma surgery. Hence, their effective role in glaucomatous optic neuropathy is multifaceted primary being improved drainage through the conventional pathway. On the other hand, certain local adverse effects like conjunctival hyperaemia have been reported in substantial proportion of patients, while some others like blepharitis, subconjunctival haemorrhages and cornea verticillata constitute less common side effects. The purpose of this review is to summarize the discovery, evolution and recent update of clinical trials on Rho kinase inhibitors as antiglaucoma medicine and to delineate their role in existing management protocol.

PurposeThe purpose of this study was to evaluate the tolerability and efficacy of topical rho-kinase inhibitor ripasudil in the treatment of primary corneal endothelial degeneration (PCED) in dogs.MethodsTwenty-one eyes of 12 client-owned, PCED-affected dogs received topical ripasudil 4 times daily. Ophthalmic examination, ultrasonic pachymetry (USP), Fourier-domain optical coherence tomography (FD-OCT), and in vivo confocal microscopy were performed at baseline and 1, 3, 6, and 12 months. Effects of treatment on corneal thickness, corneal edema extent, and endothelial cell density (ECD) were evaluated by repeated-measures ANOVA or Friedman test. Individual eyes were classified as improved, progressed, or stable at 12 months using clinical response criteria. Kaplan-Meier curves and log-rank test were used to compare ripasudil-treated eyes to age-, breed/size-, and disease stage-matched historical controls.ResultsDuring treatment, 12 dogs developed conjunctival hyperemia, 4 demonstrated reticular bullous epithelial edema, and 2 developed corneal stromal hemorrhage. No adverse event necessitated permanent cessation of ripasudil. Central corneal thickness measured by USP significantly progressed from baseline to 12 months. Corneal thickness by FD-OCT, ECD, and edema extent did not differ over time. Considered individually, 5 eyes improved, 8 remained stable, and 8 progressed. The log-rank test found less edema progression in ripasudil-treated eyes compared to historical controls.ConclusionsRipasudil was well-tolerated in PCED-affected dogs. Response to therapy varied; 62% of eyes showed improved or stable disease whereas 38% progressed. Ripasudil-treated eyes progressed more slowly than historical controls.Translational relevanceTopical ripasudil offered a therapeutic benefit in a subset of patients using a canine model of endothelial degeneration, which may guide future trials in humans.

Background: Glaucoma is a progressive, irreversible optic neuropathy that results in serious vision loss and blindness. This review aimed to summarize key concepts of primary open angle glaucoma (POAG) pharmaceutical treatment trials over the last decade. Methods: We searched PubMed/MEDLINE and clinicaltrials.gov from January 1, 2010, to August 31, 2020, using the key words “POAG” and “Ocular topical therapeutics”. This search yielded 77 and 120 papers, respectively. Results: Thirty-three records were compatible with our inclusion criteria. Pharmaceutical treatment is a common intervention in POAG for lowering IOP. Prostaglandin (PG) analogues are most commonly recommended as initial medical therapy, which are administrated either as a monotherapy or in combination with other IOP-lowering classes of medications. Alternative therapies, such as ?-blockers, ?-2 adrenergic receptor agonists, and topical carbonic anhydrase inhibitors, have been used in combination or as a monotherapy. Rho-kinase inhibitors, such as netarsudil 0.02%, AR-13324 0.02%, and ripasudil are new IOP-lowering medications. Despite IOP reduction, there is a significant number of patients with POAG that may experience disease progression, and the risk of blindness over the long term is considerable. Conclusions: Clinical trials have indicated that pharmaceutical treatment of POAG is effective and safe. In addition, the new novel Rho-kinase inhibitors have shown significant IOP reduction. The new fixed combinations have also yielded significant reductions in IOP. POAG is a cause of irreversible vision loss, if not diagnosed and treated early. The condition is likely to progress in a significant number of patients, with a considerable risk of blindness in the long-term. How to cite this article: Al-Namaeh M. Pharmaceutical treatment of primary open angle glaucoma. Med Hypothesis Discov Innov Optom. 2021 Spring; 2(1): 8-17. DOI: https://doi.org/10.51329/mehdioptometry120

Purpose Rho-associated kinase (ROCK) inhibitors have been successfully used as a rescue strategy in eyes that failed to clear after descemetorhexis without endothelial graft for treatment of Fuchs endothelial corneal dystrophy (FECD). The functional mechanisms by which ROCK inhibitors modulate corneal endothelial cell regeneration in FECD patients have, however, not been clarified. Here, we analyzed the effect of the ROCK inhibitor ripasudil on corneal endothelial cells of FECD patients and normal donors using ex vivo tissue and in vitro cellular models. Design Experimental study: laboratory investigation. Methods This institutional study used endothelial cell–Descemet membrane lamellae from FECD patients (n = 450) undergoing Descemet membrane endothelial keratoplasty (FECD ex vivo model), normal research-grade donor corneas (n = 30) after scraping off central endothelial cells (ex vivo wound healing model), normal donor corneas (n = 20) without endothelial injury, and immortalized cell lines (n = 3) generated from FECD patients (FECD in vitro model). Descemet membrane lamellae were dissected into halves and incubated for 24-72 hours in storage medium with or without a single dose of 30 μM ripasudil. The effects of ripasudil on expression of genes and proteins related to endothelial cell proliferation, migration, functionality, and endothelial-to-mesenchymal transition were analyzed and complemented by functional assays on FECD cell lines. Results A single dose of ripasudil induced significant upregulation of genes and proteins related to cell cycle progression, cell-matrix adhesion and migration, as well as endothelial barrier and pump function up to 72 hours, whereas classical markers of endothelial-to-mesenchymal transition were downregulated in both FECD and normal specimens compared to unstimulated controls ex vivo. In addition to stimulation of proliferation and migration, ripasudil-induced changes in expression of functional signature genes could be also verified in FECD cell lines in vitro. Conclusions These data support the concept that inhibition of ROCK signaling represents a potent tool in regenerative therapies in FECD patients through reactivation of cell proliferation and migration as well as restoration of endothelial pump and barrier function without inducing adverse phenotypic changes.

Purpose: To investigate the vasorelaxation effect of ripasudil (K-115), a novel Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, on isolated retinal arterioles. We determined ...

Im Jahr 2014 in Japan und 2017 in den USA wurden die Rho-Kinase-Hemmer als neue antiglaukomatose Substanzgruppe zugelassen und sollen nun auch in Europa eingefuhrt werden. Aus diesem aktuellen Anlass soll der gegenwartige Wissensstand zu den Rho-Kinase-Hemmern vorgestellt werden. In intensiver Recherche in PubMed wurde die relevante experimentelle und klinische Literatur zu den Rho-Kinase-Hemmern Ripasudil und Netarsudil sowie der Kombination aus Netarsudil und Latanoprost herausgesucht und fur diese Ubersicht zusammengestellt. Die augeninnendrucksenkende Wirksamkeit von Ripasudil und Netarsudil liegt im Bereich des Betablockers Timolol und dem Prostaglandinanalogon Latanoprost. In der fixen Kombination Netarsudil/Latanoprost ist die Augeninnendrucksenkung starker als die der Einzelkomponenten und erreicht in 32 % einen Zieldruckbereich von unter 15 mm Hg. Die konjunktivale Hyperamie mit 53–65 % ist die haufigste lokale Nebenwirkung. Systemische Nebenwirkungen sind sehr selten, und Kontraindikationen liegen bisher nicht vor. Rho-Kinase-Hemmer sind eine interessante Neueinfuhrung fur die Glaukomtherapie, da jede neue drucksenkende Therapie eine zusatzliche Chance darstellt, das individuell festgelegte Zieldruckniveau bei einem Glaukompatienten mit einer lokalen Therapie zu erreichen. Allerdings sind viele der mit den Rho-Kinase-Hemmern assoziierten pleiotropen Effekte bisher nur experimentell gefunden worden und bedurfen in Zukunft klinischer Bestatigung.

Corneal allograft survival is mediated by the variety of immunological reactions and wound healing process. Our aim was to explore the effects of topical administration of ripasudil, a selective Rho-associated coiled-coil protein kinase inhibitor, on corneal allograft survival. Ripasudil was administered to mice thrice a day after allogeneic corneal transplantation. Corneal graft survival, opacity, neovascularization, re-epithelization, immune cell infiltration, and mRNA levels of angiogenic and pro-inflammatory factors in the grafted cornea and draining lymph nodes (dLNs) were evaluated with slit-lamp microscopy, immunohistochemistry, flow cytometry, and polymerase chain reaction. Graft survival was significantly prolonged with lower graft opacity and neovascularization scores in 0.4% and 2.0% ripasudil-treated groups, and mRNA levels of angiogenic and pro-inflammatory factors in ripasudil-treated grafted corneas were reduced. Moreover, 0.4% and 2.0% ripasudil reduced CD45+-infiltrated leukocyte frequency, Cd11b and Cd11c mRNA levels, and the frequencies of mature dendritic cells, IFNγ-, and IL-17- producing CD4+T cells in the dLNs of recipients. Re-epithelization rate of the grafted cornea was significantly higher in the 0.4% and 2.0% ripasudil groups than in the control. Topically applied ripasudil prolonged graft survival by downregulating neovascularization and inflammation factors, while promoting corneal re-epithelization, suggesting that ripasudil may be useful for suppressing immunological rejection in corneal transplantation.

Purpose: To evaluate efficacy and safety of ripasudil for 1 year in addition to or replacing existing treatment regimens. Methods: We retrospectively reviewed the medical records for 128 eyes of 12...

This is the first reported case of a successful resolution of cystic-like foveal cavities in eyes with X-linked juvenile retinoschisis (XLRS) treated with topical ripasudil hydrochloride hydrate, a Rho-associated coiled/coil-containing protein kinase (ROCK) inhibitor. A chart review was performed on 1 patient to collect all relevant clinical information and the optical coherence tomographic (OCT) images. A healthy 18-year-old young man presented with bilateral visual disturbances. The patient was diagnosed with XLRS from the spoke-wheel pattern around the macula, negative electroretinograms, and retinoschisis with cystic-like foveal cavities in the OCT images. Significant reductions of the retinoschisis and cystic-like cavities were observed after treatment with topical ripasudil. This is the first case of XLRS that had a resolution of cystic-like foveal cavities after topical ripasudil, a ROCK inhibitor. Since many XLRS patients have a worsening of their visual acuities due to the progressive nature of retinoschisis and cystic-like foveal cavities, topical ripasudil offers a potential treatment option.

To evaluate the efficacy and safety of ripasudil for treatment of secondary glaucoma, a historical cohort study was conducted at 18 centres in Japan. Adults (age ≥20 years) who needed additional IOP reduction and received topical 0.4% ripasudil between 2014 and 2018 due to three secondary glaucoma subtypes, including uveitic glaucoma (UG), exfoliation glaucoma (EG) or steroid-induced glaucoma (SG) were assessed for mean IOP change from baseline prior to additional treatment with ripasudil. We further evaluated the IOP change in each glaucoma subtype, baseline characteristics of each cohort, course of uveitis-induced inflammation in UG eyes, and proportion of patients in each cohort with adverse events. In 332 eyes from 332 patients eligible for this study, the mean overall IOP reductions from baseline at 1, 3, and 6 months were −5.86 ± 9.04 mmHg (−19.4 ± 25.1%), −6.18 ± 9.03 mmHg (−20.0 ± 27.1%), and −7.00 ± 8.60 mmHg (−23.4 ± 25.6%), respectively. These changes were all statistically significant. Of 332 eyes, 109 eyes had UG, 181 had EG, and 42 eyes had SG. The IOP-lowering effects of ripasudil in UG and SG were significantly greater than those of EG at every time point. This finding could have been related to higher baseline IOP levels in UG and SG. UG patients exhibited significant decreases in mean cell score of the anterior segment after ripasudil treatment. No severe adverse events were reported. These findings suggest that treatment with ripasudil is a safe and effective therapeutic modality for IOP reduction in secondary glaucoma.

Purpose: Rho-associated kinase-inhibitor ripasudil 0.4% eye drops are reportedly effective for the reduction of intraocular pressure (IOP) in glaucoma patients. However, the previous studies invest...

Reduction of intraocular pressure (IOP) is the only reliable treatment for glaucoma that maintains the patient's visual function throughout life, and IOP-lowering eyedrops are the mainstay of therapy. Ripasudil hydrochloride hydrate (brand name: Glanatec ophthalmic solution 0.4%; Kowa Company, Ltd., Japan) is a Rho-associated coiled -coil -containing protein kinase (ROCK) inhibitor that lowers IOP by increasing conventional aqueous outflow. Since the approval of ripasudil eyedrops in 2014, a large store of clinical data has been amassed in Japan. With regard to safety, conjunctival hyperemia is the most common adverse drug reaction (ADR) and is usually transient and mild. Blepharitis and allergic conjunctivitis are other major local ADRs. Systemic ADRs are rare, but we should be wary of allergic reactions. With regard to efficacy, ripasudil is expected to lower IOP in almost all glaucoma subtypes (including primary open-angle glaucoma, secondary glaucoma, and primary angle-closure glaucoma) and in all patterns of treatment initiation (monotherapy, combination therapy, switching therapy, and add-on therapy). However, the status of the trabecular meshwork may affect the IOP-lowering effect of ripasudil. In patient selection, current evidence-based information on the safety and efficacy of ripasudil should be fully considered. As irreversible damage to the trabecular meshwork would considerably affect efficacy, it may be better to start ripasudil treatment during an early stage of glaucoma.

Background/AimsTo 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.MethodsThis 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 (ResultsMorphological 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.ConclusionDue 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.

Uveitis is an inflammatory disease that accounts for 300 thousand new cases of blindness each year in America, and is responsible for 5-10% of vision changes worldwide. First-line therapy for uveitis is topical corticosteroids. Unfortunately, corticosteroid use is a risk factor for glaucoma. About 20-40% of patients experience an increase in pathological intra-ocular pressure that requires secondary glaucoma therapy. To reduce this pressure, the first therapy is beta-blockers and adrenergic agonists. But in inflammatory conditions, therapeutic side effects decrease. Over the years, a new glaucoma therapy agent, Ripasudil, has emerged. Research shows that Ripasudil can not only reduce intraocular pressure in glaucoma, but also has the anti-inflammatory effect needed to treat uveitis. The study of the potential of Ripasudil using literature obtained from the database publications of the journal Pubmed, Clinical Trials and Science Direct. Supporting articles are sought based on specific keywords by the inclusion criteria of articles won in the UK, publications of the past 10 years (except basic science), EBM articles level 1-3 and support the discussion of literature review. Ripasudil can release inflammatory cell infiltration and exudation proteins in aqueous humor. In addition, MCPI-1 protein levels and IL-1, IL-6, TNF-dan, and MCP-1 mRNA levels in the iris-ciliary body decreased after Ripasudil administration. Clinical trials also show that Ripasudil can be used as a glaucoma therapy agent. Ripasudil can be an updated therapy to treat glaucoma uveitis through inhibition of the ROCK pathway and treatment of proinflammatory mediators.

Aim: The study aims at evaluating the lowering effect of Intraocular pressure (IOP) and tolerability of Ripasudil(0.4%) ophthalmic solution, a selective rho kinase1 inhibitor, as monotherapy in newly diagnosed primary open angle glaucoma patients. Background: Glaucoma is a chronic progressive optic neuropathy causing irreversible blindness around the world. Current treatment strategy stems from concept of lowering IOP, which is a key modiable risk factor. Ripasudil also known as K 115,is the world's rst Rho-associated coiled-coil-containing protein Kinase 1(ROCK1) inhibitor that lowers IOP by directly acting on trabecular meshwork,increasing conventional outow. Methods: This prospective, interventional study included 53 patients of newly diagnosed primary open angle glaucoma.0.4% Ripasudil ophthalmic solution was instilled twice a day as the primary treatment. The primary endpoint was the degree of IOPreduction after 6 months of treatment, whereas the secondary end points were percentage of patients reaching the predened target IOP and incidence of adverse effects. Results: We examined 53 eyes of 53 primary open angle glaucoma patients. The IOP reduction (relative percentage IOP reduction)from baseline was -2.3 mm Hg(-1.7 to -2.9 mm Hg,95%condence interval ,P

Effects of a pan-ROCK-inhibitor, ripasudil (Rip), and a ROCK2 inhibitor, KD025 on dexamethasone (DEX)-treated human trabecular meshwork (HTM) cells as a model of steroid-induced glaucoma were investigated. In the presence of Rip or KD025, DEX-treated HTM cells were subjected to permeability analysis of 2D monolayer by transendothelial electrical resistance (TEER) and FITC–dextran permeability, physical properties, size and stiffness analysis (3D), and qPCR of extracellular matrix (ECM), and their modulators. DEX resulted in a significant increase in the permeability, as well as a large and stiff 3D spheroid, and those effects were inhibited by Rip. In contrast, KD025 exerted opposite effects on the physical properties (down-sizing and softening). Furthermore, DEX induced several changes of gene expressions of ECM and their modulators were also modulated differently by Rip and KD025. The present findings indicate that Rip and KD025 induced opposite effects toward 2D and 3D cell cultures of DEX-treated HTM cells.

Producción Científica, Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having become the standard therapy for DMO worldwide. However, there is no single standard therapy for all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; therefore, there is an opportunity for further improvements in the progress and applications of new drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention.

Purpose: The effects of Rho-associated coiled-coil containing protein kinase (ROCK) 1 and 2 inhibitor, ripasudil hydrochloride hydrate (Rip), ROCK2 inhibitor, KD025 or rosiglitazone (Rosi) on two-dimension (2D) and three-dimension (3D) cultured human conjunctival fibroblasts (HconF) treated by transforming growth factor (TGFβ2) were studied. Methods: Two-dimension and three-dimension cultured HconF were examined by transendothelial electrical resistance (TEER, 2D), size and stiffness (3D), and the expression of the extracellular matrix (ECM) including collagen1 (COL1), COL4 and COL6, fibronectin (FN), and α-smooth muscle actin (αSMA) by quantitative PCR (2D, 3D) in the presence of Rip, KD025 or Rosi. Results: TGFβ2 caused a significant increase in (1) the TEER values (2D) which were greatly reduced by Rosi, (2) the stiffness of the 3D organoids which were substantially reduced by Rip or KD025, and (3) TGFβ2 induced a significant up-regulation of all ECMs, except for COL6 (2D) or αSMA (3D), and down-regulation of COL6 (2D). Rosi caused a significant up-regulation of COL1, 4 and 6 (3D), and down-regulation of COL6 (2D) and αSMA (3D). Most of these TGFβ2-induced expressions in the 2D and αSMA in the 3D were substantially inhibited by KD025, but COL4 and αSMA in 2D were further enhanced by Rip. Conclusion: The findings reported herein indicate that TGFβ2 induces an increase in fibrogenetic changes on the plane and in the spatial space, and are inhibited by Rosi and ROCK inhibitors, respectively.

Mayuresh Naik,1 Monika Kapur,2 VishnuSwarup Gupta,1 HarinderSingh Sethi,3 Kartikeya Srivastava3 1Department of Ophthalmology, H.I.M.S.R & H.A.H. Centenary Hospital, New Delhi, India; 2Department of Ophthalmology, School of Medical Sciences & Research, Sharda University, Greater Noid, Uttar Pradesh, India; 3Department of Ophthalmology, V.M.M.C & Safdarjung Hospital, New Delhi, 110029, IndiaCorrespondence: Mayuresh NaikDepartment of Ophthalmology, H.I.M.S.R & H.A.H. Centenary Hospital, Room No. 3 of Eye OPD, 1st Floor of OPD Building, Near GK-2, Alaknanda, New Delhi, 110062, IndiaTel +91-8287344576Email mayureshpnaik@gmail.comPurpose: To elucidate the use of Ripasudil in patients of advanced glaucoma on maximally tolerated medical therapy who could not be offered the option of surgery due to the global pandemic lockdown.Materials and Methods: Only patients with primary open angle glaucoma (POAG), who had a cup-disc ratio (CDR) of 0.9 or a near total cupping on maximum tolerated medical therapy for at least 4 weeks and yet could not meet the target IOP were included. Target IOP was defined as ≤ 12 mm Hg. A total of 30 patients were enrolled. All patients in study cohort were started on E/D Ripasudil BD. Patients were followed up at 1 week, 2 weeks, 4 weeks and then monthly for 6 months for their best corrected visual acuity (BCVA), intraocular pressure (IOP), disc changes (slit lamp biomicroscopy), perimetry, and retinal nerve fibre layer analysis using optical coherence tomography (OCT-RNFL).Results: Mean pre-treatment IOP on five drugs was 18.3 ± 2.1 mm Hg (range 14 to 22mmHg) on maximally tolerated medical therapy. At 1 week follow-up, mean post-treatment IOP was 15.1 ± 1.7 mm Hg (range 12 to 18mmHg) and at 2 week follow-up, mean post-treatment IOP was 12.5 ± 1.9 mmHg (range 10 to 16mmHg). Thus, target IOP ≤ 12mmHg was attained in 28 patients at 2 weeks. This target IOP was maintained throughout the 6 months of follow-up period. Of the 2 patients who could not meet target IOP, 1 patient needed rearrangement of their fixed-drug-combinations to achieve target IOP at 4 weeks. The second patient required unfixing of all fixed-drug-combinations to achieve target IOP at maximally tolerated medical therapy at 6 weeks.Conclusion: Ripasudil not only provides a better IOP control but also has a high safety profile even when started as an add-on drug to already-existing yet inadequate maximally tolerated medical therapy.Keywords: advanced glaucoma, ripausdil, ROCK1 inhibitor, maximally-tolerated-medical-therapy, COVID-19 lockdown

We performed an investigation of the temporal impact on corneal endothelial cell (CEC) shape after ophthalmic instillation of one drop of the ROCK inhibitor, ripasudil. Subjects comprised 32 healthy adult volunteers, each of whom instilled ripasudil in the right eye. CEC shape [defined as CEC density (CECD), coefficient of variation (CV), and hexagonal cell rate (6A)], central corneal thickness (CCT), intraocular pressure (IOP), and conjunctival hyperemia were evaluated before instillation (baseline) and at 15 min, 1 h, 2 h, and 4–6 h after instillation by non-contact specular microscopy and slit-lamp microscopy. The incidence of pseudo gutta was also assessed. The CECD (cells/mm2) significantly decreased after instillation as follows: 2661 cells/mm2 at baseline, 2578 cells/mm2 at 15 min, 2527 cells/mm2 at 1 h, 2575 cells/mm2 at 2 h, and 2613 cells/mm2 at 4–6 h. After instillation, CV significantly increased and 6A significantly decreased. Pseudo gutta appeared in 18 subjects (56.3%) after instillation. There was no difference in CCT before and after instillation. IOP significantly decreased after instillation. The most severe conjunctival hyperemia was observed at 15 min after instillation, but had nearly disappeared within 2 h. Pseudo gutta appeared in more than half of the subjects, and the CEC shape changed upon instillation of one drop of ripasudil; however, it recovered at 4–6 h after instillation. Therefore, these changes would not greatly impact clinical treatment. Similar to the presence of conjunctival hyperemia, changes in CEC shape occur at early stages after instillation of ripasudil.

Introduction: Glaucoma is a group of progressive optic neuropathies in which elevated intraocular pressure (IOP) as a consequence of an increased aqueous humor (AH) outflow resistance, is the main and only clinically modifiable risk factor for its development and progression. Relaxing Trabecular meshwork (TM) tissue, Rho-Kinase (ROCK) inhibitors directly decrease resistance in the conventional AH outflow, thus resulting in a significant IOP-lowering effect. Areas covered: The progress made in the field of ROCK inhibitors for glaucoma treatment will be discussed, referring to the recent patent literature published mainly in the last 3 years. Development and last studies conducted on the recently approved ripasudil and netarsudil will be described, along with newly reported combinations with other antiglaucoma agents. New molecular entities as ROCK inhibitors will be reported as well as new biological approaches to affect the Rho/ROCK pathway. Expert opinion: With three drugs currently available on the market belonging to this class, ROCK inhibitors have been definitely validated as therapeutic agents for glaucoma treatment. The literature of the last 3 years confirmed the success of the soft-drug and bis-functional approaches in the design of ROCK inhibitors. However, few completely new molecular scaffolds have been reported.

We evaluated the cellular structure changes after continuous use of ripasudil hydrochloride hydrate in rabbit eyes which might affect its own efficacy and adverse effects. Two pigmented Dutch rabbits and 1 Japanese white rabbit were instilled with 0.4% ripasudil hydrochloride hydrate to the left eye twice daily. The right eye was observed as the control. Both eyes of all 3 rabbits were then enucleated for histopathologic examination by light and electron microscope at 1mo in 1 of the pigmented Dutch rabbits, 3mo in the other pigmented Dutch rabbit, and in the Japanese white rabbit after instillation. Microscopic observations showed increase intercellular space in trabecular meshwork, ciliary body, and iris stoma, increase pigmented granule number and size in iris epithelial cells, and decrease actin filament in iris muscle fiber cells. Consequently, ripasudil hydrochloride hydrate decreases the intraocular pressure by improving the conventional outflow and may also facilitate the unconventional outflow via intercellular space widening without serious side effects.

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

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.

This article reviews our current understanding of the regenerative capacity of the corneal endothelium and critically evaluates new and important research in the treatment of endothelial dysfunction. The development and application of new surgical (Descemet’s membrane stripping only), pharmacologic (rho kinase inhibitors, such as ripasudil), and injectable cell culture modalities for the treatment of endothelial dysfunction have sparked debate in the cornea world and may revolutionize future clinical practice. The exact mechanisms involved in corneal endothelial regeneration remain elusive. The latest treatment strategies for endothelial dysfunction have the potential to transform our previous perceptions of endothelial physiology by eliciting new and exciting research questions for future investigations.

To determine how the Rho kinase inhibitor, ripasudil, affects metabolic function and cell viability in donor human corneal endothelial cells (HCECs).Endothelial cell-Descemet membrane (EDM) tissues were treated with 10 μM ripasudil and assayed for mitochondrial and glycolytic activity using extracellular flux analysis and then compared to untreated controls. In addition, EDM tissues with a 24-h ripasudil treatment and control tissues were exposed to 1 μM staurosporine to induce apoptosis and then analyzed for cell viability using apoptosis and necrosis assays.Mitochondrial respiration metrics, specifically maximal respiration (P = 0.758) and spare respiratory capacity (P = 0.777), did not differ among the 1-h ripasudil treatment, 24-h treatment, and untreated tissues. Glycolytic activity assays showed an increase in glycolytic capacity at 1 h compared to the 24-h exposure group (P = 0.049) and controls (P = 0.009). Following exposure to staurosporine, the percentage of apoptotic HCECs was lower (P = 0.009) in ripasudil-treated tissues (2.473%, standard error of the mean [SEM] 0.477%) compared to untreated controls (3.349%, SEM 0.566%). In contrast, the percentage of necrotic HCECs decreased but did not differ statistically (P = 0.158) between ripasudil-treated (3.789%, SEM 0.487%) and untreated (4.567%, SEM 0.571%) tissues.Exposures to ripasudil did not result in any detectable reduction in metabolic function for HCECs in an ex vivo donor tissue model, and an increase in glycolytic activity at the 1-h time point was detected. In addition, HCECs treated with ripasudil gained a protective effect against induced apoptosis, suggesting that ripasudil may help improve the integrity of the corneal endothelium.

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.

Purpose In the field of regenerative medicine, Rho kinase inhibitors (ROCK inhibitors) show a protective effect on the corneal endothelium and promote effective healing in acute surgical wounds. In this study, we investigated the effectiveness of eyedrops containing ripasudil, a ROCK inhibitor approved in Japan for therapeutic use for glaucoma. Methods In this retrospective observational study, 13 glaucoma patients (16 eyes) were treated with 0.4% ripasudil eyedrops twice a day after cataract surgery. The control group comprised 13 patients (17 eyes). The averaged corneal endothelial cell density from one central and four paracentral points was

Introduction We aimed to evaluate the additional effects and safety of a Rho-associated protein kinase (ROCK) inhibitor, ripasudil hydrochloride hydrate, in Japanese patients with primary open-angle glaucoma (POAG) with an intraocular pressure (IOP) of at most 15 mmHg undergoing prostaglandin F2α (FP) receptor agonist monotherapy (FP monotherapy). Methods In this prospective observational study, 30 Japanese patients with POAG and IOP of at most 15 mmHg (mean age 59.4 years; 10 men) who were undergoing FP monotherapy in both eyes were administered an additional dose of ripasudil hydrochloride hydrate (GLANATEC ophthalmic solution 0.4%: ripasudil) in one eye. The following factors were investigated at 1 and 3 months after the initiation of ripasudil treatment: (1) magnitude of change in IOP between the treated and contralateral untreated eyes, (2) number of treated eyes showing 20% and 30% IOP reduction, (3) IOP difference between treated and contralateral untreated eyes, and (4) safety during the treatment period. Both (1) and (3) were analyzed using the mixed-effect model for repeated measurements. Results The treated eyes showed significant reduction in IOP at 1 month (− 1.92 mmHg, P

We examined responsiveness to ripasudil as a potential factor for predicting the effect of selective laser trabeculoplasty (SLT) when performed for primary open-angle glaucoma (POAG). A total of 70 eyes with no history of glaucoma surgery underwent SLT between January 2015 and June 2019. Patients were divided into two groups, with an intraocular pressure (IOP) decrease of 15% or more due to ripasudil administration before SLT defined as the effective group, while an IOP decrease of less than 15% was defined as the non-effective group. Kaplan–Meier survival analysis was performed. A Cox proportional hazards model assessed the influence of baseline factors on the success. Of the 70 eyes evaluated, treatments were effective in 22 and non-effective in 48. Postoperatively, both groups exhibited IOP reductions for up to 24 months. Success ratios at 12 and 24 months after SLT were 43.5% and 18.5% in the effective versus 24.9% and 9.3% in the non-effective group, which were significantly higher in the effective group (P = 0.03). Presence of a ripasudil effective eye (P = 0.03) was associated with treatment success. Responsiveness to ripasudil may be useful in predicting the therapeutic effect of SLT.

Purpose of review Rho kinase (ROCK) inhibitors are growing increasingly relevant in ophthalmology, and the goal of this review is to summarize their mechanisms of action and potential applications in the subspecialties of glaucoma, retina, and cornea. We will focus specifically on corneal endothelial wound healing, for which ROCK inhibition demonstrates particular promise. Recent findings ROCK inhibition has been shown to promote corneal endothelial cell proliferation, increase intercellular adhesion, and suppress apoptosis. Topical ROCK inhibitor treatment has exhibited potential use in Fuchs endothelial dystrophy, corneal edema from acute surgical trauma and other etiologies, and tissue engineering therapy for the endothelial disease. Ripasudil and netarsudil, the two ROCK inhibitors available for ophthalmic use, are generally very well tolerated with mild and transient local side effects. Summary ROCK inhibitors are revolutionizing the subspecialty of cornea, and further research is needed to compare long-term outcomes of ROCK inhibitor therapy to those of conventional endothelial keratoplasty, including visual acuity and endothelial cell density. Other possible avenues include the use of ROCK inhibitors to prolong corneal graft survival, and early data appears promising.

Introduction: Uveitis can directly or indirectly lead to ocular hypertension which can lead to glaucoma. Ripasudil has a different mechanism of action than other anti-glaucoma medications available commercially and in contrary to these drugs, ripasudil also has anti-inflammatory properties providing an upper edge over other intraocular pressure lowering drugs. In addition to primary glaucoma, these new Rho kinase associated inhibitors can provide satisfactory results in glaucoma with secondary pathologies. Aim: To study the role of ripasudil as first line treatment for ocular hypertension in uveitis cases. Materials and Methods: A prospective randomised study comprising 40 patients of Ocular Hypertension (OHT) associated with uveitis was conducted in the Outpatient Department (OPD) of Ophthalmology at a tertiary care hospital in North India from October 2020 to January 2021. The diagnosis of uveitis was made clinically with detailed medical history and slit lamp biomicroscopic examination. All the diagnosed patients were started with topical ripasudil hydrochloride hydrate 0.4% eye drops twice daily along with anti-inflammatory medications. Intraocular Presure (IOP) was recorded after 4 weeks and 12 weeks at 8 am, 10 am and 4 pm. Effectiveness of the drugs was calculated in terms of mmHg fall in mean intraocular pressure using t-test and p-values. Results: Out of 40 patients with uveitis associated OHT, 20caseswere inflammation related (mean age was 56.2±16.3years,13 males, 7 females) and 20 cases were categorised as corticosteroid induced (mean age was 58.9±15.69 years, 14 males, 6 females). At 12 weeks there was 5.67±0.59 mmHg fall in IOP (22.70%) in inflammation related OHT and there was 6.37±0.07 mmHg fall in IOP (25.34%) in corticosteroid related OHT. There was statistically significant fall in IOP (p-value=0.001). Conclusion: This study demonstrated that topical ripasudil hydrochloride hydrate 0.4% eye drops is effective in lowering the IOP, also there were no side effects, so it is safe and well-tolerated. So, ripasudil can provide a safe and effective alternative for lowering of IOP among uveitis related OHT.