glanatec and Fuchs--Endothelial-Dystrophy

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.. 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.. 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.

Topics: Benzoates; beta-Alanine; Fuchs' Endothelial Dystrophy; Humans; Isoquinolines; Protein Kinase Inhibitors; rho-Associated Kinases; Sulfonamides

To summarize the recent literature regarding descemetorhexis stripping without endothelial keratoplasty (DWEK), increasingly referred to as Descemet's stripping only (DSO). To report the characteristic clinical, confocal and histologic findings associated with this procedure.. Reported clearance rates following DSO range from 63 to 100% in recent series, with variation between surgical techniques. Topical Rho-kinase inhibitor has been reported as successfully salvaging failing cases. Its use as an adjuvant to the surgery is gaining widespread adoption with the results of early series now arriving. Apart from a phenotype of central guttata with clear periphery, patient characteristics which determine success remain elusive. Surgical factors affecting success are increasingly well understood, with stromal injury felt to be a retardant to healing. Characteristic clinical signs have been observed and are described herein. Clinical, confocal and light microscopic images are obtained from patients in clinical trials of DSO with ripasudil.. DSO is gaining acceptance as a surgical option for a subset of patients with Fuchs' Dystrophy. The addition of Rho-associated kinase inhibitor appears to improve predictability but further results to this effect must be published and scrutinized.

Topics: Descemet Membrane; Descemet Stripping Endothelial Keratoplasty; Endothelium, Corneal; Fuchs' Endothelial Dystrophy; Humans; Isoquinolines; rho-Associated Kinases; Sulfonamides; Visual Acuity

Fuchs corneal dystrophy (FD) is a common cause of endothelial keratoplasty. Recently, a series of FD cases treated with Descemet stripping only (DSO) demonstrated recovery of the central endothelium without transplantation of donor cells. Ripasudil, a rho kinase inhibitor, has been shown to promote corneal endothelial wound healing in animal models. This study prospectively evaluated the use of ripasudil in patients undergoing DSO for FD.. Enrolled patients underwent DSO with or without cataract surgery, performed by 1 surgeon. On the first postoperative day, patients were assigned to topical ripasudil 0.4% (Glanatec) 4 times a day for 2 months or no ripasudil and followed up monthly for the first 6 months and then at 9 and 12 months after surgery. Endothelial cell density (ECD) and pachymetry were evaluated at each postoperative visit.. Eighteen patients were enrolled, including 8 women and 1 man in each group. Overall, patients who underwent DSO with ripasudil recovered vision more quickly (4.6 vs. 6.5 weeks, P < 0.01). In addition, the ripasudil group had a statistically significantly higher average ECD at 3, 6, and 12 months. The patients in the DSO observation group had a 10% decrease in peripheral ECD when comparing counts before surgery with counts 12 months after surgery (P < 0.05). In the DSO ripasudil group, there was no significant difference between peripheral ECD at preoperative baseline versus 12 months after surgery.. DSO with topical rho kinase inhibitors may be an alternative treatment for patients with FD and a peripheral ECD greater than 1000 cells/mm.

Topics: Aged; Cell Count; Combined Modality Therapy; Descemet Stripping Endothelial Keratoplasty; Endothelium, Corneal; Female; Fuchs' Endothelial Dystrophy; Humans; Isoquinolines; Male; Prospective Studies; Protein Kinase Inhibitors; rho-Associated Kinases; Sulfonamides; Visual Acuity

Descemet´s membrane ruptures (with a discontinuation of Descemet´s membrane and double detached coiled edges) in the context of complicated anterior segment surgery have rarely been described and its management can be challenging. We report a modified Descemet stripping only (DSO) technique associated with ripasudil drops to treat these cases when other techniques fail.. We describe two cases of large Descemet´s membrane detachments associated with Descemet´s ruptures after cataract surgery that did not respond to two SF. Both cases improved significantly in unaided and best corrected visual acuity (BCVA), corneal clearance and pachymetry, avoiding the need for an endothelial keratoplasty. Endothelial cells were observed on specular microscopy within the area of the descemetorhexis.. DSO with ripasudil drops might be a valuable tool to recover corneal clearance and avoid endothelial keratoplasty in complex Descemet´s membrane detachments with ruptures that do not respond to other treatments.

Topics: Descemet Membrane; Descemet Stripping Endothelial Keratoplasty; Endothelial Cells; Endothelium, Corneal; Fuchs' Endothelial Dystrophy; Humans; Visual Acuity

The current understanding on the clinical efficacy of Rho-associated protein kinase (ROCK) inhibitor for treating Fuchs endothelial corneal dystrophy is summarized to clarify whether the "off-label" ROCK-inhibitor eye-drop application are appropriate. ROCK-inhibitor eye drops may eventually be deemed a cutting-edge therapy for Fuchs endothelial corneal dystrophy patients with acute corneal endothelial defect.

Topics: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Administration, Ophthalmic; Benzoates; beta-Alanine; Clinical Trials as Topic; Fuchs' Endothelial Dystrophy; Humans; Isoquinolines; Ophthalmic Solutions; Protein Kinase Inhibitors; rho-Associated Kinases; Sulfonamides; Treatment Outcome

To report early safety and efficacy of Descemet stripping only (DSO) supplemented with ripasudil.. A pre-post clinical trial with a historical control group for time to heal and cell count parameters. The study received ethics approval and was conducted with oversight of a data safety monitoring board. All enrolled patients had a superior endothelial cell count of >1000 cells/mm2 and were symptomatic from the presence of central guttata degrading vision and/or producing glare. DSO was carried out with a peeling technique and not combined with any other intervention. Ripasudil 0.4% was applied topically from day 1 postoperatively at a dose of 6 times/d until corneal clearance. Cases with relapse of edema were permitted to restart on ripasudil at a reduced dose of 2 drops/d for a further 2 weeks. Stopping rules with progression to a corneal graft were established. Baseline ocular and systemic investigations were carried out and repeated at varying intervals to monitor for local and systemic adverse events.. Twenty-three eyes of 23 patients met the inclusion criteria and underwent DSO. Twenty-two of 23 eyes achieved corneal clearance at a mean time of 4.1 weeks. In all patients achieving clearance, improvement in vision was recorded. Improvement in mean uncorrected visual acuity was 0.20 Logarithm of the minimum angle of resolution (LogMar), and improvement in mean best spectacle corrected visual acuity was 0.156 LogMar. One patient failed to clear and underwent Descemet membrane endothelial keratoplasty at week 12. Twenty-one of 22 patients achieving corneal clearance expressed satisfaction with the procedure. The commonest systemic side effect of topical ripasudil was gastrointestinal upset (24%), and the commonest local side effect was ocular irritation (43%). No patient experienced a serious adverse event in the course of the trial. Thirty-nine percent of patients experienced a relapse of edema on ceasing ripasudil, with clearance again on recommencing.. This trial of DSO supplemented with ripasudil included local and systemic safety analysis. We judge that this treatment option is emerging as a reliable intervention for select patients with Fuchs' Endothelial Corneal Dystrophy (FECD) with an acceptable safety profile. The observation of relapse edema is strong evidence of a drug effect. The longevity of these results remains unknown.

Topics: Administration, Ophthalmic; Aged; Aged, 80 and over; Cell Count; Combined Modality Therapy; Contrast Sensitivity; Corneal Edema; Corneal Pachymetry; Descemet Stripping Endothelial Keratoplasty; Endothelium, Corneal; Female; Fuchs' Endothelial Dystrophy; Humans; Intraocular Pressure; Isoquinolines; Male; Middle Aged; Prospective Studies; Protein Kinase Inhibitors; rho-Associated Kinases; Slit Lamp Microscopy; Sulfonamides; Treatment Outcome; Visual Acuity

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.. Experimental study: laboratory investigation.. 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.. 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.. 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.

Topics: Aged; Cell Cycle; Cell Cycle Proteins; Cell Movement; Cell Proliferation; Cell-Matrix Junctions; Cells, Cultured; Descemet Stripping Endothelial Keratoplasty; Dose-Response Relationship, Drug; Endothelium, Corneal; Female; Fuchs' Endothelial Dystrophy; Humans; Isoquinolines; Male; Middle Aged; rho-Associated Kinases; Sulfonamides

To report the safety and efficacy of descemetorhexis without grafting as a primary intervention in Fuchs dystrophy, and the use of a ROCK inhibitor, ripasudil as a salvage agent in failing cases.. Twelve eyes of 11 patients underwent central descemetorhexis not exceeding 4 mm. All had Fuchs dystrophy-producing visual symptoms, requesting intervention. Exclusion criteria were a peripheral endothelial cell count <1000 and central edema. Corneal clearance and visual parameters were recorded monthly until corneal clearance was observed, then at intervals of 6 months. Cases failing to clear by month 2 were considered for salvage treatment. This consisted of treatment with 1 of 2 formulations of Rho-associated kinase inhibitor eye drops. Endothelial keratoplasty was planned as the final salvage procedure in unsuccessful cases.. Nine of 12 eyes cleared spontaneously between 2 and 6 months. One eye failed to clear by month 5 and topical Y-27632 was administered, without success. Endothelial keratoplasty was performed. In 2 eyes, healing stalled at 3 and 2 months. In both cases, topical ripasudil administered 6 times a day for 2 weeks resulted in complete corneal clearance. In cases achieving corneal clearance, best spectacle corrected visual acuity improved from a mean of 0.26 to 0.125 (logMAR) with subjective improvement in quality of vision.. In Fuchs dystrophy with visual degradation due to central guttae, descemetorhexis without grafting is a viable procedure for visual rehabilitation. Careful patient selection is required, but the advent of topical ripasudil as a salvage agent suggests that a broader application of the surgery may be possible. Further study into the use of this agent is now needed.

Topics: Administration, Topical; Adult; Aged; Cell Count; Combined Modality Therapy; Descemet Membrane; Descemet Stripping Endothelial Keratoplasty; Female; Follow-Up Studies; Fuchs' Endothelial Dystrophy; Humans; Isoquinolines; Male; Middle Aged; Ophthalmic Solutions; Prospective Studies; Refraction, Ocular; rho-Associated Kinases; Sulfonamides; Visual Acuity

Ripasudil (Glanatec), a selective Rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved in Japan in September 2014 for the treatment of glaucoma and ocular hypertension. The purpose of this study was to investigate the effect of ripasudil eye drops on corneal endothelial morphology, as ROCK signaling is known to modulate the actin cytoskeleton.. Morphological changes in the corneal endothelium were evaluated in human subjects by specular and slit-lamp microscopy, following topical administration of ripasudil. We also used a rabbit model to evaluate the effect of ripasudil on clinical parameters of the corneal endothelium. Twenty-four hours after ripasudil application, corneal specimens were evaluated by phalloidin staining, immunohistochemical analysis, and electron microscopy.. Specular microscopy revealed morphological changes in human eyes, and slit-lamp microscopy showed guttae-like findings. The rabbit model showed morphological changes similar to those seen in human eyes after ripasudil administration. Electron microscopy demonstrated that these alterations are due to the formation of protrusions along the cell-cell borders, but this formation is transient. Expression of corneal endothelial function-related markers was not disrupted; corneal thickness and corneal volume were not changed; and no cell death was observed following ripasudil administration.. Ripasudil induces transient guttae-like findings in humans, most likely due to protrusion formation along intracellular borders caused by the reduction in actomyosin contractility of the corneal endothelial cells. No severe adverse effects were observed. Physicians should be aware that ROCK inhibitors can cause these guttae-like findings, to avoid misdiagnosing patients as having Fuchs endothelial corneal dystrophy. (www.umin.ac.jp/ctr number, UMIN000018340.).

Topics: Adult; Animals; Endothelium, Corneal; Female; Fuchs' Endothelial Dystrophy; Humans; Immunohistochemistry; Isoquinolines; Male; Microscopy, Electron; Middle Aged; Ophthalmic Solutions; Rabbits; rho-Associated Kinases; Sulfonamides