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Noriko Koizumi, Naoki Okumura, Yugo Okazaki, Ryota Inoue, Shinichiro Nakano, Hideki Suganami, Nigel J Fullwood, Hiroko Nakagawa, Shigeru Kinoshita; Effect of rho-associated kinase inhibitor eye drop (ripasudil) on morphology of corneal endothelial cells in humans and rabbits. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5299.
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© ARVO (1962-2015); The Authors (2016-present)
Ripasudil (GLANATEC®; Kowa Co.), a selective rho-associated coiled coil-containing protein kinase (ROCK) inhibitor, was approved in Japan in 2014 for the treatment of glaucoma and ocular hypertension. Morphological changes in the corneal endothelium following instillation of ripasudil in cynomolgus monkeys were reported, but the reasons for these changes are not yet well elucidated. The purpose of this study was to investigate the effect of ripasudil eye drops on human corneal endothelial morphology and to perform histological evaluation in an animal model.
Six healthy human subjects were administered 0.4% ripasudil twice daily for 1 week. Morphological changes and corneal endothelial cell density were examined by specular microscopy, and central corneal thickness and corneal volume were analyzed by PentacamTM. Ripasudil was also applied in rabbit eyes, and the anterior segment was evaluated, as with the human eyes. In addition, corneal endothelium was evaluated by phalloidin staining and transmission electron microscopy (TEM).
In the human subjects, specular microscopy revealed an indistinct cell border after 1 hour of treatment, yet it recovered to normal by 6 hours. A guttae-like appearance of the cornea was observed by slit-lamp microscopy after 1-3 hours, and resolved within 24 hours. Corneal endothelial cell density, central corneal thickness, and corneal volume were unchanged after 7-days administration. In the rabbits, an indistinct cell border, similar to that in the human subjects, was observed. Phalloidin staining showed distribution of actin fibers at the cell cortex, and no obvious differences were observed throughout 24-hours post administration. TEM revealed the formation of protrusions at the cell border of the corneal endothelium at 1 hour, yet it reverted to the control level within 24 hours. Tight junctions, adherence junctions, and gap junctions were present, even at 1 hour when specular microscopy revealed indistinct cell borders.
Ripasudil transiently induces guttae-like findings in humans, likely due to protrusion formation along intracellular borders caused by the reduction of actomyosin contractility of corneal endothelial cells. Physicians should note that ROCK inhibitors can cause these guttae-like findings in order to avoid misdiagnosing patients as having corneal endothelial disease.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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