Safety threshold of intravitreal activated protein-C

Although activated protein C (APC) is effective in preventing the death of retinal neurons in ischemic retinopathy, it is not known at what concentrations it becomes retinotoxic. The purpose of this study was to determine the concentrations of intravitreal APC that are safe and those that are toxic for the retina, using rabbit eyes. The left eyes of 12 rabbits received an intravitreal injection of 1.5 to 150 mu g of APC in 0.1 ml of saline. The fellow eyes were treated with an intravitreal injection of the same amount of saline. Slit-lamp examination, fundus examination, fluorescein angiography (FA), and electroretinograms (ERGs) were performed before and at different times after the injection. The eyes were enucleated at 6 months after the injection and examined histologically. The clinical and histological differences between the control eyes and the eyes that had APC injections up to 15 mu g were not significant. Localized retinal edema was observed in two of three eyes with 150 mu g of APC immediately after the injection. In these two eyes, chorioretinal atrophy was observed in the area of the retinal edema at 6 months, which corresponded with a hyperfluorescent area in the FA images and focal retinal degeneration histologically. No significant changes were detected in the full-field ERGs in the eyes treated even with 150 mu g of APC throughout the observation period. Our results show that an intravitreal injection of APC at a dose a parts per thousand currency sign15 mu g is safe, but 150 mu g of APC can be toxic to the retina.