Ocular toxicologic properties of Y-39983 were evaluated in rabbits and monkeys. In the QID study, performed to test severe conditions, 100 μL of Y-39983 (0.003%–0.03%) or saline as a control was topically administered to both eyes of the rabbits at 2-hour intervals for 4 weeks (n = 5). In addition, 50 μL of Y-39983 (0.003%–0.05%) or its vehicle was topically administered four times a day at 2-hour intervals for 26 weeks (n = 8). In slit lamp examinations, the cornea (epithelial defects revealed by fluorescein biostaining, opacity, and neovascularization), conjunctiva (hyperemia, swelling), anterior chamber (flare), and iris (hyperemia, swelling) were observed. The lens, vitreous, and retina were observed in eyes under mydriasis, with a slit lamp and binocular indirect ophthalmoscope. Tear quantity was measured by phenol red thread (Zonequick; Menicon, Nagoya, Japan). The electroretinogram (ERG) was measured to evaluate retinal safety. In darkness and under mydriasis with systemic anesthetization, a contact lens-type electrode was fitted to the eye. Results of light stimulation and the ERG were recorded using a veterinary ERG system. Amplitudes of the a- and b-waves and the peak latency were determined. In addition, histologic examination was performed by the usual method after the last observation. The tissues observed were the eye including the palpebral and bulbar conjunctiva, and optic nerve, lacrimal glands, internal organs including the liver, gallbladder, kidneys, spleen, heart, aorta, gullet, stomach, intestines, lungs, and bronchial tube, sex organs, brain, bone, muscle, skin, and other tissues.
In addition, to investigate the safety of Y-39983 at various frequencies of administration, the drug was administered two and three times a day (BID and TID) to rabbits and monkeys. In rabbits in the BID study, 0.05% or 0.1% Y-39983 or saline was topically administered to both eyes twice daily (with a 6-hour interval) for 4 weeks (n = 3). In rabbits in the TID study, 0.1% Y-39983 or saline was topically administered three times a day at 5-hour intervals for 2 weeks (n = 5). In monkeys in the BID study, 0.05%, 0.1%, or 0.2% Y-39983 or saline was topically administered twice daily at a 6-hour interval for 4 weeks (n = 3). Ocular tissues were observed in the same fashion as for administration four times a day.