Abstract
Purpose: :
To assess the ocular toxicity potential of a potent EP4 agonist when administered topically to the canine eye daily for one week.
Methods: :
Beagle dogs were administered vehicle or 0.01, 0.05 or 0.1 mg/ml of an EP4 agonist topically for 7 days. Ophthalmic examinations were performed using a slit lamp and indirect ophthalmoscopy. On day 7 or day 15, eyes were fixed in 6% glutaraldehyde, processed to slides and stained with H&E or immunohistochemically for EP4 for histologic evaluation
Results: :
Dogs dosed topically with ≥ 0.01 mg/ml of an EP4 agonist for 7 days developed a dose-related ocular irritation reaction that included conjunctival redness, increased conjunctival vasculature and eye squinting. The irritation reaction started to subside 3 hours postdose for the first two days. After 2 days of treatment, the conjunctiva vasculature persisted, indicating an accumulation of the irritancy response. In dogs given ≥ 0.05 mg/ml, increased conjunctival redness and vasculature correlated with a dose-related corneal neovascularization near the limbus. Corneal neovascularization was confirmed histologically in dogs given 0.1 mg/ml on day 7 and in dogs given 0.05 mg/ml after a 7 day recovery period on day 15. No corneal neovascularization was observed in dogs given 0.01 mg/ml on day 7. At the 0.1 mg/ml dose level, neovascularization was accompanied by apoptotic cells in the corneal epithelium, neutrophilic infiltrates in the corneal stroma, and plasma cells and lymphocytes in the trabecular meshwork. Immunohistochemistry revealed an increase EP4 expression in the cornea that was dose-related in dogs given ≥ 0.05 mg/ml. EP4 staining was detected primarily in the corneal stromal cells near the limbus and in the neovascular endothelial cells. EP4 staining was also observed in infiltrating neutrophils, corneal epithelium, corneal endothelium, trabecular meshwork, conjunctival vessels, and retina.
Conclusions: :
Conjunctival redness, eye squinting, corneal neovascularization, and EP4 staining of corneal stromal cells and neovascular endothelium were dose-related in dogs given ≥ 0.05 mg/ml of an EP4-agonist for 7 days. Corneal neovascularization persisted for at least 1 week after the dosing period.
Keywords: drug toxicity/drug effects • cornea: stroma and keratocytes • pathobiology