Abstract
Abstract: :
Purpose: To assess ocular hyperemia potential of selected kinase inhibitors in rabbits and guinea pigs. Methods:New Zealand albino rabbit eyes (both eyes of 5 animals per test group) were assessed grossly for hyperemia using the scoring system of Hackett and McDonald. Hartley Outbred guinea pig eyes (both eyes of 3 animals per test group) were assessed under 3x magnification using an in–house method for grading branching of the peri–limbal vasculature. Scores of 0 or 1 in both systems are considered within normal parameters. Eyes were dosed (1x30 µL for rabbits; 3x10 µL for guinea pigs) topical ocular. Hyperemia was assessed at 1, 2, 3 and 4 hours postdose. The percentage of eyes with scores ≥2 at the 1 and 2 hour time points combined and at all time points combined was calculated. This % Incidence of Hyperemia (%IH) allows for comparison of compounds and gives an indication of duration of hyperemia. Dose response was generated in both species for fasudil, H–7, Y–27632, and HMN–1152. Results: H–7, a myosin light chain kinase inhibitor, produced very little hyperemia in either rabbits (R) or guinea pigs (G) at doses up to 600 µg. The other three compounds, ROCK inhibitors, gave differential results by species with guinea pig being more sensitive. 2–hr %IH fasudil: 100% in G at 150 µg and above; 25% and 85% in R at 500 and 1000 µg respectively. 4–hr %IH fasudil: 75% and 100% in G at 150 and 300 µg; 12% and 45% in R at 500 µg and 1000 µg respectively. 2–hr %IH Y–27632: 80% to 100% in G for 30 µg through 600 µg; 0% to 75% in R for 30 µg through 1000 µg. 4–hr %IH Y–27632: 80% to 100% in G for 30 µg through 600 µg; 3% to 53% in R for 30 µg through 1000 µg. 2–hr %IH HMN–1152: 83% to 100% in G for 100 µg through 600 µg; 65% to 90% in R for 30 µg through 600 µg. 4–hr %IH HMN–1152: 54% to 88% in G for 100 µg through 600 µg; 38% to 55% in R for 30 µg through 600 µg. Conclusions: H–7, an MLCK inhibitor, elicits minimal ocular hyperemia. For the rho kinase inhibitors, the % IH is less at 4–hr than at 2–hr in both guinea pigs and rabbits. Guinea pigs are more sensitive than rabbits to the hyperemic effects of the rho kinase inhibitors. The better model to predict human response remains to be determined.
Keywords: pharmacology • drug toxicity/drug effects • intraocular pressure