EVALUATION OF RETINAL TOXICITY AND EFFICACY OF THE ANTICYTOMEGALOVIRUS COMPOUND 2-AMINO-7-[(1,3-DIHYDROXY-2-PROPOXY)METHYL]PURINE

Compound 2242, also known as 2-amino-7-[(1,3-dihydroxy-2-propoxy)methy l]purine, is the first known antivirally active nucleoside analog with the side chain substituted at the N-7 position of the purine ring sys tem. Our purpose was to evaluate its retinal toxicity and assess the e fficacy of its highest nontoxic concentration in a rabbit model of her pes simplex retinitis. Concentrations of the drug from 0.5 to 2,000 mu M were injected intravitreally in twelve New Zealand White rabbits. F undoscopic, histologic, and electrophysiologic data revealed no eviden ce of toxicity even at the highest dose of the compound. Dutch pigment ed rabbits (n = 34) had their left eyes injected with herpes simplex v irus type 1 3 days after, concurrently, or 3 days before intravitreal injection of either 2,000 mu M compound 2242 or 480 mu M ganciclovir ( final concentration in the eye). Both compound 2242 and ganciclovir we re equally effective compared with saline when administered simultaneo usly with the virus (P < 0.0001). In the 3-day pretreatment paradigm, compound 2242 was superior to ganciclovir (P < 0.04), but there was no clear difference between the two with regard to their effects on an e stablished infection. The pharmacokinetics of compound 2242 in 10 rabb its injected intravitreally with 30 mu M showed an intravitreal half-l ife of 8 h. This compound, which may be orally active in its pro form, has a very high therapeutic index in the eye and is more efficient th an ganciclovir in this animal model of herpes retinitis.