Intraocular properties of 1–O–hexadecyloxypropyl–cyclic–cidofovir in guinea pigs

Abstract

Abstract: : Purpose: We previously reported a long–lasting crystalline lipid prodrug of cyclic cidofovir, 1–O–hexadecyloxypropyl–cyclic–cidofovir (HDP–cCDV), to treat experimental retinitis in rabbit eyes. HDP–cCDV showed longer intraocular therapeutic effect than CDV and no toxicity with 100µg/eye. It has been known that CDV and related analogues lower intraocular pressure (IOP) after local use and that the guinea pig is a better model to study this toxicity prior to human clinical trials. Methods: HDP–cCDV was intravitreally injected into 10 guinea pig eyes in doses of 4, 9, and 18 µg in 20 µl per eye. 9 µg is the equivalent dose to 100 µg/eye in the rabbit. Only one eye of each animal received drug and the fellow eye served as the control. After injection, the eyes were monitored with tonometry, ophthalmoscopy, electroretinography, and pathology. Results: Intravitreal injections of doses of 18 µg/eye or lower revealed no toxicity and a high therapeutic index (3016 times higher than the EC₅₀ for CMV) during ten weeks of observation. The drug depot was ophthalmoscopically visible in the inferior vitreous cavity for 5 to 10 weeks. There was no IOP difference between drug injected and control eyes at any time points (p>0.05) except for the day 3 after drug injection (p=0.0338). All eyes demonstrated a normal ERG waveform with no differences between treated and control eyes (p=0.85). Histology revealed normal morphology and structures of retina and ciliary body in all eyes. Conclusions: Crystalline HDP–cCDV may be an ideal local long–lasting and a safer alternative to treat CMV retinitis without the toxicity seen with cidofovir.

Keywords: retina • drug toxicity/drug effects • antiviral drugs