Prevention and Treatment of HSV-1 Retinitis in Rabbit With Intravitreal Crystalline 1- O-Hexadecyloxypropyl-Cyclic Cidofovir

Abstract

Abstract: : Purpose: To determine the clinical efficacy of crystalline 1- O-hexadecyloxypropyl-cyclic cidofovir (HDP-cCDV) as an example of a long-lasting slow release crystalline lipid prodrug delivery system. Methods: Crystalline HDP-cCDV was synthesized and 100 µg was intravitreally injected into rabbit vitreous before (pre-treatment) or after (treatment) induction of retinitis with HSV-1 intravitreal inoculation. An equimolar dose of cidofovir and 5% dextrose were used as controls. For pretreatment, drugs were injected either 21, 47, or 68 days prior to virus inoculation. 5 eyes of 5 rabbits were used for each drug at each time point (total of 45 rabbits). In the treatment study (15 rabbits), the drugs were intravitreally injected after retinitis developed and reached grade 1 or 2. Retinitis was monitored and graded with indirect ophthalmoscope at intervals until sacrifice. Results: In the pretreatment studies, HDP-cCDV provided a complete protection from infection for 3 weeks and significant protection for 47 days (p=0.03) and 68 days (p=0.02) compared with dextrose or cidofovir which only provided a 3-week protection. In the treatment study, both the crystalline HDP-cCDV and cidofovir resulted in significantly less retinal necrosis than was observed with eyes that received dextrose solution. Conclusion: Crystalline lipid prodrug intravitreal delivery appears to be a useful intraocular drug delivery system which provides a sustained therapeutic drug level over 3-10 weeks following a single intravitreal injection. Intravitreal HDP-cCDV could be a useful alternative for CMV retinitis treatment.

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