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This study was conducted to evaluate the vitreous clarity and intraocular therapeutic index of three preparations ofthe carboxymethyl ester of 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a long acting lipid derivative of foscarnet with potent anti-CMV activity. Twenty-six New Zealand white rabbits were intravitreally injected with one of three preparations of ODG-PFA-O-Me or control diluent. The vitreous clarity was graded after injection using indirect ophthalmoscopy and fundus photography. Drug intraocular toxicity was evaluated by electroretinography and by post-sacrifice tissue pathology using light and electron microscopy. Intravitreal injection of micellar ODG-PFA-O-Me showed variable local retinal toxicity and vitreal compound aggregates in eyes with the middle and high doses. The intraocular therapeutic index was lower than 465:1. Intravitreal injection of liposomal ODG-PFA-O-Me, either free acid or sodium salt, revealed clear vitreous for the 0.632 and 0.84 mM final intravitreal concentrations. No retinal toxicity was confirmed for the 1.12 mM final intravitreal concentration at the eight week observation following injection. The intraocular therapeutic index was between 585-1037:1. ODG-PFA-O-Me possesses better vitreous compatibility than ODG-PFA. Liposomal ODG-PFA-O-Me can be intravitreally injected with a resulting clear vitreous and high intraocular therapeutic index. Liposomal ODG-PFA-O-Me could be a long acting nontoxic intravitreous injectable drug for CMV retinitis.

Purpose: To evaluate the intraocular distribution and metabolism of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3- phosphonoformate (ODG-PFA), following intravitreal administration., Methods: Twenty rabbits received ODG-[14C]PFA intravitreal injection, yielding 0.632 mM resultant intravitreal concentration. Two animals per group were sacrificed at different intervals post-injection. The drug levels in ocular tissues were determined with counting the radioactivity by Tracor Mark III Liquid Scintillation Counter. Four rabbits were used for analysis of the drug metabolism in vitreous by lipid extraction technique., Results: The drug level in vitreous was 526 microM at day one and 227 microM at the fifth week. The vitreous half life was approximately four to five weeks. The retinal level of the drug was 292 microM at day one, 75 microM at the fifth week and 32 microM at the tenth week, which was still more than ten times higher than the IC90 against HCMV. Lipid extraction analysis showed that, in vivo, both ODG-PFA and PFA were present in vitreous, but in in vitro incubations with vitreous, ODG-PFA conversion to PFA was negligible., Conclusion: ODG-PFA possesses a long vitreous half life and sustained high drug level in retina. The vitreous did not metabolize drug but acted as a drug reservoir. Intravitreal liposomal ODG-PFA may be expected to be a long acting potent local therapy for CMV retinitis.

Objective: To describe a syndrome of posterior segment intraocular inflammation that causes visual loss in patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis. This syndrome was associated with immune recovery mediated by combination antiretroviral treatment including protease inhibitors., Design: A case-control study at 2 university medical centers., Participants: One hundred thirty patients with acquired immunodeficiency syndrome and cytomegalovirus retinitis were examined at 2 medical centers for 15 months. In addition, the medical records of 509 patients examined at 1 center for 11 years before the initiation of protease inhibitor therapy were analyzed retrospectively., Results: Five patients with symptomatic vitritis and papillitis with cystoid macular edema or epiretinal membrane formation were documented. In each patient there was inactive cytomegalovirus retinitis that had not caused visual decrease before the onset of inflammation. All patients had elevated CD4+ T lymphocyte levels (median increase, 86x10(6)/L [86 cells/mm3]) after combination treatment including protease inhibitors. Two patients with cystoid macular edema were treated with corticosteroids and had resolution of the cystoid macular edema and an increase in visual acuity without reactivation of the retinitis. Retrospective analysis failed to disclose similar patients with intraocular inflammation in the era before the introduction of protease inhibitors., Conclusions: This newly described syndrome of posterior segment inflammation related to cytomegalovirus retinitis is a cause of visual morbidity in patients with acquired immunodeficiency syndrome. It is associated with increased immune competence as a result of combined antiretroviral treatment with protease inhibitors and may be amenable to corticosteroid therapy without reactivation of retinitis.