Intravitreal toxicology and therapeutic efficacy of the carboxymethyl ester of the 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA-O-Me), a novel lipid antiviral prodrug for intraocular drug delivery.

Abstract

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.

• Authors: L Cheng, K Y Hostetler, M F Gardner, C P Avila Jr, G Bergeron-Lynn, K S Keefe, J R Beadle, C A Wiley, W R Freeman
• Journal: Journal of ocular pharmacology and therapeutics : the official journal of the Association for Ocular Pharmacology and Therapeutics (J Ocul Pharmacol Ther) Vol. 15 Issue 4 Pg. 363-77 (Aug 1999) ISSN: 1080-7683 [Print] United States
• PMID: 10463875 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1-O-octadecylglycerol-3-phosphonoformate carboxymetyl ester
• Antiviral Agents
• Liposomes
• Micelles
• Prodrugs
• Foscarnet

Topics

• Animals
• Antiviral Agents (administration & dosage, pharmacokinetics, toxicity)
• Cytomegalovirus Infections (drug therapy, pathology)
• Electroretinography
• Fluorescein Angiography
• Foscarnet (administration & dosage, analogs & derivatives, toxicity)
• Liposomes
• Micelles
• Prodrugs (administration & dosage, pharmacokinetics, toxicity)
• Rabbits
• Retina (drug effects, pathology)
• Retinitis (drug therapy, pathology)
• Vitreous Body (metabolism)