Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn-glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.

Abstract

PURPOSE:

To determine intraocular toxicity and efficacy of the lipid prodrug of foscarnet, 1-O-octadecyl-sn-glycerol-3-phosphonoformate (ODG-PFA), as a long-acting, nontoxic intravitreous injectable drug delivery system for cytomegalovirus (CMV) retinitis.

METHODS:

ODG-PFA was synthesized by coupling the phosphonate residue of PFA to the 3 hydroxyl of 1-O-octadecyl-sn-glycerol and formulated as micelles and liposomes at concentrations so that, after injection into the rabbit vitreous, the resultant intravitreal concentrations were 0.2 mM, 0.63 mM, and 2 mM in micellar formulation and 0.02 mM, 0.063 mM, 0.2 mM, and 0.63 mM for liposomal formulation. The compounds were injected, and toxicology evaluations were performed.

RESULTS:

Intravitreal injections of micellar ODG-PFA resulted in aggregation of the material in vitreous and variable local retinal damage. Intravitreal injections of the liposomal ODG-PFA revealed even dispersion of the compounds and a clear vitreous, using final concentration in the vitreous of 0.2 mM. No intraocular toxicity was found with the 0.632 mM final concentration. The 50% inhibitory concentration (IC50) for CMV of ODG-PFA was 0.43+/-0.27 microM, and the therapeutic index of ODG-PFA after intravitreal injection was estimated to be 1470:1.

CONCLUSIONS:

Lipid-derivatized foscarnet liposome formulations may be a useful long-acting delivery system for the therapy of CMV retinitis.

• Authors: L Cheng, K Y Hostetler, M F Gardner, C P Avila Jr, G Bergeron-Lynn, K S Keefe, C A Wiley, W R Freeman
• Journal: Investigative ophthalmology & visual science (Invest Ophthalmol Vis Sci) Vol. 40 Issue 7 Pg. 1487-95 (Jun 1999) ISSN: 0146-0404 [Print] United States
• PMID: 10359331 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1-O-octadecyl-sn-glycerol-3-phosphonoformate
• Antiviral Agents
• Delayed-Action Preparations
• Drug Carriers
• Liposomes
• Phospholipid Ethers
• Prodrugs
• Foscarnet

Topics

• Animals
• Antiviral Agents (chemical synthesis, toxicity)
• Cytomegalovirus (drug effects, physiology)
• Cytomegalovirus Retinitis (drug therapy)
• Delayed-Action Preparations
• Drug Carriers
• Electroretinography (drug effects)
• Fluorescein Angiography
• Foscarnet (analogs & derivatives, chemical synthesis, toxicity)
• Injections
• Liposomes
• Microbial Sensitivity Tests
• Phospholipid Ethers (chemical synthesis, toxicity)
• Pigment Epithelium of Eye (drug effects, ultrastructure)
• Prodrugs (chemical synthesis, toxicity)
• Rabbits
• Retina (drug effects, pathology)
• Vitreous Body (drug effects)