June 1999
Volume 40, Issue 7
Free
Articles  |   June 1999
Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn-glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.
Author Affiliations
  • L Cheng
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
  • K Y Hostetler
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
  • M F Gardner
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
  • C P Avila, Jr
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
  • G Bergeron-Lynn
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
  • K S Keefe
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
  • C A Wiley
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
  • W R Freeman
    Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.
Investigative Ophthalmology & Visual Science June 1999, Vol.40, 1487-1495. doi:
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      L Cheng, K Y Hostetler, M F Gardner, C P Avila, G Bergeron-Lynn, K S Keefe, C A Wiley, W R Freeman; Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn-glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.. Invest. Ophthalmol. Vis. Sci. 1999;40(7):1487-1495.

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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.

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