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Lingyun Cheng, Karl Y. Hostetler, Sunan Chaidhawangul, Michael F. Gardner, James R. Beadle, Kelly S. Keefe, Germaine Bergeron–Lynn, Gregory M. Severson, Kelly A. Soules, Arthur J. Mueller, William R. Freeman; Intravitreal Toxicology and Duration of Efficacy of a Novel Antiviral Lipid Prodrug of Ganciclovir in Liposome Formulation. Invest. Ophthalmol. Vis. Sci. 2000;41(6):1523-1532. doi: https://doi.org/.
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purpose. To evaluate the intraocular safety and antiviral treatment efficacy of
the sustained lipid prodrug of ganciclovir,
as an intravitreal injectable drug system for viral retinitis.
methods. HDP-P-GCV was synthesized by coupling
1-O-hexadecyl-propanediol-3-phosphate to either free
hydroxyl of ganciclovir in pyridine with dicyclohexylcarbodiimide as
catalyst. The compound was formulated into liposomes. The antiviral
activity was assessed by DNA reduction in vitro, and intraocular safety
was assessed by ophthalmoscopy, electrophysiology, and histology after
intravitreal injections, with resultant intravitreal concentrations of
0.2, 0.632, 1.12, and 2 mM. The treatment efficacy was evaluated by
simultaneous intravitreal injection of HDP-P-GCV and herpes simplex
virus type 1 (HSV-1) or by intravitreal injection of HDP-P-GCV at
various times before HSV-1 intravitreal inoculation. Retinitis was
scored with ophthalmoscopy and compared with controls.
results. In vitro, the IC50 of HDP-P-GCV against HSV-1 and human
cytomegalovirus (HCMV)-infected cells was 0.02 and 0.6 μM,
respectively. In rabbits in vivo, HDP-P-GCV dispersed evenly and
maintained a good vitreous clarity at all doses except 2 mM final
intravitreal concentration. Although cataracts were observed in some
eyes at the higher doses, they were not observed in eyes with 0.2 mM
final intravitreal concentration. No other indications of ocular
toxicity were observed. Intravitreal injection of HDP-P-GCV with
resultant 0.2 mM intravitreal concentration in the HSV-1 retinitis
rabbit model demonstrated a complete protection of the retina with the
simultaneous treatment strategy and a 4- (P = 0.03)
to 6- (P = 0.058) week significant protection of
retina with the pretreatment strategies when compared with ganciclovir
or blank liposome controls.
conclusions. In the rabbit model of HSV-1 retinitis HDP-P-GCV acts as a long-lasting
intravitreal injectable anti-CMV or anti-HSV compound. This
self-assembling liposome system could be applicable for many compounds
available for intraocular diseases.
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