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Lingyun Cheng, Karl Y. Hostetler, Sunan Chaidhawangul, Michael F. Gardner, James R. Beadle, Mitsuko Toyoguchi, Germaine Bergeron-Lynn, William R. Freeman; Treatment or Prevention of Herpes Simplex Virus Retinitis with Intravitreally Injectable Crystalline 1-O-Hexadecylpropanediol-3-Phospho-Ganciclovir. Invest. Ophthalmol. Vis. Sci. 2002;43(2):515-521.
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purpose. To evaluate an intraocular drug delivery system consisting of the
crystalline ammonium salt of
(HDP-P-GCV) as a slow-release form of the drug.
methods. A dosage of 0.885, 1.57, 2.8, 4.486, or 8.85 μmol of ammonium salt
HDP-P-GCV in 0.1 mL was intravitreally injected into rabbit vitreous.
The toxicity and safety were evaluated with ophthalmoscopy,
electroretinography, and pathology. Drug vitreous levels were
determined at various time intervals by means of HPLC. The treatment
efficacy and duration of efficacy were tested in a herpes simplex virus
(HSV)-1 retinitis rabbit model.
results. Intravitreal injections of the compound revealed clear vitreous of
optic axis, a desirable drug depot in the inferior vitreous cavity, and
no clinical toxicity, except for variable mild local posterior
subcapsular cataract and local retinal toxicity with high doses. HPLC
analysis showed free ammonium salt of HDP-P-GCV in the upper vitreous
at a level of 0.2 μM 12 weeks after the 2.8-μmol initial
intravitreal dose. Drug concentration was still 1.95 μM 20 weeks
after the 8.85-μmol initial intravitreal dose. These concentrations
(0.2 and 1.95 μM) were 10 and 100 times higher, respectively, than
the median inhibitory concentration (IC50) of HSV-1 (0.023μ
M). Treatment with the highest nontoxic dose (2.8 μmol) and the
highest dose (8.85 μmol) showed significant protection from HSV-1
infection (P < 0.05) and provided sustained
antiviral effect after a single intravitreal drug injection.
conclusions. The crystalline ammonium salt of HDP-P-GCV may be a very useful local
therapy for herpes family viral retinitis.
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