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L-Y Cheng, KY Hostetler, JR Beadle, M Toyoguchi, K Aldern, N Rodanant, G Bergeron-Lynn, WR Freeman; Intravitreal Toxicology and Pharmacokinetics of 1-O-hexadecylpropanediol-3-phospho arabinosides . Invest. Ophthalmol. Vis. Sci. 2002;43(13):2802.
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Purpose:We have demonstrated a prototype of long-lasting intraocular drug delivery system using crystalline 1-O-hexadecylpropanediol-3-phospho-ganciclovir (HDP-P-GCV) (IOVS February 2002). In order to further characterize this novel system, crystalline 1-O-hexadecylpropanediol-3-phospho cytosine arabinoside, HDP-P-Ara-C was synthesized and its intraocular profile of pharmacology was studied after intravitreal injection. Methods:HDP-Ara-C was synthesized by coupling HDP-phosphate to the 5' hydroxyl of Ara-C. The crystalline HDP-P-Ara-C was added into 5% dextrose and the solution was intravitreally injected with resultant concentrations of 0.112 mM, 1.12 mM, 2.0 mM, and 6.32 mM into rat vitreous. The toxicity and safety was evaluated with ophthalmoscopy, electroretinography (ERG), and pathology. Vitreous drug levels were determined by HPLC. Results:After intravitreal injection of different concentrations of HDP-P-Ara-C, the rat eyes demonstrated complete clear media without drug precipitates. No clinical toxicity or pathologic abnormality was found. All eyes showed normal ERG at the time of sacrifice (week 2). No HDP-P-Ara-C was detectable at week 2 following intravitreal injection. Conclusion:HDP-P-Ara-C can be synthesized and can be safely administered into vitreous. Failure to form a vitreous drug depot and shorter vitreous duration than HDP-P-GCV may be due to its constituent of cytosine that is water soluble. In contrast, HDP-P-Ara-G with a guanine base may be less water soluble and may provide long intravitreal drug duration as HDP-P-GCV that has guanine component. Such a compound may serve as a long acting antiproliferative agent for vitreoretinal disorders.
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