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Y.K. Wu, L. Cheng, K.Y. Hostetler, O. Kayikcioglu, N. Valiaeva, J. Beadle, G. Bergeron–Lynn, W.R. Freeman; A Novel Intravitreally Injectable, Crystalline Prodrug of 5–Fluorouracil (HDP–P–5f2'du) for Sustained Intraocular Drug Delivery to Treat Pathologic Intraocular Proliferation . Invest. Ophthalmol. Vis. Sci. 2005;46(13):471.
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Purpose: To evaluate the intraocular properties of a newly synthesized crystalline prodrug of 5–fluorouracil (5–FU): hexadecyloxypropyl–Phospho–5–Fluro–2'–deoxyuridine (HDP–P–5F2'DU) which can be injected into the vitreous as a crystalline slurry for long acting antiproliferative intraocular therapy. Methods: HDP–P–5F2'DU was derived by adding a long carbon chain to the sugar of phospho–5–fluro–2'–deoxyuridine to achieve hydrophobic properties for intraocular drug delivery. The compound was intravitreally injected into rabbit vitreous with resultant concentrations of 5 µg/ml, 25µg/ml, 50µg/ml and 250µg/ml respectively. The toxicity and safety was evaluated with ophthalmoscopy, tonometry, electroretinography (ERG), and histopathology. Duration of action was determined by observing crystalline dissolution in vivo over time with aide of indirect ophthalmoscope. Results: Intravitreal injections of the compound revealed no clinical and pathological toxicity, compared to the controls, at all doses except for the highest dose. The highest dose caused areas of retinal and lens damage with moderate vitritis and abnormal ERGs. The other three doses demonstrated a clear vitreous and localized drug depot in the inferior vitreous cavity. The drug depot of 50µg/ml dose was observable between 8 to 10 weeks until the point of sacrifice. Conclusions: The highest non–toxic dose of the HDP–P–5F2'DU is the 50µg/ml total calculated vitreous concentration in rabbit eyes. This crystalline HDP–P–5F2'DU warrants further investigation as a long acting local therapy for unwanted intraocular proliferation.
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