两种1-O-十八烷基-sn-甘油-3-膦酰甲酸酯（一种缓释抗巨细胞病毒药物）制剂在兔眼玻璃体内的毒理学研究

Intravitreal toxicology in rabbits of two preparations of 1-O-octadecyl-sn-glycerol-3-phosphonoformate, a sustained-delivery anti-CMV drug.

作者信息

Cheng L, Hostetler K Y, Gardner M F, Avila C P, Bergeron-Lynn G, Keefe K S, Wiley C A, Freeman W R

机构信息

Shiley Eye Center, University of California, San Diego, La Jolla 92093-0946, USA.

出版信息

Invest Ophthalmol Vis Sci. 1999 Jun;40(7):1487-95.

PMID:10359331

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.

摘要

目的

确定膦甲酸钠脂质前药1 - O - 十八烷基 - sn - 甘油 - 3 - 膦甲酸酯（ODG - PFA）作为一种长效、无毒的玻璃体内注射药物递送系统用于治疗巨细胞病毒（CMV）视网膜炎的眼内毒性和疗效。

方法

通过将膦甲酸钠的膦酸酯残基与1 - O - 十八烷基 - sn - 甘油的3 - 羟基偶联合成ODG - PFA，并将其配制成胶束和脂质体，浓度使得注射到兔玻璃体内后，胶束制剂的玻璃体内浓度为0.2 mM、0.63 mM和2 mM，脂质体制剂的浓度为0.02 mM、0.063 mM、0.2 mM和0.63 mM。注射这些化合物并进行毒理学评估。

结果

玻璃体内注射胶束型ODG - PFA导致该物质在玻璃体内聚集并引起不同程度的局部视网膜损伤。玻璃体内注射脂质体ODG - PFA显示化合物均匀分散且玻璃体清晰，玻璃体内最终浓度为0.2 mM。最终浓度为0.632 mM时未发现眼内毒性。ODG - PFA对CMV的50%抑制浓度（IC50）为0.43±0.27 microM，玻璃体内注射后ODG - PFA的治疗指数估计为1470:1。