一种用于眼内给药的新型脂质前药的评估：阿昔洛韦二磷酸二肉豆蔻酰甘油在单纯疱疹病毒-1视网膜炎兔模型中的作用

Evaluation of a novel lipid prodrug for intraocular drug delivery: effect of acyclovir diphosphate dimyristoylglycerol in a rabbit model with herpes simplex virus-1 retinitis.

作者信息

Taskintuna I, Banker A S, Flores-Aguilar M, Bergeron-Lynn G, Aldern K A, Hostetler K Y, Freeman W R

机构信息

Department of Ophthalmology, University of California, San Diego, USA.

出版信息

Retina. 1997;17(1):57-64. doi: 10.1097/00006982-199701000-00011.

DOI:10.1097/00006982-199701000-00011

PMID:9051844

Abstract

BACKGROUND

Acyclovir diphosphate dimyristoylglycerol is a lipid prodrug of acyclovir that forms liposomes and provides substantial activity against herpes simplex virus, acyclovir-resistant strains of herpes simplex virus, and human cytomegalovirus. We therefore tested this promising new drug in a rabbit model of herpes simplex retinitis.

METHODS

A total of 22 pigmented rabbits were pretreated with either acyclovir diphosphate dimyristoylglycerol, ganciclovir, acyclovir, or buffer. Retinae then were inoculated with herpes simplex virus-1 or buffer 1 week after the injection of drug. In another experiment we compared the effects of acyclovir diphosphate dimyristoylglycerol and acyclovir diphosphate dioleoylglycerol on the optical clarity of vitreous.

RESULTS

Animals injected intravitreally with acyclovir diphosphate dimyristoylglycerol showed retinitis that was less severe than that in animals injected with ganciclovir, acyclovir, and buffer; differences in grading scores of the retinitis between animals injected with acyclovir diphosphate dimyristoylglycerol and those injected with buffer were statistically significant (P = 0.0015). Vitreous and optical media became clear 4 days after acyclovir diphosphate dioleoylglycerol injection compared with 10 days after with acyclovir diphosphate dimyristoylglycerol injections.

CONCLUSION

Acyclovir diphosphate dimyristoylglycerol had prolonged antiviral activity against herpes simplex virus-1 retinitis in a rabbit model. This drug delivery system, modified to improve optical clarity, may allow long-acting intravitreal treatment of cytomegalovirus retinitis and other retinal diseases.

摘要

背景

阿昔洛韦二磷酸二肉豆蔻酰甘油是阿昔洛韦的脂质前药，可形成脂质体，对单纯疱疹病毒、单纯疱疹病毒耐药株及人巨细胞病毒具有显著活性。因此，我们在单纯疱疹性视网膜炎的兔模型中对这种有前景的新药进行了测试。

方法

总共22只有色兔分别用阿昔洛韦二磷酸二肉豆蔻酰甘油、更昔洛韦、阿昔洛韦或缓冲液进行预处理。在注射药物1周后，视网膜接种单纯疱疹病毒-1或缓冲液。在另一项实验中，我们比较了阿昔洛韦二磷酸二肉豆蔻酰甘油和阿昔洛韦二磷酸二油酰甘油对玻璃体光学清晰度的影响。

结果

玻璃体内注射阿昔洛韦二磷酸二肉豆蔻酰甘油的动物视网膜炎症比注射更昔洛韦、阿昔洛韦和缓冲液的动物轻；注射阿昔洛韦二磷酸二肉豆蔻酰甘油的动物与注射缓冲液的动物相比，视网膜分级评分差异具有统计学意义（P = 0.0015）。与注射阿昔洛韦二磷酸二肉豆蔻酰甘油10天后相比，注射阿昔洛韦二磷酸二油酰甘油4天后玻璃体和光学介质变得清晰。