In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model
In vivo antiviral efficacy of a dipeptide acyclovir prodrug, val-val-acyclovir, against HSV-1 epithelial and stromal keratitis in the rabbit eye model
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DOI：
10.1167/iovs.02-1251
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发表时间：
2003-06-01
影响因子：
4.4
通讯作者：
Mitra, AK
中科院分区：
文献类型：
--
作者：
Anand, BS;Hill, JM;Mitra, AK
目的。抗病毒核苷阿昔洛韦（ACV）的二肽前药val-val-ACV （VVACV）作为一种潜在的候选药物在体内进行了评估，以提高对疱疹性上皮性和间质性角膜炎的抗病毒疗效。比较1% VVACV对接种HSV-1 McKrae菌株（25 μ l / 105个斑块形成单位[PFU]）诱导的结痂兔角膜上皮性角膜炎和细胞内注射HSV-1 RE菌株（10 μ l / 105个斑块形成单位[PFU]）诱导的间质性角膜炎的影响，并与1%三氟胸腺嘧啶（TFT）和平衡盐溶液作为对照。每组取两只眼10只。在感染后2周内通过裂隙灯检查评估病变。在每次实验结束时，对房水样品和角膜进行药物浓度分析。细胞增殖试验评价了VVACV与val-阿昔洛韦（VACV）、ACV和TFT的细胞毒性。二肽前药VVACV在兔上皮性和间质性角膜炎模型中表现出对HSV-1的良好活性：1%的VVACV与1%的TFT一样有效。该前药的细胞毒性也低于TFT， TFT是目前在美国唯一被批准并常规用于局部治疗眼部疱疹感染的有效药物。前药VVACV具有较低的细胞毒性和高水溶性，在兔上皮性和间质性角膜炎中对HSV-1表现出良好的体内活性，是治疗眼部HSV感染的有希望的候选药物。（Invest Ophthalmol Vis Sci. 2003;44:2529-2534） DOI:10.1167/iov.s.02-1251。
Purpose. A dipeptide prodrug of the antiviral nucleoside acyclovir (ACV), val-val-ACV (VVACV), was evaluated in vivo as a potential drug candidate for improving antiviral efficacy against herpetic epithelial and stromal keratitis.Methods. The effect of 1% VVACV on epithelial keratitis induced by inoculation of HSV-1 strain McKrae (25 muL, of 105 plaque-forming units [PFU]) in the scarified rabbit cornea and stromal keratitis induced by intrastromal injection of HSV-1 strain RE (10 muL of 105 PFU) was compared with that of 1% trifluorothymidine (TFT) and balanced salt solution as the vehicle control. Both eyes of 10 rabbits were used in each treatment group. Lesions were evaluated by slit lamp examinations over a 2-week period after infection. Aqueous humor samples and corneas were analyzed for drug concentrations at the end of each experiment. Cytotoxicity of VVACV in comparison with val-acyclovir (VACV), ACV, and TFT was evaluated in cellular proliferation assays.Results. The dipeptide prodrug VVACV demonstrated excellent activity against HSV-1 in the rabbit epithelial and stromal keratitis models: 1% VVACV was as effective as 1% TFT. The prodrug was also less cytotoxic than TFT, which is the only effective drug currently licensed and routinely used for topical treatment of ocular herpes infections in the United States.Conclusions. The less cytotoxic and highly water-soluble prodrug VVACV, which showed excellent in vivo activity against HSV-1 in rabbit epithelial and stromal keratitis, is a promising drug candidate for treatment of ocular HSV infections. (Invest Ophthalmol Vis Sci. 2003;44:2529-2534) DOI:10.1167/iov.s.02-1251.