Evaluation of retinal toxicity and efficacy of the anticytomegalovirus compound 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine.
Evaluation of retinal toxicity and efficacy of the anticytomegalovirus compound 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine.
复制标题
抗巨细胞病毒化合物2-氨基-7-[(1,3-二羟基-2-丙氧基)甲基]嘌呤的视网膜毒性和功效评价。
DOI：
10.1128/aac.39.7.1485
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发表时间：
1995
影响因子：
4.9
通讯作者：
Helsberg,M
中科院分区：
文献类型：
--
作者：
Besen,G;Chavez-delaPaz,E;Tatebayashi,M;Flores-Aguilar,M;Gangan,PA;Munguia,D;Wiley,CA;Jähne,G;Winkler,I;Helsberg,M
化合物2242，也被称为2-氨基-7-[（1,3-二羟基-2-丙氧基）甲基]嘌呤，是已知的第一个在嘌呤环系统的N-7位置取代侧链的抗病毒活性核苷类似物。我们的目的是评估其视网膜毒性，并评估其在兔单纯疱疹视网膜炎模型中的最高无毒浓度的疗效。以0.5 ~ 2000 μ m的浓度对12只新西兰大白兔进行玻璃体注射。眼底镜，组织学和电生理数据显示，即使在最高剂量的化合物没有毒性的证据。荷兰着色兔（n = 34）在玻璃体内注射2000毫微克化合物2242或480毫微克更昔洛韦（眼内最终浓度）后、同时或前3天左眼注射1型单纯疱疹病毒。当与病毒同时给药时，化合物2242和更昔洛韦与生理盐水的效果相同（P < 0.0001）。在3天的预处理范式中，化合物2242优于更昔洛韦（P < 0.04），但两者对已建立感染的影响没有明显差异。化合物2242在10只家兔体内玻璃体内注射30微米的药代动力学显示，其玻璃体内半衰期为8小时。该化合物可能具有口服活性，在这种疱疹性视网膜炎动物模型中具有非常高的眼内治疗指数，比更昔洛韦更有效。
Compound 2242, also known as 2-amino-7-[(1,3-dihydroxy-2-propoxy)methyl]purine, is the first known antivirally active nucleoside analog with the side chain substituted at the N-7 position of the purine ring system. Our purpose was to evaluate its retinal toxicity and assess the efficacy of its highest nontoxic concentration in a rabbit model of herpes simplex retinitis. Concentrations of the drug from 0.5 to 2,000 microM were injected intravitreally in twelve New Zealand White rabbits. Fundoscopic, histologic, and electrophysiologic data revealed no evidence of toxicity even at the highest dose of the compound. Dutch pigmented rabbits (n = 34) had their left eyes injected with herpes simplex virus type 1 3 days after, concurrently, or 3 days before intravitreal injection of either 2,000 microM compound 2242 or 480 microM ganciclovir (final concentration in the eye). Both compound 2242 and ganciclovir were equally effective compared with saline when administered simultaneously with the virus (P < 0.0001). In the 3-day pretreatment paradigm, compound 2242 was superior to ganciclovir (P < 0.04), but there was no clear difference between the two with regard to their effects on an established infection. The pharmacokinetics of compound 2242 in 10 rabbits injected intravitreally with 30 microM showed an intravitreal half-life of 8 h. This compound, which may be orally active in its pro form, has a very high therapeutic index in the eye and is more efficient than ganciclovir in this animal model of herpes retinitis.