McSharry James J, Deziel Mark R, Zager Kris, Weng Qingmei, Drusano George L
Antiviral Pharmacodynamics Laboratory, Emerging Infections and Host Defense Group, Ordway Research Institute, Albany, New York 12208, USA.
Antimicrob Agents Chemother. 2009 Jan;53(1):129-35. doi: 10.1128/AAC.00708-08. Epub 2008 Oct 13.
Variola major virus remains a potent weapon of bioterror. There is currently an investigational-new-drug application for cidofovir for the therapy of variola major virus infections. Stittelaar and colleagues compared the levels of effectiveness of postexposure smallpox vaccination (Elstree-RIVM) and antiviral treatment with cidofovir or an acyclic nucleoside phosphonate analogue 6-[2-(phosphonomethoxy)alkoxy]-2,4-diaminopyrimidine (HPMPO-DAPy) after lethal intratracheal infection of cynomolgus monkeys with monkeypox virus, a variola virus surrogate. Their results demonstrated that either compound was more effective than vaccination with the Ellstree vaccine (K. J. Stittelaar et al., Nature 439:745-748, 2006). An unanswered question is how to translate this information into therapy for poxvirus infections in people. In a proof-of-principle study, we used a novel in vitro hollow-fiber infection model system to determine the pharmacodynamics of vaccinia virus infection of HeLa-S3 cells treated with cidofovir. Our results demonstrate that the currently licensed dose of cidofovir of 5 mg/kg of body weight weekly with probenecid (which ameliorates nephrotoxicity) is unlikely to provide protection for patients intentionally exposed to Variola major virus. We further demonstrate that the antiviral effect is independent of the schedule of drug administration. Exposures (area under the concentration-time curve) to cidofovir that will have a robust protective effect will require doses that are 5 to 10 times that currently administered to humans. Such doses may cause nephrotoxicity, and therefore, approaches that include probenecid administration as well as schedules of administration that will help ameliorate the uptake of cidofovir into renal tubular epithelial cells need to be considered when addressing such treatment for people.
天花病毒仍然是生物恐怖主义的有力武器。目前有一项关于西多福韦治疗天花病毒感染的研究性新药申请。斯蒂特勒尔及其同事比较了在食蟹猴经气管内致死性感染猴痘病毒（一种天花病毒替代物）后，暴露后接种天花疫苗（埃尔斯特里 - 荷兰国家公共卫生与环境研究所疫苗）以及用西多福韦或无环核苷膦酸类似物6 - [2 - （膦酰甲氧基）烷氧基] - 2,4 - 二氨基嘧啶（HPMPO - DAPy）进行抗病毒治疗的效果水平。他们的结果表明，这两种化合物中的任何一种都比接种埃尔斯特里疫苗更有效（K. J. 斯蒂特勒尔等人，《自然》439:745 - 748，2006年）。一个尚未解决的问题是如何将这些信息转化为针对人类痘病毒感染的治疗方法。在一项原理验证研究中，我们使用了一种新型的体外中空纤维感染模型系统来确定用西多福韦处理的HeLa - S3细胞感染痘苗病毒的药效学。我们的结果表明，目前许可的西多福韦剂量为每周5毫克/千克体重并联合丙磺舒（可减轻肾毒性），不太可能为故意接触天花病毒的患者提供保护。我们进一步证明抗病毒效果与给药方案无关。要产生强大保护作用所需的西多福韦暴露量（浓度 - 时间曲线下面积）将需要目前给予人类剂量的5至10倍。这样的剂量可能会导致肾毒性，因此，在考虑对人类进行此类治疗时，需要考虑包括丙磺舒给药以及有助于减少西多福韦被肾小管上皮细胞摄取的给药方案。
