POSTEXPOSURE PROPHYLAXIS AND TREATMENT OF AEROSOLIZED SMALLPOX

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 天花是一种由接触天花病毒引起的危及生命的疾病，天花病毒是一种高度传染性的病原体，被认为是一种生物威胁因素。在意外或故意接触天花气雾剂的情况下，目前没有推荐用于暴露后预防和/或治疗天花的药物。西多福韦是一种抗病毒药物，可用于在发生生物攻击时治疗感染。正在开发一种吸入型西多福韦干粉制剂，用于暴露后预防和治疗暴露于天花的气雾剂。吸入型西多福韦在多项小鼠研究中被证明对各种痘模型非常有效，与注射用药相比，它能在肺组织中产生长期的活性和滞留。静脉注射西多福韦虽然有效，但会导致肺水平降低，严重的肾脏毒性，并需要卫生保健工作者实施治疗。或者，吸入型西多福韦会导致肺部药物浓度升高，绕过肾脏，并自行给药。 首先，我们将评估吸入型西多福韦在兔痘病毒感染模型中的作用。兔痘是研究痘病毒的理想动物模型；当动物通过气雾剂实验感染病毒时，兔痘会引起类似于天花的症状。这一抗病毒评估模型将评估西多福韦是否有效地抑制了暴露在气雾剂中的兔子的感染，同时不会造成不必要的肾脏损害或其他有害的不良反应。根据兔痘研究的初步结果，我们将使用天花疾病的高级非人类灵长类动物模型(猴子的雾化猴痘)进行疗效研究，以证明在非人类灵长类动物中通过吸入的抗病毒药物与人类体内的抗病毒药物相似，并且当在这个致命的模型中用作暴露后治疗时，这种浓度与灵长类动物的存活率呈正相关。这些研究的结果将确定重新配制的西多福韦作为一种可行的天花抗病毒疗法的相对安全性和临床前疗效。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Smallpox is a life threatening disease caused by exposure to variola virus, a highly contagious pathogen that is considered a biological threat agent. In the event of an accidental or deliberate aerosol exposure of variola, there are currently no recommended drugs for postexposure prophylaxis and/or treatment for smallpox. Cidofovir is an antiviral drug that can be used to treat infection in the event of a biological attack. An inhaled cidofovir dry-powder formulation is being developed to be used in post-exposure prophylaxis and treatment of aerosol exposure to variola. Inhaled cidofovir has been shown in multiple mouse studies to be highly efficacious against various pox models, producing long-term activity and retention in the lung tissue compared to injectable administration. Intravenous administration of cidofovir, although efficacious, results in lower lung levels, severe kidney toxicity, and requires a health-care worker to implement treatment. Inhalable cidofovir, alternatively, results in high drug levels in the lung, bypasses the kidneys, and is self-administered. Initially, we will evaluate the inhalable version of cidofovir in a rabbit model of poxvirus infection. Rabbitpox is an ideal animal model for studying poxviruses; it causes a syndrome similar to smallpox in rabbits when the animals are experimentally infected with the virus by aerosol. This antiviral evaluation model will assess if cidofovir effectively inhibits infection in aerosol-exposed rabbits while not causing undue kidney damage or other unwanted adverse effects. Based upon the preliminary results from the rabbitpox studies, we will use an advanced nonhuman primate model of smallpox disease (aerosolized monkeypox in monkeys) to perform efficacy studies to demonstrate that delivery of the antiviral drug by inhalation in the nonhuman primate mirrors that in humans and that such concentrations are positively associated with primate survival when used as a postexposure therapeutic in this lethal model. Results of these studies will establish the relative safety and preclinical efficacy of reformulated cidofovir as a viable antiviral therapeutic against smallpox.