POSTEXPOSURE PROPHYLAXIS AND TREATMENT OF AEROSOLIZED SMALLPOX

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 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。 最初，我们使用药物级粉末版本的西多福韦(NanoFOVIR；NF)来治疗暴露于雾化兔痘病毒(RPXV)的兔，以进一步评估直接给药到肺部的效果。用RPXV的H10-50LD50气雾剂感染新生大耳白兔。3个亚组在t=0h雾化吸入NF，剂量分别为0.5、1.0或1.75 mg/kg，共3天。另一组接受静脉注射西多福韦(10 mg/kg，每天3天)，或不治疗(CRL)。结果显示，NF组的抗病毒剂量相关存活率分别为50%(0.5)、80%(1.0)和100%(1.75)。静脉注射西多福韦组动物全部存活，CRL动物均于第5~6天死亡。RPX病的急性临床症状，包括食欲减退、体温升高、鼻漏、呼吸困难、心动过速和痘病毒皮疹，在CRL+3DPI中发展到死亡。与CRLS相比，NF(0.5，1.0)组和IV-cidofovir组的临床体征较轻。与CRL或IV-Cr组相比，NF(1.75)组对RPX的临床反应最小，肺部病变呈剂量相关的钝化。在相当于静脉注射铬剂量的10%剂量下，核因子可保护兔免受RPX的伤害。NF组RPX病的临床发展存在剂量相关效应。NF(1.75)组和IV-cidofovir组RPX所致的病理改变明显减轻。结果表明，吸入性核因子可能是治疗紧急PEP的一种可行的抗病毒药物，并应在其他痘病毒病模型(例如，非人类灵长类动物的MPX)中进行评估。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. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 for 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 used a pharmaceutical-grade powder version of cidofovir (NanoFOVIR; Nf) to treat rabbits exposed to aerosolized rabbitpox virus (RPXV) to further evaluate the effectiveness of direct drug delivery to the lung. Na¿ve rabbits were infected by aerosol with H10-50 LD50 of RPXV. Three subsets received aerosolized Nf at either 0.5, 1.0 or 1.75 mg/kg daily for 3 days postinfection (PI) at t=0h. Another subset received either IV-cidofovir (10 mg/kg daily, 3 days PI), or were untreated (CRL). Results showed Nf groups showed an antiviral-dose associated survival of 50% (0.5), 80% (1.0) and 100% (1.75). All animals in the IV-cidofovir group survived; all CRL animals died day 5-6 PI. Acute clinical signs of RPX disease, including anorexia, hyperthermia, rhinorrhea, dyspnea, tachycardia and poxviral rash, developed in the CRL +3d PI until death. Nf (0.5, 1.0) and the IV-cidofovir groups experienced milder clinical signs vs CRLs. The Nf (1.75) group showed minimal clinical response to RPX and a dose-related blunting of lung lesions vs CRL or IV-Cr groups. Nf protected rabbits from RPX at H10% of the equivalent IV-Cr dose. A dose-related effect was observed in clinical development of RPX disease in Nf groups. Significant reduction of RPX-induced pathological changes was observed in Nf (1.75) and IV-cidofovir groups. Results suggest that inhalable Nf may be a viable antiviral for emergency PEP and should be evaluated in other models of poxviral disease (e.g., MPX in nonhuman primates). Results of these studies will establish the relative safety and preclinical efficacy of reformulated cidofovir as a viable antiviral therapeutic against smallpox.