POSTEXPOSURE PROPHYLAXIS AND TREATMENT OF AEROSOLIZED SMALLPOX

雾化天花的暴露后预防和治疗

• 批准号: 8173041
• 负责人: CHAD J. ROY
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173041
• 关键词: Adverse effects; Aerosols; Animal Model; Animals; Antiviral Agents; Biological; Breathing; Bypass; Cidofovir; Computer Retrieval of Information on Scientific Projects Database; Disease; Drug Formulations; Evaluation; Event; Exposure to; Funding; Grant; Health Personnel; Human; Infection; Injectable; Institution; Kidney; Life; Lung; Modeling; Monkeypox; Monkeys; Mus; Oryctolagus cuniculus; Pharmaceutical Preparations; Powder dose form; Poxviridae; Poxviridae Infections; Primates; Prophylactic treatment; Relative (related person); Research; Research Personnel; Resources; Safety; Self-Administered; Smallpox; Smallpox Viruses; Source; Structure of parenchyma of lung; Syndrome; Therapeutic; Toxic effect; United States National Institutes of Health; Virus; aerosolized; base; drug inhalation; intravenous administration; nonhuman primate; pathogen; preclinical efficacy

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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 天花是一种暴露于Variola病毒引起的威胁生命的疾病，这是一种被认为是生物威胁剂的高度传染性病原体。 如果涉及到水手的意外或故意气溶胶暴露，目前尚无推荐药物用于预防后预防和/或天花治疗。 Cidofovir是一种抗病毒药物，在生物学攻击时可用于治疗感染。 正在开发吸入的Cidofovir干粉配方，用于预防后预防和气溶胶暴露于Variola。 在多种小鼠研究中已显示吸入的cidofovir对各种痘的模型具有高效，与可注射剂相比，在肺组织中产生了长期活性和保留率。 静脉注射cidofovir虽然有效，但导致肺部较低，严重的肾脏毒性，并要求医疗保健工人实施治疗。 可吸入的cidofovir，或者，肺部的药物水平很高，绕过肾脏，并自我管理。 最初，我们将评估猪皮兔模型中Cidofovir的吸入版本。 RabbitPox是研究痘病毒的理想动物模型。当动物通过气溶胶对病毒感染，引起类似于兔子天花的综合征。 该抗病毒评估模型将评估Cidofovir是否有效地抑制了气雾剂暴露的兔子的感染，而不会造成不适当的肾脏损伤或其他不需要的不良影响。 基于兔子研究的初步结果，我们将使用节长的非人类灵长类动物模型（猴子中的雾化的蒙基氧基）进行疗效研究，以证明通过在人类和这种浓度的非人类灵长类动物镜中吸入抗病毒药物在这种浓度中与这种浓度相关时，这是一种良好的态度。 这些研究的结果将确定重新构造的Cidofovir作为对天花的可行抗病毒治疗的相对安全性和临床前疗效。