POSTEXPOSURE PROPHYLAXIS AND TREATMENT OF AEROSOLIZED SMALLPOX

雾化天花的暴露后预防和治疗

• 批准号: 8358129
• 负责人: CHAD J. ROY
• 金额: $ 3.72万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358129
• 关键词: Acute; Aerosols; Animals; Anorexia; Antiviral Agents; Biological; Breathing; Bypass; Cessation of life; Cidofovir; Clinical; Development; Disease; Dose; Drug Delivery Systems; Drug Formulations; Dyspnea; Effectiveness; Emergency Situation; Event; Exanthema; Exposure to; Fever; Funding; Grant; Health Personnel; Infection; Injectable; Kidney; Lesion; Lethal Dose 50; Life; Lung; Modeling; Mus; National Center for Research Resources; Oryctolagus cuniculus; Pharmaceutical Preparations; Pharmacologic Substance; Powder dose form; Primates; Principal Investigator; Prophylactic treatment; Rabbit Pox Virus; Relative (related person); Research; Research Infrastructure; Resources; Safety; Self-Administered; Smallpox; Smallpox Viruses; Source; Structure of parenchyma of lung; Tachycardia; Therapeutic; Toxic effect; United States National Institutes of Health; aerosolized; cost; experience; intravenous administration; nonhuman primate; pathogen; preclinical efficacy; response

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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 天花是由暴露于Variola病毒的一种威胁生命的疾病，这是一种高度传染性的病原体，被认为是生物威胁剂。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。正在开发一种遗传性的CIDOFOVIR干杯公式，用于预防后暴露后，并治疗气溶胶暴露于各种卵形。在多种小鼠研究中已显示吸入的cidofovir对各种痘病模型具有很高的效率，与可注射的给药相比，在肺组织中产生了长期活性和保留。静脉注射cidofovir虽然有效，但导致肺部较低，肾脏毒性严重，需要医疗保健工作者来实施治疗。或者，Cidofovir替代地导致肺部较高的药物水平，绕开了孩子，并且是自我管理的。 最初，我们使用了CIDOFOVIR（纳米旋转; NF）的药物级粉末版本来治疗暴露于雾化的兔病毒（RPXV）的兔子，以进一步评估直接药物递送到肺部的有效性。 Na¿ve兔子被RPXV的H10-50 LD50感染了气溶胶。三个子集以0.5、1.0或1.75 mg/kg每天收到雾化的NF，在T = 0H时3天（PI）接受3天。另一个子集接受了IV-Cidofovir（每天10 mg/kg，3天PI）或未经处理（CRL）。结果显示NF组显示抗病毒剂量相关的生存率为50％（0.5），80％（1.0）和100％（1.75）。 IV-Cidofovir组中的所有动物都幸存下来。所有CRL动物都死于5-6 Pi。 RPX疾病的急性临床症状，包括厌食症，高温，鼻血，呼吸困难，心动过速和Poxviral Rash，在CRL +3D PI中发育，直到死亡。 NF（0.5，1.0）和IV-Cidofovir组经历了Miller临床迹象与CRL。 NF（1.75）组显示了对RPX的最小临床反应，并且肺部病变与CRL或IV-CR组的剂量有关。 NF在等效IV-CR剂量的H10％以H10％保护兔子。在NF组的RPX疾病的临床发展中观察到了与剂量有关的作用。在NF（1.75）和IV-Cidofovir组中观察到RPX诱导的病理变化的显着降低。结果表明，可吸入的NF可能是紧急PEP的可行抗病毒药物，应在其他Poxviral疾病模型（例如，非人类隐私中的MPX）中进行评估。这些研究的结果将确定改革后的Cidofovir作为对天花的可行抗病毒疗法的相对安全性和临床前效率。