CORE--IN VIVO AND IN VITRO EVALUATION

核心——体内和体外评估

• 批准号: 6099544
• 负责人: EARL R KERN
• 金额: $ 17.23万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6099544
• 关键词: Alphaherpesvirinae; Betaherpesvirinae; antiviral agents; biomedical facility; drug screening /evaluation; human fetus tissue; tissue /cell culture

The objective of this project is to provide a resource for in vivo evaluation of antiviral agents in experimental animal infections which are models of severe human herpesvirus diseases. The investigation of a new antiviral compound provided by the University of Michigan NCDDG-OI will include: 1) determination of the in vitro activity of the drug against appropriate representative viruses in both mouse and human tissue culture cells, 2) establishment of the maximum tolerated dose for each new drug prior to beginning treatment studies, and 3) an evaluation of the efficacy of the compound in the treatment of appropriate experimental viral infections in animal models. To determine the potential of new antiviral compounds for use in treatment of herpesvirus infections of humans, the following animal model infections will be utilized: 1) intraperitoneal inoculation of normal mice with MCMV, a model for acute and chronic disseminated CMV disease in normal hosts; 2) Intraperitoneal inoculation of MuLV LP-BM-5-induced immunosuppressed mice (MAIDS) with MCMV, a model for acute disseminated CMV disease in the immunocompromised host; 3) intraperitoneal inoculation of weanling mice with HSV-1 or HSV-2, models for acute HSV infection. The animal model systems have been developed to: 1) simulate a human herpesvirus disease; 2) utilize a natural route of infection where possible; 3) achieve infection or mortality rates of 80-90% from the viral challenge, so that a maximum level of sensitivity in determining the activity of the drug may be obtained; 4) evaluate several doses of the drug (maximum tolerated dose to minimum effective dose) initiated at various times after viral challenge and administered 2-3 times daily throughout the course of the infection; 5) allow determination of the effect of antiviral therapy on mortality, mean day of death, and viral replication in major target organs and; 6) determine the potential of combination chemotherapy. Specific antiviral agents to be tested in each animal model will be chosen according to background data generated from tissue culture sensitivity testing and discussions with the other project leaders and NIAID Staff.

本项目的目的是为体内 抗病毒药物在实验动物感染中的评价， 严重人类疱疹病毒疾病的模型。 一个新的调查 密歇根大学NCDDG-OI提供的抗病毒化合物将 包括：1）测定药物的体外活性， 小鼠和人组织培养物中的适当代表性病毒 细胞，2）确定每种新药的最大耐受剂量 在开始治疗研究之前，和3）疗效评价 该化合物在治疗适当的实验病毒 感染动物模型。 以确定新的抗病毒药物的潜力 用于治疗人类疱疹病毒感染的化合物， 将使用以下动物模型感染：1）腹膜内 用MCMV接种正常小鼠， 正常宿主的播散性CMV病; 2）腹膜内接种 MuLV LP-BM-5诱导的MCMV免疫抑制小鼠（MAIDS）， 免疫受损宿主中的急性播散性CMV疾病; 3） 用HSV-1或HSV-2腹膜内接种断奶小鼠模型 急性HSV感染。 动物模型系统的开发目的是： 1)模拟人类疱疹病毒病; 2）利用天然途径， 在可能的情况下感染; 3）达到80-90%的感染率或死亡率 从病毒的挑战，使最高水平的敏感性， 可以获得确定药物活性的方法; 4）评估几种药物活性; 药物剂量（最大耐受剂量至最小有效剂量） 在病毒攻击后的不同时间开始，并给药2-3次 在整个感染过程中每天; 5）允许确定 抗病毒治疗对死亡率、平均死亡日和病毒感染的影响 在主要靶器官中复制; 6）确定 联合化疗 在每个试验中检测的特定抗病毒药物 将根据以下产生的背景数据选择动物模型： 组织培养敏感性测试和与其他项目的讨论 领导和NIAID工作人员。