Animal models to assess efficacy of countermeasures for SM-induced toxicity

用于评估 SM 诱导毒性对策效果的动物模型

• 批准号: 8120836
• 负责人: JANET M. BENSON
• 金额: $ 44.66万
• 依托单位: LOVELACE BIOMEDICAL & ENVIRONMENTAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8120836
• 关键词: Address; Aerosols; Animal Model; Attenuated; Biological Markers; Breathing; Cavia; Chemistry; Coupled; Data; Dermal; Development; Dose; Doxycycline; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Evaluation; Excretory function; Exposure to; Future; Goals; Guidelines; Homo; Inbred C3H Mice; Inbred F344 Rats; Indomethacin; Inhalation Exposure; Investigational New Drug Application; Label; Lesion; Long-Term Effects; Maximum Tolerated Dose; Miniature Swine; Modeling; Mustard Gas; New Zealand; Oryctolagus cuniculus; Outcome; Pharmaceutical Preparations; Practice Guidelines; Research Personnel; Research Project Grants; Respiratory System; Respiratory tract structure; Route; Sampling; System; Therapeutic; Therapeutic Uses; Time; Tissues; Toxic effect; Treatment Efficacy; United States Food and Drug Administration; Validation; base; efficacy evaluation; efficacy testing; experience; exposed human population; good laboratory practice; ilomastat; novel therapeutics; pulmonary function; research study; response; uptake; vapor

Animal Models to Assess Efficacy of Countermeasures for SM-lnduced Toxicity The overall objective of this project is to identify the most efficacious therapeutics to treat SM-induced toxicity. The specific goals of this research project are to establish and validate animal models of Sulfur Mustard (SM) toxicity following inhalation, dermal, and ocular exposure. Once animal models are established, the efficacy of existing therapeutics and potential new therapeutics to attenuate SM-induced toxicity identified in Research Projects 2, 3 and 4 will be examined. The efficacy of new formulations and alternative routes of exposure (i.e., inhalation) will also be examined. Formulations and dose routes showing the most promise for therapeutic efficacy will undergo more definitive efficacy evaluations conducted under Good Laboratory Practice Guidelines to support any future Investigational New Drug Applications to the U.S. Food and Drug Administration (FDA). This project has the following specific aims: 1) Develop and validate small animal models of SM-induced toxicity following inhalation, dermal, and ocular exposure. Provide tissue and excreta samples to Research Project 1 for biomarker identification; 2) Determine the uptake and distribution of SM administered dermally and by inhalation; 3) Examine the efficacy of currently existing therapeutics with demonstrated efficacy against SM-induced toxicity or with potential efficacy based on SM-mechanisms of action in the validated animal models. Determine the efficacy and pharmacokinetics of existing therapeutics reformulated for enhanced drug delivery. Examine the efficacy of new potential therapeutics identified during mechanistic studies conducted in Research Projects 2, 3, and 4; and 4) Conduct more extensive efficacy studies on the most promising therapeutic-dose route combination under GLP guidelines. Develop the miniature swine animal model for definitive efficacy testing of promising formulations to treat SM-induced dermal lesions. These proposed studies are significant because they will identify and provide definitive efficacy studies on new therapeutics or alternate formulations of existing therapeutics for the treatment of SMinduced toxicity. Results of definitive efficacy studies conducted under Good Laboratory Practice Guidelines can support Investigative New Drug Applications to the Food and Drug Administration.

动物模型评估对策的毒性功效 该项目的总体目的是确定最有效的治疗剂来治疗SM诱导的 毒性。该研究项目的具体目标是建立和验证硫的动物模型 吸入，皮肤和眼部暴露后芥末（SM）毒性。一旦建立动物模型， 现有治疗剂和潜在的新疗法的功效减弱了SM诱导的毒性 在研究项目2、3和4中将进行检查。新配方和替代路线的功效 还将检查暴露（即吸入）。配方和剂量路线显示出最大的希望 治疗功效将在良好的实验室下进行更明确的疗效评估 实践指南，以支持美国食品和药物的未来任何研究新药申请 管理（FDA）。该项目具有以下特定目的：1）开发和验证小动物 吸入，皮肤和眼部暴露后SM诱导的毒性模型。提供组织和排泄物 研究项目1的样本进行生物标志鉴定； 2）确定SM的摄取和分布 通过真皮和吸入施用； 3）检查当前现有治疗剂的功效 证明了对SM诱导的毒性或基于SM机制的潜在功效的功效 在经过验证的动物模型中的作用。确定现有疗法的功效和药代动力学 重新制定以增强药物输送。检查在此期间确定的新潜在治疗剂的功效 研究项目2、3和4进行的机械研究； 4）提出更广泛的功效 在GLP指南下，对最有希望的治疗剂量路线组合的研究。开发 微型猪动物模型，用于对有希望的制剂的确定疗效测试，以治疗SM诱导的 真皮病变。这些提出的研究很重要，因为它们将识别并提供确定的 关于新的治疗剂或现有疗法的替代疗法的疗效研究 毒性。根据良好的实验室实践指南进行的确定疗效研究的结果 可以为食品药物管理局提供调查新药物申请。