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

提供了 该项目的总体目标是确定治疗SM诱导的 毒性本研究项目的具体目标是建立和验证硫的动物模型 芥子气（SM）吸入、皮肤和眼部暴露后的毒性。一旦建立了动物模型， 现有治疗剂和潜在新治疗剂在减弱SM诱导毒性方面的疗效已确定 研究项目2、3和4将被审查。新制剂和替代途径的疗效 暴露（即，吸入）也将进行检查。显示最有希望的制剂和给药途径 将在药物非临床研究质量管理规范下进行更明确的疗效评价 实践指南，以支持任何未来的研究性新药申请到美国食品和药物管理局 管理局（FDA）。本项目的具体目标如下：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 样品到研究项目1进行生物标志物鉴定; 2）确定SM的摄取和分布 3）检查目前存在的治疗剂的功效， 已证明对SM诱导的毒性有效或基于SM机制具有潜在疗效 在经验证的动物模型中的作用。确定现有疗法的疗效和药代动力学 重新配制以增强药物输送。检查期间发现的新的潜在治疗方法的疗效 在研究项目2、3和4中进行的机制研究;以及4）进行更广泛的疗效研究 GLP指导原则下最有前景的治疗-给药途径组合研究。发展 小型猪动物模型，用于有前景的制剂治疗SM诱导的 皮肤损伤这些拟议的研究是重要的，因为它们将确定和提供明确的 用于治疗SM诱导的新疗法或现有疗法的替代制剂的疗效研究 毒性根据药物非临床研究质量管理规范指南进行的确定性疗效研究的结果 可以支持向食品和药物管理局提交的研究性新药申请。

PROVIDED. 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.