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.

评估SM毒性对策有效性的动物模型 该项目的总体目标是确定治疗SM诱导的最有效的治疗方法 毒性。本研究项目的具体目标是建立和验证硫磺的动物模型。 芥末(SM)在吸入、皮肤和眼睛暴露后的毒性。一旦建立了动物模型， 现有疗法和潜在新疗法对减轻SM诱导的毒性的有效性已确定 在研究项目2、3和4中，将对其进行检查。新剂型和替代途径的疗效 暴露(即吸入)也将被检查。制剂和剂量路线显示出最有希望的 治疗效果将在Good实验室的指导下进行更明确的疗效评估 支持美国食品和药物管理局未来任何研究性新药申请的操作指南 管理局(FDA)。该项目有以下具体目标：1)开发和验证小动物 SM吸入、皮肤和眼部暴露后的毒性模型。提供组织和排泄物 将样品用于研究项目1的生物标志物识别；2)确定SM的吸收和分布 经皮和吸入给药；3)检查现有疗法的疗效 根据SM-机制显示的对抗SM诱导的毒性或具有潜在疗效的效果 在经过验证的动物模型中的作用。测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。检查新发现的潜在疗法的疗效 在研究项目2、3和4中进行的机械性研究；以及4)进行更广泛的效果 GLP指南下最有希望的治疗-剂量路线组合的研究。发展 小型猪动物模型，用于治疗SM诱导的有希望的制剂的最终疗效测试 皮肤损伤。这些拟议的研究具有重要意义，因为它们将确定并提供明确的 新疗法或现有疗法替代剂型治疗单纯性痴呆的疗效研究 毒性。根据良好实验室操作规范进行的最终疗效研究的结果 可以支持向食品和药物管理局提出的调查性新药申请。