Development of antidotes for toxic gases

有毒气体解毒剂的开发

• 批准号: 9145045
• 负责人: Carl W White
• 金额: $ 343.54万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-30 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9145045
• 关键词: Accidents; Acetylcysteine; Acute; Acute Lung Injury; Advanced Development; Alkylating Agents; Animals; Antidotes; Apoptosis; Back; Binding; Biochemical; Biological Markers; Breathing; Bronchiolitis; Cardiopulmonary; Cessation of life; Chemicals; Chronic; Chronic lung disease; Coagulation Process; Collaborations; Communities; Conscious; Critical Illness; Cyanides; DNA Crosslinking; Data; Development; Disasters; Disease model; Enteral; Epithelial; Event; Exposure to; FDA approved; Failure; Family suidae; Fibrosis; Fostering; Gases; Gastric Lavage; Gastric mucosa; Goals; Human; Industry; Injury; International; Intoxication; Intramuscular; Intravenous; Lung; Mediating; Mitochondria; Modeling; Mus; Mustard Gas; Oral; Oryctolagus cuniculus; Patients; Pharmaceutical Preparations; Phase; Physicians; Physiological; Pirfenidone; Plasminogen Activator; Poison; Poisoning; Preparation; Process; Pulmonary Fibrosis; Rattus; Recovery; Respiratory Failure; Route; Scientist; Site; Stomach; Sulfhydryl Compounds; TRP channel; Testing; Therapeutic Agents; Toxic effect; United States National Institutes of Health; Vitamin B 12; absorption; analog; base; cobinamide; effective therapy; improved; inhibitor/antagonist; injured airway; mass casualty; member; methyl isocyanate; model development; nano; nanoformulation; nanoparticle; photonics; pre-clinical; prevent; programs; pulmonary function; receptor; safety study; sodium thiosulfate; success

“Development of antidotes for toxic gases” The goal of this Program is to create a systematic process for developing antidotes against toxic gaseous chemicals by capitalizing on the proven track record of a team of physician-scientists backed by accomplished basic scientists. We will examine two acute pulmonary and cardiopulmonary toxidromes caused by the gaseous chemicals sharing common injury mechanisms: 1) alkylating agents, sulfur mustard (SM) and methyl isocyanate (MIC), that cause DNA crosslinking/damage, apoptosis, airway epithelial and endothelial injury, acute lung injury, and fibrosis, and 2) rapidly absorbed gases, methylmercaptan (CH3SH) and cyanide (HCN), that cause systemic mitochondrial failure. These toxic chemicals were chosen based on: 1) capacity to cause critical illness and death, 2) perceived threat(s), 3) recent and/or important past exposures, and 4) priorities of the NIH/CounterACT, BARDA, DoD, and international community. Therapies being advanced in Projects 1, 3, and 4 are intended as rescue countermeasures for mass casualty scenarios. Two of these (Projects 1 and 3) are intended to be for acute inhalation accidents or disasters. In Project 1, for MIC, three classes of therapies directed at receptor-mediated (TRP channel antagonist(s)), coagulation-related (plasminogen activator(s)), and biochemical (thiol compounds) events will be investigated in a new preclinical acute inhalation model. Therapies would be for immediate/delayed treatment, with intramuscular, airway, and enteral and/or intravenous delivery for TRP channel antagonists, plasminogen activators, and thiol compounds, respectively. In Project 2, the anti-fibrotic drugs pirfenidone and nintedanib will be evaluated via oral/airway delivery in a fibrotic chronic lung disease model in rats following sublethal SM exposure." In Project 3, the vitamin B12 analog cobinamide and sodium thiosulfate, both of which react directly with methyl mercaptan, will be tested as countermeasures against this acutely toxic gas in mice, rabbits, and pig models. In Project 4, a nanoparticle- associated cobinamide (Cbn) will be evaluated as acute rescue countermeasure for oral NaCN intoxication in rabbit and pig models. Because oral NaCN is absorbed as a gas (HCN) at the gastric mucosa, and since victims often will not be conscious, gastric lavage delivery will be used. The Specific Aims are: 1) Determine potential of TRP channel antagonists, plasminogen activators, and thiols to decrease airway injury and lethality after MIC inhalation; 2) Define the efficacy of pirfenidone and other anti-fibrotic drugs against airway and parenchymal lung fibrosis after SM inhalation; 3) Establish efficacy of Cbn and thiosulfate for rescuing animals from lethal methylmercaptan exposures and 4) test the potential efficacy of nonabsorbable nano preparations of Cbn versus other Cbn preparations and routes in an oral NaCN poisoning and lethality model. Successful therapies from each project will be ready for advanced development and attain pre-IND status at or before the end of the cycle.

“有毒气体解毒剂的开发” 该计划的目标是创建一个系统化的流程来开发有毒气体的解毒剂 通过利用由医学专家组成的团队的可靠记录来开发化学品 我们将研究由基础科学家引起的两种急性肺和心肺中毒症。 具有共同损伤机制的气态化学品：1）烷化剂、硫芥（SM）和甲基 异氰酸酯 (MIC)，导致 DNA 交联/损伤、细胞凋亡、气道上皮和内皮损伤， 急性肺损伤和纤维化，以及 2) 快速吸收的气体、甲硫醇 (CHSH) 和氰化物 (HCN)， 选择这些有毒化学物质是基于：1) 导致线粒体系统衰竭的能力。 危重疾病和死亡，2) 感知到的威胁，3) 最近和/或过去的重要暴露，以及 4) 优先事项 NIH/CounterACT、BARDA、DoD 和国际社会在项目 1、3 中推进的疗法。 和 4 旨在作为大规模伤亡情况的救援对策，其中两个（项目 1 和 3）。 旨在用于急性吸入事故或灾难 在项目 1 中，针对 MIC，提供三类疗法。 针对受体介导（TRP 通道拮抗剂）、凝血相关（纤溶酶原激活剂）和 将在新的临床前急性吸入模型中研究生化（硫醇化合物）事件。 治疗方法为立即/延迟治疗，包括肌肉注射、气道注射、肠内注射和/或 分别静脉注射 TRP 通道拮抗剂、纤溶酶原激活剂和硫醇化合物。 在项目 2 中，抗纤维化药物吡非尼酮和尼达尼布将通过口服/气道给药的方式进行评估。 亚致死 SM 暴露后的大鼠纤维化慢性肺病模型。”在项目 3 中，维生素 B12 类似物椰酰胺和硫代硫酸钠，两者都直接与甲硫醇反应，将进行测试 在项目 4 中，针对小鼠、兔子和猪模型中的这种剧毒气体采取了对策。 联合可滨酰胺 (Cbn) 将被评估为口服 NaCN 中毒的紧急救援对策 因为口服的 NaCN 在胃粘膜处以气体 (HCN) 的形式被吸收，并且由于 受害者往往意识不清，会采用洗胃分娩。具体目的是： 1) 确定。 TRP 通道拮抗剂、纤溶酶原激活剂和硫醇降低气道损伤和致死率的潜力 MIC吸入后；2)确定吡非尼酮和其他抗纤维化药物对气道和纤维化的疗效。 吸入 SM 后肺实质纤维化；3) 确定 Cbn 和硫代硫酸盐对拯救动物的功效； 致命的甲硫醇暴露和 4) 测试不可吸收纳米制剂的潜在功效 CBN 与其他 CBN 制剂和途径在口服 NaCN 中毒和致死模型中的成功。 每个项目的疗法都将准备好进行高级开发，并在上市时或之前获得 IND 前状态 循环结束。