Development of antidotes for toxic gases

“开发有毒气体解毒剂” 该计划的目标是建立一个系统的过程，开发解毒剂，以对抗有毒气体 化学品，利用一个团队的医生，科学家支持的已证实的记录， 基础科学家我们将检查两种由细菌引起的急性肺和心肺中毒。 具有共同伤害机制的气态化学物质：1）烷基化剂、硫芥（SM）和甲基 异氰酸酯（MIC），其引起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，和2）快速吸收的气体，甲基硫（CH 3 SH）和氰化物（HCN）， 导致系统性线粒体衰竭这些有毒化学物质的选择是基于：1）造成 严重疾病和死亡，2）感知的威胁，3）最近和/或重要的过去暴露，以及4） NIH/CounterACT、巴尔达、国防部和国际社会。项目1、3、4、5、6、7、8、9、10、11、12、14、15、16、17、18、19、 和4旨在作为大规模伤亡情况下的救援对策。其中两个（项目1和3） 用于急性吸入事故或灾难。在项目1中，对于MIC，有三类治疗 针对受体介导的（TRP通道拮抗剂）、凝血相关的（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物化学（硫醇化合物）事件。 治疗将是立即/延迟治疗，肌内、气道和肠内和/或 分别用于TRP通道拮抗剂、纤溶酶原激活剂和硫醇化合物的静脉内递送。 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/气道给药进行评价， 亚致死剂量SM暴露后大鼠纤维化慢性肺病模型。“在项目3中，维生素B12 类似物可宾酰胺和硫代硫酸钠，两者都直接与甲基苯丙胺反应，将作为 在小鼠、兔子和猪模型中研究了针对这种急性毒性气体的对策。在项目4中，一种纳米颗粒- 相关的可宾酰胺（CBN）将被评估为口服NaCN中毒的急性抢救对策， 兔子和猪的模型。因为口服NaCN在胃粘膜处作为气体（HCN）被吸收， 受害者往往会意识不清，便采用洗胃分娩。具体目标是：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的疗效， SM吸入后肺实质纤维化; 3）确定CBN和硫代硫酸盐用于拯救动物的功效 和4）测试不可吸收的纳米制剂的潜在功效 在口服NaCN中毒和致死模型中，比较CBN与其他CBN制剂和途径。成功 每个项目的治疗将准备好进行高级开发，并在或之前达到IND前状态。 循环的结束。

“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.