Development of antidotes for toxic gases

“有毒气体解毒剂的发展” 该计划的目标是创建一个系统的过程，以开发针对有毒气体的解毒剂 通过利用由Entifed支持的内科-科学家团队经过验证的记录来生产化学品 基础科学家。我们将检查由该病毒引起的两种急性肺毒素和心肺毒素。 具有共同伤害机制的气体化学品：1)烷化剂、硫芥末(SM)和甲基 异氰酸酯(MIC)，可导致DNA交联/损伤、细胞凋亡、呼吸道上皮和内皮损伤， 急性肺损伤和纤维化，以及2)快速吸收气体、甲硫醇(CH3SH)和氰化物(HCN)， 会导致全身性线粒体衰竭。这些有毒化学物质的选择是基于：1)导致 危重疾病和死亡，2)感知到的威胁(S)，3)最近和/或重要的过去接触，以及4)优先事项 NIH/反政府组织、BARDA、国防部和国际社会。治疗在项目1，3， 和4是针对大规模伤亡情况的救援对策。其中两个(项目1和3) 是为急性吸入事故或灾难而设计的。在项目1中，对于MIC，有三种治疗方法 针对受体介导的(Trp通道拮抗剂(S))，凝血相关(纤溶酶原激活物(S))，以及 生化(硫醇化合物)事件将在一种新的临床前急性吸入模型中进行调查。 治疗将用于立即/延迟治疗，包括肌肉内、呼吸道、肠内和/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，将通过口服/呼吸道给药对抗纤维化药物吡非尼酮和奈替丹尼进行评估。 亚致死剂量SM暴露后大鼠的纤维化慢性肺病模型。 类似的可比酰胺和硫代硫酸钠，两者都直接与甲硫醇反应，将被测试为 在小鼠、兔和猪模型中对抗这种剧毒气体的对策。在项目4中，一种纳米颗粒- 相关可比胺(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。由于口服NaCN在胃粘膜以气体(HCN)的形式被吸收，而且由于 受害者往往会昏迷不醒，会用洗胃的方式送货。具体目标是：1)确定 色氨酸通道拮抗剂、纤溶酶原激活剂和硫醇降低呼吸道损伤和致死率的可能性 2)确定吡非尼酮和其他抗纤维化药物对呼吸道和 吸入丹参后肺实质纤维化；3)建立CBN和硫代硫酸盐的动物救治效果 和4)测试不可吸收纳米制剂的潜在疗效 比较CBN与其他CBN制剂和途径在口服NaCN中毒和致死模型中的作用。成功 来自每个项目的疗法将准备好进行高级开发，并在或之前达到Pre-IND状态 循环的末尾。

“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.