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.

“有毒气体的解毒剂的发展” 该计划的目的是创建一个系统的过程，以开发针对有毒气候的解毒剂 通过利用由成就的支持者的成熟团队的验证记录来实现的化学品。 基础科学家。我们将检查由由急性肺和心肺扭曲 共有共同损伤机制的气态化学物质：1）烷基化剂，硫芥末（SM）和甲基 异氰酸酯（MIC），会导致DNA交联/损伤，凋亡，气道上皮和内皮损伤， 急性肺损伤和纤维化，以及2）迅速吸收的气体，甲基汞（CH3SH）和氰化物（HCN）， 这会导致系统性线粒体衰竭。这些有毒化学物质是根据：1）引起的能力 重症疾病和死亡，2）感知的威胁，3）最近和/或重要的过去暴露，以及4）优先事项 NIH/Counter，Barda，DoD和国际社会。在项目1、3中进行疗法， 和4旨在作为大规模休闲场景的救援对策。其中两个（项目1和3） 在项目1中，用于麦克风，三类疗法 针对接收器介导的（TRP通道拮抗剂（S）），与凝血相关（纤溶酶原激活剂（S））和 生化（硫醇化合物）事件将在新的临床前急性吸入模型中进行研究。 疗法将用于立即/延迟治疗，并使用肌内，气道和肠内和/或 TRP通道拮抗剂，纤溶酶原激活剂和硫醇化合物的静脉输送。 在项目2中，将通过口服/气道在A中评估抗纤维化药物Pirfenidone和Nintedanib s sm暴露后大鼠的纤维化慢性肺疾病模型。”在项目3中，维生素B12 类似于类似于甲基硫酸钠，两者都直接与甲基近胃反应，将测试为 对抗小鼠，兔子和猪模型中这种急性有毒气体的对策。在项目4中，纳米颗粒 - 相关的核酰胺（CBN）将被评估为口服NACN中毒的急性救援对策 兔子和猪模型。因为口服NaCN被吸收为胃粘膜的气体（HCN），并且由于 磨碎通常不会有意识，将使用胃灌洗。具体目的是：1）确定 TRP通道拮抗剂，纤溶酶原激活剂和硫醇的潜力减少气道损伤和致死性 麦克风吸入后； 2）定义吡非酮和其他针对气道和其他抗纤维化药物的效率 吸入SM后实质性肺纤维化； 3）建立CBN和硫代硫酸盐的效率以营救动物 从致命的甲基马c暴露和4）测试不可吸收的纳米制剂的潜在有效性 在口服NACN中毒和致死性模型中，CBN与其他CBN的制剂和路线。成功的 每个项目的疗法将准备好进行高级开发，并在 周期结束。