Repurposing thiosulfate for chlorine gas exposure

重新利用硫代硫酸盐治疗氯气暴露

• 批准号: 10204655
• 负责人: Vikhyat S Bebarta
• 金额: $ 25.26万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-18 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10204655
• 关键词: Acids; Acute; Acute Lung Injury; Antioxidants; Chemical Agents; Chemical Burns; Chemical Warfare Agents; Chloramines; Chlorine; Cyanides; Data; Dose; Drug Kinetics; Edema; Enzymes; Epithelial Cells; Etiology; Exposure to; FDA approved; Family suidae; Gases; Goals; Human; Hydration status; Hydrochloric Acid; Hypochlorite; Hypochlorous Acid; Immune response; Inflammation; Injury; Innate Immune System; Intoxication; Intramuscular; Irritants; Lead; Liquid substance; Lower respiratory tract structure; Lung; Mediating; Membrane; Military Personnel; Modeling; Mole the mammal; Morbidity - disease rate; Nitrogen; Oxidants; Oxidative Stress; Oxygen; Pneumonia; Poison; Poisoning; Population; Property; Pulmonary Edema; Reaction; Regimen; Respiratory Failure; Sodium Hypochlorite; Sulfhydryl Compounds; Sulfur; Testing; Therapeutic; Thiosulfate Sulfurtransferase; Time; Tissues; Ulcer; United States National Institutes of Health; airway epithelium; alveolar epithelium; animal rule; associated symptom; base; cell injury; chemical countermeasure; chemical threat; chlorine gas; clinically relevant; detoxication; effective therapy; efficacy study; functional group; indexing; lung injury; macromolecule; medical countermeasure; mitochondrial dysfunction; mortality; oxidation; oxidative damage; porcine model; prevent; programs; response to injury; sodium thiosulfate; toxic industrial chemical

Chlorine gas is a chemical warfare agent and toxic industrial chemical (TIC) that produces respiratory failure and edema due to chemical burns of the airway and alveolar epithelium. Chemical warfare agents are an important threat to military personnel and civilians. The broad long-term goal of this project is to develop medical countermeasures against chemical agents that produce a lung toxidrome. Chlorine gas and other TICs can elevate oxidative damage leading to cellular injury and inflammation. Cellular injury from chlorine gas exposure is believed to result from its rapid hydration that generates hypochlorous acid (bleach) and hydrochloric acid. Sodium thiosulfate is an FDA approved treatment for cyanide poisoning, but also is used as an effective dechlorinating agent. We hypothesize that the dechlorinating and antioxidant actions of sodium thiosulfate will target hypochlorous acid and hypochloric acid generated during chlorine exposure along with other oxidants that are produced during oxidative stress and inflammation associated with a chlorine gas exposure. We will test our hypothesis with two specific aims. The first aim will develop a swine model of chlorine gas-induced acute lung injury model. The second aim will optimize dose, dose regimen, and rescue window of sodium thiosulfate in this swine model. These data will be used as proof of principle studies to support regulatory approval for the use of sodium thiosulfate as a medical countermeasure for chlorine gas lung injury under the FDA animal rule. If successful this FDA approved product could be rapidly developed as a medical countermeasure against chlorine gas injury.

氯气是一种化学战剂和有毒工业化学品（TIC），可导致呼吸衰竭， 由于气道和肺泡上皮的化学灼伤而引起的水肿。化学战剂是重要的 对军事人员和平民的威胁。该项目的长期目标是发展医疗 对抗产生肺毒素的化学制剂的对策。氯气和其他TIC可以 增加氧化损伤，导致细胞损伤和炎症。氯气暴露的细胞损伤 据信是由于其快速水合产生次氯酸（漂白剂）和盐酸。 硫代硫酸钠是FDA批准的氰化物中毒的治疗方法，但也被用作有效的 脱氯剂我们推测，硫代硫酸钠的脱氯和抗氧化作用， 靶向次氯酸和在氯暴露沿着其它氧化剂期间产生的次氯酸 在与氯气暴露相关的氧化应激和炎症过程中产生。我们将测试 有两个具体目标的假设。第一个目标是建立一种氯气致急性肺损伤的猪模型 损伤模型第二个目标是优化硫代硫酸钠的剂量，剂量方案和挽救窗口。 猪模型这些数据将用作原理研究的证据，以支持监管部门批准使用 根据FDA动物规则，硫代硫酸钠作为氯气肺损伤的医学对策。如果 成功的FDA批准的产品可以迅速发展为一种针对氯的医疗对策 气体伤害。