Repurposing thiosulfate for chlorine gas exposure

重新利用硫代硫酸盐治疗氯气暴露

基本信息

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
项目类别：
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

项目摘要

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)，会导致呼吸衰竭和由于气道和肺泡上皮的化学烧伤而引起的水肿。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针对产生肺中毒症的化学制剂的对策。氯气和其他 TIC 可以增加氧化损伤，导致细胞损伤和炎症。接触氯气造成的细胞损伤据信，这是由于其快速水合产生次氯酸（漂白剂）和盐酸的结果。硫代硫酸钠是 FDA 批准的治疗氰化物中毒的药物，但也被用作有效的脱氯剂。我们假设硫代硫酸钠的脱氯和抗氧化作用将目标次氯酸和氯暴露过程中产生的次氯酸以及其他氧化剂，在与氯气暴露相关的氧化应激和炎症过程中产生。我们将测试我们的有两个特定目标的假设。第一个目标是开发氯气引起的急性肺病的猪模型伤害模型。第二个目标是优化硫代硫酸钠的剂量、剂量方案和救援窗口。猪模型。这些数据将用作原理研究的证明，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疗对策。如果该 FDA 批准的成功产品可以作为抗氯的医疗对策迅速开发气伤。