Novel antioxidant therapeutics for sulfur mustard toxicity (U54)

针对硫芥毒性的新型抗氧化疗法 (U54)

• 批准号: 7932390
• 负责人: Carl W White
• 金额: $ 15万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-29 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932390
• 关键词: 2-chloroethyl ethyl sulfide; Acute; Adult Respiratory Distress Syndrome; Affect; Animal Model; Antidotes; Antioxidants; Asthma; Attenuated; Biological Availability; Bronchiectasis; Bronchiolitis Obliterans; Bronchopneumonia; Chemical Weapons; Decontamination; Drug Kinetics; Edema; Effectiveness; Epithelial; Eye; Guidelines; Inflammation; Inflammatory; Intervention; Laboratories; Lead; Liquid substance; Lung; Measurement; Medical; Military Personnel; Mono-S; Mustard; Mustard Gas; Oral; Organ; Pharmaceutical Preparations; Population; Preventive; Pulmonary Fibrosis; Rattus; Recording of previous events; Route; Skin; Stenosis; Sulfhydryl Compounds; Supplementation; Supportive care; Testing; Therapeutic; Thioctic Acid; Thioredoxin; Toxic effect; Toxicology; Tracheobronchomalacia; aerosolized; airway inflammation; analog; cytokine; dithiol; experience; in vivo; lung injury; novel; prevent; respiratory

Description (provided by applicant): Sulfur mustard (HD, mustard gas) is the most highly utilized chemical weapon in history, and currently it poses a serious threat to both military and civilian populations. In addition to stockpiles, HD remains one of the easiest chemical weapons to make in large quantities, and it is included in the list of likely choices for terrorist organizations. HD can be a severely debilitating agent for those exposed to it. The primary organs affected by HD are the lungs, skin and eyes. It results in acute airway edema, ARDS, bronchopneumonia, tracheobronchomalacia and/or airway stenosis, bronchiolitis obliterans, bronchiectasis, pulmonary fibrosis, asthma, and other respiratory complications. There are no specific treatments or antidotes for HD nor preventive medications to minimize its effects. Decontamination and supportive care are the only interventions recommended by current medical guidelines and more of these protect the airways. Decontamination is effective for skin and eyes only if enacted very early (< 5 minutes). Unfortunately, recognition of the problem usually does not occur within this timeframe. We hypothesize that supplementation or augmentation of airway mono- or dithiols will prevent or limit sulfur mustard toxicity. Using an animal model employing 2-chloroethyl ethyl sulfide (CEES, "half-mustard"), a less toxic analog of sulfur mustard, we will: 1) Determine airway inflammation, pro-inflammatory cytokines, and principal thiols following half-mustard aerosolization in rat, 2) evaluate effectiveness of oral and aerosolized mono- (GSH) and dithiols (lipoic acid, thioredoxin) in attenuating halfmustard lung injury (inflammation, cytokines, thiols), 3) develop novel compounds to stimulate mono- and dithiol efflux into lung epithelial lining fluid, and 4) examine the efficacy of these novel compounds in vivo. The latter studies will help us establish optimal compounds, route and mode of delivery, pharmacokinetics, bioavailability, and toxicology. Our laboratories have exceptional experience in measurement of the relevant, potentially protective thiol compounds to be evaluated. We anticipate these studies will lead to testing of the most effective compounds using authentic mustard gas at appropriate facilities.

描述（由申请人提供）：硫磺芥末（HD，芥末气）是历史上使用最高的化学武器，目前对军事和平民构成了严重威胁。除库存外，高清仍然是大量制造的最简单的化学武器之一，并且被包括在恐怖组织可能选择的清单中。高清可能是暴露于它的人的严重使人衰弱的代理。受高清影响的主要器官是肺，皮肤和眼睛。它导致急性气道水肿，ARDS，支气管瘤，气管脑脊液和/或气道狭窄，支气管炎闭塞性，支气管张张，肺纤维化，哮喘和其他呼吸道并发症。没有针对HD或预防药物的特定治疗方法或解毒剂可最大程度地减少其影响。净化和支持护理是当前医疗指南建议的唯一干预措施，其中更多的干预措施保护了气道。仅在非常早（<5分钟）制定时，才能对皮肤和眼睛有效。不幸的是，对问题的识别通常不会在此期限内发生。我们假设补充或增强气道单二硫醇会预防或限制硫芥末毒性。 Using an animal model employing 2-chloroethyl ethyl sulfide (CEES, "half-mustard"), a less toxic analog of sulfur mustard, we will: 1) Determine airway inflammation, pro-inflammatory cytokines, and principal thiols following half-mustard aerosolization in rat, 2) evaluate effectiveness of oral and aerosolized mono- (GSH) and dithiols (lipoic acid,硫氧还蛋白）在减弱半肌肺损伤（炎症，细胞因子，硫醇）中，3）开发新颖的化合物，以刺激单二醇外排入肺上皮衬里，以及4）4）检查这些新颖化合物在体内的效果。后者的研究将帮助我们建立最佳化合物，途径和分娩方式，药代动力学，生物利用度和毒理学。我们的实验室在测量相关的，潜在的保护性硫醇化合物方面具有卓越的经验。我们预计这些研究将导致使用适当设施的正宗芥末气体对最有效的化合物进行测试。