Nitrites as Antidotes for Hydrogen Sulfide Poisoning

亚硝酸盐作为硫化氢中毒的解毒剂

• 批准号: 8607741
• 负责人: LINDA L PEARCE
• 金额: $ 36.97万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8607741
• 关键词: Active Sites; Acute; Address; Adolescent; Adult; Affect; Affinity; Animal Testing; Animals; Anions; Antidotes; Basic Science; Behavior assessment; Binding; Binding Sites; Biochemistry; Biological Assay; Blood; Blood Circulation; Breathing; Cardiac; Cardiopulmonary; Case Study; Cessation of life; Chemicals; Clinic; Cobalamin; Conflict (Psychology); Control Animal; Cultured Cells; Cyanides; Development; Dose; Drug Metabolic Detoxication; Effectiveness; Electron Transport; Emergency Medicine; Enzymes; Equilibrium; Euthanasia; Event; FDA approved; Failure; Female; Hemeproteins; Hemoglobin; Hour; Household; Hydrogen Sulfide; Impairment; Internet; Intoxication; Measurement; Measures; Methods; Mitochondria; Mus; Musculoskeletal; Myoglobin; Neurologic; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitrites; Oxygen; Pamphlets; Pathway interactions; Poisoning; Positioning Attribute; Procedures; Process; Production; Protocols documentation; Puncture procedure; Recovery; Reporting; Rotarod Performance Test; Sampling; Site; Sodium Nitrite; Suicide; Sulfides; Testing; Therapeutic; Time; Toxic effect; Toxicology; Toxin; Treatment Protocols; Whole Blood; authority; base; compare effectiveness; cytochrome c oxidase; enzyme substrate; foot; knock-down; oxidation; pregnant; prevent; public health relevance; research study; success; weapons

Abstract At this time, there appears to be no FDA-approved antidote and/or reliable protocol for treating acute hydrogen sulfide (H2S) poisoning. Emergency medicine bulletins/pamphlets issued by several state authorities suggest the use of cyanide antidote kits containing nitrite-thiosulfate, or cobalamin, but the basic science that would justify this approach is lacking. Moreover, there are conflicting anecdotal case reports attesting to both the success and failure of cyanide therapeutics, together with supplemental oxygen delivery, employed in situations where H2S was known or suspected to be the toxic agent. Certainly the toxicology of H2S shares features in common with that of cyanide; for instance, both toxins are highly efficient disruptors of mitochondrial electron-transport chain function, with approximately identical inhibition constants (KI) for cytochrome c oxidase. It follows that in developing potential therapies for treating acute H2S intoxication, initial efforts should be directed toward overcoming inhibition of cytochrome c oxidase and the associated rapid cardiopulmonary collapse. However, suspected victims of H2S intoxication reaching the clinic sometimes succumb to the poisoning hours after the exposure, indicating slower mechanisms of toxicity subsidiary to cytochrome c oxidase inhibition. Accordingly, our specific aims are: Aim 1: To determine whether sodium nitrite ameliorates H2S intoxication in mice through a mechanism involving displacement of bound HS- from the active site of cytochrome c oxidase by NO; Aim 2: To determine whether supplemental oxygen ameliorates H2S intoxication in mice when given both alone and in conjunction with sodium nitrite. A variety of biophysical methods and behavioral assessment will be applied to investigating these matters in an effort to develop a protocol for treating H2S poisoning on a rational mechanistic basis using sodium nitrite in combination with supplemental oxygen.

摘要 目前，似乎没有FDA批准的解毒剂和/或可靠的治疗方案 急性硫化氢中毒。几个州发布的急诊医学公报/小册子 当局建议使用含有亚硝酸盐-硫代硫酸盐或钴胺的氰化物解毒剂试剂盒，但基本的 缺乏为这种方法辩护的科学依据。此外，也有相互矛盾的轶事报道。 证明氰化物疗法的成功和失败，以及补充氧气 交付，在已知或怀疑是毒剂的情况下使用。当然是那个 硫化氢的毒理学特征与氰化物有相同的特征；例如，这两种毒素都有很高的 线粒体电子传递链功能的有效干扰物，大致相同 细胞色素C氧化酶的抑制常数(Ki)。由此得出结论，在开发潜在的治疗方法时 治疗急性硫化氢中毒，最初的努力应该是克服抑制 细胞色素c氧化酶和相关的快速心肺衰竭。然而，疑似受害者 到达诊所的硫化氢中毒有时会在接触几小时后屈服于中毒， 表明伴随细胞色素c氧化酶抑制的毒性机制较慢。因此，我们的 具体目标是：目标1：确定亚硝酸钠是否能改善小鼠的硫化氢中毒 通过一种涉及结合的HS-从细胞色素C氧化酶的活性部位置换的机制 否；目标2：确定补充氧气是否能改善小鼠的硫化氢中毒 可单独使用，也可与亚硝酸钠联合使用。各种生物物理方法和行为 评估将用于调查这些问题，以努力制定处理硫化氢的方案 在合理的机械基础上使用亚硝酸钠和补充氧气进行中毒。