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.

抽象的 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（H2S）中毒。多个州发布的急诊医学公告/小册子 当局建议使用含有亚硝酸盐-硫代硫酸盐或钴胺素的氰化物解毒剂套件，但基本的 目前缺乏科学证据来证明这种方法的合理性。此外，还有相互矛盾的轶事案例报告 证明氰化物疗法以及补充氧气的成功和失败 输送，用于已知或怀疑 H2S 是有毒物质的情况。当然是 H2S 的毒理学与氰化物的毒理学有共同特征；例如，这两种毒素都高度 线粒体电子传递链功能的有效破坏者，具有大致相同的 细胞色素 c 氧化酶的抑制常数 (KI)。由此可见，在开发潜在的治疗方法时 治疗急性 H2S 中毒，首先应努力克服对 H2S 的抑制 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 H2S 中毒有时会在接触后数小时内中毒， 表明细胞色素c氧化酶抑制所伴随的较慢的毒性机制。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 H2S 中毒 通过一种机制，涉及从细胞色素 c 氧化酶的活性位点置换结合的 HS- 不;目标 2：确定补充氧气是否可以改善小鼠的 H2S 中毒 单独使用或与亚硝酸钠联合使用。多种生物物理方法和行为 评估将用于调查这些问题，以制定治疗 H2S 的方案 使用亚硝酸钠结合补充氧气在合理的机制基础上进行中毒。