Nitrites as Antidotes for Hydrogen Sulfide Poisoning

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（H2S）中毒。几个州发布的急诊医学公告/小册子 当局建议使用氰化物解毒剂包含有亚硝酸盐硫代硫酸盐，或钴胺素，但基本的 目前还缺乏证明这种做法合理性的科学依据。此外，有相互矛盾的轶事病例报告， 证明了氰化物疗法的成功和失败，以及补充氧气， 在已知或怀疑H2S是有毒物质的情况下使用。当然 H2S的毒理学与氰化物的毒理学具有共同的特征;例如，这两种毒素都是高度毒性的。 线粒体电子传递链功能的有效干扰物，具有大致相同的 细胞色素c氧化酶的抑制常数（KI）。因此，在开发潜在的治疗方法时， 治疗急性H2S中毒，最初的努力应针对克服抑制， 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 到达临床的H2S中毒有时在暴露后数小时死于中毒， 这表明毒性机制的缓慢性附属于细胞色素c氧化酶抑制。因此，我们的 具体目的是：目的1：确定亚硝酸钠是否改善小鼠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-， 目的2：确定补充氧气是否能改善小鼠H2S中毒， 单独使用和与亚硝酸钠联合使用。各种生物物理方法和行为 将对这些问题进行评估，以制定处理H2S的方案 中毒的合理机制的基础上使用亚硝酸钠结合补充氧气。

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.