Nitrites as Antidotes for Hydrogen Sulfide Poisoning

描述（由申请人提供）：目前，似乎没有FDA批准的解毒剂和/或治疗急性硫化氢（H2S）中毒的可靠方案。几个州当局发布的紧急医学公告/小册子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包，但缺乏证明这种方法合理的基础科学。此外，有相互矛盾的轶事病例报告证明氰化物治疗的成功和失败，以及补充氧气输送，在已知或怀疑硫化氢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，这两种毒素都是线粒体电子传递链功能的高效干扰剂，对细胞色素c氧化酶具有大致相同的抑制常数（KI）。因此，在开发治疗急性H2S中毒的有效疗法时，最初的努力应针对克服 细胞色素c氧化酶的抑制和相关的快速心肺衰竭。然而，到达诊所的H2S中毒的疑似受害者有时在暴露后数小时死于中毒，这表明细胞色素c氧化酶抑制的毒性机制较慢。因此，我们的具体目标是：目的1：以确定是否亚硝酸钠改善H2S中毒的小鼠通过一种机制，涉及位移的结合HS-从细胞色素c氧化酶的活性位点的NO;目的2：以确定是否补充氧气改善H2S中毒的小鼠时，单独和与亚硝酸钠。各种生物物理方法和行为评估将被应用于调查这些问题，努力开发一个合理的机制基础上使用亚硝酸钠与补充氧气相结合的治疗H2S中毒的协议。

DESCRIPTION (provided by applicant): 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 justif 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 potentil 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.