Nitrites as Antidotes for Hydrogen Sulfide Poisoning

描述（由申请人提供）：目前，似乎没有fda批准的治疗急性硫化氢（H2S）中毒的解毒剂和/或可靠的方案。一些州当局发布的紧急医学公报/小册子建议使用含有亚硝酸盐-硫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，在已知或怀疑H2S是有毒物质的情况下，使用氰化物疗法和补充氧输送疗法的成功和失败也存在相互矛盾的轶事案例报告。当然H2S的毒理学与氰化物有共同的特点；例如，这两种毒素都是线粒体电子传递链功能的高效破坏者，对细胞色素c氧化酶的抑制常数（KI）大致相同。因此，在开发治疗急性H2S中毒的潜在疗法时，最初的努力应该针对克服

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.