Nitrites as Antidotes for Hydrogen Sulfide Poisoning

描述(申请人提供)：目前，似乎还没有FDA批准的解毒剂和/或可靠的方案来治疗急性硫化氢中毒。几个州当局发布的紧急药物公报/小册子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，有相互矛盾的轶事案例报告证明氰化物疗法的成功和失败，以及在已知或怀疑硫化氢是毒剂的情况下使用的补充氧气输送。当然，硫化氢的毒理学特征与氰化物有共同的特征；例如，这两种毒素都是线粒体电子传递链功能的高效干扰物，对细胞色素C氧化酶的抑制常数(KI)大致相同。因此，在开发治疗急性硫化氢中毒的潜在疗法时，最初的努力应该指向克服 细胞色素c氧化酶的抑制和相关的快速心肺衰竭。然而，到达临床的硫化氢中毒的疑似受害者有时会在接触几个小时后死于中毒，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：目标1：确定亚硝酸钠是否通过NO取代细胞色素C氧化酶活性部位的结合HS-的机制来缓解小鼠的硫化氢中毒；目标2：确定单独和与亚硝酸钠联合使用时，补充氧气是否能缓解小鼠的硫化氢中毒。将应用各种生物物理方法和行为评估来调查这些物质，以努力制定一种合理的机制基础上使用亚硝酸钠和补充氧气来治疗硫化氢中毒的方案。

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.