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.
Methods for generating hydrogen sulfide (H2S) from household chemicals have been publicized through the Internet and there has been a report of suicide by H2S inhalation in an apartment building where dozens of other residents, not in the immediate vicinity of the release site, were affected. These and other developments have recently led to a growing concern that H2S might find application as a terrorist weapon but there currently appears to be no FDA-approved antidote and/or reliable protocol for treating acute H2S poisoning. We propose to develop a protocol for treating H2S poisoning on a rational mechanistic basis using sodium nitrite in combination with supplemental oxygen.
|Cronican, Andrea A; Frawley, Kristin L; Ahmed, Humza et al. (2015) Antagonism of Acute Sulfide Poisoning in Mice by Nitrite Anion without Methemoglobinemia. Chem Res Toxicol 28:1398-408|
|Cambal, Leah K; Weitz, Andrew C; Li, Hui-Hua et al. (2013) Comparison of the relative propensities of isoamyl nitrite and sodium nitrite to ameliorate acute cyanide poisoning in mice and a novel antidotal effect arising from anesthetics. Chem Res Toxicol 26:828-36|