Drawing on past experience of gaseous HCN poisoning through smoke inhalation, it is clear that many treatable individuals (mass casualties) will present at triage more than 30 min after exposure still exhibiting signs of acute cyanide toxicity. Compounds that lower the circulating level of free cyanide in the bloodstream have been shown to be effective antidotes to cyanide poisoning in such cases. Cobalamin and a sodium nitrite/thiosulfate combination are currently the only FDA-approved cyanide antidotes for emergency and clinic use, but they are far from ideal and cobalamin is expensive. There are some other potential cyanides antidotes in reasonably advanced stages of development, but none are without serious issues, particularly in relation to mass-casualty applications. Cobinamide, the biological precursor of cobalamin, is significantly toxic, ?-ketoglutarate requires extremely high doses for efficacy, while the active sulfur- containing compounds like sulfanegens have stability problems. Hypothesizing that many compounds in which cobalt(II/III) is surrounded by a square-planar arrangement of nitrogen- donors with two labile ligands in the axial positions might be good candidate antidotes for cyanide poisoning, we have now shown that several inexpensive complexes of cobalt(II/III) having this necessary surrounding ligand geometry are, indeed, impressively antidotal and appear to be non- toxic at the levels required to be efficacious in treating cyanide intoxication. At least some of these are also antidotal toward azide intoxication. During an earlier project (U01 NS063732: 9/08- 6/11) we demonstrated that sodium nitrite (and other NO donors) reverse cyanide inhibition of cytochrome c oxidase via a mechanism involving displacement of cyanide bound at the active site by NO ? independent of methemoglobin formation. Consequently, we now propose a combination of (i) NO donor to reverse inhibition of oxidative phosphorylation by cyanide and (ii) easily synthesized cobalt-based decorporating agents to bind the released cyanide in non-toxic forms for excretion. The antidotes will are inexpensive, some stable enough for stockpiling under ambient conditions and suitable for self-administration, or with the help untrained assistants. We have the following Specific Aims:
Aim 1. Show that some easily prepared cobalt complexes are candidate cyanide antidotes with scavenging properties better than those of hydroxocobalamin and at least comparable to those of cobinamide.
Aim 2. Show that the combined therapy (new cobalt complexes + NO donor) is better than either alone in cases of acute cyanide poisoning.
Aim 3. Demonstrate in mice that the new decorporating agents scavenge cyanide in the bloodstream and are then excreted in the urine (or feces) with toxicant bound.
Aim 4. Show that the proposed combined therapy does not lead to undesirable long-term sequelae in mice.
The release of HCN by acid treatment of cyanide salts is a fairly low-tech potential terrorist weapon that could be devastating in modern buildings and mass transport systems with air re-circulating systems. Infusion of sodium azide into beverages at retail outlets like supermarkets and restaurants, or domestic water supplies, could be similarly effective. Cyanide and azide salts are stockpiled throughout the US for manufacturing and mining purposes rendering the possibility of such attacks and/or accidents especially worrisome. Treating inhalation exposures with cyanide - decorporating (-scavenging) agents is a proven therapy, but the presently available (FDA labeled) compound, cobalamin, is a complicated biomolecule that is expensive to produce and does not have particularly high affinity for cyanide. There is presently no treatment beyond supportive care available for azide poisoning. Cognizant of the long-term desirability of easy mass production and stockpiling, we propose to develop a new class of cyanide/azide-decorporating agent that can be synthesized in no more than two steps and requiring only inexpensive starting materials.
