Summary
Context
Cyanide poisoning is a major contributor to death in smoke inhalation victims and
accidental exposure to cyanide occurs in a variety of industries. Moreover, cyanide has the
potential to be used by terrorists, particularly in a closed space such as an airport or train station.
Current therapies for cyanide poisoning must be given by intravenous administration, limiting
their use in treating mass casualties.
Objective
We are developing two new cyanide antidotes—cobinamide, a vitamin B12 analog,
and sulfanegen, a 3-mercaptopyruvate prodrug. Both drugs can be given by intramuscular
administration, and therefore could be used to treat a large number of people quickly. We now
asked if the two drugs would have an augmented effect when combined.
Materials and Methods
We used a non-lethal and two different lethal models of cyanide
poisoning in mice. The non-lethal model assesses neurologic recovery by quantitatively evaluating
the innate righting reflex time of a mouse. The two lethal models are a cyanide injection and a
cyanide inhalation model.
Results
We found that the two drugs are at least additive when used together in both the nonlethal and lethal models: at doses where all animals died with either drug alone, the combination
yielded 80 and 40% survival in the injection and inhalation models, respectively. Similarly, drug
doses that yielded 40% survival with either drug alone yielded 80 and 100% survival in the
injection and inhalatiion models, respectively. As part of the inhalation model, we developed a
new paradigm in which animals are exposed to cyanide gas, injected intramuscularly with
antidote, and then re-exposed to cyanide gas. This simulates cyanide exposure of a large number
of people in a closed space, because people would remain exposed to cyanide, even after receiving
an antidote.
Conclusion
The combination of cobinamide and sulfanegen shows great promise as a new
approach to treating cyanide poisoning.
Keywords: Inhalation exposure; intramuscular injection; lethal model; non-lethal model
