The combination of cobinamide and sulfanegen is highly effective in mouse models of cyanide poisoning

Abstract

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 non-lethal 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.

Nitrocobinamide, a New Cyanide Antidote That Can Be Administered by Intramuscular Injection

“…Since no nitrite was present in these experiments, and we have previously shown that sulfite has no antidotal effect against cyanide, we conclude that thiosulfate augments cobinamide. 25 …”

Reactions of Cobinamide with Glucose and Fructose

“…[14] Cobinamide (Cbi, Figure 1b) is a cobalamin derivative lacking DMBI moiety. Recently this compound has attracted researchers' interests due to the high efficacy of its derivatives as cyanide antidotes (sulfitocobinamide) [15][16][17] and cyanide chemosensors (monocyanocobinamide). [18][19][20] Cbi application is also of interest in the study of both Co 3+ → Co 2+ and Co…”

Sodium Nitrite and Sodium Thiosulfate Are Effective Against Acute Cyanide Poisoning When Administered by Intramuscular Injection

“…Our goal was to rigorously assess if sodium nitrite and sodium thiosulfate are effective when administered by intramuscular injection by testing them in three well-established lethal mammalian models of cyanide poisoning: ( i ) a mouse model of inhalational cyanide exposure that simulates a scenario of gaseous cyanide poisoning (8;10;11); ( ii ) a rabbit model where severe hypotension is the trigger for treatment (9;12;13), and ( iii ) a pig model where apnea is the trigger for treatment (14-16). …”