Context Cyanide is a rapidly acting cellular poison, primarily targeting cytochrome c oxidase, and is a common occupational and residential toxin, mostly via smoke inhalation. Cyanide is also a potential weapon of mass destruction, with recent credible threats of attacks focusing the need for better treatments, since current cyanide antidotes are limited and impractical for rapid deployment in mass casualty settings. Objective We have used mouse models of cyanide poisoning to compare the efficacy of cobinamide, the precursor to cobalamin (vitamin B12), to currently approved cyanide antidotes. Cobinamide has extremely high affinity for cyanide and substantial solubility in water. Materials and Methods We studied cobinamide in both an inhaled and intraperitoneal model of cyanide poisoning in mice. Results We found cobinamide more effective than hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the combination of sodium thiosulfate-sodium nitrite in treating cyanide poisoning. Compared to hydroxocobalamin, cobinamide was 3 and 11 times more potent in the intraperitoneal and inhalation models, respectively. Cobinamide sulfite was rapidly absorbed after intramuscular injection, and mice recovered from a lethal dose of cyanide even when given at a time when they had been apneic for over two minutes. In range finding studies, cobinamide sulfite at doses up to 2000 mg/kg exhibited no clinical toxicity. Discussion and Conclusion These studies demonstrate that cobinamide is a highly effective cyanide antidote in mouse models, and suggest it could be used in a mass casualty setting, because it can be given rapidly as an intramuscular injection when administered as cobinamide sulfite. Based on these animal data cobinamide sulfite appears to be an antidote worthy of further testing as a therapy for mass casualties.

Objective To determine the ability of an intramuscular cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity. Background Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B12) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigated the use of intramuscular cobinamide sulfite to reverse cyanide toxicity induced physiologic changes in a sublethal cyanide exposure animal model. Methods New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous wave near infrared spectroscopy monitoring of tissue oxy- and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with cobinamide sulfite (n=6) or inactive vehicle (controls, n=5). Results Intramuscular administration led to rapid mobilization of cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system was in a mean of 1032 minutes in the control group and 9 minutes in the cobinamide group with a difference of 1023 minutes (95% confidence interval [CI] 116, 1874 minutes). In muscle tissue, recovery times were 76 and 24 minutes with a difference of 52 minutes (95% CI 7, 98min). Red blood cell cyanide levels returned towards normal significantly faster in cobinamide sulfite-treated animals than in control animals. Conclusions Intramuscular cobinamide sulfite rapidly and effectively reverses the physiologic effects of cyanide poisoning, suggesting that a compact cyanide antidote kit can be developed for mass casualty cyanide exposures.

Cyanide, a well-known toxic substance that could be used as a weapon of mass destruction, is likely responsible for a substantial percentage of smoke inhalation deaths. The vitamin B 12 precursor cobinamide binds cyanide with high affinity, changing color and, correspondingly, its spectrophotometric spectrum in the ultraviolet/visible light range. Based on these spectral changes, we developed a new facile method to measure cyanide in blood using cobinamide. The limit of detection was 0.25 nmol, while the limit of quantitation was ~ 0.5 nmol. The method was reliable, requires minimal equipment, and correlated well with a previously established method. Moreover, we adapted it for rapid qualitative assessment of cyanide concentration, which could be used in the field to identify cyanide-poisoned subjects for immediate treatment.