Intramuscular Cobinamide Sulfite in a Rabbit Model of Sublethal Cyanide Toxicity

Abstract

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.

Cobinamides Are Novel Coactivators of Nitric Oxide Receptor That Target Soluble Guanylyl Cyclase Catalytic Domain

“…These data indicate that CN2-Cbi may be a prototype for a novel type of sGC-regulating therapeutic agent. It is unlikely that physiological concentrations of circulating cobinamides (Ͻ30 pM) or B 12 vitamins (ϳ300 pM) (Hardlei and Nexo, 2009) have any effects on sGC func- Because of high affinity to cyano groups, cobinamides are used for cyanide detoxification (Broderick et al, 2006) and doses of 800 mg/kg are deemed safe for laboratory animals (Brenner et al, 2010). Previous studies reported that nitrosyl-cobinamide functions as an NO donor (Broderick et al, 2007), increasing vasodilation and vasodilator-stimulated phosphoproteinphosphorylation, presumably through NO-dependent activation of sGC.…”

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…”

Intraosseous Versus Intravenous Infusion of Hydroxocobalamin for the Treatment Of Acute Severe Cyanide Toxicity in a Swine Model

“…It is difficult to perform it in the dark, and conditions such as shock or wearing personal protective equipment may warrant alternative routes to IV delivery. 8,9 Federal research agencies have also requested non-IV administration of chemical countermeasures, with particular emphasis on the intramuscular route. 10 Hydroxocobalamin cannot be administrated intramuscularly because of the large volume of fluid required for administration.…”

“…[5][6][7] However, in a mass casualty incident or after a structure fire involving many victims, rapid administration by non-IV routes are needed. 8 IV administration requires skilled personnel and fatigable dexterity. It is difficult to perform it in the dark, and conditions such as shock or wearing personal protective equipment may warrant alternative routes to IV delivery.…”