Cobinamide is superior to other treatments in a mouse model of cyanide poisoning.
BACKGROUND
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, as 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 (Cbi), the precursor to cobalamin (vitamin B(12)), to currently approved cyanide antidotes. Cbi has extremely high affinity for cyanide and substantial solubility in water.


METHODS
We studied Cbi in both an inhaled and intraperitoneal model of cyanide poisoning in mice.


RESULTS
We found Cbi more effective than hydroxocobalamin, sodium thiosulfate, sodium nitrite, and the combination of sodium thiosulfate-sodium nitrite in treating cyanide poisoning. Compared to hydroxocobalamin, Cbi was 3 and 11 times more potent in the intraperitoneal and inhalation models, respectively. Cobinamide sulfite (Cbi-SO(3)) 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 2 min. In range-finding studies, Cbi-SO(3) at doses up to 2000 mg/kg exhibited no clinical toxicity.


CONCLUSIONS
These studies demonstrate that Cbi 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 Cbi-SO(3). Based on these animal data Cbi-SO(3) appears to be an antidote worthy of further testing as a therapy for mass casualties.
Chan
Adriano
A
Department of Medicine, University of California, Medicine Service, VA San Diego Healthcare, 3350 La Jolla Village Drive,San Diego, CA 92161, USA.
Balasubramanian
Maheswari
M
Blackledge
William
W
Mohammad
Othman M
OM
Alvarez
Luis
L
Boss
Gerry R
GR
Bigby
Timothy D
TD
D000280:Administration, Inhalation; D000818:Animals; D000931:Antidotes / Q000627:therapeutic use*; D003038:Cobamides / Q000008:administration & dosage / Q000627:therapeutic use*; D003486:Cyanides / Q000493:pharmacokinetics / Q000506:poisoning*; D004305:Dose-Response Relationship, Drug; D006879:Hydroxocobalamin / Q000627:therapeutic use; D007273:Injections, Intramuscular; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL
D000931:Antidotes; D003038:Cobamides; D003486:Cyanides; C017142:cobinamide; D006879:Hydroxocobalamin