Publication Type:Journal Article
Source:Journal of medicinal chemistry, Volume 58, Issue 4, p.1750-9 (2015)
Keywords:Animals, Antidotes, Cercopithecus aethiops, Cobamides, COS Cells, Cyanides, Dose-Response Relationship, Drug, Injections, Intramuscular, Male, Mice, Mice, Inbred C57BL, Muscle, Skeletal, Rabbits, Sodium Nitrite, Structure-Activity Relationship, Thiosulfates, Time Factors
Currently available cyanide antidotes must be given by intravenous injection over 5-10 min, making them ill-suited for treating many people in the field, as could occur in a major fire, an industrial accident, or a terrorist attack. These scenarios call for a drug that can be given quickly, e.g., by intramuscular injection. We have shown that aquohydroxocobinamide is a potent cyanide antidote in animal models of cyanide poisoning, but it is unstable in solution and poorly absorbed after intramuscular injection. Here we show that adding sodium nitrite to cobinamide yields a stable derivative (referred to as nitrocobinamide) that rescues cyanide-poisoned mice and rabbits when given by intramuscular injection. We also show that the efficacy of nitrocobinamide is markedly enhanced by coadministering sodium thiosulfate (reducing the total injected volume), and we calculate that ∼1.4 mL each of nitrocobinamide and sodium thiosulfate should rescue a human from a lethal cyanide exposure.