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

Abstract

Currently available cyanide antidotes must be given by intravenous injection over 5–10 min, making them illsuited 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.

Decellularized skeletal muscle as an in vitro model for studying drug-extracellular matrix interactions

“…The affinity (K a ) of each of these three ligands for cobinamide is very different, ranging over a large log scale: K a overall for cyanide is ~ 10 22 M −2 , K a for sulfite is ~ 10 11 M −1 , and K a overall for nitrite is ~ 10 5 M −2 [overall affinity includes the affinity for each of the two cyanide and nitrite ligands [16]. Thus, cobinamide very readily binds cyanide, becoming saturated with two cyanide groups even at a relatively low cyanide to cobinamide ratio, whereas a much higher nitrite to cobinamide ratio is required to saturate cobinamide with two bound nitrite groups [17]. Saturation with sulfite is intermediate to that of cyanide and nitrite.…”

The Vitamin B12 Analog Cobinamide Is an Effective Antidote for Oral Cyanide Poisoning

“…Dinitrocobinamide was prepared from hydroxocobalamin as previously described [20]. Aquohydroxocobinamide was prepared from dinitrocobinamide by reducing the cobalt atom to the +1 valency state using sodium borohydride; this simultaneously removes nitrite from cobinamide and reduces nitrite to nitric oxide.…”

“…We have shown that both aquohydroxocobinamide (water and hydroxyl molecules bound to the cobalt atom) and dinitrocobinamide (two nitrite groups bound to the cobalt atom) are effective cyanide antidotes [12,15,17,20] (Fig. 1).…”

“…1). While dinitrocobinamide is better absorbed after intramuscular injection than aquohydroxocobinamide [20], the two species may not show differential absorption from the gastrointestinal tract. We investigated the effectiveness of both cobinamide species in this study.…”

“…We have been developing cobinamide as a cyanide antidote; it can be administered rapidly in small volumes by intramuscular injection [12][13][14][15][16][17][18]. Cobinamide is a promising cyanide antidote, capable of reversing LD 80-100 level exposures with an intramuscular (or intravenous) injection of~1 mL in rabbit models, and equivalently adjusted volumes in other animal models [12][13][14][15][16][17][18][19][20]. However, for oral ingestions, effects are delayed enough that much larger ingestions can occur [10].…”