Cobinamide is used generically, without specifying the ligand(s) bound to the cobalt atom. The structures of aquohydroxocobinamide ( a) and dinitrocobinamide ( b) are shown. We investigated the effectiveness of both cobinamide species in this study. While dinitrocobinamide is better absorbed after intramuscular injection than aquohydroxocobinamide, the two species may not show differential absorption from the gastrointestinal tract. 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 (Fig. This consideration must be addressed for gastric administration. However, cobinamide binding of cyanide is pH dependent, with pH > 4 required for effective binding (binding is complete at pH 6–7). The extraordinarily high-binding constant of cobinamide for cyanide allows efficient cyanide neutralization and is the basis for cobinamide’s potential use to neutralize a large dose of gastro-intestinal cyanide. This leads to several major chemical differences between cobinamide and hydroxocobalamin: (i) each cobinamide molecule can bind two ligands compared to one for hydroxocobalamin, (ii) cobinamide has a much higher affinity for ligands than hydroxocobalamin due to release of a negative trans effect of the bulky dimethylbenzimidiazole group, and (iii) cobinamide is considerably more water soluble than hydroxocobalamin. In addition to a lack of drugs for treating a large number of cyanide-poisoned victims, no effective methods exist for neutralizing large gastrointestinal cyanide reservoirs following oral ingestion.Ĭobinamide is the penultimate precursor in hydroxocobalamin biosynthesis, lacking the dimethylbenzimidazole ribonucleotide group coordinated to the lower axial position of the cobalt atom.

Intramuscular injection volumes are limited to a maximum of ~4 mL, and systemically administered doses of antidote will be limited by the drug’s side effects. Consequently, much larger antidote doses will be necessary. However, for oral ingestions, effects are delayed enough that much larger ingestions can occur. 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. We have been developing cobinamide as a cyanide antidote it can be administered rapidly in small volumes by intramuscular injection. Treatment of cyanide poisoning includes three general classes of agents: methemoglobin generators and nitric oxide (NO) donors (sodium nitrite, amyl nitrite, and dimethyl aminophenol), sulfur donors (sodium thiosulfate and glutathione), and direct binding agents (hydroxocobalamin and dicobalt edetate). In this study, we investigated a treatment approach that could be directed to casualties from oral cyanide ingestion. Moreover, a large reservoir of gastrointestinal cyanide can potentially be prevented from being absorbed following oral ingestion. Despite very rapid cyanide absorption from the gastrointestinal tract, oral cyanide exposure is more amenable to treatment than inhalation exposure, due to a longer time from exposure to poisoning: death following oral cyanide ingestion can provide therapeutic windows of 30 min to hours, compared to less than 10 min for inhaled cyanide. It would be relatively simple for terrorists to poison water supplies, and prior threats have been uncovered. While effective antidotes are available for treating individual victims, no antidote presently exists for a mass casualty scenario or for very large dose of oral ingestions, since current antidotes must be given intravenously in large volumes of fluid.

Oral ingestion or inhalation of cyanide can cause irreversible injury or death within minutes of exposure. The cyanide threat from terrorism and industrial accidents is a major concern of the US civilian and military chemical defense programs. Cyanide is inexpensive and readily accessible, with more than 5.2 billion pounds produced annually worldwide.

Doses as little as 50 mg may be fatal to humans. Cyanide poisoning can occur in a variety of settings for example, accidental exposure from industrial events, inhalation of combustion products, acts of terrorism, or chemical warfare.

Cyanide antidote kit amyl nitrite