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

Abstract

Introduction Cyanide is a major chemical threat, and cyanide ingestion carries a higher risk for a supra-lethal dose exposure compared to inhalation but provides an opportunity for effective treatment due to a longer treatment window and a gastrointestinal cyanide reservoir that could be neutralized prior to systemic absorption. We hypothesized that orally administered cobinamide may function as a high-binding affinity scavenger and that gastric alkalinization would reduce cyanide absorption and concurrently increase cobinamide binding, further enhancing antidote effectiveness. Methods Thirty New Zealand white rabbits were divided into five groups and were given a lethal dose of oral cyanide poisoning (50 mg). The survival time of animals was monitored with oral cyanide alone, oral cyanide with gastric alkalinization with oral sodium bicarbonate buffer (500 mg), and in combination with either aquohydroxocobinamide or dinitrocobinamide (250 mM). Red blood cell cyanide concentration, plasma cobinamide, and thiocyanate concentrations were measured from blood samples.Results In cyanide ingested animals, oral sodium bicarbonate alone significantly prolonged survival time to 20.3 ± 8.6 min compared to 10.5 ± 4.3 min in saline-treated controls, but did not lead to overall survival. Aquohydroxocobinamide and dinitrocobinamide increased survival time to 64 ± 41 (p < 0.05) and 75 ± 16.4 min (p < 0.001), respectively. Compared to aquohydroxocobinamide, dinitrocobinamide showed greater systemic absorption and reduced blood pressure. Dinitrocobinamide also markedly increased the red blood cell cyanide concentration. Under all conditions, the plasma thiocyanate concentration gradually increased with time. Conclusion This study demonstrates a promising new approach to treat high-dose cyanide ingestion, with gastric alkalinization alone and in combination with oral cobinamide for treating a supra-lethal dose of orally administered cyanide in rabbits.

Behavioural and physiological assessments of dimethyl trisulfide treatment for acute oral sodium cyanide poisoning

“…Oral cyanide has also been used in rabbits for the assessment of cobinamide efficacy . Similar to the current experiment, sodium cyanide was used as the challenge agent, though it was given via feeding tube to anaesthetized rabbits.…”

“…Both the dinitrocobinamide and aquohydroxocobinamide were then also given via gastric tube, with the rationale that a treatment that could be given IM as well as orally would improve the antidote's usefulness in a mass‐casualty scenario. The authors found that a single dose of dinitrocobinamide or aquohydroxocobinamide co‐administered with bicarbonate increased survival from 0% to 50% and 67%, respectively …”

“…33 Oral cyanide has also been used in rabbits for the assessment of cobinamide efficacy. 34 Similar to the current experiment, sodium cyanide was used as the challenge agent, though it was given via feeding tube to anaesthetized rabbits. Both the dinitrocobinamide and aquohydroxocobinamide were then also given via gastric tube, with the rationale that a treatment that could be given IM as well as orally would improve the antidote's usefulness in a mass-casualty scenario.…”

Oral Glycine and Sodium Thiosulfate for Lethal Cyanide Ingestion

“…High Dose Cyanide (50 mg NaCN) with Simultaneous Oral Therapy Six of the 10 animals in Group 6 were previously used as controls and reported in a prior study of oral cobinamide treatment [17].…”

“…At a pH above 10.3, >90% of ingested cyanide would be in the ionized form. We recently showed we could rescue rabbits from a lethal dose of oral cyanide using the combination of oral cobinamide and sodium carbonate [17]. However, cobinamide is relatively expensive, is absorbed from the GI tract and has some toxicity when administered parenterally at high doses, and is not FDA approved.…”