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Cobinamide is superior to other treatments in a mouse model of cyanide poisoning.

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

SUBMITTER: Chan A

PROVIDER: S-EPMC3119202 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

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Cobinamide is superior to other treatments in a mouse model of cyanide poisoning.

Chan Adriano A Balasubramanian Maheswari M Blackledge William W Mohammad Othman M OM Alvarez Luis L Boss Gerry R GR Bigby Timothy D TD

Clinical toxicology (Philadelphia, Pa.) 20100801 7

<h4>Context</h4>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.<h4>Objective</h4>We have used mouse models of cyanide poisoning to compare ...[more]

PMID: 20704457

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Project description:Background: Dicobalt edetate and hydroxocobalamin are widely used to treat hydrogen cyanide poisoning. However, comparative and quantitative efficacy data are lacking. Although post-exposure treatment is typical, it may be possible to administer these antidotes before exposure to first attenders entering a known site of cyanide release, as supplementary protection to their personal protective equipment.Methods: We established an anaesthetised Gottingen minipig model of lethal bolus potassium cyanide (KCN) injection to simulate high dose hydrogen cyanide inhalation. Doses were similar to human lethal doses of KCN. Dicobalt edetate and hydroxocobalamin were administered shortly before KCN and their effect on metabolic and cardiovascular variables and survival time were measured.Results: Increases in arterial lactate were similar after 0.08 and 0.12 mmol/kg KCN. KCN 0.08 mmol/kg was survived by 4/4 animals with moderate cardiovascular effects, while the 0.12 mmol/kg dose was lethal in 4/4 animals, with a mean time to euthanasia of 28.3 (SEM: 13.9) min. Administration of dicobalt edetate (0.021 mmol/kg, 8.6 mg/kg) or hydroxocobalamin (0.054 mmol/kg, 75 mg/kg) at clinically licenced doses had modest effect on lactate concentrations but increased survival after administration of KCN 0.12 mmol/kg (survival: dicobalt edetate 4/4, hydroxocobalamin 2/4) but not 0.15 mmol/kg (0/4 and 0/4, respectively). In a subsequent larger study, doubling the dose of hydroxocobalamin (0.108 mmol/kg, 150 mg/kg) was associated with a modest but inconsistent increased survival after 0.15 mmol/kg KCN (survival: control 0/8, 75 mg/kg 1/10, 150 mg/kg 3/10) likely due to variable pharmacokinetics.Conclusions: In this porcine study of cyanide exposure, with pre-exposure antidote administration, licenced doses of dicobalt edetate and hydroxocobalamin were effective at just lethal doses but ineffective at less than twice the estimated LD50. The efficacy of a rapidly-administered double-dose of hydroxocobalamin was limited by variable pharmacokinetics. In clinical poisoning scenarios, with delayed administration, the antidotes are likely to be even less effective. New antidotes are required for treatment of cyanide exposures appreciably above the minimum lethal dose.

Dataset Information

Cobinamide is superior to other treatments in a mouse model of cyanide poisoning.

Publications

Cobinamide is superior to other treatments in a mouse model of cyanide poisoning.

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