The combination of cobinamide and sulfanegen is highly effective in mouse models of cyanide poisoning.

Abstract

CONTEXT:

Cyanide is a component of smoke in residential and industrial fires, and accidental exposure to cyanide occurs in a variety of industries. Moreover, cyanide has the potential to be used by terrorists, particularly in a closed space such as an airport or train station. Current therapies for cyanide poisoning must be given by intravenous administration, limiting their use in treating mass casualties.

OBJECTIVE:

We are developing two new cyanide antidotes--cobinamide, a vitamin B(12) analog, and sulfanegen, a 3-mercaptopyruvate prodrug. Both drugs can be given by intramuscular administration, and therefore could be used to treat a large number of people quickly. We now asked if the two drugs would have an augmented effect when combined.

MATERIALS AND METHODS:

We used a non-lethal and two different lethal models of cyanide poisoning in mice. The non-lethal model assesses neurologic recovery by quantitatively evaluating the innate righting reflex time of a mouse. The two lethal models are a cyanide injection and a cyanide inhalation model.

RESULTS:

We found that the two drugs are at least additive when used together in both the non-lethal and lethal models: at doses where all animals died with either drug alone, the combination yielded 80 and 40% survival in the injection and inhalation models, respectively. Similarly, drug doses that yielded 40% survival with either drug alone, yielded 80 and 100% survival in the injection and inhalation models, respectively. As part of the inhalation model, we developed a new paradigm in which animals are exposed to cyanide gas, injected intramuscularly with an antidote, and then re-exposed to cyanide gas. This simulates cyanide exposure of a large number of people in a closed space, because people would remain exposed to cyanide, even after receiving an antidote.

CONCLUSION:

The combination of cobinamide and sulfanegen shows great promise as a new approach to treating cyanide poisoning.

• Authors: Adriano Chan, Daune L Crankshaw, Alexandre Monteil, Steven E Patterson, Herbert T Nagasawa, Jackie E Briggs, Joseph A Kozocas, Sari B Mahon, Matthew Brenner, Renate B Pilz, Timothy D Bigby, Gerry R Boss
• Journal: Clinical toxicology (Philadelphia, Pa.) (Clin Toxicol (Phila)) Vol. 49 Issue 5 Pg. 366-73 (Jun 2011) ISSN: 1556-9519 [Electronic] England
• PMID: 21740135 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antidotes
• Cobamides
• Cyanides
• Prodrugs
• cobinamide
• 3-mercaptopyruvic acid
• Cysteine

Topics

• Animals
• Antidotes (administration & dosage)
• Cobamides (administration & dosage)
• Cyanides (poisoning)
• Cysteine (administration & dosage, analogs & derivatives)
• Disease Models, Animal
• Drug Therapy, Combination
• Male
• Mice
• Mice, Inbred C57BL
• Prodrugs (administration & dosage)