Intramuscular Cobinamide Sulfite in a Rabbit Model of Sublethal Cyanide Toxicity - 20/08/11
, Jae G. Kim, PhD a, Sari B. Mahon, PhD a, b, Jangwoen Lee, PhD a, Kelly A. Kreuter, MS a, William Blackledge, MD c, David Mukai, BS a, Steve Patterson, PhD d, Othman Mohammad, MD c, Vijay S. Sharma, PhD c, Gerry R. Boss, MD c
Address for correspondence: Matthew Brenner, MD, 1002 Health Sciences Rd E, Irvine, CA 92612; 949-824-3924, fax 949-824-8413Résumé |
Study objective |
Exposure to cyanide in fires and industrial exposures and intentional cyanide poisoning by terrorists leading to mass casualties is an ongoing threat. Current treatments for cyanide poisoning must be administered intravenously, and no rapid treatment methods are available for mass casualty cyanide exposures. Cobinamide is a cobalamin (vitamin B12) analog with an extraordinarily high affinity for cyanide that is more water-soluble than cobalamin. We investigate the use of intramuscular cobinamide sulfite to reverse cyanide toxicity–induced physiologic changes in a sublethal cyanide exposure animal model and determine the ability of an intramuscular cobinamide sulfite injection to rapidly reverse the physiologic effects of cyanide toxicity.
Methods |
New Zealand white rabbits were given 10 mg sodium cyanide intravenously over 60 minutes. Quantitative diffuse optical spectroscopy and continuous-wave near-infrared spectroscopy monitoring of tissue oxyhemoglobin and deoxyhemoglobin concentrations were performed concurrently with blood cyanide level measurements and cobinamide levels. Immediately after completion of the cyanide infusion, the rabbits were injected intramuscularly with cobinamide sulfite (n=6) or inactive vehicle (controls, n=5).
Results |
Intramuscular administration led to rapid mobilization of cobinamide and was extremely effective at reversing the physiologic effects of cyanide on oxyhemoglobin and within deoxyhemoglobin extraction. Recovery time to 63% of their baseline values in the central nervous system occurred within a mean of 1,032 minutes in the control group and 9 minutes in the cobinamide group, with a difference of 1,023 minutes (95% confidence interval 116 to 1,874 minutes). In muscle tissue, recovery times were 76 and 24 minutes, with a difference of 52 minutes (95% confidence interval 7 to 98 minutes). RBC cyanide levels returned toward normal significantly faster in cobinamide sulfite–treated animals than in control animals.
Conclusion |
Intramuscular cobinamide sulfite rapidly and effectively reverses the physiologic effects of cyanide poisoning, suggesting that a compact cyanide antidote kit can be developed for mass casualty cyanide exposures.
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| Supervising editor: Lewis S. Nelson, MD |
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| Author contributions: MB, GRB, and SP conceived the study and obtained research funding. MB, GRB, JGK, JL, and SBM designed the experiments, supervised data collection, and performed data analysis. GRB, VSS, OM, and WB synthesized, characterized and provided the cobinamide used for all studies and provided cyanide level data. KAK, DM, and JL performed the studies. MB drafted the manuscript and all authors contributed substantially to its revision. MB takes responsibility for the paper as a whole. |
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| Funding and support: By Annals policy, all authors are required to disclose any and all commercial, financial, and other relationships in any way related to the subject of this article that might create any potential conflict of interest. See the Manuscript Submission Agreement in this issue for examples of specific conflicts covered by this statement. This work was supported by the AF (9550-04-1-0101, 9550-08-1-0384), the Laser Microbeam and Medical Program from the National Center for Research Resources (P41RR001192), and the National Institutes of Health (1U54NS063718, U01-NS058030). |
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| The views and conclusions contained herein are those of the authors and should not be interpreted as necessarily representing the official policies or endorsements, either expressed or implied, of the agencies providing support for this work. |
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| Publication date: Available online January 4, 2010. |
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| Reprints not available from the authors. |
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| Please see page 353 for the Editor's Capsule Summary of this article. |
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| Provide process.asp?qs_id=5392 on this article at the journal's Web site, www.annemergmed.com. |
Vol 55 - N° 4
P. 352-363 - avril 2010 Retour au numéro
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