Monitoring Dose Response of Cyanide Antidote Dimethyl Trisulfide in Rabbits Using Diffuse Optical Spectroscopy
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Cyanide (CN) poisoning is a serious chemical threat from accidental or intentional exposures. Current CN exposure treatments, including direct binding agents, methemoglobin donors, and sulfur donors, have several limitations. Dimethyl trisulfide (DMTS) is capable of reacting with CN to form the less toxic thiocyanate with high efficiency, even without the sulfurtransferase rhodanese. We investigated a soluble DMTS formulation with the potential to provide a continuous supply of substrate for CN detoxification which could be delivered via intramuscular (IM) injection in a mass casualty situation. We also used non-invasive technology, diffuse optical spectroscopy (DOS), to monitor physiologic changes associated with CN exposure and reversal.
Thirty-six New Zealand white rabbits were infused with a lethal dose of sodium cyanide solution (20 mg/60 ml normal saline). Animals were divided into three groups and treated with saline, low dose (20 mg), or high dose (150 mg) of DMTS intramuscularly. DOS continuously assessed changes in tissue hemoglobin concentrations and cytochrome c oxidase redox state status throughout the experiment.
IM injection of DMTS increased the survival in lethal CN poisoning. DOS demonstrated that high-dose DMTS (150 mg) reversed the effects of CN exposure on cytochrome c oxidase, while low dose (20 mg) did not fully reverse effects, even in surviving animals.
This study demonstrated potential efficacy for the novel approach of supplying substrate for non-rhodanese mediated sulfur transferase pathways for CN detoxification via intramuscular injection in a moderate size animal model and showed that DOS was useful for optimizing the DMTS treatment.
KeywordsChemical and biological weapons Cyanide toxicity reversal Optical hemodynamic monitoring Dimethyl trisulfide Lethal cyanide poisoning Diffuse optical spectroscopy
Diffuse optical spectroscopy
Cytochrome c oxidase
Compliance with Ethical Standards
All procedures were reviewed and approved by the University of California, Irvine, Institutional Animal Care and Use Committee (IACUC).
Conflict of Interest Statement
This work was supported, in part, by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD), and the National Institute of Neurological Disorders and Stroke (NINDS) grant numbers U54 NS0792, U01 NS058030, and U54 NS063718, AMRMC W81XWH-12-2-0098, CounterACT NIH No. 1U54 NS079201 and by the Air Force Office of Scientific Research award numbers FA9550-17-1-0193 and FA9550-14-1-0193, and the Robert A. Welch Foundation (x-001) at Sam Houston State University, Huntsville, TX.
Any opinions, findings, conclusions, or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the United States Air Force.
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