DMTS is an effective treatment in both inhalation and injection models for cyanide poisoning using unanesthetized mice

Abstract

Context: Cyanide (CN) is a metabolic poison, halting ATP synthesis by inhibiting complex IV of the electron transport chain. If exposed at high enough concentrations, humans and most animals can die within minutes. Because time is a crucial factor in survival of CN poisoning, a rapidly bioavailable, nontoxic, easy to administer CN medical countermeasure could improve morbidity/mortality in a mass CN exposure scenario. The most likely route of exposure to CN is via inhalation.

Objective: This study examined the efficacy of a new formulation for dimethyl trisulfide (DMTS), a countermeasure which has shown promise as a treatment for CN poisoning, using both inhalation and injection models of CN exposure.

Methods: We developed a model of acute CN inhalation intoxication, using the highly toxic agent system from CH Technologies for nose-only exposure. Both continuous and discontinuous HCN exposure paradigms were implemented. For comparison, we also utilized a potassium cyanide (KCN) injection model. In all experiments, DMTS was administered as a cyanide countermeasure via intramuscular injection in unanesthetized mice.

Results: We found DMTS administration to be highly protective against both subcutaneous KCN and HCN inhalation toxicity. In the KCN injection model, DMTS afforded protection against 3.73 times the LD50 dose of KCN. In our HCN inhalation exposure model, mice challenged with LC50 HCN doses for the duration of either 10- or 40-minute exposure paradigms demonstrated improved survival in the presence of DMTS treatment (87.5% and 90.0% survival, respectively). Animals in the DMTS treatment groups of both lethal exposure models similarly exhibited improvement in observed toxic signs.

Conclusion: We show that a newly developed formulation of DMTS is efficacious within two lethal CN exposure mouse models (inhalation and injection) and is highly effective by intramuscular injection. Within these HCN studies, we demonstrate efficacy of DMTS in both continuous and discontinuous inhalation exposure models.

Keywords:

• Cyanide
• hydrogen cyanide (HCN)
• inhalation exposure
• Fourier transform infrared spectrometer (FTIR)
• highly toxic agent system (HTAS)
• dimethyl trisulfide (DMTS)

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Acknowledgments

The authors wish to thank Amber Packer and Amy Rizkallah for technical assistance with animal exposures, the Southwest Research Institute (San Antonio, TX) for the dimethyl trisulfide formulation development, and James Abraham for the illustration of the inhalation system (Figure 2).

Disclosure statement

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or the U.S. Government.

S.D., D.H., and M.R. were supported in part by an appointment to the Research Participation Program for the U.S. Army Medical Research and Materiel Command administered by the Oak Ridge Institute for Science and Education through an agreement between the U.S. Department of Energy and U.S. Army Medical Research and Materiel Command.

A patent (US 9,375,407 B2) entitled "Dimethyl Trisulfide As A Cyanide Antidote" was granted on 28 June 2016 (inventors: Rockwood, GA, Petrikovics, I and Baskin, SI). Personal financial gain may be realized through development of this product.

Additional information

Funding

This work was supported by the CounterACT Program, the National Institute of Allergy and Infectious Diseases, and by the National Institutes of Health as an Interagency Agreement between NIH and USAMRICD (AOD16026-001-0000/A120-B.P2016-01).