A novel aqueous dimethyl trisulfide formulation is effective at low doses against cyanide toxicity in non-anesthetized mice and rats

Abstract

Background

Cyanide (CN) is a metabolic poison that is capable of intoxicating individuals through accidental or intentional means. With high concentration exposures, death can occur in minutes. In cases of mass casualty exposures, there is a need for a rapid-acting countermeasure capable of being administered in a short period of time in a pre-hospital setting to treat victims.

Objective

These studies evaluate the safety and efficacy of a novel aqueous formulation of dimethyl trisulfide (DMTS) as an intramuscular (IM) CN countermeasure using non-anesthetized rodent models.

Methods

Non-anesthetized rodents (mice and rats) were exposed to hydrogen cyanide (HCN) or potassium cyanide (KCN) along with immediate IM 10% DMTS treatment or vehicle treatment. Survival and other parameters, such as the time to recovery and assessment of clinical toxic signs (e.g., gasping, loss of righting reflex, convulsions, etc.), were quantified to determine the effectiveness of 10% DMTS treatment (12.5, 25, 75 mg/kg IM) compared to vehicle control treatment. A rat KCN delayed-treatment model with a 15-minute treatment delay was also utilized to simulate a real-life exposure/treatment scenario with 10% DMTS treatment. The stability of the 10% DMTS formulation was also assessed.

Results

A 25 mg/kg IM dose of 10% DMTS exhibits potent efficacy against subcutaneous (SC) KCN challenge in both mice and rats and inhalational HCN exposure in mice. 10% DMTS treatment also shortens the time to recovery in rats using a delayed-treatment model.

Conclusion

IM treatment with 10% DMTS improves survival and clinical outcomes in non-anesthetized rodent models of acute CN toxicity. Additionally, the use of an SC KCN delayed-treatment model in rats is advised to assess the performance of a candidate CN countermeasure in a more realistic exposure/treatment scenario.

Keywords:

• Cyanide (CN)
• dimethyl trisulfide (DMTS)
• potassium cyanide (KCN)
• hydrogen cyanide (HCN)
• delayed treatment

This article refers to:

Evaluation of aqueous dimethyl trisulfide as an antidote to a highly lethal cyanide poisoning in a large swine model

Acknowledgements

This manuscript is dedicated to the memory of Dr. Susan M. DeLeon. The authors wish to thank Ms. Robyn Lee-Stubbs for her technical expertise and assistance with statistical analyses for all KCN and HCN studies, and to all veterinary staff at USAMRICD for assistance with animal care and husbandry procedures. Additionally, the authors express gratitude to all USAMRICD administrative staff for assistance with this project, and to all internal and external collaborators for valuable insight and support with this project, especially Dr. Brian Logue for offering exceptional insight and expertise with this project.

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, the U.S. Government, the Department of Energy, Oak Ridge Associated Universities, or the Oak Ridge Institute for Science and Education.

A patent application (US 2020/0345658 A1) entitled “Compositions of dimethyl trisulfide (DMTS) as a cyanide antidote” was publicly published on 5 November 2020 (inventors: McDonough JA and Dixon H). An additional patent, (US Patent (US 9.375, 407 B2) published on 28 June 2016, titled "Dimethyl trisulfide as a cyanide antidote" (inventors: Rockwood, Petrikovics, and Baskin) is also relevant to this project. Personal financial gain may be realized through the 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 Institute of Health as an Interagency Agreement between NIH and USAMRICD [AOD18015-001-00000 and AOD16026-001-00000], and by a collaborative agreement between the Defense Threat Reduction Agency [DTRA Agreement 15-050, Projects CB3949 and CB10638] and USAMRICD. D.S.L., D.M.H., and J.N.W. were supported in part by an appointment to the Department of Defense Research Participation Program administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy (DOE) and the Department of Defense. ORISE is managed by Oak Ridge Associated Universities (ORAU) under DOE contract number DE-SC0014664.