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

<b>Context:</b> 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. <b>Objective:</b> 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. <b>Methods:</b> 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. <b>Results:</b> 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. <b>Conclusion:</b> 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.

**背景：** 氰化物（cyanide, CN）是一种代谢性毒物，可通过抑制电子传递链的复合物IV阻断三磷酸腺苷（ATP）的合成。当暴露于足够高的浓度时，人类与多数动物可在数分钟内死亡。由于氰化物中毒的救治时效对患者存活至关重要，因此开发一种可快速生物利用、无毒且易于给药的氰化物医疗对抗剂，有望在大规模氰化物暴露事件中改善患者的发病率与死亡率。氰化物最常见的暴露途径为吸入。
**目的：** 本研究针对二甲基三硫（dimethyl trisulfide, DMTS）——一种已被证实对氰化物中毒具有潜在治疗价值的对抗剂——的新型制剂开展疗效评估，实验分别采用氰化物暴露的吸入染毒与注射染毒两种模型。
**方法：** 本研究借助CH Technologies公司的高毒性试剂系统，构建了仅鼻部暴露的急性氰化物吸入中毒模型。实验采用了连续性与非连续性两种氰化氢（hydrogen cyanide, HCN）暴露范式。为便于对照，本研究同时采用了氰化钾（potassium cyanide, KCN）注射染毒模型。所有实验中，均通过肌内注射途径向未麻醉小鼠给予DMTS作为氰化物对抗剂。
**结果：** 研究结果显示，DMTS给药可对皮下注射KCN中毒与HCN吸入中毒均产生显著保护作用。在KCN注射染毒模型中，DMTS可使小鼠耐受高达3.73倍半数致死量（LD50）的KCN剂量。在本研究的HCN吸入染毒模型中，分别接受10分钟与40分钟半数致死浓度（LC50）剂量HCN暴露的小鼠，经DMTS治疗后存活率显著提升，分别达到87.5%与90.0%。两种致死暴露模型中的DMTS给药组小鼠，其观察到的中毒症状也均得到明显改善。
**结论：** 本研究证实，新型DMTS制剂在两种氰化物致死暴露小鼠模型（吸入染毒与注射染毒）中均具有疗效，且通过肌内注射途径给药即可发挥高效作用。本项HCN相关研究同时证明，DMTS在连续性与非连续性吸入暴露模型中均具备治疗效果。