Cyanide Poisoning Compromises Gene Pathways Modulating Cardiac Injury in Vivo.

Smoke inhalation from a structure fire is a common route of cyanide poisoning in the U.S. Cyanide inhibits cellular respiration, often leading to death. Its rapid distribution throughout the body can result in injuries to multiple organs, and cyanide victims were reported to experience myocardial infarction and other cardiac complications. However, molecular mechanisms of such complications are yet to be elucidated. While FDA-approved CN antidotes such as sodium thiosulfate and hydroxocobalamin are clinically used, they have foreseeable limitations during mass casualty situations because they require intravenous administration. To facilitate the development of better antidotes and therapeutic treatments, a global view of molecular changes induced by cyanide exposure is necessary. As an exploratory pursuit, we performed oligonucleotide microarrays to establish cardiac transcriptomes of an animal model of nose-only inhalation exposure to hydrogen cyanide (HCN), which is relevant to smoke inhalation. We also profiled cardiac transcriptomes after subcutaneous injection of potassium cyanide (KCN). Although the KCN injection model has often been used to evaluate medical countermeasures, this study demonstrated that cardiac transcriptomes are largely different from that of the HCN inhalation model at multiple time points within 24 h after exposure. Pathway analysis identified that HCN-induced transcriptomes were enriched with genes encoding mediators of pathways critical in modulation of cardiac complications and that a large number of such genes were significantly decreased in expression. We utilized the upstream regulatory analysis to propose drugs that can be potentially employed to treat cyanide-induced cardiac complications.

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

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.