A pilot study in the swine model of lethal cyanide intoxication indicates efficacy of a platinum-methionine complex countermeasure

Cyanide presents a chemical security threat because of its wide availability, due to industrial uses, and significant toxicity. Platinum-thioether complexes are a recent addition to candidate antidotes, showing efficacy in mouse models of hydrogen cyanide inhalation and reversing toxicity measures in rabbits. This pilot study evaluated the effectiveness of a platinum-methionine complex (Met2Pt), a potent lead candidate, in a lethal swine model, which provides a solid foundation for future research. Potassium cyanide (0.2 mg/kg/min; IV) was infused into anesthetized swine until 6 min post-apnea. Met2Pt (2.9 mg Pt/kg in 3 mL) or 100 mM phosphate buffer vehicle (3 mL) were then administered intravenously (IV) or intramuscularly (IM). Vital signs, metabolites, and pharmacokinetics were monitored for > 90 min. IV Met2Pt was highly efficacious compared to all other treatments, rescuing all swine in the group and reversing cyanide-derangements in lactate concentration (Welch One-Way ANOVA, p < 10− 4), blood oxygenation (p = 0.002), etc. IM Met2Pt did not significantly improve survival due to lower systemic availability (7%). The results of this pilot study indicate that Met2Pt is efficacious via the IV route, while IM availability of Met2Pt is a limiting factor.