Intramuscular administration of hexachloroplatinate reverses cyanide-induced metabolic derangements and counteracts severe cyanide poisoning

Abstract

Cyanide is a highly toxic industrial chemical that is widely used by manufactures. Smoke inhalation during household fires is the most common source of cyanide poisoning while additional risks to civilians include industrial accidents and terrorist attacks. Despite the risks to large numbers of individuals, an antidote capable of administration at scale adequate for a mass casualty, prehospital scenario does not yet exist. Previously, we demonstrated that intravenous cisplatin analogues accelerate recovery from cyanide poisoning in mice and rabbits. Of the dozens of platinum‐based organometallic complexes tested, hexachloroplatinate (HCP) emerged as a promising lead compound, exhibiting strong affinity for cyanide and efficacy across model systems. Here, we show HCP is an antidote to lethal cyanide exposure and is importantly effective when delivered intramuscularly. The pharmacokinetic profile of HCP exhibited bioavailability in the systemic circulation 2.5 minutes post‐treatment and subsequent renal clearance of HCP‐cyanide. HCP restored parameters of cellular physiology including cytochrome c oxidase redox state and TCA cycle metabolism. We next validated these findings in a large animal model (swine). Finally, preclinical safety studies in mice revealed minimal toxicity. Cumulatively, these findings demonstrate that HCP is a promising lead compound for development of an intramuscular injectable cyanide antidote for mass casualty scenarios.

Glyoxylate protects against cyanide toxicity through metabolic modulation

“…S7H), suggesting pyruvate is not simply being reduced to lactate. This pattern appears to be specific to glyoxylate since we previously demonstrated in this model that the effective cyanide-scavenging countermeasure, HCP, does not rapidly normalize pyruvate levels 8 . In contrast, following HCP administration, pyruvate levels continue to rise 8 .…”

“…This pattern appears to be specific to glyoxylate since we previously demonstrated in this model that the effective cyanide-scavenging countermeasure, HCP, does not rapidly normalize pyruvate levels 8 . In contrast, following HCP administration, pyruvate levels continue to rise 8 . To rule out the possibility that glyoxylate is reacting directly with pyruvate to result in its consumption, we analyzed products of glyoxylate and pyruvate in vitro by ESI–MS and could only identify a non-covalent interaction that would be unlikely to contribute to this phenomenon (Supplementary Fig.…”

“…Cyanide infusion inhibits cellular respiration and concomitantly slows the consumption of pyruvate and TCA cycle metabolites which leads to increased levels of these metabolites 8 . As expected, we observed a significant increase in pyruvate levels during the 40-min cyanide infusion prior to glyoxylate treatment (Fig.…”

“…This rapid response to glyoxylate treatment is further demonstrated by the rapid consumption of pyruvate observed in glyoxylate treatment of cyanide-exposed rabbits. Rescue with other cyanide countermeasures, such as HCP, demonstrates no immediate change in pyruvate metabolism after treatment 8 . This immediate consumption of pyruvate, upon treatment with glyoxylate, is not accompanied by a corresponding increase in lactate, a phenomenon that would be expected if pyruvate were being reduced to lactate as occurs during anaerobic metabolism.…”

Identification and Characterization of mRNA Biomarkers for Sodium Cyanide Exposure

“…Sodium cyanide, a highly poisonous inorganic compound, is widely used as an important precursor for many organic and inorganic chemicals in chemical manufacturing, including pharmaceuticals [23]. Smoke inhalation by household fire smoke and cigarette smoking is also common source of cyanide poisoning [24,25]. Cyanide is also released from bacteria such as P. aeruginosa through the metabolic pathway of bacterial cyanogenesis, leading to chronic lung disease and respiratory failure [26].…”