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

  • Author(s): Morningstar, Jordan;
  • Lee, Jangwoen;
  • Hendry-Hofer, Tara;
  • Witeof, Alyssa;
  • Lyle, L Tiffany;
  • Knipp, Gregg;
  • MacRae, Calum A;
  • Boss, Gerry R;
  • Peterson, Randall T;
  • Davisson, Vincent J;
  • Gerszten, Robert E;
  • Bebarta, Vikhyat S;
  • Mahon, Sari;
  • Brenner, Matt;
  • Nath, Anjali K
  • et al.

Published Web Location

https://doi.org/10.1096/fba.1024
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 importantly is 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 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 hexachloroplatinate is a promising lead compound for development of an intramuscular injectable cyanide antidote for mass casualty scenarios.

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