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.
Highlights
Cyanide is a well‐known metabolic poison that is readily absorbed through dermal, bronchial, and digestive routes, rapidly distributes to tissues throughout the body, and causes multi‐ organ toxicity.[1,2] Exposure to the poison in the low milligram range induces symptoms that appear within minutes of exposure.[3]
Of the many small molecules tested, we observed concordant protective effects of hexachloroplatinate (HCP) in three vertebrate models of cyanide toxicity.[13]. This compound exhibits an ∼33‐fold improvement in solubility over cisplatin and an ~20‐fold lower reported toxicity in mice than cisplatin (LD50 = 133 vs 6.6 mg/kg).[14]. These results provided proof‐of‐concept that cisplatin analogues are effective cyanide antidotes in zebrafish, mice, and rabbits; these compounds were administered through intravenous or intraperitoneal administration, limiting their utility in a mass casualty scenario
We previously demonstrated that intravenous administration of HCP to rabbits exposed to a sublethal dose of cyanide rapidly reverses cyanide‐induced inhibition of oxygen offloading from hemoglobin and accelerates recovery from cyanide toxicity.[13]
Summary
Cyanide is a well‐known metabolic poison that is readily absorbed through dermal, bronchial, and digestive routes, rapidly distributes to tissues throughout the body, and causes multi‐ organ toxicity.[1,2] Exposure to the poison in the low milligram range induces symptoms that appear within minutes of exposure.[3]. Current therapeutic interventions for cyanide poisoning include hydroxocobalamin which acts by reducing the intracellular concentration of cyanide through direct chelation of cyanide anions.[6,7] Others, sodium nitrite, work by converting hemoglobin to methemoglobin which avidly binds cyanide, thereby diverting it from binding to cytochrome oxidase.[8,9] nitrite antidotes induce methemoglobinemia which may be deleterious to victims of smoke inhalation, a major accidental cause of cyanide poisoning, because free hemoglobin levels are already lowered due to carbon monoxide.[7] The third class of FDA approved antidotes, thiosulfates, utilize the endogenous enzyme rhodanese to detoxify cyanide by converting it into thiocyanate; the reaction occurs too slowly to effectively rescue a poison victim Though these three classes of antidotes are effective in hospital settings, they require intravenous administration over 15 minutes and often require repeat dosing.[10] an antidote capable of administration at scale adequate for a mass casualty scenario does not yet exist.[7] the development of a cyanide antidote that can be rapidly deployed, preferably by intramuscular injection, could have a transformative effect on the management of cyanide poisoning. This study establishes the efficacy, pharmacokinetic profile, and metabolic effects of intramuscular administration of HCP in two clinically relevant mammalian models
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