Cargando…
Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning
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 indi...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660183/ https://www.ncbi.nlm.nih.gov/pubmed/31355359 http://dx.doi.org/10.1096/fba.1024 |
_version_ | 1783439267465265152 |
---|---|
author | Morningstar, Jordan Lee, Jangwoen Hendry‐Hofer, Tara Witeof, Alyssa Lyle, 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. |
author_facet | Morningstar, Jordan Lee, Jangwoen Hendry‐Hofer, Tara Witeof, Alyssa Lyle, 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. |
author_sort | Morningstar, Jordan |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6660183 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-66601832020-02-01 Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning Morningstar, Jordan Lee, Jangwoen Hendry‐Hofer, Tara Witeof, Alyssa Lyle, 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. FASEB Bioadv Research Articles 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. John Wiley and Sons Inc. 2018-11-15 /pmc/articles/PMC6660183/ /pubmed/31355359 http://dx.doi.org/10.1096/fba.1024 Text en © 2018 The Authors. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Articles Morningstar, Jordan Lee, Jangwoen Hendry‐Hofer, Tara Witeof, Alyssa Lyle, 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. Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning |
title | Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning |
title_full | Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning |
title_fullStr | Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning |
title_full_unstemmed | Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning |
title_short | Intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning |
title_sort | intramuscular administration of hexachloroplatinate reverses cyanide‐induced metabolic derangements and counteracts severe cyanide poisoning |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6660183/ https://www.ncbi.nlm.nih.gov/pubmed/31355359 http://dx.doi.org/10.1096/fba.1024 |
work_keys_str_mv | AT morningstarjordan intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT leejangwoen intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT hendryhofertara intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT witeofalyssa intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT lyletiffany intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT knippgregg intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT macraecaluma intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT bossgerryr intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT petersonrandallt intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT davissonvincentj intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT gersztenroberte intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT bebartavikhyats intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT mahonsari intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT brennermatt intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning AT nathanjalik intramuscularadministrationofhexachloroplatinatereversescyanideinducedmetabolicderangementsandcounteractsseverecyanidepoisoning |