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Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam

BACKGROUND AND PURPOSE: Resurgence in the use of chloroquine as a potential treatment for COVID‐19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy i...

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Autor principal: Hughes, Dyfrig A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572456/
https://www.ncbi.nlm.nih.gov/pubmed/32415690
http://dx.doi.org/10.1111/bph.15101
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author Hughes, Dyfrig A.
author_facet Hughes, Dyfrig A.
author_sort Hughes, Dyfrig A.
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description BACKGROUND AND PURPOSE: Resurgence in the use of chloroquine as a potential treatment for COVID‐19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy in this context. The aim was to assess the effects of diazepam in experimental models of chloroquine cardiotoxicity. EXPERIMENTAL APPROACH: In vitro experiments involved cardiac tissues isolated from rats and incubated with chloroquine alone or in combination with diazepam. In vivo models of toxicity involved chloroquine administered intravenously to pentobarbitone‐anaesthetised rats and rabbits. Randomised, controlled treatment studies in rats assessed diazepam, clonazepam and Ro5‐4864 administered: (i) prior, (ii) during and (iii) after chloroquine and the effects of diazepam: (iv) at high dose, (v) in urethane‐anaesthetised rats and (vi) co‐administered with adrenaline. KEY RESULTS: Chloroquine decreased the developed tension of left atria, prolonged the effective refractory period of atria, ventricular tissue and right papillary muscles, and caused dose‐dependent impairment of haemodynamic and electrocardiographic parameters. Cardiac arrhythmias indicated impairment of atrioventricular conduction. Studies (i), (ii) and (v) showed no differences between treatments and control. Diazepam increased heart rate in study (iv) and as with clonazepam also prolonged the QTc interval in study (iii). Combined administration of diazepam and adrenaline in study (vi) improved cardiac contractility but caused hypokalaemia. CONCLUSION AND IMPLICATIONS: Neither diazepam nor other ligands for benzodiazepine binding sites protect against or attenuate chloroquine cardiotoxicity. However, diazepam may augment the effects of positive inotropes in reducing chloroquine cardiotoxicity. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc
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spelling pubmed-75724562020-10-23 Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam Hughes, Dyfrig A. Br J Pharmacol Themed Issue: Research Paper BACKGROUND AND PURPOSE: Resurgence in the use of chloroquine as a potential treatment for COVID‐19 has seen recent cases of fatal toxicity due to unintentional overdoses. Protocols for the management of poisoning recommend diazepam, although there are uncertainties in its pharmacology and efficacy in this context. The aim was to assess the effects of diazepam in experimental models of chloroquine cardiotoxicity. EXPERIMENTAL APPROACH: In vitro experiments involved cardiac tissues isolated from rats and incubated with chloroquine alone or in combination with diazepam. In vivo models of toxicity involved chloroquine administered intravenously to pentobarbitone‐anaesthetised rats and rabbits. Randomised, controlled treatment studies in rats assessed diazepam, clonazepam and Ro5‐4864 administered: (i) prior, (ii) during and (iii) after chloroquine and the effects of diazepam: (iv) at high dose, (v) in urethane‐anaesthetised rats and (vi) co‐administered with adrenaline. KEY RESULTS: Chloroquine decreased the developed tension of left atria, prolonged the effective refractory period of atria, ventricular tissue and right papillary muscles, and caused dose‐dependent impairment of haemodynamic and electrocardiographic parameters. Cardiac arrhythmias indicated impairment of atrioventricular conduction. Studies (i), (ii) and (v) showed no differences between treatments and control. Diazepam increased heart rate in study (iv) and as with clonazepam also prolonged the QTc interval in study (iii). Combined administration of diazepam and adrenaline in study (vi) improved cardiac contractility but caused hypokalaemia. CONCLUSION AND IMPLICATIONS: Neither diazepam nor other ligands for benzodiazepine binding sites protect against or attenuate chloroquine cardiotoxicity. However, diazepam may augment the effects of positive inotropes in reducing chloroquine cardiotoxicity. LINKED ARTICLES: This article is part of a themed issue on The Pharmacology of COVID‐19. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.21/issuetoc John Wiley and Sons Inc. 2020-06-18 2020-11 /pmc/articles/PMC7572456/ /pubmed/32415690 http://dx.doi.org/10.1111/bph.15101 Text en © 2020 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society 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 Themed Issue: Research Paper
Hughes, Dyfrig A.
Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
title Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
title_full Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
title_fullStr Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
title_full_unstemmed Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
title_short Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
title_sort acute chloroquine poisoning: a comprehensive experimental toxicology assessment of the role of diazepam
topic Themed Issue: Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572456/
https://www.ncbi.nlm.nih.gov/pubmed/32415690
http://dx.doi.org/10.1111/bph.15101
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