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Acute chloroquine poisoning: A comprehensive experimental toxicology assessment of the role of diazepam
  • Dyfrig Hughes
Dyfrig Hughes
Bangor University College of Health and Behavioural Sciences
Author Profile

Abstract

Background and Purpose: Resurgence in the use of chloroquine as a putative 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 interventional 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 interventions 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.

Peer review status:ACCEPTED

10 Apr 2020Submitted to British Journal of Pharmacology
11 Apr 2020Submission Checks Completed
11 Apr 2020Assigned to Editor
14 Apr 2020Reviewer(s) Assigned
21 Apr 2020Editorial Decision: Revise Minor
23 Apr 20201st Revision Received
28 Apr 2020Submission Checks Completed
28 Apr 2020Assigned to Editor
29 Apr 2020Reviewer(s) Assigned
03 May 2020Editorial Decision: Accept