19.05.2020

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

Therapeutic NeurologyCardiology and metabolic diseasesInfectiology
Hughes DA et al
Br J Pharmacol

Main result

Effect of chloroquine in vitro: Decrease in pressure in left atria, prolongation of the effective refractory period of the atria, of the ventricular tissue and of the right papillary muscles, and dose-dependent alteration of hemodynamic and electrocardiographic parameters (with alteration of atrioventricular conduction).

In vivo studies:

  • Administration of diazepam / clonazepam / Ro5-4864 before chloroquine: no difference between intervention and control.
  • Administration of diazepam / clonazepam / Ro5-4864 during chloroquine: no difference between intervention and control.
  • Administration diazepam / clonazepam / Ro5-4864 after chloroquine: QTc interval prolongation for diazepam and clonazepam
  • Administration of high-dose diazepam: an increase in heart rate
  • Administration of diazepam in urethane-anesthetized rats (without barbiturate): no difference between procedure and control.
  • Concomitant administration of diazepam and adrenaline: improved cardiac contractility but led to hypokalemia.

Takeaways

Neither diazepam nor other ligands of the benzodiazepine binding sites protect against or attenuate the cardiotoxicity of chloroquine. Diazepam appears to enhance the effects of positive inotropes in reducing chloroquine cardiotoxicity.

Strenght of evidence Weak

In vitro and in vivo in mice, rats, and rabbits
No blinding

Objectives

Evaluate the potential protective effects of diazepam (indicated in case of intoxication) in experimental cardiotoxicity models related to chloroquine.

Method

In vitro experiments: on rat heart tissue, incubated with chloroquine +/- diazepam.

In vivo experiments: Toxicity models in rats and rabbits anesthetized with pentobarbitone. Intravenous administration of chloroquine.

A randomized controlled study in rats: with an evaluation of diazepam, clonazepam and Ro5-4864 administered: before / during/after chloroquine + the effects of diazepam: high dose / in rats anesthetized with urethane / co-administered with adrenaline.

Ro5-4864: translocating protein agonist (TSPO) Ro5-4864 (4'-chlorodiazepam)

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