Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity

Clemessy, Jean‐Luc; Angel, G; Borron, Stephen W.; Ndiaye, Mamadou; Brun, Francisco; Julien, Howard; Galliot, M; Vicaut, Éric; Baud, Frédéric J.

doi:10.1007/bf01709558

Cited by 28 publications

(14 citation statements)

References 11 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Chloroquine and hydroxychloroquine are dangerous in overdose [47,93,[109][110][111][112][113][114][115][116]. In selfpoisoning, nausea, vomiting, diplopia, hypoacusis, and dysphoria are sometimes followed by tremors, athetoid movements, dysarthria, difficulty swallowing, lethargy and drowsiness, and then seizures, coma, hypotension, hypokalaemia, arrhythmias, and ventricular fibrillation.…”

Section: Chloroquine Poisoningmentioning

confidence: 99%

“…Hypokalaemia, resulting from intracellular accumulation, is an important complication, an indicator of prognosis, and a contributor to arrhythmias [93]. It has been suggested that diazepam is a specific antidote [109] for chloroquine poisoning, but more recent studies do not support a specific role for this drug above good haemodynamic and ventilatory support [111,112]. There is a loose relationship between the self-administered chloroquine dose and the resulting blood concentrations.…”

Section: Chloroquine Poisoningmentioning

confidence: 99%

See 1 more Smart Citation

COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

et al. 2020

View full text Add to dashboard Cite

• Chloroquine and hydroxychloroquine have been used for over 60 years in the treatment of malaria, amoebic liver abscess, and several rheumatological conditions, but their clinical pharmacology is not well understood. COVID-19 is a new potential indication, although these drugs have only moderate in vitro activity against the SARS-CoV-2 virus and there is no convincing evidence at this time of significant clinical efficacy. • Chloroquine and hydroxychloroquine both have unusual pharmacokinetic properties with enormous apparent volumes of distribution (chloroquine > hydroxychloroquine) and very slow elimination from the body (terminal elimination half-lives > 1 month). • The free plasma concentrations that drive potentially serious adverse reactions (hypotension, cardiac conduction disturbances, delayed ventricular repolarization, and neurotoxicity) are determined largely by distribution processes. • Hydroxychloroquine was slightly safer than chloroquine in preclinical testing and is considered better tolerated over the long term. Both drugs are dangerous when overdosed, and parenteral administration needs careful control. • There are different salts, each with a different base equivalent. This has led to confusion and sometimes mistakes in dosing. As different salts are available in different places, malaria treatment is usually recommended in terms of base equivalent. Tablets of the two most widely available forms, chloroquine diphosphate 250 mg salt and hydroxychloroquine sulphate 200 mg salt, both contain 155 mg base.

show abstract

Section: Chloroquine Poisoningmentioning

confidence: 99%

Section: Chloroquine Poisoningmentioning

confidence: 99%

COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

et al. 2020

View full text Add to dashboard Cite

show abstract

“…Il s'agit de l'apparition d'une oligurie, l'élévation de la créatinémie, la persistance ou l'augmentation d'une hyperlactacidémie, en sachant que sa valeur initiale n'a pas de valeur pronostique et de l'augmentation de la chloroquinémie ( ≥ 20 % dans les six heures). Il est prudent d'admettre en réanimation toute intoxication aiguë à la chloroquine, mais il est inutile de distinguer les formes mineures et modérées, car il n'en résulte pas de différence de prise en charge [26]. La surveillance rapprochée de ces patients permet de dépister tout facteur de pronostic péjoratif, impliquant la mise en route du traitement maximaliste.…”

Section: La Chloroquineunclassified

Intoxication grave de l'adulte : épidémiologie, définition, critères d'admission en réanimation

2006

View full text Add to dashboard Cite

“…Subsequent case reports (Jaeger, Sauder, Kopferschmitt, & Flesch, 1987;Meeran & Jacobs, 1993;Rajah, 1990) and a prospective non-randomised trial (Riou, Barriot, Rimailho, & Baud, 1988), in which the odds of survival significantly favoured diazepam therapy, led to the recommendation of diazepam in the management of acute chloroquine toxicity. However, there remains controversy given some conflicting evidence of benefit (Demaziere et al, 1992;Clemessy et al, 1996) and limitations in study designs (Yanturali, 2004).…”

Section: Introductionmentioning

confidence: 99%

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

Hughes

2020

British J Pharmacology

View full text Add to dashboard Cite

of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Conflict of interest statement:The author declares no conflicts of interest. Declaration of transparency and scientific rigour:This Declaration acknowledges that this paper adheres to the principles for transparent reporting and scientific rigour of preclinical research as stated in the BJP guidelines for Design and Analysis, and Animal Experimentation, and as recommended by funding agencies, publishers and other organisations engaged with supporting research. AbstractBackground 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 effe This article is protected by copyright. All rights reserved.cts of positive inotropes in reducing chloroquine cardiotoxicity. Abbreviations:COVID-19 coronavirus disease 2019; FDA Food and Drug Administration; TSPO translocator protein;LV dP/dt time derivative of left ventricular pressure; MTBE methyl-tertiary-butyl ether What is already knownAcute chloroquine poisoning manifests as cardiotoxicity and is often managed using diazepam. What this study addsDiazepam does not attenuate the effects of chloroquine in isolated cardiac tissues, nor in vivo. Clinical significanceInotropic support, which is essential ...

show abstract

Therapeutic trial of diazepam versus placebo in acute chloroquine intoxications of moderate gravity

Abstract: Diazepam, at the dose studied, does not appear to reverse the chloroquine-induced membrane-stabilising effect in acute moderately severe chloroquine intoxication. Supportive intensive care of these intoxications appears to be all that is necessary.

Cited by 28 publications

References 11 publications

COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

COVID-19 prevention and treatment: A critical analysis of chloroquine and hydroxychloroquine clinical pharmacology

Intoxication grave de l'adulte : épidémiologie, définition, critères d'admission en réanimation

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

Contact Info

Product

Resources

About