Introduction
Chloroquine and hydroxychloroquine are being repurposed for use as
treatment options for coronavirus disease 2019 (COVID-19) (Ferner and
Aronson, 2020). The Food and Drug Administration sanctioned their
emergency use in the USA (FDA, 2020), and clinical guidelines in
Belgium, China, France, India, Iran, Italy, South Korea, and The
Netherlands make recommendations for uses ranging from prophylaxis
(Indian Council of Medical Research, 2020) to the treatment of the most
severely affected patients.
Case reports of cardiotoxicity and fatal poisoning relating to the use
of chloroquine and hydroxychloroquine for COVID-19 have emerged
(Binding, 2020; Agence Régionale de Santé, 2020; Xuan, 2020; Busari and
Adebayo, 2020; SimpliCity, 2020). The acute toxic effects of these drugs
are well recognised (WHO, 2016), and relate to their cardiotoxic effects
of widening of the QRS complex, atrioventricular block, ventricular
arrhythmias, negative inotropy, hypotension and severe hypokalaemia,
which occur within 1-3 hours of ingesting doses >2g in
adults. Without intensive, supportive treatment, circulatory collapse
and death can rapidly follow acute overdose. Mortality due to acute
toxicity is high, with 134 of the 387 cases reported in the literature
between 1955 and 1975 (Bondurand et al., 1980), and a further 135 from
335 suicide attempts (Weniger and World Health Organization, 1979)
resulting in death.
Current recommendations for the management of acute toxicity include
ensuring adequate ventilation, gastric lavage, administration of
activated charcoal, adrenaline for its inotropic and vasoconstrictor
effects, diazepam, and correction of metabolic acidosis and hypokalaemia
(Jones, 2015). The observation in 1976 of a patient who took 5g of
chloroquine together with 500mg of diazepam, and survived without
symptoms of chloroquine toxicity (Djelardje, 1976), drew attention to
the possible role of diazepam in chloroquine poisoning. Subsequent case
reports (Jaeger et al., 1987; Rajah, 1990; Meeran and Jacobs, 1993) and
a prospective non-randomised trial (Riou et al., 1988a), 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 (Damaziere et al., 1992; Clemessy et al., 1996) and
limitations in study designs (Yanturali, 2004).
Experimental toxicity studies are also inconclusive. Crouzette et al.,
(1983) demonstrated that an intraperitoneal injection of diazepam caused
a significant decrease in the mortality of rats treated with
chloroquine. Riou et al., (1988b) observed an improvement in
haemodynamics and a correction of the QRS interval prolongation when
diazepam was administered to chloroquine-intoxicated pigs. Gnassounou et
al., (1988) observed that clonazepam protected anaesthetized rats
against chloroquine toxicity, and that diazepam – but not the
translocator protein (TSPO) agonist Ro5-4864 (4’-chlorodiazepam) –
protected against the decrease in contractions observed when guinea-pig
atria were exposed to chloroquine. In other studies, however, diazepam
failed to improve the mechanical performance of rat cardiac papillary
muscle exposed to chloroquine (Riou et al., 1989); and was ineffective
in reversing chloroquine toxicity in anaesthetized rats (Buckley et al.,
1996).
It would therefore appear that the effectiveness of diazepam in
reversing chloroquine toxicity is equivocal and that the mechanism(s) by
which diazepam may exert its effects remain unclear. Due to the
resurgence in the use of chloroquine and its structural analogue
hydroxychloroquine for COVID-19, the aim of the present study was to
investigate the potential cardioprotective effects of diazepam in
experimental models of chloroquine toxicity.