Introduction.-COVID-19 is an unprecedented challenge for physicians and scientists. Several publicized drugs are being used with not much evidence of their efficacy such as hydroxychloroquine, azithromycin or lopinavir-ritonavir. Yet, the cardiac safety of these drugs in COVID-19 deserves scrutiny as they are known to foster cardiac adverse ADRs, notably QTc interval prolongation on the electrocardiogram and its arrhythmogenic consequences. Methods.-Since March 27th, 2020, the French Pharmacovigilance Network directed all cardiac adverse drug reactions associated with ''off-label'' use of hydroxychloroquine, azithromycin and lopinavir-ritonavir in COVID-19 to the Nice Regional Center of Pharmacovigilance. Each Regional Center of Pharmacovigilance first assessed causality of drugs. We performed a specific analysis of these cardiac adverse drug reactions amidst an array of risk factors, reassessed the electrocardiograms and estimated their incidence in coronavirus disease 2019.
1 In the present study, two new peptides, phrixotoxins PaTx1 and PaTx2 (29 ± 31 amino acids), which potently block A-type potassium currents, have been puri®ed from the venom of the tarantula Phrixotrichus auratus. 2 Phrixotoxins speci®cally block Kv4.3 and Kv4.2 currents that underlie I to1 , with an 55IC 50 570 nM, by altering the gating properties of these channels. 3 Neither are the Shaker (Kv1), Shab (Kv2) and Shaw (Kv3) subfamilies of currents, nor HERG, KvLQT1/IsK, inhibited by phrixotoxins which appear speci®c of the Shal (Kv4) subfamily of currents and also block I to1 in isolated murine cardiomyocytes. 4 In order to evaluate the physiological consequences of the Ito1 inhibition, mice were injected intravenously with PaTx1, which resulted in numerous transient cardiac adverse reactions including the occurrence of premature ventricular beats, ventricular tachycardia and di erent degrees of atrioventricular block. 5 The analysis of the mouse electrocardiogram showed a dose-dependent prolongation of the QT interval, chosen as a surrogate marker for their ventricular repolarization, from 249+11 to 265+8 ms (P50.05). 6 It was concluded that phrixotoxins, are new and speci®c blockers of Kv4.3 and Kv4.2 potassium currents, and hence of I to1 that will enable further studies of Kv4.2 and Kv4.3 channel and/or I to1 expression.
1 Acetylcholine (ACh) is an important neuromodulator of cardiac function that is released upon stimulation of the vagus nerve. Despite numerous reports on activation of I KACh by acetylcholine in cardiomyocytes, it has yet to be demonstrated what role this channel plays in cardiac conduction. We studied the eect of tertiapin, a bee venom peptide blocking I KACh , to evaluate the role of I KACh in Langendor preparations challenged with ACh. 2 ACh (0.5 mM) reproducibly and reversibly induced complete atrioventricular (AV) blocks in retroperfused guinea-pig isolated hearts (n=12). 3 Tertiapin (10 to 300 nM) dose-dependently and reversibly prevented the AV conduction decrements and the complete blocks in unpaced hearts (n=8, P50.01). 4 Tertiapin dose-dependently blunted the ACh-induced negative chronotropic response from an ACh-induced decrease in heart rate of 39+16% in control conditions to 3+3% after 300 nM tertiapin (P=0.01). These eects were not accompanied by any signi®cant change in QT intervals. 5 Tertiapin blocked I KACh with an IC 50 of 30+4 nM with no signi®cant eect on the major currents classically associated with cardiac repolarisation process (I Kr , I Ks , I to1 , I sus , I K1 or I KATP ) or AV conduction (I Na and I Ca(L) ). 6 In summary, tertiapin prevents dose-dependently ACh-induced AV blocks in mammalian hearts by inhibiting I KACh .
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