Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel

Zheng, Zongheng; Wu, Yujia; Dingding, Qian; Lian, Jing

doi:10.1016/j.ejphar.2020.173813

Cited by 38 publications

(37 citation statements)

References 104 publications

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“…The mechanism of QTc time prolongation by LPV/r, HCQ and erythromycin is through inhibition of the cardiac hERG (human ether-a-go-go related gene) potassium channels 13 . Inhibition of hERG channels is largely dose-/concentration-dependent and can be additively increased if hERG blockers are given together 13 . If QTc time increases by more than 60 msec or over 500 msec, the causative drugs should be discontinued right away 14 .…”

Section: Pharmacovigilance Discussionmentioning

confidence: 99%

Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre

Istampoulouoglou

Zimmermanns

Grandinetti

et al. 2021

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In this article we summarize the cardiovascular adverse events that were observed in three patients during their treatment for COVID-19 and discuss their association with lopinavir/ritonavir (LPV/r) and hydroxychloroquine (HCQ). The cases were reported to our regional pharmacovigilance centre in April 2020. All three patients were above 75 years in age, male and multimorbid, and had been hospitalized for treatment of COVID-19. As part of their treatment, all of them received a very strictly monitored off-label therapy with LPV/r and HCQ, for which they had given their prior, written, informed consent. In one patient, erythromycin was also administered. All three patients developed a significant QTc time prolongation during or shortly after therapy with the above drugs. On account of this, the treatment had to be discontinued early in each case and QTc time recovered in all three patients.

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Section: Pharmacovigilance Discussionmentioning

confidence: 99%

Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre

Istampoulouoglou

Zimmermanns

Grandinetti

et al. 2021

gcsp

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“…Azithromycin is mainly associated with gastrointestinal adverse reactions (22). Of note, it can extend the duration of action-potential and cardiac repolarization via blocking the delayed rectifier potassium channels (IKr), which can intensify the risk of developing ventricular tachyarrhythmia such as torsades de point (TdP) (23). Gen-erally, hydroxychloroquine has been favored over chloroquine due to having less tendency to produce cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

An Umbrella Review of Clinical Efficacy and Adverse Cardiac Events Associated with Hydroxychloroquine or Chloroquine with or Without Azithromycin in Patients with COVID-19

et al. 2021

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Context: The safety and efficacy of several repurposed drugs, including hydroxychloroquine and chloroquine, with or without azithromycin, were presumed to be miraculous in treating patients with COVID-19. However, as it later transpired, these therapeutic agents seem to be associated with critical adverse cardiac events. Objectives: Given the skepticism around the advantages and disadvantages of the aforementioned treatment strategies, the present study aimed to investigate the clinical efficacy and cardiac toxicity of hydroxychloroquine or chloroquine with or without azithromycin in the setting of COVID-19 infection. Method: This was an umbrella review conducted on patients with COVID-19 who received hydroxychloroquine or chloroquine with or without azithromycin from January 2020 to November 2020. We systematically searched PubMed, Scopus, Cochrane, ProQuest, Web of Science, and Embase databases. Results: Three studies (systematic review and meta-analysis) were analyzed to evaluate the arrhythmogenic potential of hydroxychloroquine or chloroquine with or without azithromycin in patients with COVID-19 and identify the clinical efficacy of such a combination. Conclusions: We found no benefit for patients with COVID-19 who received hydroxychloroquine or chloroquine alone or in combination with azithromycin. Moreover, it is noteworthy that these medications, particularly when considering co-administration, could result in both statistically and clinically elevated risks of notorious arrhythmias, such as TdP.

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“…Similarly, cardiotoxic drugs bind directly to highly sensitive aromatic amino acid residues (Y652, F656, etc.) in the channel that have a direct blocking effect or prevent the mature expression of channel proteins on the membrane ( Vandenberg et al, 2017 ; Helliwell et al, 2018 ; Zequn et al, 2021 ). For example, the antimalarial drugs quinidine and diastereoisomers of quinine show stereoselectivity for the hERG channel, with quinine 14-fold less potent than quinidine, and the hERG-F656C mutation reverses this stereoselectivity, suggesting that residue F656 contributes to the stereoselective pocket for quinidine and quinine ( Yan et al, 2016 ).…”

Section: The Most Important Repolarization Reservementioning

confidence: 99%

“…Compared with drugs that affect the maturation of hERG channel proteins to decrease the I Kr current, drugs that bind directly to the amino acid sites of the hERG channel to change the gating kinetics result in a more rapid channel failure. As mentioned above, these direct effects may sometimes produce extremely serious or even fatal cellular or clinical phenotypes ( Zequn et al, 2021 ).…”

Section: Summary and Perspectivesmentioning

confidence: 99%

Molecular Insights Into the Gating Kinetics of the Cardiac hERG Channel, Illuminated by Structure and Molecular Dynamics

Zheng

Lian

2021

Front. Pharmacol.

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The rapidly activating delayed rectifier K+ current generated by the cardiac hERG potassium channel encoded by KCNH2 is the most important reserve current for cardiac repolarization. The unique inward rectification characteristics of the hERG channel depend on the gating regulation, which involves crucial structural domains and key single amino acid residues in the full-length hERG channel. Identifying critical molecules involved in the regulation of gating kinetics for the hERG channel requires high-resolution structures and molecular dynamics simulation models. Based on the latest progress in hERG structure and molecular dynamics simulation research, summarizing the molecules involved in the changes in the channel state helps to elucidate the unique gating characteristics of the channel and the reason for its high affinity to cardiotoxic drugs. In this review, we aim to summarize the significant advances in understanding the voltage gating regulation of the hERG channel based on its structure obtained from cryo-electron microscopy and computer simulations, which reveal the critical roles of several specific structural domains and amino acid residues.

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Off-label use of chloroquine, hydroxychloroquine, azithromycin and lopinavir/ritonavir in COVID-19 risks prolonging the QT interval by targeting the hERG channel

Cited by 38 publications

References 104 publications

Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre

Cardiovascular adverse effects of lopinavir/ritonavir and hydroxychloroquine in COVID-19 patients: Cases from a single pharmacovigilance centre

An Umbrella Review of Clinical Efficacy and Adverse Cardiac Events Associated with Hydroxychloroquine or Chloroquine with or Without Azithromycin in Patients with COVID-19

Molecular Insights Into the Gating Kinetics of the Cardiac hERG Channel, Illuminated by Structure and Molecular Dynamics

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