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2.
BMB Rep ; 53(10): 545-550, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-979311

ABSTRACT

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].


Subject(s)
Azithromycin/adverse effects , Cardiotoxicity/etiology , Chloroquine/adverse effects , Embryonic Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Action Potentials , Animals , Arrhythmias, Cardiac/chemically induced , Azithromycin/administration & dosage , COVID-19 , Cell Differentiation , Chloroquine/administration & dosage , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Humans , Mice , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy
3.
BMB Rep ; 53(10): 545-550, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-783912

ABSTRACT

Combination therapy using chloroquine (CQ) and azithromycin (AZM) has drawn great attention due to its potential anti-viral activity against SARS-CoV-2. However, clinical trials have revealed that the co-administration of CQ and AZM resulted in severe side effects, including cardiac arrhythmia, in patients with COVID-19. To elucidate the cardiotoxicity induced by CQ and AZM, we examined the effects of these drugs based on the electrophysiological properties of human embryonic stem cellderived cardiomyocytes (hESC-CMs) using multi-electrode arrays. CQ treatment significantly increased the field potential duration, which corresponds to prolongation of the QT interval, and decreased the spike amplitude, spike slope, and conduction velocity of hESC-CMs. AZM had no significant effect on the field potentials of hESC-CMs. However, CQ in combination with AZM greatly increased the field potential duration and decreased the beat period and spike slope of hESC-CMs when compared with CQ monotherapy. In support of the clinical data suggesting the cardiovascular side effects of the combination therapy of CQ and AZM, our results suggest that AZM reinforces the cardiotoxicity induced by CQ in hESC-CMs. [BMB Reports 2020; 53(10): 545-550].


Subject(s)
Azithromycin/adverse effects , Cardiotoxicity/etiology , Chloroquine/adverse effects , Embryonic Stem Cells/drug effects , Myocytes, Cardiac/drug effects , Action Potentials , Animals , Arrhythmias, Cardiac/chemically induced , Azithromycin/administration & dosage , COVID-19 , Cell Differentiation , Chloroquine/administration & dosage , Coronavirus Infections/complications , Coronavirus Infections/drug therapy , Humans , Mice , Pandemics , Pneumonia, Viral/complications , Pneumonia, Viral/drug therapy
4.
Science ; 369(6504): 712-717, 2020 08 07.
Article in English | MEDLINE | ID: covidwho-594812

ABSTRACT

Excessive cytokine signaling frequently exacerbates lung tissue damage during respiratory viral infection. Type I (IFN-α and IFN-ß) and III (IFN-λ) interferons are host-produced antiviral cytokines. Prolonged IFN-α and IFN-ß responses can lead to harmful proinflammatory effects, whereas IFN-λ mainly signals in epithelia, thereby inducing localized antiviral immunity. In this work, we show that IFN signaling interferes with lung repair during influenza recovery in mice, with IFN-λ driving these effects most potently. IFN-induced protein p53 directly reduces epithelial proliferation and differentiation, which increases disease severity and susceptibility to bacterial superinfections. Thus, excessive or prolonged IFN production aggravates viral infection by impairing lung epithelial regeneration. Timing and duration are therefore critical parameters of endogenous IFN action and should be considered carefully for IFN therapeutic strategies against viral infections such as influenza and coronavirus disease 2019 (COVID-19).


Subject(s)
Alveolar Epithelial Cells/pathology , Cytokines/metabolism , Interferon Type I/metabolism , Interferons/metabolism , Lung/pathology , Orthomyxoviridae Infections/immunology , Orthomyxoviridae Infections/pathology , Alveolar Epithelial Cells/immunology , Animals , Apoptosis , Bronchoalveolar Lavage Fluid/immunology , Cell Differentiation , Cell Proliferation , Cells, Cultured , Cytokines/administration & dosage , Cytokines/immunology , Female , Influenza A Virus, H3N2 Subtype , Interferon Type I/administration & dosage , Interferon Type I/pharmacology , Interferon-alpha/administration & dosage , Interferon-alpha/metabolism , Interferon-alpha/pharmacology , Interferon-beta/administration & dosage , Interferon-beta/metabolism , Interferon-beta/pharmacology , Interferons/administration & dosage , Interferons/pharmacology , Male , Mice , Orthomyxoviridae Infections/metabolism , Receptor, Interferon alpha-beta/genetics , Receptor, Interferon alpha-beta/metabolism , Receptors, Interferon/genetics , Receptors, Interferon/metabolism , Signal Transduction , Tumor Suppressor Protein p53/metabolism
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