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1.
J Clin Lab Anal ; 36(6): e24427, 2022 Jun.
Article in English | MEDLINE | ID: covidwho-1877605

ABSTRACT

BACKGROUND: Azithromycin (AZM), sold under the name Zithromax, is classified as a macrolide. It has many benefits due to its immunomodulatory, anti-inflammatory, and antibacterial effects. This review aims to study different clinical and biochemisterial aspects and properties of this drug which has a priority based on literature published worldwide. METHODS: Several databases including Web of Science, Google Scholar, PubMed, and Scopus were searched to obtain the relevant studies. RESULTS: AZM mechanism of action including the inhibition of bacterial protein synthesis, inhibition of proinflammatory cytokine production, inhibition of neutrophil infestation, and macrophage polarization alteration, gives it the ability to act against a wide range of microorganisms. Resistant organisms are spreading and being developed because of the irrational use of the drug in the case of dose and duration. AZM shows synergistic effects with other drugs against a variety of organisms. This macrolide is considered a valuable antimicrobial agent because of its use as a treatment for a vast range of diseases such as asthma, bronchiolitis, COPD, cystic fibrosis, enteric infections, STIs, and periodontal infections. CONCLUSIONS: Our study shows an increasing global prevalence of AZM resistance. Thus, synergistic combinations are recommended to treat different pathogens. Moreover, continuous monitoring of AZM resistance by registry centers and the development of more rapid diagnostic assays are urgently needed.


Subject(s)
Azithromycin , Cystic Fibrosis , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azithromycin/pharmacology , Azithromycin/therapeutic use , Bacterial Proteins , Cystic Fibrosis/drug therapy , Cystic Fibrosis/microbiology , Humans
2.
J Infect Chemother ; 28(7): 948-954, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1851524

ABSTRACT

INTRODUCTION: Macrolide antibiotics have immunomodulatory properties which may be beneficial in viral infections. However, the precise effects of macrolides on T cell responses to COVID, differences between different macrolides, and synergistic effects with other antibiotics have not been explored. METHODS: We investigated the effect of antibiotics (amoxicillin, azithromycin, clarithromycin, and combined amoxicillin with clarithromycin) on lymphocyte intracellular cytokine levels and monocyte phagocytosis in healthy volunteer PBMCs stimulated ex vivo with SARS-CoV-2 S1+2 spike protein. A retrospective cohort study was performed on intensive care COVID-19 patients. RESULTS: Co-incubation of clarithromycin with spike protein-stimulated healthy volunteer PBMCs ex vivo resulted in an increase in CD8+ (p = 0.004) and CD4+ (p = 0.007) IL-2, with a decrease in CD8+ (p = 0.032) and CD4+ (p = 0.007) IL-10. The addition of amoxicillin to clarithromycin resulted in an increase in CD8+ IL-6 (p = 0.010), decrease in CD8+ (p = 0.014) and CD4+ (p = 0.022) TNF-alpha, and decrease in CD8+ IFN-alpha (p = 0.038). Amoxicillin alone had no effect on CD4+ or CD8+ cytokines. Co-incubation of azithromycin resulted in increased CD8+ (p = 0.007) and CD4+ (p = 0.011) IL-2. There were no effects on monocyte phagocytosis. 102 COVID-19 ICU patients received antibiotics on hospital admission; 62 (61%) received clarithromycin. Clarithromycin use was associated with reduction in mortality on univariate analysis (p = 0.023), but not following adjustment for confounders (HR = 0.540; p = 0.076). CONCLUSIONS: Clarithromycin has immunomodulatory properties over and above azithromycin. Amoxicillin in addition to clarithromycin is associated with synergistic ex vivo immunomodulatory properties. The potential benefit of clarithromycin in critically ill patients with COVID-19 and other viral pneumonitis merits further exploration.


Subject(s)
COVID-19 , Clarithromycin , Amoxicillin , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azithromycin/pharmacology , Azithromycin/therapeutic use , COVID-19/drug therapy , Clarithromycin/pharmacology , Clarithromycin/therapeutic use , Cytokines , Humans , Interleukin-2 , Macrolides/pharmacology , Retrospective Studies , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
3.
J Med Microbiol ; 71(5)2022 May.
Article in English | MEDLINE | ID: covidwho-1831592

ABSTRACT

During this global pandemic of the COVID-19 disease, a lot of information has arisen in the media and online without scientific validation, and among these is the possibility that this disease could be aggravated by a secondary bacterial infection such as Prevotella, as well as the interest or not in using azithromycin, a potentially active antimicrobial agent. The aim of this study was to carry out a systematic literature review, to prove or disprove these allegations by scientific arguments. The search included Medline, PubMed, and Pubtator Central databases for English-language articles published 1999-2021. After removing duplicates, a total of final eligible studies (n=149) were selected. There were more articles showing an increase of Prevotella abundance in the presence of viral infection like that related to Human Immunodeficiency Virus (HIV), Papillomavirus (HPV), Herpesviridae and respiratory virus, highlighting differences according to methodologies and patient groups. The arguments for or against the use of azithromycin are stated in light of the results of the literature, showing the role of intercurrent factors, such as age, drug consumption, the presence of cancer or periodontal diseases. However, clinical trials are lacking to prove the direct link between the presence of Prevotella spp. and a worsening of COVID-19, mainly those using azithromycin alone in this indication.


Subject(s)
COVID-19 , Coinfection , Azithromycin/pharmacology , Humans , Pandemics , Prevotella , SARS-CoV-2
4.
Biomed Pharmacother ; 147: 112682, 2022 Mar.
Article in English | MEDLINE | ID: covidwho-1664682

ABSTRACT

Viral infections have a great impact on human health. The urgent need to find a cure against different viruses led us to investigations in a vast range of drugs. Azithromycin (AZT), classified as a macrolide, showed various effects on different known viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV), Zika, Ebola, Enterovirus (EVs) and Rhinoviruses (RVs), and Influenza A previously; namely, these viruses, which caused global concerns, are considered as targets for AZT different actions. Due to AZT background in the treatment of known viral infections mentioned above (which is described in this study), in the early stages of COVID-19 (a new zoonotic disease caused by a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) development, AZT drew attention to itself due to its antiviral and immunomodulatory effects as a valuable candidate for COVID-19 treatment. AZT usage instructions for treating different viral infections have always been under observation, and COVID-19 is no exception. There are still debates about the use of AZT in COVID-19 treatment. However, eventually, novel researches convinced WHO to announce the discontinuation of AZT use (alone or in combination with hydroxychloroquine) in treating SARS-CoV-2 infection. This research aims to study the structure of all of the viruses mentioned above and the molecular and clinical effects of AZT against the virus.


Subject(s)
Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Anti-Bacterial Agents , Antiviral Agents/pharmacology , Azithromycin/pharmacology , Ebolavirus/drug effects , Humans , Influenza A virus/drug effects , SARS Virus/drug effects , SARS-CoV-2/drug effects , Zika Virus/drug effects
5.
Sci Rep ; 12(1): 1075, 2022 01 20.
Article in English | MEDLINE | ID: covidwho-1642005

ABSTRACT

Inflammatory diseases including COVID-19 are associated with a cytokine storm characterized by high interleukin-6 (IL-6) titers. In particular, while recent studies examined COVID-19 associated arrhythmic risks from cardiac injury and/or from pharmacotherapy such as the combination of azithromycin (AZM) and hydroxychloroquine (HCQ), the role of IL-6 per se in increasing the arrhythmic risk remains poorly understood. The objective is to elucidate the electrophysiological basis of inflammation-associated arrhythmic risk in the presence of AZM and HCQ. IL-6, AZM and HCQ were concomitantly administered to guinea pigs in-vivo and in-vitro. Electrocardiograms, action potentials and ion-currents were analyzed. IL-6 alone or the combination AZM + HCQ induced mild to moderate reduction in heart rate, PR-interval and corrected QT (QTc) in-vivo and in-vitro. Notably, IL-6 alone was more potent than the combination of the two drugs in reducing heart rate, increasing PR-interval and QTc. In addition, the in-vivo or in-vitro combination of IL-6 + AZM + HCQ caused severe bradycardia, conduction abnormalities, QTc prolongation and asystole. These electrocardiographic abnormalities were attenuated in-vivo by tocilizumab (TCZ), a monoclonal antibody against IL-6 receptor, and are due in part to the prolongation of action potential duration and selective inhibition of Na+, Ca2+ and K+ currents. Inflammation confers greater risk for arrhythmia than the drug combination therapy. As such, in the setting of elevated IL-6 during inflammation caution must be taken when co-administering drugs known to predispose to fatal arrhythmias and TCZ could be an important player as a novel anti-arrhythmic agent. Thus, identifying inflammation as a critical culprit is essential for proper management.


Subject(s)
Arrhythmias, Cardiac , Azithromycin/pharmacology , COVID-19 , Hydroxychloroquine/pharmacology , Interleukin-6/metabolism , SARS-CoV-2/metabolism , Animals , Antibodies, Monoclonal, Humanized/pharmacology , Arrhythmias, Cardiac/etiology , Arrhythmias, Cardiac/metabolism , Arrhythmias, Cardiac/physiopathology , Arrhythmias, Cardiac/prevention & control , COVID-19/complications , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/physiopathology , Female , Guinea Pigs , Humans , Inflammation/drug therapy , Inflammation/metabolism , Inflammation/physiopathology , Interleukin-6/antagonists & inhibitors , Male
6.
Front Biosci (Landmark Ed) ; 26(12): 1493-1502, 2021 12 30.
Article in English | MEDLINE | ID: covidwho-1614662

ABSTRACT

BACKGROUND: Despite the fact that the clinical efficacy of hydroxychloroquine is still controversial, it has been demonstrated in vitro to control SARS-CoV-2 multiplication on Vero E6 cells. In this study, we tested the possibility that some patients with prolonged virus excretion could be infected by less susceptible strains. METHOD: Using a high-content screening method, we screened 30 different selected isolates of SARS-CoV-2 from different patients who received azithromycin ± hydroxychloroquine. We focused on patients with viral persistence, i.e., positive virus detection in a nasopharyngeal sample ≥10 days, and who were tested during two French epidemic waves, late winter-spring of 2020 and the summer of 2020. Dose-response curves in single-molecule assays with hydroxychloroquine were created for isolates with suspected reduced susceptibility. Genome clustering was performed for all isolates. RESULTS: Of 30 tested strains, three were detected as replicating in the presence of azithromycin + hydroxychloroquine, each at 5 µM. The dose-response model showed a decrease in susceptibility of these three strains to hydroxychloroquine. Whole genome sequencing revealed that these three strains are all from the second epidemic wave and two cluster with isolates from Africa. CONCLUSIONS: Reduced susceptibility to hydroxychloroquine was not associated with viral persistence in naso-pharyngeal samples. Rather, it was associated with occurring during the second epidemic wave, which began in the summer and with strains clustering with those with a common genotype in Africa, where hydroxychloroquine was the most widely used.


Subject(s)
COVID-19 , Hydroxychloroquine , Azithromycin/pharmacology , COVID-19/drug therapy , Humans , Hydroxychloroquine/pharmacology , SARS-CoV-2
7.
Antiviral Res ; 197: 105212, 2022 01.
Article in English | MEDLINE | ID: covidwho-1530602

ABSTRACT

Drug repositioning has been used extensively since the beginning of the COVID-19 pandemic in an attempt to identify antiviral molecules for use in human therapeutics. Hydroxychloroquine and azithromycin have shown inhibitory activity against SARS-CoV-2 replication in different cell lines. Based on such in vitro data and despite the weakness of preclinical assessment, many clinical trials were set up using these molecules. In the present study, we show that hydroxychloroquine and azithromycin alone or combined does not block SARS-CoV-2 replication in human bronchial airway epithelia. When tested in a Syrian hamster model, hydroxychloroquine and azithromycin administrated alone or combined displayed no significant effect on viral replication, clinical course of the disease and lung impairments, even at high doses. Hydroxychloroquine quantification in lung tissues confirmed strong exposure to the drug, above in vitro inhibitory concentrations. Overall, this study does not support the use of hydroxychloroquine and azithromycin as antiviral drugs for the treatment of SARS-CoV-2 infections.


Subject(s)
Anti-Infective Agents/pharmacology , Azithromycin/pharmacology , COVID-19/drug therapy , Hydroxychloroquine/pharmacology , SARS-CoV-2/drug effects , Animals , Anti-Infective Agents/administration & dosage , Anti-Infective Agents/therapeutic use , Azithromycin/administration & dosage , Azithromycin/pharmacokinetics , Azithromycin/therapeutic use , Bronchi/cytology , Bronchi/virology , Chlorocebus aethiops , Cricetinae , Disease Models, Animal , Drug Therapy, Combination , Female , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/therapeutic use , Lung/pathology , Mesocricetus , Middle Aged , Plasma/virology , Real-Time Polymerase Chain Reaction , Vero Cells
8.
Pharmacol Rev ; 73(4): 233-262, 2021 10.
Article in English | MEDLINE | ID: covidwho-1494905

ABSTRACT

Macrolides are among the most widely prescribed broad spectrum antibacterials, particularly for respiratory infections. It is now recognized that these drugs, in particular azithromycin, also exert time-dependent immunomodulatory actions that contribute to their therapeutic benefit in both infectious and other chronic inflammatory diseases. Their increased chronic use in airway inflammation and, more recently, of azithromycin in COVID-19, however, has led to a rise in bacterial resistance. An additional crucial aspect of chronic airway inflammation, such as chronic obstructive pulmonary disease, as well as other inflammatory disorders, is the loss of epithelial barrier protection against pathogens and pollutants. In recent years, azithromycin has been shown with time to enhance the barrier properties of airway epithelial cells, an action that makes an important contribution to its therapeutic efficacy. In this article, we review the background and evidence for various immunomodulatory and time-dependent actions of macrolides on inflammatory processes and on the epithelium and highlight novel nonantibacterial macrolides that are being studied for immunomodulatory and barrier-strengthening properties to circumvent the risk of bacterial resistance that occurs with macrolide antibacterials. We also briefly review the clinical effects of macrolides in respiratory and other inflammatory diseases associated with epithelial injury and propose that the beneficial epithelial effects of nonantibacterial azithromycin derivatives in chronic inflammation, even given prophylactically, are likely to gain increasing attention in the future. SIGNIFICANCE STATEMENT: Based on its immunomodulatory properties and ability to enhance the protective role of the lung epithelium against pathogens, azithromycin has proven superior to other macrolides in treating chronic respiratory inflammation. A nonantibiotic azithromycin derivative is likely to offer prophylactic benefits against inflammation and epithelial damage of differing causes while preserving the use of macrolides as antibiotics.


Subject(s)
COVID-19 , Macrolides , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Azithromycin/pharmacology , Humans , Macrolides/pharmacology , SARS-CoV-2
10.
Pharmacol Rep ; 73(6): 1520-1538, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1377631

ABSTRACT

The global spread of COVID-19 has imparted significant economic, medical, and social burdens. Like adults, children are affected by this pandemic. However, milder clinical symptoms are often experienced by them. Only a minimal proportion of the affected patients may develop severe and complicated COVID-19. Supportive treatment is recommended in all patients. Antiviral and immunomodulatory medications are spared for hospitalized children with respiratory distress or severe to critical disease. Up till now, remdesivir is the only USFDA-approved anti-COVID-19 medication indicated in the majority of symptomatic patients with moderate to severe disease. Dexamethasone is solely recommended in patients with respiratory distress maintained on oxygen or ventilatory support. The use of these medications in pediatric patients is founded on evidence deriving from adult studies. No randomized controlled trials (RCTs) involving pediatric COVID-19 patients have assessed these medications' efficacy and safety, among others. Similarly, three novel monoclonal anti-SARS-CoV-2 spike protein antibodies, bamlanivimab, casirivimab and imdevimab, have been recently authorized by the USFDA. Nonetheless, their efficacy has not been demonstrated by multiple RCTs. In this review, we aim to dissect the various potential therapeutics used in children with COVID-19. We aspire to provide a comprehensive review of the available evidence and display the mechanisms of action and the pharmacokinetic properties of the studied therapeutics. Our review offers an efficient and practical guide for treating children with COVID-19.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Antiviral Agents/pharmacology , COVID-19/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal, Humanized/pharmacology , Azithromycin/pharmacology , Child , Dexamethasone/pharmacology , Humans , Hydroxychloroquine/pharmacology , Ivermectin/pharmacology , Lopinavir/pharmacology , Oseltamivir/pharmacology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
11.
PLoS One ; 16(6): e0251731, 2021.
Article in English | MEDLINE | ID: covidwho-1285198

ABSTRACT

Immunotherapy using checkpoint blockade (ICB) with antibodies such as anti-PD-1 has revolutionised the treatment of many cancers. Despite its use to treat COVID-19 patients and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis, the effect of hydroxychloroquine (HCQ) on cancer immunotherapy has not been examined. In this study, remarkably, we find that HCQ alone, or in combination with azithromycin (AZ), at doses used to treat patients, decreased the therapeutic benefit of anti-PD-1 in cancer immunotherapy. No deleterious effect was seen on untreated tumors. Mechanistically, HCQ and HCQ/AZ inhibited PD-L1 expression on tumor cells, while specifically targeting the anti-PD-1 induced increase in progenitor CD8+CD44+PD-1+TCF1+ tumor infiltrating T cells (TILs) and the generation of CD8+CD44+PD-1+ effectors. Surprisingly, it also impaired the appearance of a subset of terminally exhausted CD8+ TILs. No effect was seen on the presence of CD4+ T cells, FoxP3+ regulatory T cells (Tregs), thymic subsets, B cells, antibody production, myeloid cells, or the vasculature of mice. This study indicates for the first time that HCQ and HCQ/AZ negatively impact the ability of anti-PD-1 checkpoint blockade to promote tumor rejection.


Subject(s)
Hydroxychloroquine/pharmacology , Immune Checkpoint Inhibitors/pharmacology , Immunotherapy , Programmed Cell Death 1 Receptor/immunology , Animals , Azithromycin/pharmacology , Cell Line, Tumor , Drug Antagonism , Immune Checkpoint Inhibitors/immunology , Melanoma/pathology , Mice , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
12.
Commun Biol ; 4(1): 682, 2021 06 03.
Article in English | MEDLINE | ID: covidwho-1260957

ABSTRACT

An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of Coronavirus Disease-2019 (COVID-19), a respiratory disease, has infected almost one hundred million people since the end of 2019, killed over two million, and caused worldwide social and economic disruption. Because the mechanisms of SARS-CoV-2 infection of host cells and its pathogenesis remain largely unclear, there are currently no antiviral drugs with proven efficacy. Besides severe respiratory and systematic symptoms, several comorbidities increase risk of fatal disease outcome. Therefore, it is required to investigate the impacts of COVID-19 on pre-existing diseases of patients, such as cancer and other infectious diseases. In the current study, we report that SARS-CoV-2 encoded proteins and some currently used anti-COVID-19 drugs are able to induce lytic reactivation of Kaposi's sarcoma-associated herpesvirus (KSHV), one of major human oncogenic viruses, through manipulation of intracellular signaling pathways. Our data indicate that those KSHV + patients especially in endemic areas exposure to COVID-19 or undergoing the treatment may have increased risks to develop virus-associated cancers, even after they have fully recovered from COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/complications , Herpesvirus 8, Human/physiology , SARS-CoV-2/physiology , Sarcoma, Kaposi/etiology , Virus Activation , Azithromycin/pharmacology , Benzamidines/pharmacology , COVID-19/drug therapy , Cell Line , Guanidines/pharmacology , Herpesviridae Infections/chemically induced , Herpesviridae Infections/etiology , Herpesvirus 8, Human/drug effects , Humans , Oncogenic Viruses/drug effects , Oncogenic Viruses/physiology , SARS-CoV-2/drug effects , Sarcoma, Kaposi/chemically induced , Viral Proteins/metabolism , Virus Activation/drug effects
14.
J Pharmacol Exp Ther ; 377(2): 265-272, 2021 05.
Article in English | MEDLINE | ID: covidwho-1234275

ABSTRACT

Drug-induced long QT syndrome (LQTS) is an established cardiac side effect of a wide range of medications and represents a significant concern for drug safety. The rapidly and slowly activating delayed rectifier K+ currents, mediated by channels encoded by the human ether-a-go-go-related gene (hERG) and KCNQ1 + KCNE1, respectively, are two main currents responsible for ventricular repolarization. The common cause for drugs to induce LQTS is through impairing the hERG channel. For the recent emergence of COVID-19, caused by severe acute respiratory syndrome coronavirus 2, several drugs have been investigated as potential therapies; however, there are concerns about their QT prolongation risk. Here, we studied the effects of chloroquine, hydroxychloroquine, azithromycin, and remdesivir on hERG channels. Our results showed that although chloroquine acutely blocked hERG current (IhERG), with an IC50 of 3.0 µM, hydroxychloroquine acutely blocked IhERG 8-fold less potently, with an IC50 of 23.4 µM. Azithromycin and remdesivir did not acutely affect IhERG When these drugs were added at 10 µM to the cell culture medium for 24 hours, remdesivir increased IhERG by 2-fold, which was associated with an increased mature hERG channel expression. In addition, these four drugs did not acutely or chronically affect KCNQ1 + KCNE1 channels. Our data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns. SIGNIFICANCE STATEMENT: This work demonstrates that, among off-label potential COVID-19 treatment drugs chloroquine, hydroxychloroquine, azithromycin, and remdesivir, the former two drugs block hERG potassium channels, whereas the latter two drugs do not. All four drugs do not affect KCNQ1 + KCNE1. As hERG and KCNQ1 + KCNE1 are two main K+ channels responsible for ventricular repolarization, and most drugs that induce long QT syndrome (LQTS) do so by impairing hERG channels, these data provide insight into COVID-19 drug-associated LQTS and cardiac safety concerns.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Azithromycin/pharmacology , COVID-19/drug therapy , Chloroquine/pharmacology , ERG1 Potassium Channel/antagonists & inhibitors , Hydroxychloroquine/pharmacology , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Antimalarials/pharmacology , Antimalarials/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/metabolism , Chloroquine/therapeutic use , Dose-Response Relationship, Drug , ERG1 Potassium Channel/metabolism , HEK293 Cells , Humans , Hydroxychloroquine/therapeutic use , Potassium Channel Blockers/pharmacology , Potassium Channel Blockers/therapeutic use
15.
Eur J Pharmacol ; 905: 174191, 2021 Aug 15.
Article in English | MEDLINE | ID: covidwho-1230459

ABSTRACT

Azithromycin, a member of the macrolide family of antibiotics, is commonly used to treat respiratory bacterial infections. Nevertheless, multiple pharmacological effects of the drug have been revealed in several investigations. Conceivably, the immunomodulatory properties of azithromycin are among its critical features, leading to its application in treating inflammatory diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Additionally, azithromycin may directly inhibit viral load as well as its replication, or it could demonstrate indirect inhibitory impacts that might be associated with the expression of antiviral genes. Currently, coronavirus disease 2019 (COVID-19) is an extra urgent issue affecting the entire world, and it is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Acute respiratory distress syndrome (ARDS), which is associated with hyper inflammation due to cytokine release, is among the leading causes of death in COVID-19 patients with critical conditions. The present paper aims to review the immunomodulatory and antiviral properties of azithromycin as well as its potential clinical applications in the management of COVID-19 patients.


Subject(s)
Azithromycin/pharmacology , COVID-19 , Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/immunology , Humans , Immunologic Factors/pharmacology , SARS-CoV-2
16.
Viruses ; 13(5)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1227067

ABSTRACT

SARS-CoV-2 nasopharyngeal shedding contributes to the spread of the COVID-19 epidemic. Among 3271 COVID-19 patients treated at the Hospital University Institute Méditerranée Infection, Marseille, France from 3 March to 27 April 2020, tested at least twice by qRT-PCR, the median SARS-CoV-2 nasopharyngeal shedding duration was 6 days (range 2-54 days). Compared with short shedders (qRT-PCR positivity < 10 days), 34 (1.04%) persistent shedders (qRT-PCR positivity ≥ 17 days; mean ± SD: 23.3 ± 3.8 days) were significantly older, with associated comorbidities, exhibiting lymphopenia, eosinopenia, increased D-dimer and increased troponin (p < 0.05), and were hospitalized in intensive care unit in 17.7% vs. 1.1% of cases (p < 0.0001). Viral culture was positive in six persistent shedders after day 10, including in one patient after day 17, and no viral co-pathogen was detected in 33 tested patients. Persistent shedders received azithromycin plus hydroxychloroquine ≥ 3 days in 26/34 (76.5%) patients, a figure significantly lower than in short shedders (86.6%) (p = 0.042). Accordingly, mortality was 14.7% vs. 0.5% (p < 0.0001). Persistent shedding was significantly associated with persistent dyspnea and anosmia/ageusia (p < 0.05). In the context of COVID-19 treatment, including treatment with azithromycin plus hydroxychloroquine, the persistence of SARS-CoV-2 nasopharyngeal shedding was a rare event, most frequently encountered in elderly patients with comorbidities and lacking azithromycin plus hydroxychloroquine treatment.


Subject(s)
COVID-19/metabolism , Hydroxychloroquine/pharmacology , Virus Shedding/drug effects , Adult , Aged , Azithromycin/metabolism , Azithromycin/pharmacology , COVID-19/drug therapy , Comorbidity , Drug Therapy, Combination , Female , France/epidemiology , Hospitalization , Humans , Hydroxychloroquine/metabolism , Male , Middle Aged , Nasopharynx , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
17.
Ann Noninvasive Electrocardiol ; 26(4): e12846, 2021 Jul.
Article in English | MEDLINE | ID: covidwho-1218078

ABSTRACT

BACKGROUND: Since there was no proven treatment of coronavirus disease 2019 (COVID-19), hydroxychloroquine-azithromycin (HCQ-AZM) combination is being used in different countries as a treatment option. Many controversies exist related to the safety and effectiveness of this combination, and questions about how HCQ-AZM combination affects the ventricular repolarization are still unknown. OBJECTIVE: The aim of the study was to show whether the hydroxychloroquine-azithromycin (HCQ-AZM) combination prolonged Tpeak-to-end (TpTe) duration and TpTe/QT interval ratio or not. METHODS: One hundred and twenty-six consequent COVID-19(+) patients meeting the study criteria were enrolled in this study. Baseline ECGs were obtained immediately after hospitalization and before commencing the HCQ-AZM combination. On-treatment ECG was obtained 24-48 hr after the loading dose of HCQ/AZM. ECG parameters including PR interval, QRS duration, QT interval, QTc interval, TpTe duration, and TpTe/QT interval ratio were assessed. Demographic and laboratory findings were collected from an electronic recording system. RESULTS: ECGs of 126 COVID-19(+) patients who received HCQ-AZM combination were assessed. Mean baseline QTc (by Fridericia formula), TpTe, and TpTe/QT ratio were 420.0 ± 26.5 ms, 82.43 ± 9.77 ms, and 0.22 ± 0.02, respectively. On-treatment QTc, TpTe and TpTe/QT ratio were 425.7 ± 27.18 ms, 85.17 ± 11.17 ms, and 0.22 ± 0.03, respectively. No statistically significant acute impacts of HCQ-AZM combination on TpTe duration and TpTe/QT interval ratio were observed compared with baseline values. No ventricular tachycardia/fibrillation and the significant conduction delays were seen during in-hospital follow-up. CONCLUSION: HCQ-AZM combination increased TpTe duration. However, no significant impact on TpTe/QT interval ratio was observed.


Subject(s)
Azithromycin/pharmacology , COVID-19/drug therapy , Electrocardiography/drug effects , Heart Ventricles/drug effects , Hydroxychloroquine/pharmacology , Anti-Bacterial Agents/pharmacology , Drug Administration Schedule , Drug Therapy, Combination , Enzyme Inhibitors/pharmacology , Female , Humans , Male , Middle Aged , Retrospective Studies , SARS-CoV-2 , Treatment Outcome
18.
Mini Rev Med Chem ; 21(19): 2860-2873, 2021.
Article in English | MEDLINE | ID: covidwho-1167203

ABSTRACT

As winter is approaching us, the possibility of respiratory tract infection is rising in the current scenario due to the lack of Covid-19 prophylaxis. So no one could be safe until everyone is safe. Researchers are looking for the vaccine to remove the need for social distancing, mask-wearing, and social gathering worldwide. We cannot say about the vaccine's effectiveness if the vaccine is available. Several drugs are being tested to save people's life from the pandemic; azithromycin is one of them. This work is a review article with the updated findings of azithromycin in the context of COVID-19. The option of azithromycin regarding COVID-19 is justified by its anti-inflammatory, immunomodulatory, and anti-fibrotic effects and their pharmacokinetic properties, leading to effective concentrations in the target tissue. Azithromycin tends to be an effective candidate for SARS-CoV-2 replication inhibition that blocks the initial stage of the viral life cycle. Clinical trials at a preliminary scale and final stage show the significant results of azithromycin in supportive care therapy. Azithromycin was an early candidate for the medication of Covid-19 with or without hydroxychloroquine. It is exercised mainly as an outpatient antibiotic in COVID-19. In summing up, any primary anti-viral and antibiotic treatment is not the only possibility of fighting COVID-19 pharmacologically. It will be an injustice to those who require broader spectrum antibiotics if we do not use azithromycin. So significant research priority is needed to determine whether azithromycin is useful in the treatment of COVID-19.


Subject(s)
Azithromycin/pharmacology , Azithromycin/therapeutic use , COVID-19/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , COVID-19/immunology , COVID-19/pathology , COVID-19/virology , Humans , SARS-CoV-2/drug effects , SARS-CoV-2/growth & development
19.
Microb Drug Resist ; 27(3): 281-290, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1137930

ABSTRACT

The coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2, has recently emerged worldwide. In this context, there is an urgent need to identify safe and effective therapeutic strategies for treatment of such highly contagious disease. We recently reported promising results of combining hydroxychloroquine and azithromycin as an early treatment option. Although ongoing clinical trials are challenging the efficacy of this combination, many clinicians claim the authorization to or have already begun to use it to treat COVID-19 patients worldwide. The aim of this article is to share pharmacology considerations contributing to the rationale of this combination, and to provide safety information to prevent toxicity and drug-drug interactions, based on available evidence.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , Azithromycin/therapeutic use , COVID-19/drug therapy , Hydroxychloroquine/therapeutic use , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacology , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Antiviral Agents/pharmacology , Azithromycin/administration & dosage , Azithromycin/adverse effects , Azithromycin/pharmacology , Dose-Response Relationship, Drug , Drug Interactions , Drug Therapy, Combination , Humans , Hydroxychloroquine/administration & dosage , Hydroxychloroquine/adverse effects , Hydroxychloroquine/pharmacology , SARS-CoV-2
20.
Biochem Biophys Res Commun ; 538: 132-136, 2021 01 29.
Article in English | MEDLINE | ID: covidwho-1125012

ABSTRACT

Covid-19 is an infectious respiratory disease due to a coronavirus named SARS-CoV-2. A critical step of the infection cycle is the binding of the virus spike S protein to the cellular ACE-2 receptor. This interaction involves a receptor binding domain (RBD) located at the center of the S trimer, whereas the lateral N-terminal domain (NTD) displays a flat ganglioside binding site that enables the virus to bind to lipid rafts of the plasma membrane, where the ACE-2 receptor resides. S protein binding to lipid rafts can be blocked by hydroxychloroquine, which binds to gangliosides, and by azithromycin, which binds to the NTD. Based on these data, we identified the NTD of SARS-CoV-2 as a promising target for both therapeutic and vaccine strategies, a notion later supported by the discovery, in convalescent Covid-19 patients, of a neutralizing antibody (4A8) that selectively binds to the NTD. The 4A8 epitope overlaps the ganglioside binding domain, denying any access of the virus to lipid rafts when the antibody is bound to the S protein. Thus, our data explain why antibody binding to the tip of the NTD results in SARS-CoV-2 neutralization. The high level of conservation of the ganglioside binding domain of SARS-CoV-2 (100% identity in 584 of 600 isolates analyzed worldwide) offers unique opportunities for innovative vaccine/therapeutic strategies.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19 Vaccines/chemistry , COVID-19/therapy , Gangliosides/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Angiotensin-Converting Enzyme 2/immunology , Antibodies, Neutralizing/chemistry , Azithromycin/chemistry , Azithromycin/pharmacology , Azithromycin/therapeutic use , Binding Sites , COVID-19 Vaccines/immunology , COVID-19 Vaccines/therapeutic use , Gangliosides/chemistry , Humans , Hydroxychloroquine/chemistry , Hydroxychloroquine/pharmacology , Hydroxychloroquine/therapeutic use , Protein Domains , SARS-CoV-2/chemistry , Spike Glycoprotein, Coronavirus/chemistry
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