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2.
J Transl Med ; 18(1): 405, 2020 10 21.
Article in English | MEDLINE | ID: covidwho-1477432

ABSTRACT

BACKGROUND: Tocilizumab blocks pro-inflammatory activity of interleukin-6 (IL-6), involved in pathogenesis of pneumonia the most frequent cause of death in COVID-19 patients. METHODS: A multicenter, single-arm, hypothesis-driven trial was planned, according to a phase 2 design, to study the effect of tocilizumab on lethality rates at 14 and 30 days (co-primary endpoints, a priori expected rates being 20 and 35%, respectively). A further prospective cohort of patients, consecutively enrolled after the first cohort was accomplished, was used as a secondary validation dataset. The two cohorts were evaluated jointly in an exploratory multivariable logistic regression model to assess prognostic variables on survival. RESULTS: In the primary intention-to-treat (ITT) phase 2 population, 180/301 (59.8%) subjects received tocilizumab, and 67 deaths were observed overall. Lethality rates were equal to 18.4% (97.5% CI: 13.6-24.0, P = 0.52) and 22.4% (97.5% CI: 17.2-28.3, P < 0.001) at 14 and 30 days, respectively. Lethality rates were lower in the validation dataset, that included 920 patients. No signal of specific drug toxicity was reported. In the exploratory multivariable logistic regression analysis, older age and lower PaO2/FiO2 ratio negatively affected survival, while the concurrent use of steroids was associated with greater survival. A statistically significant interaction was found between tocilizumab and respiratory support, suggesting that tocilizumab might be more effective in patients not requiring mechanical respiratory support at baseline. CONCLUSIONS: Tocilizumab reduced lethality rate at 30 days compared with null hypothesis, without significant toxicity. Possibly, this effect could be limited to patients not requiring mechanical respiratory support at baseline. Registration EudraCT (2020-001110-38); clinicaltrials.gov (NCT04317092).


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adult , Aged , Aged, 80 and over , Betacoronavirus/immunology , COVID-19 , Cohort Studies , Coronavirus Infections/epidemiology , Female , Humans , Italy/epidemiology , Male , Middle Aged , Mortality , Off-Label Use , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Treatment Outcome , Validation Studies as Topic
3.
Anaesthesist ; 70(2): 121-126, 2021 Feb.
Article in German | MEDLINE | ID: covidwho-1453674

ABSTRACT

A 59-year-old male patient was admitted to hospital diagnosed with moderate pneumonia associated with COVID-19. Upfront treatment with hydroxychloroquine and azithromycin was started. Due to a clinical deterioration (ARDS, circulatory shock) and greatly increased inflammation markers 6 days after admission, a cytokine storm was suspected and off-label treatment with the IL­6 receptor antagonist tocilizumab was initiated. Subsequently there was a dramatic rise of D­dimers indicating pulmonary intravascular coagulopathy and respiratory insufficiency worsened. After a second dose of tocilizumab was administered severe perimyocarditis with cardiac arrhythmia, hemodynamic instability and ST elevation occurred. Shortly afterwards the patient died due to multiorgan failure. From our experience, exacerbation of COVID-19 following treatment with tocilizumab cannot be ruled out. Randomized controlled studies are necessary to further investigate the efficacy, safety and patient selection criteria for tocilizumab treatment in COVID-19.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , Blood Coagulation Disorders/etiology , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Myocarditis/etiology , Receptors, Interleukin-6/antagonists & inhibitors , Fatal Outcome , Humans , Male , Middle Aged , Multiple Organ Failure/etiology , Off-Label Use , Respiratory Distress Syndrome/etiology , Respiratory Insufficiency , Treatment Outcome
5.
Drug Des Devel Ther ; 15: 3349-3378, 2021.
Article in English | MEDLINE | ID: covidwho-1352763

ABSTRACT

Dalbavancin is a novel, long-acting lipoglycopeptide characterized by a long elimination half-life coupled with excellent in vitro activity against multidrug-resistant Gram-positives. Although it is currently approved only for the treatment of acute bacterial skin and skin structure infections, an ever-growing amount of evidence supports the efficacy of dalbavancin as a long-term therapy in osteomyelitis, prosthetic joint infections, endocarditis, and bloodstream infections. This article provides a critical reappraisal of real-world use of dalbavancin for off-label indications. A search strategy using specific keywords (dalbavancin, osteomyelitis, endocarditis, long-term suppressive therapy, bloodstream infection, pharmacokinetic/pharmacodynamic profile) until April 2021 was performed on the PubMed-MEDLINE database. As for other novel antibiotics, a conundrum between approved indications and potential innovative therapeutic uses has emerged for dalbavancin as well. The promising efficacy in challenging scenarios (i.e., osteomyelitis, endocarditis, prosthetic joint infections), coupled with the unique pharmacokinetic/pharmacodynamic properties, makes dalbavancin a valuable alternative to daily in-hospital intravenous or outpatient antimicrobial regimens in the treatment of long-term Gram-positive infections. This makes dalbavancin valuable in the current COVID-19 scenario, in which hospitalization and territorial medicine empowerment are unavoidable.


Subject(s)
Ambulatory Care , Anti-Bacterial Agents/therapeutic use , COVID-19 , Gram-Positive Bacterial Infections/drug therapy , Off-Label Use , Patient Participation , Teicoplanin/analogs & derivatives , Algorithms , Anti-Bacterial Agents/adverse effects , Anti-Bacterial Agents/pharmacokinetics , Clinical Decision-Making , Decision Support Techniques , Gram-Positive Bacterial Infections/diagnosis , Gram-Positive Bacterial Infections/microbiology , Humans , Teicoplanin/adverse effects , Teicoplanin/pharmacokinetics , Teicoplanin/therapeutic use , Treatment Outcome
6.
Swiss Med Wkly ; 150: w20281, 2020 May 04.
Article in English | MEDLINE | ID: covidwho-1348747
7.
Eur J Pharmacol ; 908: 174374, 2021 Oct 05.
Article in English | MEDLINE | ID: covidwho-1322083

ABSTRACT

The efficacy of corticosteroids and its use for the treatment of SARS-CoV-2 infections is controversial. In this study, using data sets of SARS-CoV-2 infected lung tissues and nasopharyngeal swabs, as well as in vitro experiments, we show that SARS-CoV-2 infection significantly downregulates DUSP1 expression. This downregulation of DUSP1 could be the mechanism regulating the enhanced activation of MAPK pathway as well as the reported steroid resistance in SARS-CoV-2 infection. Moreover, chloroquine, an off labeled COVID-19 drug is able to induce DUSP1 and attenuate MAPK pathway; and is expected to improve sensitivity to steroid treatment. However, further mechanistic studies are required to confirm this effect.


Subject(s)
COVID-19/drug therapy , Chloroquine/pharmacology , Dual Specificity Phosphatase 1/genetics , Glucocorticoids/pharmacology , p38 Mitogen-Activated Protein Kinases/metabolism , Adult , Aged , COVID-19/pathology , COVID-19/virology , Case-Control Studies , Cells, Cultured , Chloroquine/therapeutic use , Datasets as Topic , Down-Regulation/drug effects , Drug Resistance/drug effects , Drug Resistance/genetics , Drug Synergism , Dual Specificity Phosphatase 1/metabolism , Fibroblasts , Glucocorticoids/therapeutic use , Healthy Volunteers , Humans , Lung/cytology , Lung/pathology , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/genetics , Middle Aged , Nasopharynx/virology , Off-Label Use , Primary Cell Culture , SARS-CoV-2/isolation & purification , SARS-CoV-2/pathogenicity
8.
Am J Manag Care ; 27(6): 234-240, 2021 06.
Article in English | MEDLINE | ID: covidwho-1289744

ABSTRACT

OBJECTIVES: To determine (1) factors linked to hospitalizations among managed care patients (MCPs), (2) outcome improvement with use of outpatient off-label treatment, and (3) outcome comparison between MCPs and a mirror group. STUDY DESIGN: Retrospective cohort study comparing MCPs with an age- and gender-matched mirror group in Florida from April 1, 2020, to May 31, 2020. METHODS: A total of 38,193 MCPs in a Florida primary care group were monitored for COVID-19 incidence, hospitalization, and mortality. The highest-risk patients were managed by the medical group's COVID-19 Task Force. As part of a population health program, the COVID-19 Task Force contacted patients, conducted medical encounters, and tracked data including comorbidities and medical outcomes. The MCPs enrolled in the medical group were compared with a mirror group from the state of Florida. RESULTS: The mean (SD) age among the MCPs was 67.9 (15.2) years, and 60% were female. Older age and hypertension were the most important factors in predicting COVID-19. Obesity, chronic kidney disease (CKD), and congestive heart failure (CHF) were linked to higher rates of hospitalizations. Patients prescribed off-label outpatient medications had 73% lower likelihood of hospitalization (P < .05). Compared with the mirror group, MCPs had 60% lower COVID-19 mortality (P < .05). CONCLUSIONS: MCPs have risk factors similar to the general population for COVID-19 incidence and progression, including older age, hypertension, obesity, CHF, and CKD. Outpatient treatment with off-label medicines decreased hospitalizations. A comprehensive population health program decreased COVID-19 mortality.


Subject(s)
COVID-19/therapy , Managed Care Programs/organization & administration , Pneumonia, Viral/therapy , Aged , COVID-19/mortality , Comorbidity , Female , Florida/epidemiology , Hospitalization/statistics & numerical data , Humans , Incidence , Male , Off-Label Use , Pandemics , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Retrospective Studies , Risk Factors , SARS-CoV-2
9.
Kardiologiia ; 61(5): 41-50, 2021 May 31.
Article in Russian, English | MEDLINE | ID: covidwho-1267003

ABSTRACT

Aim      To evaluate the frequency of off-label prescription of medicines in practice of clinical specialists and the awareness of respondents of the procedure of justified off-label prescription.Material and methods  The sample included 542 clinical specialists who worked in definite medical organizations in 26 entities of the Russian Federation. The respondents were proposed to fill in remotely an anonymous questionnaire to evaluate the experience of prescribing medicines off-label to adult patients.Results Prescribing medicines not in consistence with the officially approved instruction for medical use (off-label or "outside instruction") is a relevant issue of global medical care since convincing scientific evidence for safety of such use is scarce. Analysis of information about off-label prescription is one of current tasks of national medical research centers according to the Federal Project "Development of a network of national medical research centers and implementation of innovative medical technologies". According to the responses about the frequency of off-label prescriptions 67.5 % of respondents reported of no experience of off-label prescription, 27.7 % said "rarely" or "sometimes", and 4.8 % said "frequently" and "very frequently". Specialties of physicians who have more often used medicines off-label (50% and more) included obstetrics and gynecology, pediatrics, rheumatology, hematology, and pulmonology. Cardiologists, neurologists and clinical pharmacologists use medicines off-label relatively rarely (19.6%, 28.6 %, and 22.2 %, respectively). 40 % of medicines used off-label were those designed for the treatment of coronavirus infection SARS-CoV-2. The medicines most frequently used off-label included metformin, rituximab, and thioctic acid. 65 % of respondents assessed their knowledge of off-label prescription as insufficient. In addition, 75 % of respondents consider it useful to receive additional information about risks and benefits of off-label prescription in clinical practice.Conclusion      The survey revealed the need of physicians for information about risks of the off-label use of medicines in clinical practice.


Subject(s)
COVID-19 , Pharmaceutical Preparations , Physicians , Adult , Child , Female , Humans , Off-Label Use , Practice Patterns, Physicians' , Pregnancy , Russia , SARS-CoV-2
10.
Crit Rev Ther Drug Carrier Syst ; 38(3): 75-115, 2021.
Article in English | MEDLINE | ID: covidwho-1236628

ABSTRACT

The outbreak of novel coronavirus (nCoV) or severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in December 2019 in Wuhan, China, has posed an international public health emergency worldwide and forced people to be confined in their homes. This virus is of high-risk category and is declared a pandemic by the World Health Organization (WHO). The worldwide researchers and various health professionals are working together to determine the best way to stop its spread or halt this virus's spread and circumvent this pandemic condition threatening millions of human lives. The absence of definitive treatment is possible to explore to reduce virus infection and enhance patient recovery. Along with off-label medicines, plasma therapy, vaccines, the researchers exploit the various plants/herbs and their constituents to effectively treat nCoV infection. The present study aimed to present brief and most informative salient features of the numerous facts regarding the SARS-CoV-2, including the structure, genomic sequence, recent mutation, targeting possibility, and various hurdles in research progress, and off-labeled drugs, convalescent plasma therapy, vaccine and plants/herbs for the treatment of coronavirus disease-2019 (COVID-19). Results showed that off-labeled drugs such as hydroxychloroquine, dexamethasone, tocilizumab, antiviral drug (remdesivir, favipiravir), etc., give positive results and approved for use or approved for restricted use in some countries like India. Future research should focus on these possibilities that may allow the development of an effective treatment for COVID-19.


Subject(s)
Antiviral Agents/pharmacology , COVID-19 Vaccines/administration & dosage , COVID-19/drug therapy , Plant Extracts/pharmacology , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Antiviral Agents/therapeutic use , COVID-19/epidemiology , COVID-19/immunology , COVID-19/virology , Clinical Trials as Topic , Drug Therapy, Combination/methods , Humans , Molecular Targeted Therapy/methods , Mutation , Off-Label Use , Pandemics/prevention & control , Plant Extracts/therapeutic use , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Treatment Outcome , Viral Structural Proteins/antagonists & inhibitors , Viral Structural Proteins/genetics , Viral Structural Proteins/metabolism
11.
Recenti Prog Med ; 112(5): 338-342, 2021 05.
Article in Italian | MEDLINE | ID: covidwho-1232488

ABSTRACT

The Italian Medicines Agency has started, since the first months of 2020, a monitoring of drug use during the covid-19 pandemic. This made it possible to identify specific trends in hospital and local purchases, such as the extensive use of off-label drugs with little evidence of efficacy during the first weeks of the epidemic, and to progressively assess the degree of implementation of regulatory and ministerial recommendations.Fin dalle prime fasi dell'emergenza covid-19 è emersa per l'Agenzia Italiana del Farmaco (AIFA) la necessità di monitorare in modo specifico l'uso dei farmaci utilizzati nel corso dell'epidemia. È infatti fondamentale, in un contesto caratterizzato da grande incertezza e da continui aggiornamenti delle linee guida, disporre di informazioni utili a una corretta lettura e interpretazione dei dati. È stato quindi realizzato un primo rapporto dell'Osservatorio Nazionale sull'Impiego dei Medicinali (OsMed) sull'uso dei farmaci utilizzati, a livello ospedaliero e territoriale, nella fase iniziale dell'epidemia1. Questo metteva a confronto i consumi relativi al periodo compreso tra marzo a maggio del 2020 con quelli del trimestre immediatamente precedente, da dicembre 2019 a febbraio 2020. In seguito, il 4 marzo 2021, è stato pubblicato un aggiornamento dei dati in riferimento alle fasi successive dell'epidemia2. Il monitoraggio ha preso in considerazione diverse categorie di farmaci, andando a valutare le oscillazioni negli acquisti in riferimento al progressivo aggiornamento degli indirizzi regolatori. I volumi osservati per ciascun farmaco sono stati standardizzati per 10.000 abitanti/die, andando a valutare le differenze pre- e post-covid-19 in termini di differenza assoluta, differenza percentuale e di p-value (p).


Subject(s)
COVID-19/drug therapy , Drug Utilization Review/statistics & numerical data , Off-Label Use/statistics & numerical data , Pandemics , COVID-19/epidemiology , Compassionate Use Trials , Humans , Italy/epidemiology , Time Factors
12.
Medicine (Baltimore) ; 100(18): e25832, 2021 May 07.
Article in English | MEDLINE | ID: covidwho-1216697

ABSTRACT

ABSTRACT: Tocilizumab (TCZ), a monoclonal recombinant antibody against IL-6 receptor, is currently used in managing the cytokine release syndrome (CRS) that occurred in coronavirus disease 2019 (COVID-19) selected cases. The primary objective of our study was to establish the effectiveness of TCZ in patients with severe or critical severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pneumonia.We retrospectively analyzed 25 consecutive patients, admitted in the Academic Emergency Hospital Sibiu, Romania from April 1, 2020 until May 25, 2020, all with confirmed SARS-CoV-2 infection and severe pneumonia. All patients were treated off-label with TCZ, beside their standard care. Adjuvant iron chelator was associated in 11 patients.Six female and 19 male patients admitted in our hospital all with confirmed SARS-CoV-2 infection and severe pneumonia as defined by Chinese Centers for Disease Control and Prevention were enrolled in this study. Seventeen of the 25 enrolled patients (68%) were seriously ill requiring noninvasive ventilation or oxygen mask, and 8 cases (32%) were critically ill requiring invasive mechanical ventilation. All patients received TCZ, and also received hydroxychloroquine, and lopinavir/ritonavir 200/50 mg for 10 days. Adjuvant iron chelator (deferasirox - marketed as Exjade) was associated in 11 patients who had ferritin serum levels above 1000 ng/mL. No side effects were encountered during infusions or after TCZ. We observed a rapid increase in arterial oxygen saturation for 20 of the 25 cases (80%) with a favorable evolution toward healing. Survivors were younger than 60 years old (80%), had less comorbidities (10% no comorbidities, 70% with 1 or 2 comorbidities), lower serum ferritin levels (30% under 1000 ng/mL), and 50% had no serum glucose elevation. Our patients with CRS had no response to corticosteroid therapy. Five out of the 25 patients had an unfavorable evolution to death. The off-label use of TCZ in patients with severe or critically ill form of SARS-CoV-2 infection had good results in our study.Off-label use of TCZ in severe and critical cases of COVID-19 pneumonia is effective in managing the "cytokine storm." Better outcomes were noted in younger patients. Associated adjuvant iron chelators may contribute to a good outcome and needs to be confirmed in larger studies.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Cytokine Release Syndrome/drug therapy , Deferasirox/therapeutic use , Iron Chelating Agents/therapeutic use , Pneumonia, Viral/drug therapy , Adult , Aged , Aged, 80 and over , Comorbidity , Drug Therapy, Combination , Female , Humans , Male , Middle Aged , Off-Label Use , Pneumonia, Viral/virology , Respiration, Artificial , Retrospective Studies , Romania , SARS-CoV-2
13.
Nat Rev Immunol ; 21(5): 330-335, 2021 05.
Article in English | MEDLINE | ID: covidwho-1164868

ABSTRACT

When vaccines are in limited supply, expanding the number of people who receive some vaccine, such as by halving doses or increasing the interval between doses, can reduce disease and mortality compared with concentrating available vaccine doses in a subset of the population. A corollary of such dose-sparing strategies is that the vaccinated individuals may have less protective immunity. Concerns have been raised that expanding the fraction of the population with partial immunity to SARS-CoV-2 could increase selection for vaccine-escape variants, ultimately undermining vaccine effectiveness. We argue that, although this is possible, preliminary evidence instead suggests such strategies should slow the rate of viral escape from vaccine or naturally induced immunity. As long as vaccination provides some protection against escape variants, the corresponding reduction in prevalence and incidence should reduce the rate at which new variants are generated and the speed of adaptation. Because there is little evidence of efficient immune selection of SARS-CoV-2 during typical infections, these population-level effects are likely to dominate vaccine-induced evolution.


Subject(s)
COVID-19/prevention & control , Off-Label Use , SARS-CoV-2/genetics , SARS-CoV-2/immunology , Vaccination/methods , Vaccines/administration & dosage , Biological Evolution , COVID-19/immunology , Humans , Immune Evasion/genetics , Immune Evasion/immunology , Vaccination/psychology
14.
Drug Saf ; 44(4): 399-402, 2021 04.
Article in English | MEDLINE | ID: covidwho-1157034
15.
BMC Bioinformatics ; 22(1): 150, 2021 Mar 23.
Article in English | MEDLINE | ID: covidwho-1148209

ABSTRACT

BACKGROUND: Currently, no proven effective drugs for the novel coronavirus disease COVID-19 exist and despite widespread vaccination campaigns, we are far short from herd immunity. The number of people who are still vulnerable to the virus is too high to hamper new outbreaks, leading a compelling need to find new therapeutic options devoted to combat SARS-CoV-2 infection. Drug repurposing represents an effective drug discovery strategy from existing drugs that could shorten the time and reduce the cost compared to de novo drug discovery. RESULTS: We developed a network-based tool for drug repurposing provided as a freely available R-code, called SAveRUNNER (Searching off-lAbel dRUg aNd NEtwoRk), with the aim to offer a promising framework to efficiently detect putative novel indications for currently marketed drugs against diseases of interest. SAveRUNNER predicts drug-disease associations by quantifying the interplay between the drug targets and the disease-associated proteins in the human interactome through the computation of a novel network-based similarity measure, which prioritizes associations between drugs and diseases located in the same network neighborhoods. CONCLUSIONS: The algorithm was successfully applied to predict off-label drugs to be repositioned against the new human coronavirus (2019-nCoV/SARS-CoV-2), and it achieved a high accuracy in the identification of well-known drug indications, thus revealing itself as a powerful tool to rapidly detect potential novel medical indications for various drugs that are worth of further investigation. SAveRUNNER source code is freely available at https://github.com/giuliafiscon/SAveRUNNER.git , along with a comprehensive user guide.


Subject(s)
Antiviral Agents/pharmacology , Drug Repositioning , SARS-CoV-2/drug effects , Software , COVID-19 , Humans , Off-Label Use
17.
Drug Saf ; 44(4): 399-402, 2021 04.
Article in English | MEDLINE | ID: covidwho-1118293
18.
Eur J Pharmacol ; 893: 173813, 2021 Feb 15.
Article in English | MEDLINE | ID: covidwho-1116627

ABSTRACT

Coronavirus disease-2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), poses an enormous challenge to the medical system, especially the lack of safe and effective COVID-19 treatment methods, forcing people to look for drugs that may have therapeutic effects as soon as possible. Some old drugs have shown clinical benefits after a few small clinical trials that attracted great attention. Clinically, however, many drugs, including those currently used in COVID-19, such as chloroquine, hydroxychloroquine, azithromycin, and lopinavir/ritonavir, may cause cardiotoxicity by acting on cardiac potassium channels, especially hERG channel through their off-target effects. The blocking of the hERG channel prolongs QT intervals on electrocardiograms; thus, it might induce severe ventricular arrhythmias and even sudden cardiac death. Therefore, while focusing on the efficacy of COVID-19 drugs, the fact that they block hERG channels to cause arrhythmias cannot be ignored. To develop safer and more effective drugs, it is necessary to understand the interactions between drugs and the hERG channel and the molecular mechanism behind this high affinity. In this review, we focus on the biochemical and molecular mechanistic aspects of drug-related blockade of the hERG channel to provide insights into QT prolongation caused by off-label use of related drugs in COVID-19, and hope to weigh the risks and benefits when using these drugs.


Subject(s)
Azithromycin/adverse effects , Azithromycin/therapeutic use , COVID-19/complications , COVID-19/drug therapy , Chloroquine/adverse effects , Chloroquine/therapeutic use , ERG1 Potassium Channel/drug effects , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Long QT Syndrome/chemically induced , Lopinavir/adverse effects , Lopinavir/therapeutic use , Ritonavir/adverse effects , Ritonavir/therapeutic use , Drug Combinations , Humans , Long QT Syndrome/epidemiology , Off-Label Use
19.
Clin Transl Sci ; 14(3): 1133-1146, 2021 05.
Article in English | MEDLINE | ID: covidwho-1096723

ABSTRACT

We applied a set of in silico and in vitro assays, compliant with the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm, to assess the risk of chloroquine (CLQ) or hydroxychloroquine (OH-CLQ)-mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin (ERT) and azithromycin (AZI), drugs repurposed during the first wave of coronavirus disease 2019 (COVID-19). Each drug or drug combination was tested in patch clamp assays on seven cardiac ion channels, in in silico models of human ventricular electrophysiology (Virtual Assay) using control (healthy) or high-risk cell populations, and in human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes. In each assay, concentration-response curves encompassing and exceeding therapeutic free plasma levels were generated. Both CLQ and OH-CLQ showed blocking activity against some potassium, sodium, and calcium currents. CLQ and OH-CLQ inhibited IKr (half-maximal inhibitory concentration [IC50 ]: 1 µM and 3-7 µM, respectively) and IK1 currents (IC50 : 5 and 44 µM, respectively). When combining OH-CLQ with AZI, no synergistic effects were observed. The two macrolides had no or very weak effects on the ion currents (IC50  > 300-1000 µM). Using Virtual Assay, both antimalarials affected several TdP indicators, CLQ being more potent than OH-CLQ. Effects were more pronounced in the high-risk cell population. In hiPSC-derived cardiomyocytes, all drugs showed early after-depolarizations, except AZI. Combining CLQ or OH-CLQ with a macrolide did not aggravate their effects. In conclusion, our integrated nonclinical CiPA dataset confirmed that, at therapeutic plasma concentrations relevant for malaria or off-label use in COVID-19, CLQ and OH-CLQ use is associated with a proarrhythmia risk, which is higher in populations carrying predisposing factors but not worsened with macrolide combination.


Subject(s)
Antimalarials/adverse effects , Arrhythmias, Cardiac/chemically induced , COVID-19/drug therapy , Chloroquine/adverse effects , Hydroxychloroquine/adverse effects , Off-Label Use , SARS-CoV-2 , Animals , CHO Cells , Cricetulus , Dose-Response Relationship, Drug , Electrocardiography/drug effects , Humans , Ion Channels/drug effects
20.
Genet Test Mol Biomarkers ; 25(2): 85-101, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1091280

ABSTRACT

Coronavirus disease 2019 (COVID-19) displays a broad spectrum of clinical presentations ranging from lack of symptoms to severe multiorgan system complications and death. Various laboratory assays have been employed in the diagnosis of COVID-19, including: nucleic acid-based tests; antigen tests; and serum testing for anti-severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) antibodies. The disease can also be diagnosed based on suggestive clinical features and radiological findings. Until now, remdesivir is the only medication approved for the treatment of COVID-19 by the U.S. Food and Drug Administration (FDA); however, it is anticipated that several anti-SARS-CoV-2 monoclonal antibodies will gain soon approval. Other methods of treatment include supportive care directed toward treating the symptoms. Nevertheless, many studies have recently emerged, showing controversial preliminary results with the off-label medication hydroxychloroquine. Given that all results are still preliminary, including those seen by remdesivir, additional evidence and research are required to identify effective medications that are broadly effective and well tolerated. Importantly, two RNA-based vaccines have recently gained approval from Pfizer and Moderna, with many others still in clinical trials. This article reviews various aspects of COVID-19, including its epidemiology; its evolution and mutational spectrum; and its clinical dynamics, symptoms and complications, diagnosis, and treatment.


Subject(s)
COVID-19 , Global Burden of Disease/statistics & numerical data , Pandemics/statistics & numerical data , SARS-CoV-2/pathogenicity , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/therapeutic use , Alanine/analogs & derivatives , Alanine/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/therapy , COVID-19/virology , COVID-19 Testing/methods , COVID-19 Vaccines/therapeutic use , Clinical Trials as Topic , Evolution, Molecular , Humans , Hydroxychloroquine/therapeutic use , Mutation , Off-Label Use , Pandemics/prevention & control , RNA, Viral/genetics , RNA, Viral/isolation & purification , SARS-CoV-2/genetics , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , Severity of Illness Index
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