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1.
Sci Rep ; 10(1): 14290, 2020 08 31.
Article in English | MEDLINE | ID: covidwho-738236

ABSTRACT

Several drug candidates have been proposed and tested as the latest clinical treatment for coronavirus pneumonia (COVID-19). Chloroquine, hydroxychloroquine, ritonavir/lopinavir, and favipiravir are under trials for the treatment of this disease. The hyperpolarization technique has the ability to further provide a better understanding of the roles of these drugs at the molecular scale and in different applications in the field of nuclear magnetic resonance/magnetic resonance imaging. This technique may provide new opportunities in diagnosis and research of COVID-19. Signal amplification by reversible exchange-based hyperpolarization studies on large-sized drug candidates were carried out. We observed hyperpolarized proton signals from whole structures, due to the unprecedented long-distance polarization transfer by para-hydrogen. We also found that the optimal magnetic field for the maximum polarization transfer yield was dependent on the molecular structure. We can expect further research on the hyperpolarization of other important large molecules, isotope labeling, as well as polarization transfer on nuclei with a long spin relaxation time. A clinical perspective of these features on drug molecules can broaden the application of hyperpolarization techniques for therapeutic studies.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/virology , Drug Discovery , Pneumonia, Viral/virology , Amides/chemistry , Amides/pharmacology , Antiviral Agents/chemistry , Chloroquine/chemistry , Chloroquine/pharmacology , Coronavirus Infections/diagnosis , Drug Discovery/methods , Humans , Lopinavir/chemistry , Lopinavir/pharmacology , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Pandemics , Pneumonia, Viral/diagnosis , Pyrazines/chemistry , Pyrazines/pharmacology , Ritonavir/chemistry , Ritonavir/pharmacology
2.
CMAJ ; 192(27): E734-E744, 2020 07 06.
Article in English | MEDLINE | ID: covidwho-661875

ABSTRACT

BACKGROUND: Antiviral medications are being given empirically to some patients with coronavirus disease 2019 (COVID-19). To support the development of a COVID-19 management guideline, we conducted a systematic review that addressed the benefits and harms of 7 antiviral treatments for COVID-19. METHODS: We searched MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and 3 Chinese databases (CNKI, WANFANG and SinoMed) through Apr. 19, medRxiv and Chinaxiv through Apr. 27, and Chongqing VIP through Apr. 30, 2020. We included studies of ribavirin, chloroquine, hydroxychloroquine, umifenovir (arbidol), favipravir, interferon and lopinavir/ritonavir. If direct evidence from COVID-19 studies was not available, we included indirect evidence from studies of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) for efficacy outcomes and other acute respiratory viral infections for safety outcomes. RESULTS: In patients with nonsevere COVID-19 illness, the death rate was extremely low, precluding an important effect on mortality. We found only very low-quality evidence with little or no suggestion of benefit for most treatments and outcomes in both nonsevere and severe COVID-19. An exception was treatment with lopinavir/ritonavir, for which we found low-quality evidence for a decrease in length of stay in the intensive care unit (risk difference 5 d shorter, 95% confidence interval [CI] 0 to 9 d) and hospital stay (risk difference 1 d shorter, 95% CI 0 to 2 d). For safety outcomes, evidence was of low or very low quality, with the exception of treatment with lopinavir/ritonavir for which moderate-quality evidence suggested likely increases in diarrhea, nausea and vomiting. INTERPRETATION: To date, persuasive evidence of important benefit in COVID-19 does not exist for any antiviral treatments, although for each treatment evidence has not excluded important benefit. Additional randomized controlled trials involving patients with COVID-19 will be needed before such treatments can be administered with confidence.


Subject(s)
Antiviral Agents , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Influenza, Human/drug therapy , Lopinavir/pharmacology , Pneumonia, Viral/drug therapy , Amides , Antiviral Agents/pharmacology , Chloroquine , Evidence-Based Medicine , Humans , Hydroxychloroquine , Indoles , Observational Studies as Topic , Pandemics , Pyrazines , Ribavirin , Ritonavir
3.
Antiviral Res ; 181: 104878, 2020 09.
Article in English | MEDLINE | ID: covidwho-645295

ABSTRACT

In response to the current pandemic caused by the novel SARS-CoV-2, identifying and validating effective therapeutic strategies is more than ever necessary. We evaluated the in vitro antiviral activities of a shortlist of compounds, known for their cellular broad-spectrum activities, together with drugs that are currently under evaluation in clinical trials for COVID-19 patients. We report the antiviral effect of remdesivir, lopinavir, chloroquine, umifenovir, berberine and cyclosporine A in Vero E6 cells model of SARS-CoV-2 infection, with estimated 50% inhibitory concentrations of 0.99, 5.2, 1.38, 3.5, 10.6 and 3 µM, respectively. Virus-directed plus host-directed drug combinations were also investigated. We report a strong antagonism between remdesivir and berberine, in contrast with remdesivir/diltiazem, for which we describe high levels of synergy, with mean Loewe synergy scores of 12 and peak values above 50. Combination of host-directed drugs with direct acting antivirals underscore further validation in more physiological models, yet they open up interesting avenues for the treatment of COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Drug Repositioning , Pandemics , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Berberine/pharmacology , Chlorocebus aethiops , Chloroquine/pharmacology , Coronavirus Infections/virology , Cyclosporine/pharmacology , Drug Antagonism , Drug Combinations , Drug Synergism , Humans , Indoles/pharmacology , Lopinavir/pharmacology , Pneumonia, Viral/virology , Vero Cells
4.
Antimicrob Agents Chemother ; 64(9)2020 08 20.
Article in English | MEDLINE | ID: covidwho-639066

ABSTRACT

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 µg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC50) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.


Subject(s)
Antiviral Agents/pharmacokinetics , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Cytokine Release Syndrome/drug therapy , Hydroxychloroquine/pharmacokinetics , Lopinavir/pharmacokinetics , Pneumonia, Viral/drug therapy , Ritonavir/pharmacokinetics , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/blood , Antiviral Agents/pharmacology , Betacoronavirus/immunology , Betacoronavirus/pathogenicity , Biomarkers/blood , C-Reactive Protein/metabolism , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Coronavirus Infections/virology , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Drug Administration Schedule , Drug Combinations , Female , Hospitals, University , Humans , Hydroxychloroquine/blood , Hydroxychloroquine/pharmacology , Length of Stay/statistics & numerical data , Lopinavir/blood , Lopinavir/pharmacology , Male , Middle Aged , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Pneumonia, Viral/virology , Retrospective Studies , Ritonavir/blood , Ritonavir/pharmacology , Severity of Illness Index , Survival Analysis
6.
Eur Heart J Acute Cardiovasc Care ; 9(3): 209-214, 2020 Apr.
Article in English | MEDLINE | ID: covidwho-165340

ABSTRACT

Therapeutic options for coronavirus disease 2019 are desperately needed to respond to the ongoing severe acute respiratory syndrome coronavirus 2 pandemic. Both antiviral drugs and immunomodulators might have their place in the management of coronavirus disease 2019. Unfortunately, no drugs have been approved yet to treat infections with human coronaviruses. As it will take years to develop new therapies for severe acute respiratory syndrome coronavirus 2, the current focus is on the repurposing of drugs that have been approved or are in development for other conditions. Several clinical trials have already been conducted or are currently ongoing to evaluate the efficacy of such drugs. Here, we discuss the potential of these therapies for the treatment of coronavirus disease 2019.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Betacoronavirus/drug effects , Chloroquine/toxicity , Coronavirus Infections/drug therapy , Pneumonia, Viral/drug therapy , Adenosine Monophosphate/administration & dosage , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Administration, Intravenous , Alanine/administration & dosage , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal, Humanized/therapeutic use , Antiviral Agents/administration & dosage , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , Chloroquine/adverse effects , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Cytochrome P-450 CYP3A Inhibitors/pharmacology , Cytochrome P-450 CYP3A Inhibitors/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/pharmacology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , Immunologic Factors/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Pandemics , Pneumonia, Viral/epidemiology , Pyrazines/pharmacology , Pyrazines/therapeutic use , RNA, Viral/drug effects , Recombinant Proteins/administration & dosage , Recombinant Proteins/pharmacology , Recombinant Proteins/therapeutic use
7.
Biochemistry ; 59(18): 1769-1779, 2020 05 12.
Article in English | MEDLINE | ID: covidwho-59683

ABSTRACT

Since the emergence of a novel coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported from Wuhan, China, neither a specific vaccine nor an antiviral drug against SARS-CoV-2 has become available. However, a combination of two HIV-1 protease inhibitors, lopinavir and ritonavir, has been found to be effective against SARS-CoV, and both drugs could bind well to the SARS-CoV 3C-like protease (SARS-CoV 3CLpro). In this work, molecular complexation between each inhibitor and SARS-CoV-2 3CLpro was studied using all-atom molecular dynamics simulations, free energy calculations, and pair interaction energy analyses based on MM/PB(GB)SA and FMO-MP2/PCM/6-31G* methods. Both anti-HIV drugs interacted well with the residues at the active site of SARS-CoV-2 3CLpro. Ritonavir showed a somewhat higher number atomic contacts, a somewhat higher binding efficiency, and a somewhat higher number of key binding residues compared to lopinavir, which correspond with the slightly lower water accessibility at the 3CLpro active site. In addition, only ritonavir could interact with the oxyanion hole residues N142 and G143 via the formation of two hydrogen bonds. The interactions in terms of electrostatics, dispersion, and charge transfer played an important role in the drug binding. The obtained results demonstrated how repurposed anti-HIV drugs could be used to combat COVID-19.


Subject(s)
Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Enzyme Inhibitors/pharmacology , Lopinavir/chemistry , Lopinavir/pharmacology , Pneumonia, Viral/drug therapy , Ritonavir/chemistry , Ritonavir/pharmacology , Antiviral Agents/therapeutic use , Betacoronavirus/drug effects , Betacoronavirus/enzymology , Catalytic Domain , Coronavirus Infections/enzymology , Coronavirus Infections/virology , Cysteine Endopeptidases/chemistry , Cysteine Endopeptidases/metabolism , Drug Repositioning , Enzyme Inhibitors/therapeutic use , Humans , Lopinavir/therapeutic use , Molecular Dynamics Simulation , Pandemics , Pneumonia, Viral/enzymology , Pneumonia, Viral/virology , Protein Binding , Protein Structure, Tertiary , Ritonavir/therapeutic use , Viral Nonstructural Proteins/chemistry , Viral Nonstructural Proteins/metabolism
8.
Antiviral Res ; 178: 104786, 2020 06.
Article in English | MEDLINE | ID: covidwho-30820

ABSTRACT

An escalating pandemic by the novel SARS-CoV-2 virus is impacting global health and effective therapeutic options are urgently needed. We evaluated the in vitro antiviral effect of compounds that were previously reported to inhibit coronavirus replication and compounds that are currently under evaluation in clinical trials for SARS-CoV-2 patients. We report the antiviral effect of remdesivir, lopinavir, homorringtonine, and emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 23.15 µM, 26.63 µM, 2.55 µM and 0.46 µM, respectively. Ribavirin or favipiravir that are currently evaluated under clinical trials showed no inhibition at 100 µM. Synergy between remdesivir and emetine was observed, and remdesivir at 6.25 µM in combination with emetine at 0.195 µM may achieve 64.9% inhibition in viral yield. Combinational therapy may help to reduce the effective concentration of compounds below the therapeutic plasma concentrations and provide better clinical benefits.


Subject(s)
Antimetabolites/pharmacology , Antiviral Agents/pharmacology , Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Coronavirus Infections/virology , Emetine/pharmacology , Homoharringtonine/pharmacology , Lopinavir/pharmacology , Pneumonia, Viral/drug therapy , Pneumonia, Viral/virology , Virus Replication/drug effects , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Amides/pharmacology , Animals , Betacoronavirus/physiology , Chlorocebus aethiops , Drug Combinations , Epithelial Cells , Humans , Pandemics , Pyrazines/pharmacology , Ribavirin/pharmacology , Vero Cells
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