scholarly journals Antiviral Activity of Digoxin and Ouabain against SARS-CoV-2 Infection and Its Implication for COVID-19

2020 ◽  
Author(s):  
Junhyung Cho ◽  
Young Jae Lee ◽  
Je-Hyoung Kim ◽  
Sang il Kim ◽  
Sung Soon Kim ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Therapeutic Effect ◽  
Heart Diseases ◽  
Cardiac Injury ◽  
Drug Repurposing ◽  
Progeny Virus ◽  
Viral Inhibition ◽  
Virus Life Cycle ◽  
Post Entry ◽  
Single Dose Treatment

Abstract The current coronavirus (COVID-19) pandemic is exacerbated by the absence of effective therapeutic agents. Notably, among patients with COVID-19, 10–40% of those with cardiac injury have more comorbidities such as acute heart failure and lymphocytopenia. An efficient strategy to response this issue is drug repurposing with expecting antiviral activity and therapeutic effect. Digoxin (DIG) and ouabain (OUA) are FDA drugs for heart diseases and have antiviral activity against several coronaviruses. Thus, we aimed this study to assess antiviral activity of DIG and OUA against SARS-CoV-2 infection. The half-maximal inhibitory concentration (IC50) of DIG, and OUA were determined at a nanomolar concentration. Progeny virus titers of single dose treatment of DIG and OUA were approximately 103 and 104-fold lower (> 99% inhibition) than that of non-treated control or chloroquine at 48 hour post-infection (hpi). Furthermore, therapeutic treatment of DIG and OUA inhibited over 99 % of SARS-CoV-2 replication, leading to viral inhibition at post entry stage of the virus life cycle. Collectively, these results suggested that DIG and OUA could be an alternative treatment for COVID-19 with potential therapeutic effect for patients with cardiovascular disease.

scholarly journals Antiviral activity of digoxin and ouabain against SARS-CoV-2 infection and its implication for COVID-19

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Junhyung Cho ◽  
Young Jae Lee ◽  
Je Hyoung Kim ◽  
Sang il Kim ◽  
Sung Soon Kim ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Heart Diseases ◽  
Therapeutic Agents ◽  
Progeny Virus ◽  
Therapeutic Effects ◽  
Cardiac Diseases ◽  
Viral Inhibition ◽  
Nanomolar Concentration ◽  
Post Entry ◽  
Single Dose Treatment

Abstract The current coronavirus (COVID-19) pandemic is exacerbated by the absence of effective therapeutic agents. Notably, patients with COVID-19 and comorbidities such as hypertension and cardiac diseases have a higher mortality rate. An efficient strategy in response to this issue is repurposing drugs with antiviral activity for therapeutic effect. Digoxin (DIG) and ouabain (OUA) are FDA drugs for heart diseases that have antiviral activity against several coronaviruses. Thus, we aimed to assess antiviral activity of DIG and OUA against SARS-CoV-2 infection. The half-maximal inhibitory concentrations (IC50) of DIG and OUA were determined at a nanomolar concentration. Progeny virus titers of single-dose treatment of DIG, OUA and remdesivir were approximately 103-, 104- and 103-fold lower (> 99% inhibition), respectively, than that of non-treated control or chloroquine at 48 h post-infection (hpi). Furthermore, therapeutic treatment with DIG and OUA inhibited over 99% of SARS-CoV-2 replication, leading to viral inhibition at the post entry stage of the viral life cycle. Collectively, these results suggest that DIG and OUA may be an alternative treatment for COVID-19, with potential additional therapeutic effects for patients with cardiovascular disease.

scholarly journals Subversion of the Heme Oxygenase-1 Antiviral Activity by Zika Virus

Viruses ◽  
2018 ◽  
Vol 11 (1) ◽  
pp. 2 ◽  
Author(s):  
Chaker El Kalamouni ◽  
Etienne Frumence ◽  
Sandra Bos ◽  
Jonathan Turpin ◽  
Brice Nativel ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Heme Oxygenase ◽  
Zika Virus ◽  
Fluorescent Protein ◽  
Human Cells ◽  
Heme Oxygenase 1 ◽  
Viral Inhibition ◽  
Reporter Protein ◽  
Wide Range ◽  
Rna Replicon

Heme oxygenase-1 (HO-1), a rate-limiting enzyme involved in the degradation of heme, is induced in response to a wide range of stress conditions. HO-1 exerts antiviral activity against a broad range of viruses, including the Hepatitis C virus, the human immunodeficiency virus, and the dengue virus by inhibiting viral growth. It has been reported that HO-1 displays antiviral activity against the Zika virus (ZIKV) but the mechanisms of viral inhibition remain largely unknown. Using a ZIKV RNA replicon with the Green Fluorescent Protein (GFP) as a reporter protein, we were able to show that HO-1 expression resulted in the inhibition of viral RNA replication. Conversely, we observed a decrease in HO-1 expression in cells replicating the ZIKV RNA replicon. The study of human cells infected with ZIKV showed that the HO-1 expression level was significantly lower once viral replication was established, thereby limiting the antiviral effect of HO-1. Our work highlights the capacity of ZIKV to thwart the anti-replicative activity of HO-1 in human cells. Therefore, the modulation of HO-1 as a novel therapeutic strategy against ZIKV infection may display limited effect.

scholarly journals Screening a library of FDA-approved and bioactive compounds for antiviral activity against SARS-CoV-2

2020 ◽  
Author(s):  
Scott B. Biering ◽  
Erik Van Dis ◽  
Eddie Wehri ◽  
Livia H. Yamashiro ◽  
Xammy Nguyenla ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Combination Therapy ◽  
Global Health ◽  
Antiviral Activity ◽  
Drug Repurposing ◽  
Rapid Identification ◽  
Screening Strategy ◽  
Combination Therapies ◽  
Pulmonary Epithelial Cells ◽  
Compound Screening

AbstractSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has emerged as a major global health threat. The COVID-19 pandemic has resulted in over 80 million cases and 1.7 million deaths to date while the number of cases continues to rise. With limited therapeutic options, the identification of safe and effective therapeutics is urgently needed. The repurposing of known clinical compounds holds the potential for rapid identification of drugs effective against SARS-CoV-2. Here we utilized a library of FDA-approved and well-studied preclinical and clinical compounds to screen for antivirals against SARS-CoV-2 in human pulmonary epithelial cells. We identified 13 compounds that exhibit potent antiviral activity across multiple orthogonal assays. Hits include known antivirals, compounds with anti-inflammatory activity, and compounds targeting host pathways such as kinases and proteases critical for SARS-CoV-2 replication. We identified seven compounds not previously reported to have activity against SARS-CoV-2, including B02, a human RAD51 inhibitor. We further demonstrated that B02 exhibits synergy with remdesivir, the only antiviral approved by the FDA to treat COVID-19, highlighting the potential for combination therapy. Taken together, our comparative compound screening strategy highlights the potential of drug repurposing screens to identify novel starting points for development of effective antiviral mono- or combination therapies to treat COVID-19.

Abstract 3899: SDF-1α Mediates the Therapeutic Effect of Human Adipose-Derived Stem Cells on Acute Myocardial Infarction Recruiting Bone Marrow-Derived Endothelial Progenitor Cells

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Masaaki Ii ◽  
Ayumi Yokoyama ◽  
Miki Horii ◽  
Hiroshi Akimaru ◽  
Takayuki Asahara
Keyword(s):  
Myocardial Infarction ◽  
Stem Cells ◽  
Cardiac Function ◽  
Therapeutic Effect ◽  
Heart Diseases ◽  
Capillary Density ◽  
Ischemic Myocardium ◽  
Control Group ◽  
Adipose Derived Stem Cells ◽  
Ischemic Heart Diseases

Background: Recently, human multipotent adipose-derived stem cells (hMADSs) have been isolated featuring extensive expansion capacity ex vivo. However, little is known about the therapeutic efficacy of hMADS in ischemic heart diseases. We tested the hypothesis that hMADS transplantation may contribute to cardiac functional recovery following myocardial infarction (MI). Methods and Results: Nude rats were either transplanted with hMADSs (5x10 5 /rat, n=10) or PBS (control, n=9) in ischemic myocardium immediately following MI induction. The cardiac function, infarct size and capillary density in the peri-infarct area were evaluated by echocardiography and immunostaining 28 days after surgery. The cardiac function was significantly greater with increased capillary density and reduced fibrosis area in the hMADS group than that in the control group. Next, we examined tissue regeneration in the infarct heart by the transplanted hMADSs. However, remarkable differentiation of hMADSs into any cardiac cell lineages was not detected. To explore another mechanism for the favorable effect of hMADSs, we further examined mRNA expression of cytokines in hMADSs under hypoxic conditions. Although hypoxia decreased the expressions, robust VEGF, bFGF, and SDF-1α expressions were detected in hMADSs. Notably, the stem/progenitor chemokine SDF-1α expression in hMADSs was significantly greater than that in human mesenchymal stem cells that are well known to have a therapeutic effect on ischemic heart diseases. We then focused on SDF-1α /CXCR4 axis and examined the contribution of bone marrow (BM)-derived endothelial progenitor cells (EPCs), that have CXCR4 receptor for SDF-1v, to ischemic myocardium using a Tie2/LacZ BM transplantation nude mouse model. β-gal positive EPCs are frequently observed in ischemic myocardium in the hMADS group compared to the control group. Conclusion: hMADSs exhibit a therapeutic effect on cardiac function following MI with the production of VEGF, bFGF, and SDF-1α demonstrating paracrine effects rather than direct contribution to cardiac regeneration. These findings suggest that transplanted hMADSs and recruited EPCs may synergistically promote angiogenesis playing a role in ischemic myocardium.

scholarly journals Hydroxychloroquine in Patients with Rheumatic Disease Complicated by COVID-19: Clarifying Target Exposures and the Need for Clinical Trials

2020 ◽  
Vol 47 (9) ◽  
pp. 1424-1430 ◽  
Author(s):  
Stephen J. Balevic ◽  
Christoph P. Hornik ◽  
Thomas P. Green ◽  
Megan E.B. Clowse ◽  
Daniel Gonzalez ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiviral Activity ◽  
Rheumatic Disease ◽  
Rheumatic Diseases ◽  
Pharmacokinetic Model ◽  
Therapeutic Window ◽  
Total Serum ◽  
Viral Inhibition ◽  
Target Exposure

Objective.To characterize hydroxychloroquine (HCQ) exposure in patients with rheumatic disease receiving longterm HCQ compared to target concentrations with reported antiviral activity against the coronavirus disease 2019 caused by SARS-CoV-2 (COVID-19).Method.We evaluated total HCQ concentrations in serum and plasma from published literature values, frozen serum samples from a pediatric systemic lupus erythematosus trial, and simulated concentrations using a published pharmacokinetic model during pregnancy. For each source, we compared observed or predicted HCQ concentrations to target concentrations with reported antiviral activity against SARS-CoV-2.Results.The average total serum/plasma HCQ concentrations were below the lowest SARS-CoV-2 target of 0.48 mg/l in all studies. Assuming the highest antiviral target exposure (total plasma concentration of 4.1 mg/l), all studies had about one-tenth the necessary concentration for in vitro viral inhibition. Pharmacokinetic model simulations confirmed that pregnant adults receiving common dosing for rheumatic diseases did not achieve target exposures; however, the models predict that a dosage of 600 mg once a day during pregnancy would obtain the lowest median target exposure for most patients after the first dose.Conclusion.We found that the average patient receiving treatment with HCQ for rheumatic diseases, including children and non-pregnant/pregnant adults, are unlikely to achieve total serum or plasma concentrations shown to inhibit SARS-CoV-2 in vitro. Nevertheless, patients receiving HCQ long term may have tissue concentrations far exceeding that of serum/plasma. Because the therapeutic window for HCQ in the setting of SARS-CoV-2 is unknown, well-designed clinical trials that include patients with rheumatic disease are urgently needed to characterize the efficacy, safety, and target exposures for HCQ.

Nilotinib Exhibits an in Vitro Antiviral Activity Against Human Cytomegalovirus (HCMV): Potential Clinical Applications

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4666-4666 ◽  
Author(s):  
Dana Wolf ◽  
Esther Djian ◽  
Katia Beider ◽  
Avichai Shimoni ◽  
Arnon Nagler
Keyword(s):  
Antiviral Activity ◽  
Antiviral Therapy ◽  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Host Cells ◽  
Viral Inhibition ◽  
Advanced Phase ◽  
Hcmv Disease

Abstract Abstract 4666 Chronic myeloid leukemia (CML) is a clonal disorder associated with chromosomal translocation t (9; 22), which produces the Philadelphia chromosome. The fusion gene encodes for the chimeric oncoprotein BCR-ABL, associated with deregulated constitutive tyrosine kinase (TK) activity, leading to leukemogenesis. Imatinib mesylate, the first potent selective inhibitor of BCR-ABL TK, has revolutionized the current management of CML. The second generation TK inhibitor (TKI) Nilotinib (Novartis, East Hanover, NJ) is an aminopyrimidine derivative of imatinib with an increased binding affinity to the chimeric p210 BCR-ABL. Nilotinib is active in imatinib-resistant or -intolerant patients in chronic phase, accelerated phase (AP), and blast crisis (BC) CML. Allogeneic stem cell transplantation (SCT) is currently reserved for patients(pts) in CP after the failure of second line TKI or for patients in advanced phase disease.SCT remains the treatment of choice in patients with Ph+ALL. TKIs can be used successfully pre -SCT as a bridge to SCT in advanced disease and post-SCT in order to prevent disease recurrence. HCMV is one of the leading causes of morbidity and mortality post SCT in particular in pts transplanted for advance CML and pts with graft vs. host disease (GVHD) While preemptive antiviral therapy has reduced the occurrence of HCMV disease post SCT, the use of all currently available antiviral drugs is often limited by toxicity, low oral bioavailability, and drug resistance. The mechanisms facilitating HCMV entry into the host cells are not clearly understood. Blocking of the platelet – derived growth factor receptor-α (PDGFRα) has been shown to inhibit HCMV internalization and gene expression. Recently, Imatinib have been shown to inhibit PDGFRα phosphorylation. As Nilotinib is a more potent PDGFR inhibitor, we assessed the in vitro antiviral activity of Nilotinib against HCMV. Nilotinib exhibited a significant dose-dependent inhibition of the virus upon pre-incubation with the drug. Moreover, Nilotinib demonstrated a ∼4.5-fold higher antiviral activity against HCMV when compared to imatinib, with IC50 values of 0.39 μM and 1.75 μM, respectively. No viral inhibition was found upon addition of the drugs after viral adsorption – compatible with inhibition of an early step of infection, involving viral binding/entry into the cell. These findings identify a promising new target for antiviral therapy, representing an alternative paradigm for treatment with compounds combining anti-cancer and antiviral activity. It remains to be determined if the anti-HCMV activity demonstrated for Nilotinib is of clinical relevance in patients undergoing SCT Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Small-Compound Inhibitor K22 Displays Broad Antiviral Activity against Different Members of the Family Flaviviridae and Offers Potential as a Panviral Inhibitor

2018 ◽  
Vol 62 (11) ◽  
Author(s):  
Obdulio García-Nicolás ◽  
Philip V'kovski ◽  
Nathalie J. Vielle ◽  
Nadine Ebert ◽  
Roland Züst ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Host Cell ◽  
Rna Viruses ◽  
Close Association ◽  
Viral Inhibition ◽  
Virus Family ◽  
Positive Strand ◽  
Content Type ◽  
Small Compound ◽  
Positive Strand Rna

ABSTRACT The virus family Flaviviridae encompasses several viruses, including (re)emerging viruses which cause widespread morbidity and mortality throughout the world. Members of this virus family are positive-strand RNA viruses and replicate their genome in close association with reorganized intracellular host cell membrane compartments. This evolutionarily conserved strategy facilitates efficient viral genome replication and contributes to evasion from host cell cytosolic defense mechanisms. We have previously described the identification of a small-compound inhibitor, K22, which exerts a potent antiviral activity against a broad range of coronaviruses by targeting membrane-bound viral RNA replication. To analyze the antiviral spectrum of this inhibitor, we assessed the inhibitory potential of K22 against several members of the Flaviviridae family, including the reemerging Zika virus (ZIKV). We show that ZIKV is strongly affected by K22. Time-of-addition experiments revealed that K22 acts during a postentry phase of the ZIKV life cycle, and combination regimens of K22 together with ribavirin (RBV) or interferon alpha (IFN-α) further increased the extent of viral inhibition. Ultrastructural electron microscopy studies revealed severe alterations of ZIKV-induced intracellular replication compartments upon infection of K22-treated cells. Importantly, the antiviral activity of K22 was demonstrated against several other members of the Flaviviridae family. It is tempting to speculate that K22 exerts its broad antiviral activity against several positive-strand RNA viruses via a similar mechanism and thereby represents an attractive candidate for development as a panviral inhibitor.

scholarly journals 394 Incidence and prevalence of acute myocarditis and pericarditis prior to and during COVID-19 pandemic

2021 ◽  
Vol 23 (Supplement_G) ◽  
Author(s):  
Roberto Licordari ◽  
Chrysanthos Grigoratos ◽  
Giancarlo Todiere ◽  
Andrea Barison ◽  
Antonio Micari ◽  
...  
Keyword(s):  
Heart Disease ◽  
Heart Diseases ◽  
Acute Myocarditis ◽  
Cardiac Injury ◽  
Annual Incidence ◽  
Time Intervals ◽  
Inflammatory Heart Disease ◽  
Heart Disorders ◽  
Areas Of Interest

Abstract Aims Myocarditis and pericarditis have been proposed to account for a proportion of cardiac injury during SARS-CoV-2 infection. During the COVID-19 pandemic, it is reasonable to expect an increasing trend in incidence of this acute inflammatory cardiac diseases. To examine the incidence and prevalence of inflammatory heart disorders prior to and during the COVID-19 pandemic. Methods and results This is a retrospective cohort study examining the incidence and prevalence of acute inflammatory heart diseases (myocarditis, pericarditis) in provinces of Pisa, Lucca and Livorno (total population of 11421285 inhabitants) in two time-intervals: (i) prior to (PRECOVID, from 1 June 2018 to 31 May 2019) and (ii) during the COVID-19 pandemic (COVID, from 1 June 2020 to May 2021). Overall 259 cases of inflammatory heart disease (myocarditis and/or pericarditis) occurred in the areas of interest. The annual incidence was of 11.3 cases per 100 000 inhabitants. Particularly, 138 cases occurred in the PRECOVID, and 121 in the COVID period. The annual incidence of inflammatory heart disease was not significantly different (12.1/100 000 in PRECOVID vs. 10.3/100 000 in COVID; P = 0.22). The annual incidence of acute myocarditis was significantly higher in PRECOVID than in the COVID: respectively, 8.1/100 000/year vs. 5.9/100 000 year (P = 0.047), consisting in a net reduction of 27% of cases. Particularly the incidence of myocarditis was significantly lower in COVID than in PRECOVID in the class of age 18–24 (P = 0.048) (Figure). The annual incidence of pericarditis was not significantly different (4.03/100 000 vs. 4.47/100 000; P = 0.61). Conclusions Despite a possible etiologic role of SARS-CoV-2 and an expectable increased incidence of myocarditis and pericarditis, data suggest a decrease of acute myocarditis and a stable incidence pericarditis and both diseases.

A Comparative Analysis of Clinical Characteristics and Laboratory Findings of COVID-19 between Intensive Care Unit and Non-Intensive Care Unit Pediatric Patients: A Multicenter, Retrospective, Observational Study from Iranian Network for Research in Viral

2021 ◽  
Author(s):  
Alireza Fahimzad ◽  
Iraj Sedighi ◽  
Neda Pak ◽  
Mitra Khalili ◽  
Mohammad Farahmand ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Heart Diseases ◽  
Cardiac Injury ◽  
Healthcare Providers ◽  
High Risk Group ◽  
Positive Real ◽  
Laboratory Findings ◽  
Clinical Presentations ◽  
Underlying Diseases

Introduction: To date, little is known about the clinical features of pediatric COVID-19 patients admitted to intensive care units (ICUs). Objective: Herein, we aimed to describe the differences in demographic characteristics, laboratory findings, clinical presentations, and outcomes of Iranian pediatric COVID-19 patients admitted to ICU versus those in non-ICU settings. Methods: This multicenter investigation involved 15 general and pediatrics hospitals and included cases with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection based on positive real-time reverse transcription polymerase chain reaction (RT-PCR) admitted to these centers between March and May 2020, during the initial peak of the COVID-19 pandemic in Iran. Results: Overall, 166 patients were included, 61 (36.7%) of whom required ICU admission. The highest number of admitted cases to ICU were in the age group of 1–5 years old. Malignancy and heart diseases were the most frequent underlying conditions. Dyspnea was the major symptom for ICU-admitted patients. There were significant decreases in PH, HCO3 and base excess, as well as increases in creatinine, creatine phosphokinase (CPK), lactate dehydrogenase (LDH), and potassium levels between ICU-admitted and non-ICU patients. Acute respiratory distress syndrome (ARDS), shock, and acute cardiac injury were the most common features among ICU-admitted patients. The mortality rate in the ICU-admitted patients was substantially higher than non-ICU cases (45.9% vs. 1.9%, respectively; p<0.001). Conclusions: Underlying diseases were the major risk factors for the increased ICU admissions and mortality rates in pediatric COVID-19 patients. There were few paraclinical parameters that could differentiate between pediatrics in terms of prognosis and serious outcomes of COVID-19. Healthcare providers should consider children as a high-risk group, especially those with underlying medical conditions.

scholarly journals Investigation of Commiphora myrrha (Nees) Engl. Oil and Its Main Components for Antiviral Activity

2021 ◽  
Vol 14 (3) ◽  
pp. 243
Author(s):  
Valentina Noemi Madia ◽  
Marta De Angelis ◽  
Daniela De Vita ◽  
Antonella Messore ◽  
Alessandro De Leo ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Extraction Method ◽  
Influenza A ◽  
Volatile Component ◽  
Tocopheryl Acetate ◽  
Gas Chromatography Mass Spectrometry ◽  
Bioactive Components ◽  
Vitamin E Acetate ◽  
Virus Life Cycle ◽  
Main Components

The resinous exudate produced by Commiphora myrrha (Nees) Engl. is commonly known as true myrrh and has been used since antiquity for several medicinal applications. Hundreds of metabolites have been identified in the volatile component of myrrh so far, mainly sesquiterpenes. Although several efforts have been devoted to identifying these sesquiterpenes, the phytochemical analyses have been performed by gas-chromatography/mass spectrometry (GC–MS) where the high temperature employed can promote degradation of the components. In this work, we report the extraction of C. myrrha by supercritical CO2, an extraction method known for the mild extraction conditions that allow avoiding undesired chemical reactions during the process. In addition, the analyses of myrrh oil and of its metabolites were performed by HPLC and GC–MS. Moreover, we evaluated the antiviral activity against influenza A virus of the myrrh extracts, that was possible to appreciate after the addition of vitamin E acetate (α-tocopheryl acetate) to the extract. Further, the single main bioactive components of the oil of C. myrrha commercially available were tested. Interestingly, we found that both furanodienone and curzerene affect viral replication by acting on different steps of the virus life cycle.

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