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MeSH Disease

Human Phenotype

Transmission

Seroprevalence
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    A New Model of SARS-CoV-2 Infection MESHD Based on (Hydroxy)Chloroquine Activity

    Authors: Robert J. Sheaff

    doi:10.1101/2020.08.02.232892 Date: 2020-08-02 Source: bioRxiv

    Chloroquine and hydroxychloroquine (H)CQ are well known anti-malarial drugs, while their use against COVID-19 is more controversial. (H)CQ activity was examined in tissue culture cells to determine if their anti-viral benefits or adverse effects might be due to altering host cell pathways. Metabolic analysis revealed (H)CQ inhibit oxidative phosphorylation in mitochondria, likely by sequestering protons needed to drive ATP synthase. This activity could cause cardiotoxicity MESHD because heart muscle relies on beta oxidation of fatty acids. However, it might also explain their therapeutic benefit against COVID-19. A new model of SARS-CoV-2 infection MESHD postulates virus enters host cell mitochondria and uses its protons for genome release. Oxidative phosphorylation is eventually compromised, so glycolysis is upregulated to maintain ATP levels. (H)CQ could prevent viral infection MESHD and/or slow its replication by sequestering these protons. In support of this model other potential COVID-19 therapeutics also targeted mitochondria, as did tobacco smoke, which may underlie smokers protection. The mitochondria of young people are naturally more adaptable and resilient, providing a rationale for their resistance to disease MESHD progression. Conversely, obesity MESHD obesity HP and diabetes could exacerbate disease MESHD severity by providing extra glucose to infected cells dependent on glycolysis. The description of (H)CQ function presented here, together with its implications for understanding SARS-CO-V2 infection MESHD, makes testable predictions about disease progression MESHD and identifies new approaches for treating COVID-19.

    A Strategy to Treat COVID-19 Disease MESHD with Targeted Delivery of Inhalable Liposomal Hydroxychloroquine: A Non-clinical Pharmacokinetic Study

    Authors: Tien-Tzu Tai; Tzung-Ju Wu; Huey-Dong Wu; Yi-Chen Tsai; Hui-Ting Wang; An-Min Wang; Sheue-Fang Shih; Yee-Chun Chen

    doi:10.1101/2020.07.09.196618 Date: 2020-07-10 Source: bioRxiv

    Severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) is a newly identified pathogen causing coronavirus disease MESHD 2019 (COVID-19) pandemic. Hydroxychloroquine (HCQ), an antimalarial and anti-inflammatory drug, has been shown to inhibit SARS-CoV-2 infection MESHD in vitro and tested in clinical studies. However, lung concentration (6.7 {micro}g/mL) to predict the in vivo antiviral efficacy might not be achievable with the currently proposed oral dosing regimen. Further, a high cumulative doses of HCQ may raise concerns of systemic toxicity, including cardiotoxicity MESHD. Here, we described a non-clinical study to investigate the pharmacokinetics of a novel formulation of liposomal HCQ administrated by intratracheal (IT) instillation in Sprague-Dawley (SD) rats which achieved 129.4 {micro}g/g (Cmax) in the lung. Compared to unformulated HCQ administered intravenous (IV), liposomal HCQ with normalized dose showed higher ([~]30-fold) lung exposure, longer ([~]2.5-fold) half-life in lung, but lower blood SERO exposure with [~]20% of Cmax and 74% of AUC and lower heart exposure with 24% of Cmax and 58% of AUC. In conclusion, the pharmacokinetics results in an animal model demonstrate the proof of concept that inhalable liposomal HCQ may provide clinical benefit and serve as a potential treatment for COVID-19.

    SARS-CoV-2 infects and induces cytotoxic effects in human cardiomyocytes

    Authors: Denisa Bojkova; Julian Wagner; Mariana Shumliakivska; Galip Aslan; Umber Saleem; Arne Hansen; Guillermo Luxan; Stefan Guenther; Minh Duc Pham; Jaya Krishnan; Patrick Harter; Utz Ermel; Achilleas S Frangakis; Andreas Zeiher; Hendrik Milting; Jindrich Cinatl Jr.; Andreas Dendorfer; Thomas Eschenhagen; Sandra Ciesek; Stefanie Dimmeler

    doi:10.1101/2020.06.01.127605 Date: 2020-06-01 Source: bioRxiv

    BackgroundThe coronavirus disease MESHD 2019 (COVID-19) is caused by severe acute respiratory syndrome MESHD coronavirus 2 (SARS-CoV-2) and has emerged as global pandemic. SARS-CoV-2 infection MESHD can lead to elevated markers of cardiac injury associated with higher risk of mortality in COVID-19 patients. It is unclear whether cardiac injury may have been caused by direct infection MESHD of cardiomyocytes or is mainly secondary to lung injury MESHD and inflammation MESHD. Here we investigate whether human cardiomyocytes are permissive for SARS-CoV-2 infection MESHD. MethodsInfection was induced by two strains of SARS-CoV-2 (FFM1 and FFM2) in human induced pluripotent stem cells-derived cardiomyocytes (hiPS-CM) and in two models of human cardiac tissue. ResultsWe show that SARS-CoV-2 infects hiPS-CM as demonstrated by detection of intracellular double strand viral RNA and viral spike glycoprotein protein expression. Increasing concentrations of virus RNA are detected in supernatants of infected cardiomyocytes, which induced infections MESHD in CaCo-2 cell lines documenting productive infections MESHD. SARS-COV-2 infection MESHD induced cytotoxic and pro-apoptotic effects and abolished cardiomyocyte beating. RNA sequencing confirmed a transcriptional response to viral infection MESHD as demonstrated by the up-regulation of genes associated with pathways related to viral response and interferon signaling, apoptosis and reactive oxygen stress. SARS-CoV-2 infection MESHD and cardiotoxicity MESHD was confirmed in a iPS-derived human 3D cardiosphere tissue models. Importantly, viral spike protein and viral particles were detected in living human heart slices after infection MESHD with SARS-CoV-2. ConclusionsThe demonstration that cardiomyocytes are permissive for SARS-CoV-2 infection MESHD in vitro warrants the further in depth monitoring of cardiotoxic effects in COVID-19 patients. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LIThis study demonstrates that human cardiac myocytes are permissive for SARS-CoV-2 infection MESHD. C_LIO_LIThe study documents that SARS-CoV-2 undergoes a full replicatory circle and induces a cytotoxic response in cardiomyocytes. C_LIO_LIInfection was confirmed in two cardiac tissue models, including living human heart slices. C_LI What are the Clinical Implications?O_LIThe study may provide a rational to explain part of the cardiotoxicity MESHD observed in COVID-19 patients C_LIO_LIThe demonstration of direct cardiotoxicity MESHD induced by SARS-CoV-2 warrants an in depth further analysis of cardiac tissue of COVID-19 patients and a close monitoring for putative direct cardiomyocyte injury. C_LIO_LIThe established models can be used to test novel therapeutic approaches targeting COVID-19. C_LI

    Determinants of cardiac adverse events of chloroquine and hydroxychloroquine in 20 years of drug safety surveillance reports

    Authors: Isaac V Cohen; Tigran Makunts; Talar Moumedjian; Masara Issa; Ruben Abagyan

    doi:10.1101/2020.05.19.20107227 Date: 2020-05-26 Source: medRxiv

    Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization's List of Essential Medications for treating non-resistant malaria MESHD, rheumatoid arthritis MESHD rheumatoid arthritis HP (RA) and systemic lupus erythematosus MESHD systemic lupus erythematosus HP (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection MESHD. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male TRANS sex, NSAID coadministration, advanced age TRANS, and prior diagnoses contributing to the risk of drug related cardiotoxicity MESHD. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.

The ZB MED preprint Viewer preVIEW includes all COVID-19 related preprints from medRxiv and bioRxiv, from ChemRxiv, from ResearchSquare, from arXiv and from Preprints.org and is updated on a daily basis (7am CET/CEST).

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MeSH Disease
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Transmission
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