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      Emerging preclinical evidence does not support broad use of hydroxychloroquine in COVID-19 patients

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          Abstract

          There is an urgent need for drugs, therapies and vaccines to be available to protect the human population against COVID-19. One of the first approaches taken in the COVID-19 global response was to consider repurposing licensed drugs. This commentary highlights an extraordinary international collaborative effort of independent researchers who have recently all come to the same conclusion—that chloroquine or hydroxchloroquine are unlikely to provide clinical benefit against COVID-19.

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          Most cited references 6

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          The Genome Landscape of the African Green Monkey Kidney-Derived Vero Cell Line

          Continuous cell lines that originate from mammalian tissues serve as not only invaluable tools for life sciences, but also important animal cell substrates for the production of various types of biological pharmaceuticals. Vero cells are susceptible to various types of microbes and toxins and have widely contributed to not only microbiology, but also the production of vaccines for human use. We here showed the genome landscape of a Vero cell line, in which 25,877 putative protein-coding genes were identified in the 2.97-Gb genome sequence. A homozygous ∼9-Mb deletion on chromosome 12 caused the loss of the type I interferon gene cluster and cyclin-dependent kinase inhibitor genes in Vero cells. In addition, an ∼59-Mb loss of heterozygosity around this deleted region suggested that the homozygosity of the deletion was established by a large-scale conversion. Moreover, a genomic analysis of Vero cells revealed a female Chlorocebus sabaeus origin and proviral variations of the endogenous simian type D retrovirus. These results revealed the genomic basis for the non-tumourigenic permanent Vero cell lineage susceptible to various pathogens and will be useful for generating new sub-lines and developing new tools in the quality control of Vero cells.
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            FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro

            SARS-CoV-2 emerged in China at the end of 2019 and has rapidly become a pandemic with over 400,000 recorded COVID-19 cases and greater than 19,000 recorded deaths by March 24th, 2020 (www.WHO.org). There are no FDA approved antivirals or vaccines for any coronavirus, including SARS-CoV-2. Current treatments for COVID-19 are limited to supportive therapies and off-label use of FDA approved drugs. Rapid development and human testing of potential antivirals is greatly needed. A potentially quicker way to test compounds with antiviral activity is through drug re-purposing. Numerous drugs are already approved for use in humans and subsequently there is a good understanding of their safety profiles and potential side effects, making them easier to test in COVID-19 patients. Here, we present data on 20 FDA approved drugs tested for antiviral activity against SARS-CoV-2 that we have previously found to inhibit SARS-CoV and MERS-CoV. We find that 17 of these also inhibit SARS-CoV-2 at a range of IC50 values at non-cytotoxic concentrations. From these we specifically followed up with hydroxychloroquine sulfate and chloroquine phosphate.
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              Hydroxychloroquine Proves Ineffective in Hamsters and Macaques Infected with SARS-CoV-2

              We remain largely without effective prophylactic/therapeutic interventions for COVID-19. Although many human clinical trials are ongoing, there remains a deficiency of supportive preclinical drug efficacy studies. Here we assessed the prophylactic/therapeutic efficacy of hydroxychloroquine (HCQ), a drug of interest for COVID-19 management, in two animal models. When used for prophylaxis or treatment neither the standard human malaria dose (6.5 mg/kg) nor a high dose (50 mg/kg) of HCQ had any beneficial effect on clinical disease or SARS-CoV-2 kinetics (replication/shedding) in the Syrian hamster disease model. Similarly, HCQ prophylaxis/treatment (6.5 mg/kg) did not significantly benefit clinical outcome nor reduce SARS-CoV-2 replication/shedding in the upper and lower respiratory tract in the rhesus macaque disease model. In conclusion, our preclinical animal studies do not support the use of HCQ in prophylaxis/treatment of COVID-19.
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                Author and article information

                Contributors
                simon.funnell@phe.gov.uk
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                26 August 2020
                26 August 2020
                2020
                : 11
                Affiliations
                [1 ]GRID grid.271308.f, ISNI 0000 0004 5909 016X, National Infection Service, , Public Health England, ; Porton Down, Manor Farm Road, Salisbury, Wiltshire SP40JG UK
                [2 ]Coalition for Epidemic Preparedness Innovations, 1901 Pennsylvania Avenue, NW, Suite 1003, Washington, DC 20006 USA
                [3 ]GRID grid.424065.1, ISNI 0000 0001 0701 3136, Bernhard Nocht Institute for Tropical Medicine, ; Bernhard Nocht Strasse. 74, 20359 Hamburg, Germany
                [4 ]GRID grid.3575.4, ISNI 0000000121633745, World Health Organisation, ; Avenue Appia, 1211, Geneva, Switzerland
                [5 ]GRID grid.38142.3c, ISNI 000000041936754X, Wyss Institute for Biologically Inspired Engineering, , Harvard University, ; CLSB5, 3 Blackfan Circle, Boston, MA 02115 USA
                [6 ]Emulate Inc., 27 Drydock Avenue, 5th Floor, Boston, MA 02210 USA
                [7 ]GRID grid.5596.f, ISNI 0000 0001 0668 7884, Laboratory of Virology and Chemotherapy, Department of Microbiology, Immunology and Transplantation, Rega Institute, Global Virus Network, , KU Leuven, ; 3000 Leuven, Belgium
                [8 ]GRID grid.94365.3d, ISNI 0000 0001 2297 5165, Laboratory of Virology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, , National Institute of Health, ; Hamilton, 59840 MT USA
                [9 ]GRID grid.7429.8, ISNI 0000000121866389, Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-immune, Hematological and Bacterial diseases » (IMVA-HB/IDMIT), ; Fontenay-aux-Roses & Le Kremlin-Bicêtre, 92265 France
                [10 ]GRID grid.411024.2, ISNI 0000 0001 2175 4264, Department of Microbiology and Immunology, , University of Maryland School of Medicine, ; Baltimore, MD 21201 USA
                [11 ]School of Life Sciences, University of Nottingham, Queen’s Medical Centre, Nottingham, NG7 2UH UK
                Article
                17907
                10.1038/s41467-020-17907-w
                7450055
                32848158
                © Crown 2020

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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                animal disease models, respiratory system models, sars-cov-2, preclinical research

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