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      COVID-19 pandemic and therapy with ibuprofen or renin-angiotensin system blockers: no need for interruptions or changes in ongoing chronic treatments

      review-article
      1 , 2 , , 2 , 2 , on behalf of the German Society for Experimental and Clinical Pharmacology and Toxicology (DGPT)
      Naunyn-Schmiedeberg's Archives of Pharmacology
      Springer Berlin Heidelberg
      COVID-19, SARS-CoV-2, Angiotensin-converting enzyme inhibitors, Angiotensin receptor antagonists, Non-steroidal anti-inflammatory agents

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          Abstract

          Scientists hypothesized that drugs such as ibuprofen or renin-angiotensin system (RAS) blockers could exacerbate the novel coronavirus disease COVID-19 by upregulating the angiotensin-converting enzyme 2 (ACE2), which serves as an entry receptor for the coronavirus SARS-CoV-2. This hypothesis was taken up by the lay press and led to concerns among doctors and patients whether the use of these drugs was still safe and justified against the background of the pandemic spread of SARS-CoV-2 with an increasing number of cases and deaths. In this article, we summarize what is known about the effect of RAS blockers or non-steroidal anti-inflammatory drugs (NSAIDs) on the course of COVID-19 disease. In the case of RAS inhibition, we also find evidence for the opposite hypothesis, namely, that RAS inhibition in COVID-19 could be protective. In view of the inconsistent and limited evidence and after weighing up the benefits and risks, we would not currently recommend discontinuing or switching an effective treatment with RAS blockers. NSAIDs should be used at the lowest effective dose for the shortest possible period. The choice of drug to treat COVID-19-associated fever or pain should be based on a benefit-risk assessment for known side effects (e.g., kidney damage, gastrointestinal ulceration).

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          Most cited references22

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          SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

          Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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            Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

            Summary The emergence of SARS-CoV-2 has resulted in >90,000 infections and >3,000 deaths. Coronavirus spike (S) glycoproteins promote entry into cells and are the main target of antibodies. We show that SARS-CoV-2 S uses ACE2 to enter cells and that the receptor-binding domains of SARS-CoV-2 S and SARS-CoV S bind with similar affinities to human ACE2, correlating with the efficient spread of SARS-CoV-2 among humans. We found that the SARS-CoV-2 S glycoprotein harbors a furin cleavage site at the boundary between the S1/S2 subunits, which is processed during biogenesis and sets this virus apart from SARS-CoV and SARS-related CoVs. We determined cryo-EM structures of the SARS-CoV-2 S ectodomain trimer, providing a blueprint for the design of vaccines and inhibitors of viral entry. Finally, we demonstrate that SARS-CoV S murine polyclonal antibodies potently inhibited SARS-CoV-2 S mediated entry into cells, indicating that cross-neutralizing antibodies targeting conserved S epitopes can be elicited upon vaccination.
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              A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus–induced lung injury

              During several months of 2003, a newly identified illness termed severe acute respiratory syndrome (SARS) spread rapidly through the world 1,2,3 . A new coronavirus (SARS-CoV) was identified as the SARS pathogen 4,5,6,7 , which triggered severe pneumonia and acute, often lethal, lung failure 8 . Moreover, among infected individuals influenza such as the Spanish flu 9,10 and the emergence of new respiratory disease viruses 11,12 have caused high lethality resulting from acute lung failure 13 . In cell lines, angiotensin-converting enzyme 2 (ACE2) has been identified as a potential SARS-CoV receptor 14 . The high lethality of SARS-CoV infections, its enormous economic and social impact, fears of renewed outbreaks as well as the potential misuse of such viruses as biologic weapons make it paramount to understand the pathogenesis of SARS-CoV. Here we provide the first genetic proof that ACE2 is a crucial SARS-CoV receptor in vivo. SARS-CoV infections and the Spike protein of the SARS-CoV reduce ACE2 expression. Notably, injection of SARS-CoV Spike into mice worsens acute lung failure in vivo that can be attenuated by blocking the renin-angiotensin pathway. These results provide a molecular explanation why SARS-CoV infections cause severe and often lethal lung failure and suggest a rational therapy for SARS and possibly other respiratory disease viruses. Supplementary information The online version of this article (doi:10.1038/nm1267) contains supplementary material, which is available to authorized users.
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                Author and article information

                Contributors
                oliver.zolk@mhb-fontane.de
                Journal
                Naunyn Schmiedebergs Arch Pharmacol
                Naunyn Schmiedebergs Arch. Pharmacol
                Naunyn-Schmiedeberg's Archives of Pharmacology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0028-1298
                1432-1912
                15 May 2020
                15 May 2020
                : 1-5
                Affiliations
                [1 ]GRID grid.4488.0, ISNI 0000 0001 2111 7257, Institute of Clinical Pharmacology, Brandenburg Medical School Theodor Fontane, Immanuel Klinik, ; Seebad 82/83, Rüdersdorf, 15562 Germany
                [2 ]GRID grid.6582.9, ISNI 0000 0004 1936 9748, Institute of Pharmacology of Natural Products and Clinical Pharmacology, , Ulm University, ; 89081 Ulm, Germany
                Author information
                https://orcid.org/0000-0002-8220-3834
                Article
                1890
                10.1007/s00210-020-01890-6
                7225250
                32415494
                389be245-a134-4394-ad84-893b3831693c
                © The Author(s) 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 15 April 2020
                : 28 April 2020
                Funding
                Funded by: Medizinische Hochschule Brandenburg CAMPUS gGmbH (5634)
                Categories
                Review Article

                Pharmacology & Pharmaceutical medicine
                covid-19,sars-cov-2,angiotensin-converting enzyme inhibitors,angiotensin receptor antagonists,non-steroidal anti-inflammatory agents

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