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      Available medications used as potential therapeutics for COVID-19: What are the known safety profiles in pregnancy

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          Abstract

          Background

          Medications already available to treat other conditions are presently being studied in clinical trials as potential treatments for COVID-19. Given that pregnant women are excluded from these trials, we aimed to investigate their safety when used during pregnancy within a unique population source.

          Methods

          Using the population-based Quebec Pregnancy Cohort, we identified women who delivered a singleton liveborn (1998–2015). Taking potential confounders into account including indications for use, the risk of prematurity, low birth weight (LBW), small for gestational age (SGA), and major congenital malformation (MCM) associated with COVID-19 repurposed drug use during pregnancy were quantified using generalized estimation equations.

          Results

          Of the 231,075 eligible pregnancies, 107 were exposed to dexamethasone (0.05%), 31 to interferons (0.01%), 1,398 to heparins (0.60%), 24 to angiotensin-receptor blockers (ARB) (0.01%), 182 to chloroquine (0.08%), 103 to hydroxychloroquine (0.05%), 6,206 to azithromycin (2.70%), 230 to oseltamivir (0.10%), and 114 to HIV medications (0.05%). Adjusting for potential confounders, we observed an increased risk of prematurity related to dexamethasone (aOR 1.92, 95%CI 1.11–3.33; 15 exposed cases), anti-thrombotics (aOR 1.58, 95%CI 1.31–1.91; 177 exposed cases), and HIV medications (aOR 2.04, 95%CI 1.01–4.11; 20 exposed cases) use. An increased risk for LBW associated with anti-thrombotics (aOR 1.72, 95%CI 1.41–2.11; 152 exposed cases), and HIV medications (aOR 2.48, 95%CI 1.25–4.90; 21 exposed cases) use were also found. Gestational exposure to anti-thrombotics (aOR 1.20, 95%CI 1.00–1.44; 176 exposed cases), and HIV medications (aOR 2.61, 95%CI 1.51–4.51; 30 exposed cases) were associated with SGA. First-trimester dexamethasone (aOR 1.66, 95%CI 1.02–2.69; 20 exposed cases) and azithromycin (aOR 1.10, 95%CI 1.02–1.19; 747 exposed cases) exposures were associated with MCM.

          Conclusions

          Many available medications considered as treatments for COVID-19 are associated with adverse pregnancy outcomes. Caution is warranted when considering these medications during the gestational period.

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          Most cited references78

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          Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial

          Background Chloroquine and hydroxychloroquine have been found to be efficient on SARS-CoV-2, and reported to be efficient in Chinese COV-19 patients. We evaluate the role of hydroxychloroquine on respiratory viral loads. Patients and methods French Confirmed COVID-19 patients were included in a single arm protocol from early March to March 16th, to receive 600mg of hydroxychloroquine daily and their viral load in nasopharyngeal swabs was tested daily in a hospital setting. Depending on their clinical presentation, azithromycin was added to the treatment. Untreated patients from another center and cases refusing the protocol were included as negative controls. Presence and absence of virus at Day6-post inclusion was considered the end point. Results Six patients were asymptomatic, 22 had upper respiratory tract infection symptoms and eight had lower respiratory tract infection symptoms. Twenty cases were treated in this study and showed a significant reduction of the viral carriage at D6-post inclusion compared to controls, and much lower average carrying duration than reported of untreated patients in the literature. Azithromycin added to hydroxychloroquine was significantly more efficient for virus elimination. Conclusion Despite its small sample size our survey shows that hydroxychloroquine treatment is significantly associated with viral load reduction/disappearance in COVID-19 patients and its effect is reinforced by azithromycin.
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            Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

            Spike (S) proteins of coronaviruses, including the coronavirus that causes severe acute respiratory syndrome (SARS), associate with cellular receptors to mediate infection of their target cells 1,2 . Here we identify a metallopeptidase, angiotensin-converting enzyme 2 (ACE2) 3,4 , isolated from SARS coronavirus (SARS-CoV)-permissive Vero E6 cells, that efficiently binds the S1 domain of the SARS-CoV S protein. We found that a soluble form of ACE2, but not of the related enzyme ACE1, blocked association of the S1 domain with Vero E6 cells. 293T cells transfected with ACE2, but not those transfected with human immunodeficiency virus-1 receptors, formed multinucleated syncytia with cells expressing S protein. Furthermore, SARS-CoV replicated efficiently on ACE2-transfected but not mock-transfected 293T cells. Finally, anti-ACE2 but not anti-ACE1 antibody blocked viral replication on Vero E6 cells. Together our data indicate that ACE2 is a functional receptor for SARS-CoV. Supplementary information The online version of this article (doi:10.1038/nature02145) contains supplementary material, which is available to authorized users.
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              Structural basis of receptor recognition by SARS-CoV-2

              Summary A novel SARS-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans 1,2 . A key to tackling this epidemic is to understand the virus’s receptor recognition mechanism, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor - human ACE2 (hACE2) 3,4 . Here we determined the crystal structure of SARS-CoV-2 receptor-binding domain (RBD) (engineered to facilitate crystallization) in complex of hACE2. Compared with SARS-CoV RBD, a hACE2-binding ridge in SARS-CoV-2 RBD takes a more compact conformation; moreover, several residue changes in SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD/hACE2 interface. These structural features of SARS-CoV-2 RBD enhance its hACE2-binding affinity. Additionally, we showed that RaTG13, a bat coronavirus closely related to SARS-CoV-2, also uses hACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in hACE2 recognition shed light on potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies targeting receptor recognition by SARS-CoV-2.

                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                19 May 2021
                2021
                19 May 2021
                : 16
                : 5
                : e0251746
                Affiliations
                [1 ] Research Center, CHU Sainte-Justine, Montreal, Quebec, Canada
                [2 ] Faculty of Pharmacy, University of Montreal, Montreal, Quebec, Canada
                [3 ] Faculty of Medicine, Université Claude Bernard, Lyon, France
                [4 ] Faculty of Medicine, McGill University, Montreal, Quebec, Canada
                [5 ] Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada
                University of Insubria, ITALY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0001-7535-5517
                Article
                PONE-D-20-40139
                10.1371/journal.pone.0251746
                8133446
                34010282
                37a8ca34-9e6a-4192-b51c-2c1467e6fe54
                © 2021 Bérard et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 21 December 2020
                : 30 April 2021
                Page count
                Figures: 1, Tables: 3, Pages: 24
                Funding
                Funded by: Canadian Institutes of Health Research (CIHR) – CAN-AIM
                Award ID: grant number 132750
                Award Recipient :
                Funded by: Fonds de la recherche du Québec – Santé (FRQS) - Réseau de recherche sur les médicaments
                Award ID: grant number 30962
                Award Recipient :
                AB. Grant number 132750. Canadian Institutes of Health Research (CIHR) – CAN-AIM. AB. Grant number 30962. Fonds de la recherche du Québec – Santé (FRQS) - Réseau de recherche sur les médicaments. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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