Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2

Background: To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. Methods: In this work, we present a complete pre-clinical evalu...

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Main Authors: Jean Sélim Driouich, Maxime Cochin, Franck Touret, Paul Rémi Petit, Magali Gilles, Grégory Moureau, Karine Barthélémy, Caroline Laprie, Thanaporn Wattanakul, Palang Chotsiri, Richard M. Hoglund, Joel Tarning, Laurent Fraisse, Peter Sjö, Charles E. Mowbray, Fanny Escudié, Ivan Scandale, Eric Chatelain, Xavier de Lamballerie, Caroline Solas, Antoine Nougairède
Other Authors: Faculty of Tropical Medicine, Mahidol University
Format: Article
Published: 2022
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Online Access:https://repository.li.mahidol.ac.th/handle/123456789/73234
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spelling th-mahidol.732342022-08-04T10:38:53Z Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2 Jean Sélim Driouich Maxime Cochin Franck Touret Paul Rémi Petit Magali Gilles Grégory Moureau Karine Barthélémy Caroline Laprie Thanaporn Wattanakul Palang Chotsiri Richard M. Hoglund Joel Tarning Laurent Fraisse Peter Sjö Charles E. Mowbray Fanny Escudié Ivan Scandale Eric Chatelain Xavier de Lamballerie Caroline Solas Antoine Nougairède Faculty of Tropical Medicine, Mahidol University Aix Marseille Université Hopital La Timone Nuffield Department of Medicine Drugs for Neglected Diseases Initiative Laboratoire Vet-Histo Biochemistry, Genetics and Molecular Biology Background: To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. Methods: In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. Findings: First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. Interpretation: These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19. Funding: This work was supported by the Fondation de France “call FLASH COVID-19”, project TAMAC, by “Institut national de la santé et de la recherche médicale” through the REACTing (REsearch and ACTion targeting emerging infectious diseases), by REACTING/ANRS MIE under the agreement No. 21180 (‘Activité des molécules antivirales dans le modèle hamster’), by European Virus Archive Global (EVA 213 GLOBAL) funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 871029 and DNDi under support by the Wellcome Trust Grant ref: 222489/Z/21/Z through the COVID-19 Therapeutics Accelerator”. 2022-08-04T03:38:53Z 2022-08-04T03:38:53Z 2022-08-01 Article eBioMedicine. Vol.82, (2022) 10.1016/j.ebiom.2022.104148 23523964 2-s2.0-85134563590 https://repository.li.mahidol.ac.th/handle/123456789/73234 Mahidol University SCOPUS https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85134563590&origin=inward
institution Mahidol University
building Mahidol University Library
continent Asia
country Thailand
Thailand
content_provider Mahidol University Library
collection Mahidol University Institutional Repository
topic Biochemistry, Genetics and Molecular Biology
spellingShingle Biochemistry, Genetics and Molecular Biology
Jean Sélim Driouich
Maxime Cochin
Franck Touret
Paul Rémi Petit
Magali Gilles
Grégory Moureau
Karine Barthélémy
Caroline Laprie
Thanaporn Wattanakul
Palang Chotsiri
Richard M. Hoglund
Joel Tarning
Laurent Fraisse
Peter Sjö
Charles E. Mowbray
Fanny Escudié
Ivan Scandale
Eric Chatelain
Xavier de Lamballerie
Caroline Solas
Antoine Nougairède
Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2
description Background: To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy. Methods: In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2. Findings: First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro EC50. Interpretation: These preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19. Funding: This work was supported by the Fondation de France “call FLASH COVID-19”, project TAMAC, by “Institut national de la santé et de la recherche médicale” through the REACTing (REsearch and ACTion targeting emerging infectious diseases), by REACTING/ANRS MIE under the agreement No. 21180 (‘Activité des molécules antivirales dans le modèle hamster’), by European Virus Archive Global (EVA 213 GLOBAL) funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 871029 and DNDi under support by the Wellcome Trust Grant ref: 222489/Z/21/Z through the COVID-19 Therapeutics Accelerator”.
author2 Faculty of Tropical Medicine, Mahidol University
author_facet Faculty of Tropical Medicine, Mahidol University
Jean Sélim Driouich
Maxime Cochin
Franck Touret
Paul Rémi Petit
Magali Gilles
Grégory Moureau
Karine Barthélémy
Caroline Laprie
Thanaporn Wattanakul
Palang Chotsiri
Richard M. Hoglund
Joel Tarning
Laurent Fraisse
Peter Sjö
Charles E. Mowbray
Fanny Escudié
Ivan Scandale
Eric Chatelain
Xavier de Lamballerie
Caroline Solas
Antoine Nougairède
format Article
author Jean Sélim Driouich
Maxime Cochin
Franck Touret
Paul Rémi Petit
Magali Gilles
Grégory Moureau
Karine Barthélémy
Caroline Laprie
Thanaporn Wattanakul
Palang Chotsiri
Richard M. Hoglund
Joel Tarning
Laurent Fraisse
Peter Sjö
Charles E. Mowbray
Fanny Escudié
Ivan Scandale
Eric Chatelain
Xavier de Lamballerie
Caroline Solas
Antoine Nougairède
author_sort Jean Sélim Driouich
title Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2
title_short Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2
title_full Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2
title_fullStr Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2
title_full_unstemmed Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2
title_sort pre-clinical evaluation of antiviral activity of nitazoxanide against sars-cov-2
publishDate 2022
url https://repository.li.mahidol.ac.th/handle/123456789/73234
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