Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2
Summary: 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-clin...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-08-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422003292 |
| _version_ | 1818529941834170368 |
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| 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_facet | 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 |
| collection | DOAJ |
| description | Summary: 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”. |
| first_indexed | 2024-12-11T17:13:25Z |
| format | Article |
| id | doaj.art-2c868ce6fdee4c09b5bfe87564b64a94 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-11T17:13:25Z |
| publishDate | 2022-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-2c868ce6fdee4c09b5bfe87564b64a942022-12-22T00:57:26ZengElsevierEBioMedicine2352-39642022-08-0182104148Pre-clinical evaluation of antiviral activity of nitazoxanide against SARS-CoV-2Jean-Sélim Driouich0Maxime Cochin1Franck Touret2Paul-Rémi Petit3Magali Gilles4Grégory Moureau5Karine Barthélémy6Caroline Laprie7Thanaporn Wattanakul8Palang Chotsiri9Richard M. Hoglund10Joel Tarning11Laurent Fraisse12Peter Sjö13Charles E. Mowbray14Fanny Escudié15Ivan Scandale16Eric Chatelain17Xavier de Lamballerie18Caroline Solas19Antoine Nougairède20Unité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, France; Corresponding author.Unité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceLaboratoire Vet-Histo, Marseille, FranceMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United KingdomMahidol Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand; Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United KingdomDrugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, SwitzerlandDrugs for Neglected Diseases initiative, Geneva, SwitzerlandUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, France; APHM, Laboratoire de Pharmacocinétique et Toxicologie, Hôpital La Timone, Marseille, FranceUnité des Virus Émergents (UVE: Aix-Marseille University -IRD 190-Inserm 1207), Marseille, FranceSummary: 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”.http://www.sciencedirect.com/science/article/pii/S2352396422003292COVID-19SARS-CoV-2Antiviral therapyPre-clinical researchNitazoxanideAnimal model |
| spellingShingle | 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 EBioMedicine COVID-19 SARS-CoV-2 Antiviral therapy Pre-clinical research Nitazoxanide Animal model |
| title | 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_short | 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 |
| topic | COVID-19 SARS-CoV-2 Antiviral therapy Pre-clinical research Nitazoxanide Animal model |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422003292 |
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