Clementi: Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro [HCQ]

Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro

Clementi et al., Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704 (date from earlier preprint) (In Vitro)

Clementi et al., Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704 (date from earlier preprint) (In Vitro)

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In Vitro study showing greater inhibition for combined pre and post-exposure treatment for Vero E6 and Caco-2 cells.

14 In Vitro studies support the efficacy of HCQ [Andreani, Clementi, Dang, Delandre, Faísca, Hoffmann, Liu, Ou, Purwati, Sheaff, Wang, Wang (B), Yao, Yuan].

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1. Andreani et al., Microbial Pathogenesis, doi:/10.1016/j.micpath.2020.104228, In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, https://www.sciencedirect.com/science/article/pii/S0882401020305155.

2. Clementi et al., Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704 (preprint 3/31), Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, https://www.frontiersin.org/articl..ign=ECO_FCIMB_XXXXXXXX_auto-dlvrit.

3. Dang et al., bioRxiv, doi:10.1101/2021.03.16.435741, Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein, https://www.biorxiv.org/content/10.1101/2021.03.16.435741v1.

4. Delandre et al., Pharmaceuticals, doi:10.3390/ph15040445, Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, https://www.mdpi.com/1424-8247/15/4/445.

5. Faísca et al., Pharmaceutics, doi:10.3390/pharmaceutics14040877, Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2, https://www.mdpi.com/1999-4923/14/4/877.

6. Hoffmann et al., Nature, (2020), doi:10.1038/s41586-020-2575-3, Chloroquine does not inhibit infection of human lung cells with SARS-CoV-2, https://www.nature.com/articles/s41586-020-2575-3.

7. Liu et al., Cell Discovery 6, 16 (2020), doi:10.1038/s41421-020-0156-0, Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, https://www.nature.com/articles/s41421-020-0156-0.

8. Ou et al., PLOS Pathogens, doi:10.1371/journal.ppat.1009212 (preprint 7/22), Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, https://journals.plos.org/plospath..le?id=10.1371/journal.ppat.1009212.

9. Purwati et al., PLOS One, doi:10.1371/journal.pone.0252302, An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, https://journals.plos.org/plosone/..le?id=10.1371/journal.pone.0252302.

10. Sheaff, R., bioRxiv, doi:10.1101/2020.08.02.232892, A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, https://www.biorxiv.org/content/10.1101/2020.08.02.232892v1.

11. Wang et al., Phytomedicine, doi:10.1016/j.phymed.2020.153333, Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467095/.

12. Wang (B) et al., Cell Res. 30, 269–271, doi:L10.1038/s41422-020-0282-0, Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, https://www.nature.com/articles/s4..iVs8_7R1KkwOuqjRhx7psfHV6iSDRD1cM0.

13. Yao et al., Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237, In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), https://academic.oup.com/cid/advan..le/doi/10.1093/cid/ciaa237/5801998.

14. Yuan et al., Communications Biology, doi:10.1038/s42003-022-03841-8, Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, https://www.nature.com/articles/s42003-022-03841-8.

Clementi et al., 31 Mar 2020, peer-reviewed, 10 authors.

In Vitro studies are an important part of preclinical research, however results may be very different in vivo.

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Abstract: ORIGINAL RESEARCH published: 10 July 2020 doi: 10.3389/fmicb.2020.01704 Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro Nicola Clementi 1,2 , Elena Criscuolo 1 , Roberta Antonia Diotti 1 , Roberto Ferrarese 1 , Matteo Castelli 1 , Lorenzo Dagna 3 , Roberto Burioni 1 , Massimo Clementi 1,2 and Nicasio Mancini 1,2* 1 Laboratory of Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy, 2 Laboratory of Microbiology and Virology, IRCCS San Raffaele Scientific Institute, Milan, Italy, 3 Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR), IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy Edited by: Lars Kaderali, Universitätsmedizin Greifswald, Germany Reviewed by: Sibylle Haid, Twincore Center for Experimental and Clinical Infection Research GmbH, Germany Alexander Freiberg, The University of Texas Medical Branch at Galveston, United States *Correspondence: Nicasio Mancini mancini.nicasio@hsr.it Specialty section: This article was submitted to Virology, a section of the journal Frontiers in Microbiology Received: 09 April 2020 Accepted: 29 June 2020 Published: 10 July 2020 Citation: Clementi N, Criscuolo E, Diotti RA, Ferrarese R, Castelli M, Dagna L, Burioni R, Clementi M and Mancini N (2020) Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro. Front. Microbiol. 11:1704. doi: 10.3389/fmicb.2020.01704 While the SARS-CoV-2 pandemic is heavily hitting the world, it is of extreme importance that significant in vitro observations guide the quick set up of clinical trials. In this study, we evidence that the anti-SARS-CoV2 activity of a clinically achievable hydroxychloroquine concentration is maximized only when administered before and after the infection of Vero E6 and Caco-2 cells. This suggests that only a combined prophylactic and therapeutic use of hydroxychloroquine may be effective in limiting viral replication in patients. Keywords: hydroxychloroquine, SARS-CoV-2, COVID-19, prophylaxis, therapy

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