Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients
De Forni et al.
, Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients
, PLoS ONE, doi:10.1371/journal.pone.0276751 (In Vitro)
Vero E6 In Vitro
study showing remdesivir and ivermectin or azithromycin to be highly synergistic with 4-13 times lower concentration required for 100% inhibition.[Gérard, Zhou]
show significantly increased risk of acute kidney injury with remdesivir.
3 In Vitro
studies support the efficacy of remdesivir [De Forni, Delandre, Jeffreys]
De Forni et al., 10 Nov 2022, peer-reviewed, 6 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
Abstract: PLOS ONE
Synergistic drug combinations designed to
fully suppress SARS-CoV-2 in the lung of
Davide De Forni1☯, Barbara Poddesu1☯, Giulia Cugia1, James Chafouleas1,
Julianna Lisziewicz2, Franco Lori1,2*
1 ViroStatics s.r.l., Tramariglio, Italy, 2 Research Institute for Genetic and Human Therapy, Colorado
Springs, CO, United States of America
Citation: De Forni D, Poddesu B, Cugia G,
Chafouleas J, Lisziewicz J, Lori F (2022)
Synergistic drug combinations designed to fully
suppress SARS-CoV-2 in the lung of COVID-19
patients. PLoS ONE 17(11): e0276751. https://doi.
Editor: Hiroj Bagde, Rama Dental College and
Hospital and Research Centre, INDIA
Received: March 22, 2022
Accepted: October 12, 2022
Published: November 10, 2022
Copyright: © 2022 De Forni 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.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
Funding: Funds were collected by the not-for-profit
Research Institute for Genetic and Human Therapy
(RIGHT) through a crowdfunding campaign named
GoFundMe "COVID-19: ora serve una Cura"
(https://www.gofundme.com/manage/emergenzacoronavirus-ora-serve-una-cura). RIGHT acted as
the sponsor of the study and, as institution, had no
role in the writing of the manuscript or the decision
☯ These authors contributed equally to this work.
Despite new antivirals are being approved against SARS-CoV-2 they suffer from significant
constraints and are not indicated for hospitalized patients, who are left with few antiviral
options. Repurposed drugs have previously shown controversial clinical results and it
remains difficult to understand why certain trials delivered positive results and other trials
failed. Our manuscript contributes to explaining the puzzle: this might have been caused by
a suboptimal drug exposure and, consequently, an incomplete virus suppression, also
because the drugs have mostly been used as add-on monotherapies. As with other viruses
(e.g., HIV and HCV) identifying synergistic combinations among such drugs could overcome
monotherapy-related limitations. In a cell culture model for SARS-CoV-2 infection the following stringent criteria were adopted to assess drug combinations: 1) identify robust, synergistic antiviral activity with no increase in cytotoxicity, 2) identify the lowest drug concentration
inhibiting the virus by 100% (LIC100) and 3) understand whether the LIC100 could be reached
in the lung at clinically indicated drug doses. Among several combinations tested, remdesivir
with either azithromycin or ivermectin synergistically increased the antiviral activity with no
increase in cytotoxicity, improving the therapeutic index and lowering the LIC100 of every
one of the drugs to levels that are expected to be achievable and maintained in the lung for a
therapeutically relevant period of time. These results are consistent with recent clinical
observations showing that intensive care unit admission was significantly delayed by the
combination of AZI and RDV, but not by RDV alone, and could have immediate implications
for the treatment of hospitalized patients..
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