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All Studies   Meta Analysis       

Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients

De Forni et al., PLoS ONE, doi:10.1371/journal.pone.0276751
Nov 2022  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020, now with p < 0.00000000001 from 105 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments.
5,000+ studies for 104 treatments. c19ivm.org
Vero E6 In Vitro study showing ivermectin and remdesivir to be highly synergistic with 6-13 times lower concentration required for 100% inhibition.
69 preclinical studies support the efficacy of ivermectin for COVID-19:
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N767, Dengue33,68,69, HIV-169, Simian virus 4070, Zika33,71,72, West Nile72, Yellow Fever73,74, Japanese encephalitis73, Chikungunya74, Semliki Forest virus74, Human papillomavirus53, Epstein-Barr53, BK Polyomavirus75, and Sindbis virus74.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins67,69,70,76, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing34, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination37,77, shows dose-dependent inhibition of wildtype and omicron variants32, exhibits dose-dependent inhibition of lung injury57,62, may inhibit SARS-CoV-2 via IMPase inhibition33, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation6, inhibits SARS-CoV-2 3CLpro50, may inhibit SARS-CoV-2 RdRp activity25, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages56, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation78, may interfere with SARS-CoV-2's immune evasion via ORF8 binding1, may inhibit SARS-CoV-2 by disrupting CD147 interaction79-82, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1955,83, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage5, may minimize SARS-CoV-2 induced cardiac damage36,44, increases Bifidobacteria which play a key role in the immune system84, has immunomodulatory47 and anti-inflammatory66,85 properties, and has an extensive and very positive safety profile86.
Study covers remdesivir and ivermectin.
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.
This PaperIvermectinAll
Synergistic drug combinations designed to fully suppress SARS-CoV-2 in the lung of COVID-19 patients
Davide De Forni, Barbara Poddesu, Giulia Cugia, James Chafouleas, Julianna Lisziewicz, Franco Lori
PLOS ONE, doi:10.1371/journal.pone.0276751
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% (LIC 100 ) and 3) understand whether the LIC 100 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 LIC 100 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 with COVID-19 as the proposed "drug cocktails" should have antiviral activity against present and future SARS-CoV-2 variants without significant overlapping toxicity, while minimizing the onset of drug resistance. Our results also provide a validated methodology to help sort out which combination of drugs are most likely to be efficacious in vivo, based on their in vitro activity, potential synergy and PK profiles.
Author Contributions Conceptualization: Julianna Lisziewicz, Franco Lori. Data curation: Davide De Forni, Barbara Poddesu, Giulia Cugia, Franco Lori.
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