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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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Vero E6 In Vitro study showing ivermectin and remdesivir to be highly synergistic with 6-13 times lower concentration required for 100% inhibition.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Yang, West Nile Yang, Yellow Fever Mastrangelo, Varghese, Japanese encephalitis Mastrangelo, Chikungunya Varghese, Semliki Forest virus Varghese, Human papillomavirus Li, Epstein-Barr Li, BK Polyomavirus Bennett, and Sindbis virus Varghese.
Ivermectin is an inhibitor of importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), a SARS-CoV-2 3CLpro inhibitor Mody, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model of severe infection/inflammation that shares key pathological features of severe COVID-19 DiNicolantonio, Zhang, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage Zhao, may minimize SARS-CoV-2 induced cardiac damage Liu, Liu (B), has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.
This study includes 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.
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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.
References
Archive, Human 2019-nCoV strain 2019-nCoV/Italy-INMI1, clade V
Brussow, Clinical trials with antiviral drugs against COVID-19: some progress and many shattered hopes, Environ Microbiol
Bryant, Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines, American Journal of Therapeutics
Bugatti, SARS-CoV-2 Infects Human ACE2-Negative Endothelial Cells through an αvβ3 Integrin-Mediated Endocytosis Even in the Presence of Vaccine-Elicited Neutralizing Antibodies, Viruses
Caccuri, A persistently replicating SARS-CoV-2 variant derived from an asymptomatic individual, J Transl Med
Caruso, methotrexate inhibits SARS-CoV-2 virus replication "in vitro, J Med Virol
Conway, Mathematical Modeling of Remdesivir to Treat COVID-19: Can Dosing Be Optimized?, Pharmaceutics
Ding, Crucial Mutations of Spike Protein on SARS-CoV-2 Evolved to Variant Strains Escaping Neutralization of Convalescent Plasmas and RBD-Specific Monoclonal Antibodies, Fron Immunol
Eweas, Molecular Docking Reveals Ivermectin and Remdesivir as Potential Repurposed Drugs Against SARS-CoV-2, Front Microbiol
Fantini, Synergistic antiviral effect of hydroxychloroquine and azithromycin in combination against SARS-CoV-2: What molecular dynamics studies of virus-host interactions reveal, Int JAntimicrob Agents
Gedikli, Are clarithromycin, azithromycin and their analogues effective in the treatment of COVID19?, Bratisl. Med J
Gordon, Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency, J Biol Chem
Humeniuk, Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of Remdesivir, a SARS-CoV-2 Replication Inhibitor, Clin Pharmackinet
Jermain, Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing, J Pharm Sci
Kaplan, Hepatitis C Virus, Ann Intern Med
Kozlov, Why scientists are racing to develop more COVID antivirals, Nature
Labriola, Peptide-Antibody Fusions Engineered by Phage Display Exhibit an Ultrapotent and Broad Neutralization of SARS-CoV-2 Variants, ACS Chem Biol
Ledford, COVID antiviral pills: what scientists still want to know, Nature
Liu, Viral dynamics in mild and severe cases of COVID-19, Lancet Infect Dis
Looney, HIV therapy-the state of art, Curr Top Microbiol Immunol
Luke, Safety, toleration, and Pharmacokinetics of intravenous azithromycin, Antimicrob Agents Chemother, doi:10.1128/aac.40.11.2577
Mangkuliguna, Efficacy and Safety of Azithromycin for the Treatment of COVID-19: A Systematic Review and Meta-analysis, Tuberc Respir Dis
Pfizer, Pfizer's Novel COVID-19 Oral Antiviral Treatment Candidate Reduced Risk of Hospitalization or Death by 89% in Interim Analysis of Phase 2/3 EPIC-HR Study
Phanuphak, HIV treatment and prevention 2019: current standards of care, Curr Opin HIV AIDS
Poupaert, Study of the Interaction of Zinc Cation with Azithromycin and its Significance in the COVID-19 Treatment: A Molecular Approach, The Open Biochemistry Journal
Prichard, Strategic design adn three-dimensional analysis of antiviral drug combinations, Antimicrob Agents Chemother
Rodrı ´guez-Molinero, Azithromycin: can its benefit be ruled out in mild COVID-19?, Lancet Respir Med
Sandeep, Energetics Based Modeling of Hydroxychloroquine and Azithromycin Binding to the SARS-CoV-2 Spike (S)Protein-ACE2 Complex
Sun, Remdesivir for Treatment of COVID-19: Combination of Pulmonary and IV Administration May Offer Additional Benefit, Aaps J
Ticinesi, Co-Administration of Remdesivir and Azithromycin May Protect against Intensive Care Unit Admission in COVID-19 Pneumonia Requiring Hospitalization: A Real-Life Observational Study, Antibiotics
Wu, Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods, Acta Pharm Sin B
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