Ivermectin reduces in vivo coronavirus infection in a mouse experimental model
et al., Scientific Reports, doi:10.1038/s41598-021-86679-0, Nov 2020 (preprint)
Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.00000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective. Protocols
combine treatments.
6,300+ studies for
210+ treatments. c19early.org
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Mouse study showing ivermectin reducing MHV viral load and disease. MHV is a type 2 family RNA coronavirus similar to SARS-CoV2.
74 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 H7N771, Dengue37,72,73 , HIV-173, Simian virus 4074, Zika37,75,76 , West Nile76, Yellow Fever77,78, Japanese encephalitis77, Chikungunya78, Semliki Forest virus78, Human papillomavirus57, Epstein-Barr57, BK Polyomavirus79, and Sindbis virus78.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins71,73,74,80 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing38, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination41,81, shows dose-dependent inhibition of wildtype and omicron variants36, exhibits dose-dependent inhibition of lung injury61,66, may inhibit SARS-CoV-2 via IMPase inhibition37, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation9, inhibits SARS-CoV-2 3CLpro54, may inhibit SARS-CoV-2 RdRp activity28, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages60, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation82, may interfere with SARS-CoV-2's immune evasion via ORF8 binding4, may inhibit SARS-CoV-2 by disrupting CD147 interaction83-86, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1959,87, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage8, may minimize SARS-CoV-2 induced cardiac damage40,48, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation88, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses1, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways35, increases Bifidobacteria which play a key role in the immune system89, has immunomodulatory51 and anti-inflammatory70,90 properties, and has an extensive and very positive safety profile91.
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12.
Alvarado et al., Interaction of the New Inhibitor Paxlovid (PF-07321332) and Ivermectin With the Monomer of the Main Protease SARS-CoV-2: A Volumetric Study Based on Molecular Dynamics, Elastic Networks, Classical Thermodynamics and SPT, Computational Biology and Chemistry, doi:10.1016/j.compbiolchem.2022.107692.
13.
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14.
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15.
Francés-Monerris et al., Microscopic interactions between ivermectin and key human and viral proteins involved in SARS-CoV-2 infection, Physical Chemistry Chemical Physics, doi:10.1039/D1CP02967C.
16.
González-Paz et al., Comparative study of the interaction of ivermectin with proteins of interest associated with SARS-CoV-2: A computational and biophysical approach, Biophysical Chemistry, doi:10.1016/j.bpc.2021.106677.
17.
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18.
Rana et al., A Computational Study of Ivermectin and Doxycycline Combination Drug Against SARS-CoV-2 Infection, Research Square, doi:10.21203/rs.3.rs-755838/v1.
19.
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20.
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21.
Schöning et al., Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains, Research Square, doi:10.21203/rs.3.rs-379291/v1.
22.
Bello et al., Elucidation of the inhibitory activity of ivermectin with host nuclear importin α and several SARS-CoV-2 targets, Journal of Biomolecular Structure and Dynamics, doi:10.1080/07391102.2021.1911857.
23.
Udofia et al., In silico studies of selected multi-drug targeting against 3CLpro and nsp12 RNA-dependent RNA-polymerase proteins of SARS-CoV-2 and SARS-CoV, Network Modeling Analysis in Health Informatics and Bioinformatics, doi:10.1007/s13721-021-00299-2.
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Arévalo et al., 2 Nov 2020, peer-reviewed, 12 authors.
Ivermectin reduces in vivo coronavirus infection in a mouse experimental model
Scientific Reports, doi:10.1038/s41598-021-86679-0
The objective of this study was to test the effectiveness of ivermectin for the treatment of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2. Female BALB/cJ mice were infected with 6,000 PFU of MHV-A59 (group infected, n = 20) or infected and then immediately treated with a single dose of 500 µg/kg ivermectin (group infected + IVM, n = 20) or were not infected and treated with PBS (control group, n = 16). Five days after infection/treatment, the mice were euthanized and the tissues were sampled to assess their general health status and infection levels. Overall, the results demonstrated that viral infection induced typical MHV-caused disease, with the livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while mice treated with ivermectin showed a better health status with a lower viral load (23,192 AU; p < 0.05), with only a few having histopathological liver damage (p < 0.05). No significant differences were found between the group infected + IVM and control group mice (P = NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in the treated mice than in the infected animals. In conclusion, ivermectin diminished the MHV viral load and disease in the mice, being a useful model for further understanding this therapy against coronavirus diseases. Mouse hepatitis virus (MHV) is a single-stranded RNA coronavirus that targets different organs 1 . The virus is highly contagious, has natural respiratory or oral transmission, and shows high morbidity and low mortality rates. There is no vaccine or treatment available; therefore, upon infection, an entire laboratory mouse colony must be sacrificed to control the disease. Recent studies have shown that the mechanism of infection has similarities to that of SARS-CoV-2 2,3 : therefore, it has been proposed that MHV may be an interesting infection model to test new therapies against COVID-19 in animals. Although different therapies have been evaluated, no effective treatment is available, and the mechanism by which the virus enters the cell is being explored 4 . After entry into the cytoplasm of the host cell, coronaviruses rely on a nuclear transport system mediated by the importin α/β1 heterodimer to facilitate replication and infection 5, 6 . Some drugs have been demonstrated to act by impairing importin α/β1 heterodimer formation to prevent viral entry. Because both MHV and SARS-CoV-2 enter the nucleus via the same mechanism, MHV may be an interesting target for the development of candidate therapies against coronavirus infection in a mouse model. Ivermectin is an efficient and inexpensive drug usually applied to treat parasitic infestations. It has been approved by the FDA for animal and human use and is available worldwide. It has a wide margin of safety with an LD 50 of 30..
www.nature.com/scientificreports/ 15 min with an antibody mixture. The following fluorophore-conjugated antibodies were used: anti-CD4-FITC (#11,004,181, clone GK1.5) and anti-CD8-PE-Cy7 (#25,008,182, clone 53-6.7) from eBioscience (San Diego, CA, US) and anti-CD19-PerCP-Cy 5.5 (#551,001, clone ID3) from BD Pharmingen (San Diego, CA, US). Flow cytometry analysis was performed using an Attune Nxt Acoustic Focusing Cytometer (Thermo Fisher) equipped with a 488 nm laser. Emissions were detected using 530/30, 695/40 and 780/60 nm bandpass filters for FITC, PerCP-Cy5.5 and PE-Cy7, respectively. FlowJo software, version 10.6.1 (Tree Star, Ashland, Oregon, US), was used for data analysis. Unstained controls, single-color controls and fluorescence-minus-one controls were used to establish baseline gate settings for each respective antibody combination. Lymphocytes were gated based on their FSC and SSC dot plot profiles, and an FSC area vs FSC height dot plot was used to exclude doublets. B lymphocytes were defined as CD19-PerCP-Cy5.5-positive cells. For T lymphocyte analysis, a gate was placed on the CD19-negative population, and based on the PE-Cy7 vs FITC dot plot, CD8-PE-Cy7-positive cells and CD4-FITC-positive cells were defined as CD8 + and CD4 + lymphocytes, respectively. A minimum of 10,000 events in a single cell region were collected. The results are expressed as percentage of the specific cell type from the analyzed single-cell population.
Statistical analysis...
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Jans, Wagstaff, Ivermectin as a broad-spectrum host-directed antiviral: The real deal?, Cells, doi:10.3390/cells9092100
Johansen, Animal and translational models of SARS-CoV-2 infection and COVID-19, Mucosal Immunol, doi:10.1038/s41385-020-00340-z
Korner, Majjouti, Alcazar, Mahabir, Of mice and men: The coronavirus MHV and mouse models as a translational approach to understand SARS-CoV-2, Viruses, doi:10.3390/v12080880
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Krolewiecki, Antiviral effect of high-dose ivermectin in adults with COVID-19: A pilot randomised, controlled, open label multicentre trial, The Lancet, doi:10.2139/ssrn.3714649
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Procter, Clinical outcomes after early ambulatory multidrug therapy for high-risk SARS-CoV-2 (COVID-19) infection, Rev Cardiovasc Med, doi:10.31083/j.rcm.2020.04.260
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"abstract": "<jats:title>Abstract</jats:title><jats:p>The objective of this study was to test the effectiveness of ivermectin for the treatment of mouse hepatitis virus (MHV), a type 2 family RNA coronavirus similar to SARS-CoV-2. Female BALB/cJ mice were infected with 6,000 PFU of MHV-A59 (group infected, n = 20) or infected and then immediately treated with a single dose of 500 µg/kg ivermectin (group infected + IVM, n = 20) or were not infected and treated with PBS (control group, n = 16). Five days after infection/treatment, the mice were euthanized and the tissues were sampled to assess their general health status and infection levels. Overall, the results demonstrated that viral infection induced typical MHV-caused disease, with the livers showing severe hepatocellular necrosis surrounded by a severe lymphoplasmacytic inflammatory infiltration associated with a high hepatic viral load (52,158 AU), while mice treated with ivermectin showed a better health status with a lower viral load (23,192 AU; p < 0.05), with only a few having histopathological liver damage (p < 0.05). No significant differences were found between the group infected + IVM and control group mice (P = NS). Furthermore, serum transaminase levels (aspartate aminotransferase and alanine aminotransferase) were significantly lower in the treated mice than in the infected animals. In conclusion, ivermectin diminished the MHV viral load and disease in the mice, being a useful model for further understanding this therapy against coronavirus diseases.</jats:p>",
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