Ivermectin for COVID-19
4th treatment shown to reduce risk in
August 2020, now with p < 0.0000000001 from 106 studies, recognized in 24 countries.
No treatment is 100% effective.
Protocols combine treatments.
Analysis of ivermectin's effects in mouse models of lethal endotoxemia, which mimics key pathological features seen in severe and critical COVID-19 cases.
Pretreatment with ivermectin significantly improved survival rates in mice given a lethal dose of LPS. Ivermectin also substantially reduced inflammatory cytokine levels (TNF-α, IL-1β, IL-6) in the mouse model and in LPS-stimulated macrophages. The anti-inflammatory effects were associated with inhibition of NF-kB activation, a key inflammatory pathway. Overall, the results show promising anti-inflammatory and protective effects in models of severe infection/inflammation.
The LPS mouse model reflects several key pathological features of severe and critical COVID-19, including:
- excessive inflammation - LPS administration in mice and severe COVID-19 can lead to an uncontrolled inflammatory response, involving a dramatic increase in inflammatory cytokines like TNF-α, IL-1β, and IL-6. This cytokine storm is thought to underlie much of the organ damage in severe COVID-19.
- tissue damage/organ failure - the excessive inflammation can lead to damage of lung tissue as well as failure of other organs like the kidneys in both LPS models and COVID-19.
- activation of the NF-kB pathway - the inflammatory response in both cases involves activation of the NF-kB pathway in immune cells like macrophages. NF-kB drives transcription of inflammatory cytokines.
80 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 H7N776, Dengue41,77,78 , HIV-178, Simian virus 4079, Zika41,80,81 , West Nile81, Yellow Fever82,83, Japanese encephalitis82, Chikungunya83, Semliki Forest virus83, Human papillomavirus61, Epstein-Barr61, BK Polyomavirus84, and Sindbis virus83.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins76,78,79,85 , shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing42, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination45,86, shows dose-dependent inhibition of wildtype and omicron variants40, exhibits dose-dependent inhibition of lung injury66,71, may inhibit SARS-CoV-2 via IMPase inhibition41, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation10, inhibits SARS-CoV-2 3CLpro58, may inhibit SARS-CoV-2 RdRp activity1,29, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages65, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation87, may interfere with SARS-CoV-2's immune evasion via ORF8 binding5, may inhibit SARS-CoV-2 by disrupting CD147 interaction88-91, may inhibit SARS-CoV-2 attachment to lipid rafts via spike NTD binding3, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1963,92, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage9, significantly mitigates bleomycin-induced pulmonary fibrosis by reducing collagen accumulation and inflammatory cell infiltration64, improves oxidative stress markers while suppressing myofibroblast proliferation64, mitigates lung pathology and anosmia in vivo while regulating the CXCL10/CXCL5 inflammatory axis via P2X4 and α7nAChR receptor modulation36, may minimize SARS-CoV-2 induced cardiac damage44,52, may counter immune evasion by inhibiting NSP15-TBK1/KPNA1 interaction and restoring IRF3 activation93, may disrupt SARS-CoV-2 N and ORF6 protein nuclear transport and their suppression of host interferon responses2, reduces TAZ/YAP nuclear import, relieving SARS-CoV-2-driven suppression of IRF3 and NF-κB antiviral pathways39, increases Bifidobacteria which play a key role in the immune system94, has immunomodulatory55 and anti-inflammatory75,95 properties, and has an extensive and very positive safety profile96.
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Zhao et al., Identification of the shared gene signatures between pulmonary fibrosis and pulmonary hypertension using bioinformatics analysis, Frontiers in Immunology, doi:10.3389/fimmu.2023.1197752.
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Vottero et al., Computational Prediction of the Interaction of Ivermectin with Fibrinogen, Molecular Sciences, doi:10.3390/ijms241411449.
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18.
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Zhang et al., 13 Nov 2008, peer-reviewed, 10 authors.
Contact: xumingdeng@jluhp.edu.cn, jcui@wyeth.com.
Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice
Inflammation Research, doi:10.1007/s00011-008-8007-8
Objective and Design: To investigate whether ivermectin, a semi-synthetic derivative of a family of macrocyclic lactones could inhibit lipopolysaccharide (LPS)-induced inflammation in vivo and in vitro. Materials and Methods: C57BL/6 mice were administered ivermectin (or saline) orally and challenged intraperitoneally with LPS at a lethal dose of 32 mg/kg. RAW 264.7 murine macrophages were stimulated with LPS at 1 µg/ml, with or without ivermectin for 6, 12 and 24 h. The production of tumor necrosis factor-a (TNF-a), interleukin-1ß (IL-1ß) and interleukin-6 (IL-6) in serum from mice and supernatants from cells were measured by ELISA. Nuclear factor-kB (NF-kB) translocation with subunit p65 was evaluated by immunocytochemical analysis. Results: Ivermectin improved mouse survival rate induced by a lethal dose of LPS. In addition, ivermectin significantly decreased the production of TNF-a, IL-1ß and IL-6 in vivo and in vitro. Furthermore, ivermectin suppressed NF-kB translocation induced by LPS.
Conclusions: The results indicate that ivermectin may inhibit LPS-induced production of inflammatory cytokines by blocking NF-kB pathway and improve LPS-induced survival in mice. This finding might provide a new strategy for the treatment of endotoxemia and associated inflammation.
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