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Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice

Zhang et al., Inflammation Research, doi:10.1007/s00011-008-8007-8

Nov 2008

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Ivermectin for COVID-19

4th treatment shown to reduce risk in August 2020

^*, now known with p < 0.00000000001 from 102 studies, recognized in 22 countries.

Lower risk for mortality, ventilation, ICU admission, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19ivm.org

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.

66 preclinical studies support the efficacy of ivermectin for COVID-19:

14 In Vivo animal studies Abd-Elmawla, Albariqi, Arévalo, Chaccour, de Melo, Errecalde, Gao, Ma, Madrid, Mountain Valley MD, Uematsu, Yan, Zhang, Zheng

Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Jitobaom, Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, Jitobaom, 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 inhibits importin-α/β-dependent nuclear import of viral proteins Götz, Kosyna, Wagstaff, Wagstaff (B), shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing Fauquet, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination Boschi, Scheim, shows dose-dependent inhibition of wildtype and omicron variants Shahin, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 via IMPase inhibition Jitobaom, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, inhibits SARS-CoV-2 3CL^pro Mody, may inhibit SARS-CoV-2 RdRp activity Parvez (B), may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages Gao, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation Liu (C), shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing 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), increases Bifidobacteria which play a key role in the immune system Hazan, has immunomodulatory Munson and anti-inflammatory DiNicolantonio (B), Yan properties, and has an extensive and very positive safety profile Descotes.

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Zhang et al., 13 Nov 2008, peer-reviewed, 10 authors. Contact: xumingdeng@jluhp.edu.cn, jcui@wyeth.com.

This Paper Ivermectin All

Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice

X Zhang, Y Song, X Ci, N An, Y Ju, H Li, X Wang, C Han, J Cui, X Deng

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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