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Attenuation of clinical and immunological outcomes during SARS-CoV-2 infection by ivermectin

de Melo et al., EMBO Mol. Med., doi:10.15252/emmm.202114122 (date from preprint)
Nov 2020  
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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
Animal study showing that standard doses of ivermectin prevented clinical deterioration, reduced olfactory deficit, and limited inflammation in the upper and lower respiratory tracts of SARS-CoV-2-infected hamsters.
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.
de Melo et al., 22 Nov 2020, peer-reviewed, 11 authors.
This PaperIvermectinAll
Attenuation of clinical and immunological outcomes during SARS‐CoV‐2 infection by ivermectin
Guilherme Dias Melo, Françoise Lazarini, Florence Larrous, Lena Feige, Etienne Kornobis, Sylvain Levallois, Agnès Marchio, Lauriane Kergoat, David Hardy, Thomas Cokelaer, Pascal Pineau, Marc Lecuit, Pierre‐marie Lledo, Jean‐pierre Changeux, Hervé Bourhy
EMBO Molecular Medicine, doi:10.15252/emmm.202114122
The devastating pandemic due to SARS-CoV-2 and the emergence of antigenic variants that jeopardize the efficacy of current vaccines create an urgent need for a comprehensive understanding of the pathophysiology of COVID-19, including the contribution of inflammation to disease. It also warrants for the search of immunomodulatory drugs that could improve disease outcome. Here, we show that standard doses of ivermectin (IVM), an antiparasitic drug with potential immunomodulatory activities through the cholinergic anti-inflammatory pathway, prevent clinical deterioration, reduce olfactory deficit, and limit the inflammation of the upper and lower respiratory tracts in SARS-CoV-2infected hamsters. Whereas it has no effect on viral load in the airways of infected animals, transcriptomic analyses of infected lungs reveal that IVM dampens type I interferon responses and modulates several other inflammatory pathways. In particular, IVM dramatically reduces the Il-6/Il-10 ratio in lung tissue and promotes macrophage M2 polarization, which might account for the more favorable clinical presentation of IVM-treated animals. Altogether, this study supports the use of immunomodulatory drugs such as IVM, to improve the clinical condition of SARS-CoV-2-infected patients.
Author contributions JPC and HB conceived the experimental hypothesis. GDM, FLaz, FLar, and HB designed the experiments. GDM, FLaz, FLar, LF, LK, SL, AM, and DH performed the experiments. GDM, FLaz, FLar, LF, EK, SL, AM, TC, PP, ML, and P-ML analyzed the data. GDM, J-PC, and HB wrote the manuscript, and all authors edited it. Conflict of interest The authors declare that they have no conflict of interest. For more information • COVID-19 section of the WHO website: https://covid19.who.int/ References Aamir K, Khan HU, Sethi G, Hossain MA, Arya A (2020) Wnt signaling mediates TLR pathway and promote unrestrained adipogenesis and The paper explained Problem The current pandemic of COVID-19 has caused more than 3.5 million deaths and more than 150 million laboratory-confirmed cases worldwide since December 2019 (as of May 2021). COVID-19, caused by SARS-CoV-2, commonly brings about upper airways and pulmonary symptoms and in severe cases can lead to respiratory distress and death. Different therapeutic approaches have been proposed to fight this disease but comprehensive therapeutic studies are still lacking. Results We report that ivermectin, used at the standard anti-parasitic dose of 400 µg/kg, protects infected hamsters from developing clinical signs and from losing the sense of smell during SARS-CoV-2 infection. The treated animals exhibited a specific inflammatory response, presenting a reduced type I/III interferon stimulation and a modulation in several..
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