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All Studies   Meta Analysis    Recent:   

Ivermectin reduces in vivo coronavirus infection in a mouse experimental model

Arévalo et al., Scientific Reports, doi:10.1038/s41598-021-86679-0 (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 104 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,400+ studies for 79 treatments. c19ivm.org
Mouse study showing ivermectin reducing MHV viral load and disease. MHV is a type 2 family RNA coronavirus similar to SARS-CoV2.
68 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 H7N766, Dengue32,67,68, HIV-168, Simian virus 4069, Zika32,70,71, West Nile71, Yellow Fever72,73, Japanese encephalitis72, Chikungunya73, Semliki Forest virus73, Human papillomavirus52, Epstein-Barr52, BK Polyomavirus74, and Sindbis virus73.
Ivermectin inhibits importin-α/β-dependent nuclear import of viral proteins66,68,69,75, shows spike-ACE2 disruption at 1nM with microfluidic diffusional sizing33, binds to glycan sites on the SARS-CoV-2 spike protein preventing interaction with blood and epithelial cells and inhibiting hemagglutination36,76, shows dose-dependent inhibition of wildtype and omicron variants31, exhibits dose-dependent inhibition of lung injury56,61, may inhibit SARS-CoV-2 via IMPase inhibition32, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation5, inhibits SARS-CoV-2 3CLpro49, may inhibit SARS-CoV-2 RdRp activity24, may minimize viral myocarditis by inhibiting NF-κB/p65-mediated inflammation in macrophages55, may be beneficial for COVID-19 ARDS by blocking GSDMD and NET formation77, may inhibit SARS-CoV-2 by disrupting CD147 interaction78-81, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1954,82, may be beneficial in severe COVID-19 by binding IGF1 to inhibit the promotion of inflammation, fibrosis, and cell proliferation that leads to lung damage4, may minimize SARS-CoV-2 induced cardiac damage35,43, increases Bifidobacteria which play a key role in the immune system83, has immunomodulatory46 and anti-inflammatory65,84 properties, and has an extensive and very positive safety profile85.
Arévalo et al., 2 Nov 2020, peer-reviewed, 12 authors.
This PaperIvermectinAll
Ivermectin reduces in vivo coronavirus infection in a mouse experimental model
A P Arévalo, R Pagotto, J L Pórfido, H Daghero, M Segovia, K Yamasaki, B Varela, M Hill, J M Verdes, M Duhalde Vega, M Bollati-Fogolín, M Crispo
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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S., Iqbal, Z., Muhammad, G. & Iqbal, M. U. Immunomodulatory ' 'effect of various anti-parasitics: A review. Parasitology 132, 301–313. ' 'https://doi.org/10.1017/s0031182005009108 (2006).', 'journal-title': 'Parasitology'}, { 'key': '86679_CR35', 'doi-asserted-by': 'publisher', 'first-page': '2100', 'DOI': '10.3390/cells9092100', 'volume': '9', 'author': 'DA Jans', 'year': '2020', 'unstructured': 'Jans, D. A. & Wagstaff, K. M. Ivermectin as a broad-spectrum ' 'host-directed antiviral: The real deal?. Cells 9, 2100. ' 'https://doi.org/10.3390/cells9092100 (2020).', 'journal-title': 'Cells'}, { 'key': '86679_CR36', 'doi-asserted-by': 'publisher', 'first-page': '23', 'DOI': '10.1186/s12941-020-00368-w', 'volume': '19', 'author': 'K Sharun', 'year': '2020', 'unstructured': 'Sharun, K. et al. Ivermectin, a new candidate therapeutic against ' 'SARS-CoV-2/COVID-19. Ann. Clin. Microbiol. Antimicrob. 19, 23. ' 'https://doi.org/10.1186/s12941-020-00368-w (2020).', 'journal-title': 'Ann. Clin. Microbiol. Antimicrob.'}, { 'key': '86679_CR37', 'doi-asserted-by': 'publisher', 'first-page': '449', 'DOI': '10.1111/j.1472-8206.2009.00684.x', 'volume': '23', 'author': 'X Ci', 'year': '2009', 'unstructured': 'Ci, X. et al. Avermectin exerts anti-inflammatory effect by ' 'downregulating the nuclear transcription factor kappa-B and ' 'mitogen-activated protein kinase activation pathway. Fundam. Clin. ' 'Pharmacol. 23, 449–455. https://doi.org/10.1111/j.1472-8206.2009.00684.x ' '(2009).', 'journal-title': 'Fundam. Clin. Pharmacol.'}, { 'key': '86679_CR38', 'doi-asserted-by': 'publisher', 'first-page': '524', 'DOI': '10.1007/s00011-008-8007-8', 'volume': '57', 'author': 'X Zhang', 'year': '2008', 'unstructured': 'Zhang, X. et al. Ivermectin inhibits LPS-induced production of ' 'inflammatory cytokines and improves LPS-induced survival in mice. ' 'Inflamm. Res. 57, 524–529. https://doi.org/10.1007/s00011-008-8007-8 ' '(2008).', 'journal-title': 'Inflamm. 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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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