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Moxidectin and ivermectin inhibit SARS-CoV-2 replication in Vero E6 cells but not in human primary airway epithelium cells

Dinesh Kumar et al., Antimicrobial Agents and Chemotherapy, doi:10.1128/AAC.01543-21 (date from preprint)
Mar 2021  
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Ivermectin for COVID-19
4th treatment shown to reduce risk in August 2020
*, now known with p < 0.00000000001 from 100 studies, recognized in 22 countries.
No treatment is 100% effective. Protocols combine complementary and synergistic treatments. * >10% efficacy in meta analysis with ≥3 clinical studies.
3,800+ studies for 60+ treatments.
In Vitro study showing moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Authors indicate that no statistically significant effect was seen in Calu-3/PBEC cells, however Figure 3 shows a dose dependent reduction with ivermectin and moxidectin, and the actual values are not provided. Calu-3 is one of many cell lines derived from human lung carcinomas Calu-3 cells resemble serous gland cells. They do not express 15-lipoxygenase, an enzyme specifically localized to the surface epithelium, but they do express secretory component, secretory leukocyte protease inhibitor, lysozyme, and lactoferrin, all markers of serous gland cells. note that the absence of systemic inflammation, circulatory factors, and other paracrine systemic influences is a potential limitation of the isolated cell system.
Ivermectin, better known for antiparasitic activity, is a broad spectrum antiviral with activity against many viruses including H7N7 Götz, Dengue Tay, Wagstaff, HIV-1 Wagstaff, Simian virus 40 Wagstaff (B), Zika Barrows, 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), inhibits SARS-CoV-2 3CLpro Mody, 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, exhibits dose-dependent inhibition of lung injury Abd-Elmawla, Ma, may inhibit SARS-CoV-2 induced formation of fibrin clots resistant to degradation Vottero, 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 Bifidobacterium which plays 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.
Dinesh Kumar et al., 17 Mar 2021, peer-reviewed, 14 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Moxidectin and Ivermectin Inhibit SARS-CoV-2 Replication in Vero E6 Cells but Not in Human Primary Bronchial Epithelial Cells
Nilima Dinesh Kumar, Bram M Ter Ellen, Ellen M Bouma, Berit Troost, Denise P I Van De Pol, Heidi H Van Der Ende-Metselaar, Djoke Van Gosliga, Leonie Apperloo, Orestes A Carpaij, Maarten Van Den Berge, Martijn C Nawijn, Ymkje Stienstra, Izabela A Rodenhuis-Zybert, Nilima Dinesh Kumar, Bram M Ter, Jolanda M Smit
Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 mM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. However, in April 2021, the World Health Organization stated the following: "The current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive." It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to-head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that these compounds predominantly act on the steps following virus cell entry. Surprisingly, however, in human-airway-derived cell models, both moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at concentrations of 10 mM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on their activity in Vero cells. Altogether, these findings suggest that even using a high-dose regimen of ivermectin, or switching to another drug in the same class, is unlikely to be useful for treatment of SARS-CoV-2 in humans. KEYWORDS moxidectin, ivermectin, antiviral, SARS-CoV-2, ALI, in vitro W ithin less than 1.5 years, the pandemic SARS coronavirus 2 (SARS-CoV-2) has infected over 153 million individuals and resulted in over 3.2 million deaths worldwide (1-3). The social and economic burden of this still-ongoing pandemic is staggering, and, besides vaccine development, it is of utmost importance to develop therapeutic interventions to reduce disease symptoms. To date, multiple compounds have been shown to exert SARS-CoV-2 antiviral activity in vitro and several compounds have reached clinical trials (4, 5). Remdesivir and hydroxychloroquine were thought to be effective early in the pandemic, but after a careful evaluation in an interim solidarity trial, the WHO released a conditional yet strong recommendation against the usage of
% cytotoxicity ¼ ðcompound-treated LDH activity 2 spontaneous LDH activityÞ ðmaximum LDH activity 2 spontaneous LDH activityÞ Â 100 Live/dead staining and flow cytometry. PBECs cultured under ALI conditions were treated with 10 mM moxidectin, ivermectin, or an equivalent volume of EtOH at the basolateral side for 48 h at 37°C. Subsequently, cells were harvested by trypsinization and stained with fixable viability dye eFluor780 (Thermo Fisher Scientific) for 20 min at 4°C. Next, cells were washed with fluorescence-activated cell sorter (FACS) buffer (1X phosphate-buffered saline, 2% FBS, 1% EDTA), centrifuged, and fixed with 4% paraformaldehyde for 10 min at 4°C. After fixation, cells were washed, centrifuged, and resuspended in FACS buffer. Flow cytometry analyses were performed using the LSR-2 flow cytometer (BD Biosciences, San Jose, CA, USA) and data was further analyzed using Kaluza analysis software, version 2.1 (Beckman Coulter, Fullerton, CA, USA). Antiviral assays in Vero E6 and Calu-3. Vero E6 cells were seeded at a density of 1.3 Â 10 5 cells/well in 12-well plates. The next day, the medium was replaced with 0.25 ml of DMEM (2% FBS) containing the virus inoculum (MOI 1), in the presence of either increasing concentrations of compounds or the equivalent volume of EtOH. Following 2 h adsorption at 37°C, the virus inoculum was removed, after which the cells were washed twice and fresh DMEM (10% FBS) containing either the compounds or EtOH was added. At 8 hpi, cell..
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