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Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line

Munson et al., British Society For Nanomedicine Early Career Researcher Summer Meeting, 2021
Jun 2021  
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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.
In Vitro study showing potential therapeutic effects of ivermectin and niclosamide on the immune system by reducing inflammation and modulating key proteins involved in the inflammatory response. Ivermectin and niclosamide reduced proinflammatory markers and NLRP3 formation, and reduced caspase-1 activity.
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.
Munson et al., 16 Jun 2021, preprint, 5 authors.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line
Micheal C Munson, Danielle Brain, Christopher David, Andrew Owen, Dr Neill J Liptrott
The COVID-19 pandemic has led to an unprecedented demand for new and repurposed therapeutics to ameliorate the morbidity and mortality associated with SARS-CoV-2 infection. However, there is still a paucity of information relating to successful antiviral compounds. The repurposing of immune modulators, such as dexamethasone and tocilizumab, has shown significant improvement in survival rates. Repurposing of small molecules that may have antiviral and immunomodulatory potential may have significant impact on the pandemic. Niclosamide and ivermectin are being investigated for repurposing as potential treatments for COVID-19 patients. Both niclosamide and ivermectin have been proposed and studied based upon possible immunomodulatory and antiviral activity. To improve their posology, there are also ongoing efforts to nano-formulate these drugs, but a much greater understanding of their mechanisms of action is required to rationalise their plausibility as candidates. We have previously shown that niclosamide can affect responses to immune stimulation in ex vivo cells from healthy rats exposed via a long-acting injectable formulation. The current study aimed to further understand the effects of niclosamide and ivermectin on inflammasome activity in human cells due to the involvement of inflammasomes in the hyperinflammation and coagulation observed in severely ill COVID-19 patients. Caspase-1 activity and proinflammatory cytokine secretion in THP1 cells exposed to physiologically-relevant concentrations of niclosamide and ivermectin were measured as markers of inflammasome activity. Exposure to both niclosamide and ivermectin led to lower caspase-1 activity compared to untreated cells as well as resulting in lower secretion of IL-1β, IL-18, and TNF-α if treated prior to LPS induction. These data in their own right should not be interpreted as being a conclusive indicator of the utility of these drugs in COVID-19. However, the data presented suggests a putative mechanism for the proposed immune modulation. Substantive further work is still needed to determine the precise mechanism(s) that underpin these findings and whether the observations are relevant in vivo.
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Zhang, Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice, Inflamm. res
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