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All Studies   Meta Analysis    Recent:   

Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains

Schöning et al., Research Square, doi:10.21203/rs.3.rs-379291/v1
Apr 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. c19ivm.org
In Silico study of ivermectin treatment predicting greater efficacy for variants with higher R0.
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.
Schöning et al., 15 Apr 2021, preprint, 4 authors.
In Silico studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Highly-transmissible Variants of SARS-CoV-2 May Be More Susceptible to Drug Therapy Than Wild Type Strains
Verena Schöning, Charlotte Kern, Carlos Chaccour, Felix Hammann
doi:10.21203/rs.3.rs-379291/v1
As of March 2021, no antiviral drug regimen has proved effective against SARS-CoV-2 infection. With the pandemic showing no signs of slowing down, and vaccine campaigns only starting to be rolled out, we appear to have few options other than non-pharmacological measures. Emerging Variants of Concern (VOCs), e.g. B1.1.7, B.1.351, and B.1.1.248, however, are characterized by higher transmissibility (R0). Here we model and simulate the effect of altered R0 on viral load profiles, and its impact on antiviral therapy. As a hypothetical case study, we simulated treatment with ivermectin 600µg/kg for 3 days initiated at different time points around the infection. Simulated mutations range from 1.25 to 2-fold greater infectivity, but also include putative co-adapted variants with lower transmissibility (0.75-fold). Antiviral efficacy was correlated with R0, making highly transmissible VOCs more sensitive to antiviral therapy. Viral exposure was reduced by 42% compared to 22% in wild type if treatment was started on inoculation. Less transmissible variants appear less susceptible. Our findings suggest there may be a role for pre-or post-exposure prophylactic antiviral treatment in areas with presence of highly transmissible variants. Furthermore, clinical trials with borderline efficacious results should consider identifying VOCs and examine their impact in post-hoc analysis.
Author contributions VS: formal analysis, investigation, methodology, software, visualisation, writing -review & editing; CK: methodology, software, writing -review & editing; CC: validation, funding acquisition, writing -review & editing; FH: conceptualisation, formal analysis, funding acquisition, methodology, software, supervision, validation, visualisation, writing -original draft, writing -review & editing. All authors contributed to the final version. Additional Information Competing interests The author(s) declare no competing interests. above the serological positivity threshold (b). Black: wild type, blue: less transmissible, orange to red: highly transmissible. Supplementary Files This is a list of supplementary les associated with this preprint. Click to download. 20210330Sars2variantssupplements.pdf
References
Baric, Emergence of a Highly Fit SARS-CoV-2 Variant, N Engl J Med, doi:10.1056/NEJMcibr2032888
Canini, Perelson, Viral kinetic modeling: state of the art, Journal of pharmacokinetics and pharmacodynamics, doi:10.1007/s10928-014-9363-3
Chaccour, Hammann, Ramon-Garcia, Rabinovich, Ivermectin and COVID-19: Keeping Rigor in Times of Urgency, Am J Trop Med Hyg, doi:10.4269/ajtmh.20-0271
Chaccour, The effect of early treatment with ivermectin on viral load, symptoms and humoral response in patients with non-severe COVID-19: A pilot, double-blind, placebocontrolled, randomized clinical trial, EClinicalMedicine, doi:10.1016/j.eclinm.2020.100720
Cohen, South Africa suspends use of AstraZeneca's COVID-19 vaccine after it fails to clearly stop virus variant, Science
Duthaler, Population pharmacokinetics of oral ivermectin in venous plasma and dried blood spots in healthy volunteers, Br J Clin Pharmacol, doi:10.1111/bcp.13840
Fajnzylber, SARS-CoV-2 viral load is associated with increased disease severity and mortality, Nat Commun, doi:10.1038/s41467-020-19057-5
Faria, Genomic characterisation of an emergent SARS-CoV-2 lineage in Manaus: preliminary findings
Goncalves, Timing of Antiviral Treatment Initiation is Critical to Reduce SARS-CoV-2 Viral Load, CPT Pharmacometrics Syst Pharmacol, doi:10.1002/psp4.12543
He, Temporal dynamics in viral shedding and transmissibility of COVID-19, Nat Med, doi:10.1038/s41591-020-0869-5
Kern, Schoening, Chaccour, Hammann, Modeling of SARS-CoV-2 treatment effects for informed drug repurposing, Front Pharmacol
Kim, Modelling SARS-CoV-2 Dynamics: Implications for Therapy, medRxiv, doi:10.1101/2020.03.23.20040493
Rambaut, Preliminary genomic characterisation of an emergent SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations
Schmith, Zhou, Lohmer, The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19, Clin Pharmacol Ther, doi:10.1002/cpt.1889
Siemieniuk, Drug treatments for covid-19: living systematic review and network meta-analysis, Bmj, doi:10.1136/bmj.m2980
Tegally, Emergence and rapid spread of a new severe acute respiratory syndromerelated coronavirus 2 (SARS-CoV-2) lineage with multiple spike mutations in South Africa, medrXiv, doi:10.1101/2020.12.21.20248640
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