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All Studies   Meta Analysis    Recent:   

Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations

Jitobaom et al., BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8 (date from preprint)
Jun 2022  
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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 22 countries.
No treatment is 100% effective. Protocols combine treatments. * >10% efficacy, ≥3 studies.
4,300+ studies for 75 treatments. c19ivm.org
In Vitro study showing a strong synergistic effect of combinations of ivermectin, niclosamide, and chloroquine, with >10x reduction in IC50 compared to individual drugs.
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, shows protection against inflammation, cytokine storm, and mortality in an LPS mouse model sharing key pathological features of severe COVID-1954,78, 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 system79, has immunomodulatory46 and anti-inflammatory65,80 properties, and has an extensive and very positive safety profile81.
Jitobaom et al., 18 Jun 2022, peer-reviewed, 8 authors. Contact: prasert.aue@mahidol.ac.th (corresponding author).
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperIvermectinAll
Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations
Kunlakanya Jitobaom, Chompunuch Boonarkart, Suwimon Manopwisedjaroen, Nuntaya Punyadee, Suparerk Borwornpinyo, Arunee Thitithanyanont, Panisadee Avirutnan, Prasert Auewarakul
BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8
Background: COVID-19 pandemic has claimed millions of lives and devastated the health service system, livelihood, and economy in many countries worldwide. Despite the vaccination programs in many countries, the spread of the pandemic continues, and effective treatment is still urgently needed. Although some antiviral drugs have been shown to be effective, they are not widely available. Repurposing of anti-parasitic drugs with in vitro anti-SARS-CoV-2 activity is a promising approach being tested in many clinical trials. Combination of these drugs is a plausible way to enhance their effectiveness. Methods: The in vitro anti-SARS-CoV-2 activity of combinations of niclosamide, ivermectin and chloroquine were evaluated in Vero E6 and lung epithelial cells, Calu-3. Results: All the two-drug combinations showed higher potency resulting in up to 4-fold reduction in the half maximal inhibitory concentration (IC 50 ) values compared to individual drugs. Among these combinations, niclosamideivermectin achieved the highest inhibitory level of over 99%. Combination synergy analysis showed niclosamideivermectin combination to have the best synergy score with a mean Loewe synergy score of 4.28 and a peak synergy score of 24.6 in Vero E6 cells and a mean Loewe synergy score of 3.82 and a peak synergy score of 10.86 in Calu-3 cells. Conclusions: The present study demonstrated the benefit of drug combinations on anti-SARS-CoV-2 activity. Niclosamide and ivermectin showed the best synergistic profile and should be further tested in clinical trials.
Abbreviations Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s40360-022-00580-8. Additional file 1. Authors' contributions KJ performed drug treatment experiments, viral quantifications, analysis and was a major contributor in writing and revising the manuscript. CB performed virus infection, viral quantifications, and the optimization of the plaque assay for SARS-CoV-2 and prepared virus stock. SM performed virus isolation and the optimization of the plaque assay for SARS-CoV-2. NP performed analysis and prepared drug stock solutions. SB prepared cell lines and drug stock solutions. AT designed the study and edited the manuscript. PA 3, 4 reviewed and edited the manuscript. PA 1* designed and supervised the study, performed funding acquisitions, writing, and editing the manuscript. All authors read and approved the final manuscript. Declarations Ethics approval and consent to participate Not applicable. This work does not involve the use of human subjects and animals. All the procedures do not require IRB approval. Consent for publication Not applicable. This work does not contain data from any individual person. Competing interests The authors declare that they have no competing interests. • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types •..
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Ivermectin accelerates circulating nonstructural ' 'protein 1 (NS1) clearance in adult dengue patients: a combined phase 2/3 ' 'randomized double-blinded placebo controlled trial. Clin Infect Dis. ' '2021;72:e586–93.', 'journal-title': 'Clin Infect Dis'}, { 'key': '580_CR61', 'doi-asserted-by': 'publisher', 'first-page': '873', 'DOI': '10.1016/j.ymthe.2020.12.016', 'volume': '29', 'author': 'T Bobrowski', 'year': '2021', 'unstructured': 'Bobrowski T, Chen L, Eastman RT, Itkin Z, Shinn P, Chen CZ, et al. ' 'Synergistic and antagonistic drug combinations against SARS-CoV-2. Mol ' 'Ther. 2021;29:873–85.', 'journal-title': 'Mol Ther'}], 'container-title': 'BMC Pharmacology and Toxicology', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s40360-022-00580-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s40360-022-00580-8/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s40360-022-00580-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 6, 18]], 'date-time': '2022-06-18T09:12:48Z', 'timestamp': 1655543568000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-022-00580-8'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 6, 18]]}, 'references-count': 61, 'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2022, 12]]}}, 'alternative-id': ['580'], 'URL': 'http://dx.doi.org/10.1186/s40360-022-00580-8', 'relation': {}, 'ISSN': ['2050-6511'], 'subject': ['Pharmacology (medical)', 'Pharmacology'], 'container-title-short': 'BMC Pharmacol Toxicol', 'published': {'date-parts': [[2022, 6, 18]]}, 'assertion': [ { 'value': '5 January 2022', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '9 June 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '18 June 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'Not applicable. This work does not involve the use of human subjects and ' 'animals. All the procedures do not require IRB approval.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable. This work does not contain data from any individual person.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'The authors declare that they have no competing interests.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '41'}
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