Antiviral effect of high-dose ivermectin in adults with COVID-19: A proof-of-concept randomized trial

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"author": "Matamoros", "first-page": "ciab365", "journal-title": "Clin Infect Dis", "key": "10.1016/j.eclinm.2021.100959_bib0012", "year": "2021" }, { "DOI": "10.1016/S1473-3099(20)30424-2", "article-title": "RT-PCR for SARS-CoV-2:quantitative versus qualitative", "author": "Han", "doi-asserted-by": "crossref", "first-page": "165", "issue": "2", "journal-title": "Lancet Infect Dis", "key": "10.1016/j.eclinm.2021.100959_bib0013", "volume": "21", "year": "2021" }, { "DOI": "10.1128/CMR.00074-09", "article-title": "Validation of laboratory-developed molecular assays for infectious diseases", "author": "Burd", "doi-asserted-by": "crossref", "first-page": "550", "issue": "3", "journal-title": "Clin Microbiol Rev", "key": "10.1016/j.eclinm.2021.100959_bib0014", "volume": "23", "year": "2010" }, { "DOI": "10.1373/clinchem.2008.112797", "article-title": "The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments", "author": "Bustin", "doi-asserted-by": "crossref", "first-page": "611", "issue": "4", "journal-title": "Clin Chem", "key": "10.1016/j.eclinm.2021.100959_bib0015", "volume": "55", "year": "2009" }, { "DOI": "10.1016/S0304-4017(99)00175-2", "article-title": "Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle", "author": "Lifschitz", "doi-asserted-by": "crossref", "first-page": "327", "issue": "4", "journal-title": "Vet Parasitol", "key": "10.1016/j.eclinm.2021.100959_bib0016", "volume": "87", "year": "2000" }, { "author": "Gibaldi", "key": "10.1016/j.eclinm.2021.100959_bib0017", "series-title": "Pharmacokinetics", "year": "1982" }, { "DOI": "10.1002/sim.4780132309", "article-title": "Internal pilot studies for estimating sample size", "author": "Birkett", "doi-asserted-by": "crossref", "first-page": "2455", "issue": "23–24", "journal-title": "Stat Med", "key": "10.1016/j.eclinm.2021.100959_bib0018", "volume": "13", "year": "1994" }, { "DOI": "10.1016/j.jclinepi.2012.09.002", "article-title": "Sample size calculations for pilot randomized trials: a confidence interval approach", "author": "Cocks", "doi-asserted-by": "crossref", "first-page": "197", "issue": "2", "journal-title": "J Clin Epidemiol", "key": "10.1016/j.eclinm.2021.100959_bib0019", "volume": "66", "year": "2013" }, { "author": "Cohen", "key": "10.1016/j.eclinm.2021.100959_bib0020", "series-title": "Statistical power analysis for the behavioral sciences", "year": "1988" }, { "DOI": "10.1152/ajpendo.00178.2020", "article-title": "COVID-19-associated SIADH : a clue in the times of pandemic!", "author": "Yousaf", "doi-asserted-by": "crossref", "first-page": "E882", "issue": "6", "journal-title": "Am J Physiol Endocrinol Metab", "key": "10.1016/j.eclinm.2021.100959_bib0021", "volume": "318", "year": "2020" }, { "DOI": "10.4269/ajtmh.20-0271", "article-title": "Ivermectin and COVID-19 : keeping rigor in times of urgency", "author": "Chaccour", "doi-asserted-by": "crossref", "first-page": "1156", "issue": "6", "journal-title": "Am J Trop Med Hyg", "key": "10.1016/j.eclinm.2021.100959_bib0022", "volume": "102", "year": "2020" }, { "DOI": "10.1016/j.xphs.2021.01.017", "article-title": "Safety and pharmacokinetic assessments of a novel ivermectin nasal spray formulation in a pig model", "author": "Errecalde", "doi-asserted-by": "crossref", "journal-title": "J Pharm Sci", "key": "10.1016/j.eclinm.2021.100959_bib0023", "year": "2021" }, { "DOI": "10.1016/j.xphs.2020.08.024", "article-title": "Development of a minimal physiologically-based pharmacokinetic model to simulate lung exposure in humans following oral administration of ivermectin for COVID-19 drug repurposing", "author": "Jermain", "doi-asserted-by": "crossref", "first-page": "3574", "issue": "12", "journal-title": "J Pharm Sci", "key": "10.1016/j.eclinm.2021.100959_bib0024", "volume": "109", "year": "2020" }, { "DOI": "10.1016/S0140-6736(20)31022-9", "article-title": "Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial", "author": "Wang", "doi-asserted-by": "crossref", "first-page": "1569", "issue": "10236", "journal-title": "Lancet", "key": "10.1016/j.eclinm.2021.100959_bib0025", "volume": "395", "year": "2020" }, { "DOI": "10.1016/j.eclinm.2020.100720", "article-title": "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, placebo-controlled, randomized clinical trial", "author": "Chaccour", "doi-asserted-by": "crossref", "journal-title": "EClinicalMedicine", "key": "10.1016/j.eclinm.2021.100959_bib0026", "volume": "32", "year": "2021" }, { "DOI": "10.1371/journal.pntd.0006020", "article-title": "Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers", "author": "Muñoz", "doi-asserted-by": "crossref", "issue": "1", "journal-title": "PLoS Negl Trop Dis", "key": "10.1016/j.eclinm.2021.100959_bib0027", "volume": "12", "year": "2018" }, { "article-title": "Interaction of macrocyclic lactones with P-glycoprotein : structure–affinity relationship", "author": "Lespine", "first-page": "84", "journal-title": "Eur J Pharm Sci", "key": "10.1016/j.eclinm.2021.100959_bib0028", "volume": "0", "year": "2006" }, { "DOI": "10.1111/j.1365-2885.2007.00848.x", "article-title": "Involvement of P-glycoprotein on ivermectin kinetic behaviour in sheep : itraconazole-mediated changes on gastrointestinal disposition", "author": "Ballent", "doi-asserted-by": "crossref", "first-page": "242", "journal-title": "J Vet Pharmacol Ther", "key": "10.1016/j.eclinm.2021.100959_bib0029", "year": "2007" }, { "DOI": "10.1371/journal.pone.0158237", "article-title": "How can viral dynamics models inform endpoint measures in clinical trials of therapies for acute viral infections?", "author": "Vegvari", "doi-asserted-by": "crossref", "issue": "7", "journal-title": "PLoS ONE", "key": "10.1016/j.eclinm.2021.100959_bib0030", "volume": "11", "year": "2016" }, { "DOI": "10.1371/journal.pone.0156622", "article-title": "Using clinical trial simulators to analyse the sources of variance in clinical trials of novel therapies for acute viral infections", "author": "Vegvari", "doi-asserted-by": "crossref", "issue": "6", "journal-title": "PLoS ONE", "key": "10.1016/j.eclinm.2021.100959_bib0031", "volume": "11", "year": "2016" }, { "DOI": "10.1056/NEJMoa2015294", "article-title": "Interferon beta-1b and lopinavir–ritonavir for middle east respiratory syndrome", "author": "Arabi", "doi-asserted-by": "crossref", "first-page": "1645", "issue": "17", "journal-title": "N Engl J Med", "key": "10.1016/j.eclinm.2021.100959_bib0032", "volume": "383", "year": "2020" }, { "DOI": "10.1038/s41586-020-2196-x", "article-title": "Virological assessment of hospitalized patients with COVID-2019", "author": "Wölfel", "doi-asserted-by": "crossref", "first-page": "465", "issue": "7809", "journal-title": "Nature", "key": "10.1016/j.eclinm.2021.100959_bib0033", "volume": "581", "year": "2020" }, { "DOI": "10.1038/srep16222", "article-title": "Modulation of P2X4 /P2X7 / Pannexin-1 sensitivity to extracellular ATP via Ivermectin induces a non-apoptotic and inflammatory form of cancer cell death", "author": "Draganov", "doi-asserted-by": "crossref", "first-page": "16222", "journal-title": "Sci Rep", "key": "10.1016/j.eclinm.2021.100959_bib0034", "volume": "5", "year": "2015" }, { "DOI": "10.1016/j.ijantimicag.2020.106125", "article-title": "Repurposing of host-based therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19): a link between antiviral and anticancer mechanisms?", "author": "Alonso", "doi-asserted-by": "crossref", "issue": "3", "journal-title": "Int J Antimicrob Agents", "key": "10.1016/j.eclinm.2021.100959_bib0035", "volume": "56", "year": "2020" } ], "reference-count": 35, "references-count": 35, "relation": {}, "resource": { "primary": { 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