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Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19

Kory et al., American Journal of Therapeutics, doi:10.1097/MJT.0000000000001377
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 105 studies, recognized in 23 countries.
No treatment is 100% effective. Protocols combine treatments.
5,100+ studies for 110 treatments. c19ivm.org
Review of ivermectin trials and epidemiological data, concluding that ivermectin is effective for prophylaxis and treatment, and should be globally and systematically deployed in the prevention and treatment of COVID-19.
An update notes potentially inaccurate data collection and/or reporting in some sources1.
Reviews covering ivermectin for COVID-19 include2-46.
Kory et al., 30 Apr 2021, peer-reviewed, 5 authors.
This PaperIvermectinAll
Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19
MD Pierre Kory, MD Gianfranco Umberto Meduri, MD Joseph Varon, DO Jose Iglesias, MD Paul E Marik, Jose Iglesias Analysis
Background: After COVID-19 emerged on U.S shores, providers began reviewing the emerging basic science, translational, and clinical data to identify potentially effective treatment options. In addition, a multitude of both novel and repurposed therapeutic agents were used empirically and studied within clinical trials. Areas of Uncertainty: The majority of trialed agents have failed to provide reproducible, definitive proof of efficacy in reducing the mortality of COVID-19 with the exception of corticosteroids in moderate to severe disease. Recently, evidence has emerged that the oral antiparasitic agent ivermectin exhibits numerous antiviral and anti-inflammatory mechanisms with trial results reporting significant outcome benefits. Given some have not passed peer review, several expert groups including Unitaid/World Health Organization have undertaken a systematic global effort to contact all active trial investigators to rapidly gather the data needed to grade and perform meta-analyses. Data Sources: Data were sourced from published peer-reviewed studies, manuscripts posted to preprint servers, expert meta-analyses, and numerous epidemiological analyses of regions with ivermectin distribution campaigns. Therapeutic Advances: A large majority of randomized and observational controlled trials of ivermectin are reporting repeated, large magnitude improvements in clinical outcomes. Numerous prophylaxis trials demonstrate that regular ivermectin use leads to large reductions in transmission. Multiple, large "natural experiments" occurred in regions that initiated "ivermectin distribution" campaigns followed by tight, reproducible, temporally associated decreases in case counts and case fatality rates compared with nearby regions without such campaigns. Conclusions: Meta-analyses based on 18 randomized controlled treatment trials of ivermectin in COVID-19 have found large, statistically significant reductions in mortality, time to clinical recovery, and time to viral clearance. Furthermore, results from numerous controlled prophylaxis trials report significantly
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'volume': '94', 'author': 'King', 'year': '2020', 'journal-title': 'J Virol.'}, { 'key': 'R18-20230917', 'doi-asserted-by': 'crossref', 'first-page': '104787', 'DOI': '10.1016/j.antiviral.2020.104787', 'article-title': 'The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 ' 'in vitro', 'volume': '178', 'author': 'Caly', 'year': '2020', 'journal-title': 'Antivir Res'}, { 'key': 'R19-20230917', 'doi-asserted-by': 'crossref', 'first-page': '104805', 'DOI': '10.1016/j.antiviral.2020.104805', 'article-title': 'Ivermectin and COVID-19: a report in Antiviral Research, widespread ' "interest, an FDA warning, two letters to the editor and the authors' " 'responses', 'volume': '178', 'author': 'Bray', 'year': '2020', 'journal-title': 'Antiviral Res.'}, { 'key': 'R20-20230917', 'first-page': '214', 'article-title': 'The approved dose of ivermectin alone is not the ideal dose for the ' 'treatment of COVID‐19', 'volume': '103', 'author': 'Schmith', 'year': '2020', 'journal-title': 'Clin Pharmacol Ther.'}, { 'key': 'R21-20230917', 'article-title': 'Coronavirus (2019-nCoV) deactivation via spike glycoprotein shielding ' 'by old drugs, bioinformatic study', 'author': 'Dayer', 'year': '2020', 'journal-title': 'Preprints'}, { 'key': 'R22-20230917', 'article-title': 'A combination of ivermectin and doxycycline possibly blocks the viral ' 'entry and modulate the innate immune response in COVID-19 patients', 'author': 'Maurya', 'year': '2020', 'journal-title': 'ChemRxiv'}, { 'key': 'R23-20230917', 'doi-asserted-by': 'crossref', 'first-page': '56', 'DOI': '10.1007/s13721-020-00263-6', 'article-title': 'Molecular docking suggests repurposing of brincidofovir as a potential ' 'drug targeting SARS-CoV-2 ACE2 receptor and main protease', 'volume': '9', 'author': 'Hussien', 'year': '2020', 'journal-title': 'Netw Model Anal Health Inform Bioinform'}, { 'key': 'R26-20230917', 'doi-asserted-by': 'crossref', 'first-page': '3023', 'DOI': '10.21873/invivo.12134', 'article-title': 'Ivermectin docks to the SARS-CoV-2 spike receptor-binding domain ' 'attached to ACE2', 'volume': '34', 'author': 'Lehrer', 'year': '2020', 'journal-title': 'Vivo'}, { 'key': 'R28-20230917', 'article-title': 'Nsp7 and spike glycoprotein of SARS-CoV-2 are envisaged as potential ' 'targets of vitamin D and ivermectin', 'author': 'Dasgupta', 'year': '2020', 'journal-title': 'Preprints'}, { 'key': 'R29-20230917', 'first-page': '1', 'article-title': 'Binding mechanism and structural insights into the identified protein ' 'target of COVID-19 and importin-alpha with in-vitro effective drug ' 'ivermectin', 'author': 'Sen Gupta', 'year': '2020', 'journal-title': 'J Biomol Struct Dyn.'}, { 'key': 'R31-20230917', 'article-title': 'Ivermectin reduces coronavirus infection in vivo: a mouse experimental ' 'model', 'author': 'Arevalo', 'year': '2020', 'journal-title': 'bioRxiv'}, { 'key': 'R32-20230917', 'article-title': 'Anti-COVID-19 efficacy of ivermectin in the golden hamster', 'author': 'de Melo', 'year': '2020', 'journal-title': 'bioRxiv'}, { 'key': 'R33-20230917', 'article-title': 'SARS-CoV-2 virus culture from the upper respiratory tract: correlation ' 'with viral load, subgenomic viral RNA and duration of illness', 'author': 'Perera', 'year': '2020', 'journal-title': 'MedRXiv'}, { 'key': 'R34-20230917', 'doi-asserted-by': 'crossref', 'first-page': '2128', 'DOI': '10.1038/s41379-020-0603-3', 'article-title': 'A systematic review of pathological findings in COVID-19: a ' 'pathophysiological timeline and possible mechanisms of disease ' 'progression', 'volume': '33', 'author': 'Polak', 'year': '2020', 'journal-title': 'Mod Pathol.'}, { 'key': 'R35-20230917', 'article-title': 'Viral dynamics and immune correlates of COVID-19 disease severity', 'author': 'Young', 'year': '2020', 'journal-title': 'Clin Infect Dis.'}, { 'key': 'R36-20230917', 'doi-asserted-by': 'crossref', 'first-page': '88', 'DOI': '10.1016/j.micinf.2012.10.008', 'article-title': 'Extraordinary GU-rich single-strand RNA identified from SARS ' 'coronavirus contributes an excessive innate immune response', 'volume': '15', 'author': 'Li', 'year': '2013', 'journal-title': 'Microbes Infect.'}, { 'key': 'R37-20230917', 'doi-asserted-by': 'crossref', 'first-page': '354', 'DOI': '10.1016/j.intimp.2008.12.016', 'article-title': 'Inhibitory effects of ivermectin on nitric oxide and prostaglandin E2 ' 'production in LPS-stimulated RAW 264.7 macrophages', 'volume': '9', 'author': 'Zhang', 'year': '2009', 'journal-title': 'Int Immunopharmacol'}, { 'key': 'R38-20230917', 'doi-asserted-by': 'crossref', 'first-page': '449', 'DOI': '10.1111/j.1472-8206.2009.00684.x', 'article-title': 'Avermectin exerts anti-inflammatory effect by downregulating the ' 'nuclear transcription factor kappa-B and mitogen-activated protein ' 'kinase activation pathway', 'volume': '23', 'author': 'Ci', 'year': '2009', 'journal-title': 'Fundam Clin Pharmacol.'}, { 'key': 'R39-20230917', 'doi-asserted-by': 'crossref', 'first-page': '524', 'DOI': '10.1007/s00011-008-8007-8', 'article-title': 'Ivermectin inhibits LPS-induced production of inflammatory cytokines ' 'and improves LPS-induced survival in mice', 'volume': '57', 'author': 'Zhang', 'year': '2008', 'journal-title': 'Inflamm Res.'}, { 'key': 'R41-20230917', 'article-title': 'Role of ivermectin in the prevention of COVID-19 infection among ' 'healthcare workers in India: a matched case-control study', 'author': 'Behera', 'year': '2020', 'journal-title': 'medRxiv'}, { 'key': 'R42-20230917', 'doi-asserted-by': 'crossref', 'first-page': '106248', 'DOI': '10.1016/j.ijantimicag.2020.106248', 'article-title': 'A COVID-19 Prophylaxis? Lower incidence associated with prophylactic ' 'administration of Ivermectin', 'volume': '57', 'author': 'Hellwig', 'year': '2021', 'journal-title': 'Int J Antimicrob Agents'}, { 'key': 'R46-20230917', 'first-page': 'NCT04701710', 'article-title': 'Covid-19 in healthcare agents by intensive treatment with ivermectin ' 'and iota-carrageenan (Ivercar-Tuc)', 'author': 'Prophylaxis', 'year': '2020', 'journal-title': 'ClinicalTrials.gov'}, { 'key': 'R47-20230917', 'first-page': '1', 'article-title': 'Ivermectin as pre-exposure prophylaxis for COVID 19 among healthcare ' 'providers in a selected tertiary hospital in Dhaka an observational ' 'study', 'volume': '2', 'author': 'Alam', 'year': '2020', 'journal-title': 'Eur J Med Health Sci.'}, { 'key': 'R50-20230917', 'article-title': 'Safety and Efficacy of the combined use of ivermectin, dexamethasone, ' 'enoxaparin and aspirin against COVID-19', 'author': 'Carvallo', 'year': '2020', 'journal-title': 'medRxiv'}, { 'key': 'R51-20230917', 'doi-asserted-by': 'crossref', 'first-page': '828', 'DOI': '10.1016/j.arbres.2020.08.007', 'article-title': 'Ivermectin treatment may improve the prognosis of patients with ' 'COVID-19', 'volume': '56', 'author': 'Khan', 'year': '2020', 'journal-title': 'Archivos de Bronconeumología'}, { 'key': 'R52-20230917', 'article-title': 'Effectiveness of ivermectin as add-on therapy in COVID-19 management ' '(pilot trial)', 'author': 'Gorial', 'year': '2020', 'journal-title': 'medRxiv'}, { 'key': 'R53-20230917', 'article-title': 'Controlled randomized clinical trial on using Ivermectin with ' 'Doxycycline for treating COVID-19 patients in Baghdad, Iraq', 'author': 'Hashim', 'year': '2020', 'journal-title': 'medRxiv'}, { 'key': 'R55-20230917', 'first-page': '1', 'article-title': 'Outcome of ivermectin treated mild to moderate COVID-19 cases: a ' 'single-centre, open-label, randomised controlled study', 'volume': '14', 'author': 'Podder', 'year': '2020', 'journal-title': 'IMC J Med Sci.'}, { 'key': 'R56-20230917', 'article-title': 'Early COVID-19 therapy with azithromycin plus nitazoxanide, ivermectin ' 'or hydroxychloroquine in outpatient settings significantly reduced ' 'symptoms compared to known outcomes in untreated patients', 'author': 'Cadegiani', 'year': '2020', 'journal-title': 'medRxiv'}, { 'key': 'R59-20230917', 'article-title': 'Ivermectin shows clinical benefits in mild to moderate Covid19 disease: ' 'a randomised controlled double blind dose response study in Lagos', 'author': 'Babalola', 'year': '2021', 'journal-title': 'medRxiv'}, { 'key': 'R60-20230917', 'article-title': 'Ivermectin as a potential treatment for mild to moderate COVID-19 – a ' 'double blind randomized placebo-controlled trial', 'author': 'Ravikirti', 'year': '2021', 'journal-title': 'medRxiv'}, { 'key': 'R61-20230917', 'article-title': 'The use of compassionate Ivermectin in the management of symptomatic ' 'outpatients and hospitalized patients with clinical diagnosis of ' 'COVID-19 at the Medical Center Bournigal and the Medical Center Punta ' 'Cana, Rescue Group, Dominican Republic, from may 1 to august 10, 2020', 'author': 'Morgenstern', 'year': '2020', 'journal-title': 'medRxiv'}, { 'key': 'R62-20230917', 'first-page': '10', 'article-title': 'A case series of 100 COVID-19 positive patients treated with ' 'combination of ivermectin and doxycycline', 'volume': '38', 'author': 'Robin', 'year': '2020', 'journal-title': 'J Bangladesh Coll Physicians Surgeons'}, { 'key': 'R63-20230917', 'doi-asserted-by': 'crossref', 'first-page': '85', 'DOI': '10.1016/j.chest.2020.10.009', 'article-title': 'Use of ivermectin is associated with lower mortality in hospitalized ' 'patients with COVID-19 (ICON study)', 'volume': '159', 'author': 'Rajter', 'year': '2021', 'journal-title': 'Chest'}, { 'key': 'R64-20230917', 'first-page': '177', 'article-title': 'Utility of ivermectin and doxycycline combination for the treatment of ' 'SARS-CoV2', 'volume': '7', 'author': 'Spoorthi', 'year': '2020', 'journal-title': 'Int Arch Integrated Med.'}, { 'key': 'R66-20230917', 'doi-asserted-by': 'crossref', 'first-page': '831', 'DOI': '10.1016/j.arbres.2020.06.011', 'article-title': 'Antiviral and anti-inflammatory properties of ivermectin and its ' 'potential use in covid-19', 'volume': '56', 'author': 'Portmann-Baracco', 'year': '2020', 'journal-title': 'Arch Bronconeumol'}, { 'key': 'R67-20230917', 'doi-asserted-by': 'crossref', 'first-page': '214', 'DOI': '10.1016/j.ijid.2020.11.191', 'article-title': 'A five day course of ivermectin for the treatment of COVID-19 may ' 'reduce the duration of illness', 'volume': '103', 'author': 'Ahmed', 'year': '2021', 'journal-title': 'Int J Infect Dis.'}, { 'key': 'R68-20230917', 'first-page': '31', 'article-title': 'Effectiveness of ivermectin in SARS-CoV-2/COVID-19 patients', 'volume': '9', 'author': 'Chachar', 'year': '2020', 'journal-title': 'Int J Sci.'}, { 'key': 'R70-20230917', 'article-title': 'Clinical Profile of First 1000 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'first-page': '325', 'article-title': 'Over 25 Years of clinical experience with ivermectin: an overview of ' 'safety for an increasing number of indications', 'volume': '15', 'author': 'Kircik', 'year': '2016', 'journal-title': 'J Drugs Dermatol.'}, { 'key': 'R76-20230917', 'doi-asserted-by': 'crossref', 'first-page': '18', 'DOI': '10.1016/S0140-6736(96)11094-1', 'article-title': 'Serious reactions after mass treatment of onchocerciasis with ' 'ivermectin in an area endemic for Loa loa infection', 'volume': '350', 'author': 'Gardon', 'year': '1997', 'journal-title': 'Lancet'}, { 'key': 'R77-20230917', 'doi-asserted-by': 'crossref', 'first-page': '1122', 'DOI': '10.1177/009127002237994', 'article-title': 'Safety, tolerability, and pharmacokinetics of escalating high doses of ' 'ivermectin in healthy adult subjects', 'volume': '42', 'author': 'Guzzo', 'year': '2002', 'journal-title': 'J Clin Pharmacol.'}, { 'key': 'R78-20230917', 'doi-asserted-by': 'crossref', 'first-page': '795', 'DOI': '10.1016/j.trstmh.2006.02.003', 'article-title': 'First case of ivermectin-induced severe hepatitis', 'volume': '100', 'author': 'Veit', 'year': '2006', 'journal-title': 'Trans R Soc Trop Med Hyg.'}, { 'key': 'R79-20230917', 'first-page': '784', 'article-title': 'Systemic adverse reactions with ivermectin treatment of scabies', 'volume': '133', 'author': 'Sparsa', 'year': '2006'}, { 'key': 'R80-20230917', 'doi-asserted-by': 'crossref', 'first-page': '382', 'DOI': '10.4269/ajtmh.17-0042', 'article-title': 'Serious neurological adverse events after ivermectin—do they occur ' 'beyond the indication of onchocerciasis?', 'volume': '98', 'author': 'Chandler', 'year': '2018', 'journal-title': 'Am J Trop Med Hyg.'}, { 'key': 'R81-20230917', 'first-page': 'MR000034', 'article-title': 'Healthcare outcomes assessed with observational study designs compared ' 'with those assessed in randomized trials', 'author': 'Anglemyer', 'year': '2014', 'journal-title': 'Cochrane Database Syst Rev.'}, { 'key': 'R82-20230917', 'doi-asserted-by': 'crossref', 'first-page': '1893', 'DOI': '10.1093/eurheartj/ehs114', 'article-title': 'Do observational studies using propensity score methods agree with ' 'randomized trials? A systematic comparison of studies on acute coronary ' 'syndromes', 'volume': '33', 'author': 'Dahabreh', 'year': '2012', 'journal-title': 'Eur Heart J.'}, { 'key': 'R83-20230917', 'doi-asserted-by': 'crossref', 'first-page': '1870', 'DOI': '10.1097/CCM.0000000000001135', 'article-title': 'Can we trust observational studies using propensity scores in the ' 'critical care literature? A systematic comparison with randomized ' 'clinical trials', 'volume': '43', 'author': 'Kitsios', 'year': '2015', 'journal-title': 'Crit Care Med.'}, { 'key': 'R84-20230917', 'doi-asserted-by': 'crossref', 'first-page': '18', 'DOI': '10.1097/SLA.0000000000000256', 'article-title': 'Comparison of treatment effect estimates from prospective nonrandomized ' 'studies with propensity score analysis and randomized controlled trials ' 'of surgical procedures', 'volume': '259', 'author': 'Lonjon', 'year': '2014', 'journal-title': 'Ann Surg.'}], 'container-title': 'American Journal of Therapeutics', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://journals.lww.com/10.1097/MJT.0000000000001377', 'content-type': 'unspecified', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2023, 9, 17]], 'date-time': '2023-09-17T04:17:18Z', 'timestamp': 1694924238000}, 'score': 1, 'resource': {'primary': {'URL': 'https://journals.lww.com/10.1097/MJT.0000000000001377'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2021, 4, 22]]}, 'references-count': 67, 'journal-issue': {'issue': '3', 'published-online': {'date-parts': [[2021]]}}, 'URL': 'http://dx.doi.org/10.1097/MJT.0000000000001377', 'relation': {}, 'ISSN': ['1075-2765'], 'subject': [], 'published': {'date-parts': [[2021, 4, 22]]}}
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Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.
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