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Potential role for nitazoxanide in treating SARS-CoV-2 infection
2020; American Physical Society; Volume: 319; Issue: 1 Linguagem: Inglês
10.1152/ajplung.00170.2020
ISSN1522-1504
AutoresPaulo Ricardo Martins‐Filho, José Antônio Barreto-Alves, Ricardo Fakhouri,
Tópico(s)Long-Term Effects of COVID-19
ResumoLetter to the EditorThe Pathophysiology of COVID-19 and SARS-CoV-2 InfectionPotential role for nitazoxanide in treating SARS-CoV-2 infectionPaulo Ricardo Martins-Filho, José Antônio Barreto-Alves, and Ricardo FakhouriPaulo Ricardo Martins-FilhoInvestigative Pathology Laboratory, Federal University of Sergipe, Aracaju, Brazil, José Antônio Barreto-AlvesDepartment of Nursing, Federal University of Sergipe, Aracaju, Brazil, and Ricardo FakhouriDepartment of Medicine, Federal University of Sergipe, Aracaju, BrazilPublished Online:17 Jun 2020https://doi.org/10.1152/ajplung.00170.2020MoreSectionsPDF (57 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat to the editor: Until specific and effective antiviral therapies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) become available, the management of coronavirus disease (COVID-19) is primarily based on supportive care and treatment of complications. On April 13, 2020, Sanders et al. (7) published in the Journal of the American Medical Association a comprehensive review summarizing current evidence regarding major proposed treatments, repurposed or experimental, for COVID-19. Despite that remdesivir seems to be the most promising antiviral agent in ongoing randomized trials, the authors mentioned nitazoxanide as a potential treatment option for SARS-CoV-2.Nitazoxanide is an FDA-approved drug for the treatment of parasite-mediated infectious diarrhea and enteritis with a favorable safety profile. However, this thiazolide antimicrobial agent has been considered a prospective candidate for viral respiratory infections. A previous study (1) with cell cultures found that nitazoxanide may have antiviral effects by depleting ATP-sensitive intracellular Ca2+ stores leading to phosphorylation of protein kinase R (PKR) and eukaryotic translation initiation factor 2α (eIF2α), downregulation of cellular translation machinery, and impairment of viral reproduction and spread. It has been found that SARS-CoV envelope (E) protein induces ionic disturbances especially related to Ca2+ homeostasis with important consequences on cell physiology and overproduction of proinflammatory cytokines (5). Moreover, existing literature suggested a potential role for nitazoxanide in treating Middle East respiratory syndrome (MERS)-CoV infection (6) and suppression of interleukin-6 (IL-6) production in mice (4). Hypothetically, nitazoxanide can have a potential antiviral effect and can influence host immune responses against SARS-CoV-2.Efficacy results of nitazoxanide in humans with respiratory infections are limited to a small number of trials and the results are contrasting. In a double-blind, randomized, placebo-controlled, phase 2b/3 trial (3) enrolling 624 participants aged 12–65 years with influenza-like illness, it was shown that 600 mg nitazoxanide twice daily for 5 days decreased the time from first dose to alleviation of symptoms compared with placebo with a low rate of severe adverse events (4%). In addition, a significant reduction of viral titers was recorded during the treatment. Recently, contrasting findings were reported in a small phase 2 clinical study (2) evaluating hospital discharge for patients with severe acute respiratory illness treated with nitazoxanide. However, the need for ongoing hospitalization may be driven by factors other than respiratory symptoms. To date, 10 clinical trials protocols are registered in the ClinicalTrials.gov evaluating the effects of nitazoxanide in the treatment of COVID-19 but preliminary results have not yet been reported.Although theoretical considerations are reasonable and there is potential for in vitro activity against coronaviruses, controlled clinical trials evaluating the safety and efficacy of nitazoxanide as a potential antiviral treatment of COVID-19 are still lacking. High-quality trial evidence on nitazoxanide in the treatment of SARS-CoV-2 infection is urgently needed.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the authors.AUTHOR CONTRIBUTIONSP.R.M.-F. drafted manuscript; P.R.M.-F., J.A.B.-A., and R.F. edited and revised manuscript; P.R.M.-F., J.A.B.-A., and R.F. approved final version of manuscript.REFERENCES1. Ashiru O, Howe JD, Butters TD. Nitazoxanide, an antiviral thiazolide, depletes ATP-sensitive intracellular Ca2+ stores. Virology 462-463: 135–148, 2014. doi:10.1016/j.virol.2014.05.015. Crossref | PubMed | Web of Science | Google Scholar2. Gamiño-Arroyo AE, Guerrero ML, McCarthy S, Ramírez-Venegas A, Llamosas-Gallardo B, Galindo-Fraga A, Moreno-Espinosa S, Roldán-Aragón Y, Araujo-Meléndez J, Hunsberger S, Ibarra-González V, Martínez-López J, García-Andrade LA, Kapushoc H, Holley HP, Smolskis MC, Ruiz-Palacios GM, Beigel JH, Guerrero ML, Gamiño-Arroyo AE, Ramírez-Venegas A, Bautista N, Nolasco-Reza A, Llamosas-Gallardo B, Ortiz-Hernández AA, Andrade-Platas D, Estevez-Jimenez J, Galindo-Fraga A, Roa-Martínez B, Cruz-Gaona I, Aguilar-Cruz D, Moreno-Espinosa S, González-Matus M, Mendoza-Garcés L, Araujo-Meléndez J, Perea-Guzmán N, Sandoval-Gutiérrez A, Hernández-Ramírez D, Hernández-Sánchez PG, Roldán-Aragón YA, Davila-Cruz AN, Ibarra-González V, Martínez-López J, García-Andrade LA, Ruiz-Palacios GM, Beigel JH, Smolskis M, Hunsberger S, Sean McCarthy H, Grue L, Burge G, Cox R, Holley P Jr, Cristillo A, Nahed N, López W, Becerril-Ruiz EX, Quidgley P, Arroyo-Figueroa H; Mexico Emerging Infectious Diseases Clinical Research Network (LaRed). Efficacy and safety of nitazoxanide in addition to standard of care for the treatment of severe acute respiratory illness. Clin Infect Dis 69: 1903–1911, 2019. doi:10.1093/cid/ciz100. Crossref | PubMed | Web of Science | Google Scholar3. Haffizulla J, Hartman A, Hoppers M, Resnick H, Samudrala S, Ginocchio C, Bardin M, Rossignol J-F; US Nitazoxanide Influenza Clinical Study Group. Effect of nitazoxanide in adults and adolescents with acute uncomplicated influenza: a double-blind, randomised, placebo-controlled, phase 2b/3 trial. Lancet Infect Dis 14: 609–618, 2014. doi:10.1016/S1473-3099(14)70717-0. Crossref | PubMed | Web of Science | Google Scholar4. Hong SK, Kim HJ, Song CS, Choi IS, Lee JB, Park SY. Nitazoxanide suppresses IL-6 production in LPS-stimulated mouse macrophages and TG-injected mice. Int Immunopharmacol 13: 23–27, 2012. doi:10.1016/j.intimp.2012.03.002. Crossref | PubMed | Web of Science | Google Scholar5. Nieto-Torres JL, Verdiá-Báguena C, Jimenez-Guardeño JM, Regla-Nava JA, Castaño-Rodriguez C, Fernandez-Delgado R, Torres J, Aguilella VM, Enjuanes L. Severe acute respiratory syndrome coronavirus E protein transports calcium ions and activates the NLRP3 inflammasome. Virology 485: 330–339, 2015. doi:10.1016/j.virol.2015.08.010. Crossref | PubMed | Web of Science | Google Scholar6. Rossignol JF. Nitazoxanide, a new drug candidate for the treatment of Middle East respiratory syndrome coronavirus. J Infect Public Health 9: 227–230, 2016. doi:10.1016/j.jiph.2016.04.001. Crossref | PubMed | Web of Science | Google Scholar7. Sanders JM, Monogue ML, Jodlowski TZ, Cutrell JB. Pharmacologic treatments for coronavirus disease 2019 (COVID-19): a review. JAMA 323: 1824–1836, 2020. doi:10.1001/jama.2020.6019. Crossref | PubMed | Web of Science | Google ScholarAUTHOR NOTESCorrespondence: P. R. Martins-Filho (martins-filho@ufs.br). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation CollectionsAPS Cross-Journal CollectionsCoronavirus-Related PapersAJP-Lung CollectionsThe Pathophysiology of COVID-19 and SARS-CoV-2 Infection More from this issue > Volume 319Issue 1July 2020Pages L35-L36 Copyright & PermissionsCopyright © 2020 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00170.2020PubMed33496642History Received 23 April 2020 Accepted 22 May 2020 Published online 17 June 2020 Published in print 1 July 2020 Metrics
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