Use of ivermectin and nitazoxanide for treatment and prophylaxis of COVID-19: A systematic review

Authors

DOI:

https://doi.org/10.33448/rsd-v11i8.31090

Keywords:

COVID-19; Pre-Exposure Prophylaxis; Systematic Review; Antiparasitic Agents; Therapeutics.

Abstract

Purpose: Systematically review the scientific literature on evidence on the use of ivermectin and nitazoxanide as treatment and prophylaxis for COVID-19. Methodology: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). PubMed, Lilacs, and SciELO databases were searched on October 14, 2021, to identify studies that evaluated the use of ivermectin and nitazoxanide for treatment or prophylaxis of confirmed or suspected cases of COVID-19. Results: 105 articles were retrieved, of which 9 were included for the final review, four randomized controlled trials, one nonrandomized clinical trial, one retrospective cohort, one cross-sectional study, one case series, and one case report. Most studies were from Brazil, Egypt, and Mexico, evaluated nitazoxanide, and addressed the disease treatment. Conclusions: There is no sufficiently robust scientific evidence to support treatment and/or prophylaxis with ivermectin and nitazoxanide for COVID-19. Although the results found do not indicate an increased risk of adverse events to the drugs analyzed, it should not be assumed that their use is risk-free and should be used rationally.

Author Biographies

Camila Neto Santos, Universidade Federal da Bahia

Farmacêutica graduada pela Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira. Especialista em Farmácia clínica, Hospitalar e Prescrição Farmacêutica.

João Gomes da Silva Neto, Universidade Federal da Bahia

Farmacêutico graduado pela Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira.  Especialista em Farmácia clínica, Hospitalar e Prescrição Farmacêutica.

Izabel Cristina Pereira Rocha, Universidade Federal da Bahia

Farmacêutica graduada pela Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira. Especialista em Farmácia clínica hospitalar e prescrição farmacêutica. Especialista em Saúde da Família.

Milena Soares dos Santos, Universidade Federal da Bahia

Farmacêutica com habilitação em Análises Clínicas e Saúde Pública e Bioquímica de Alimentos. Pós graduação em Ciências. Docente Adjunto do Curso de Farmácia da Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde, Campus Anísio Teixeira, Vitória da Conquista, Bahia, Brasil.

References

Baek, S., Park, S. H., Won, E., Park, Y. R., & Kim, H. J. (2015). Propensity score matching: A conceptual review for radiology researchers. Korean Journal of Radiology, 16(2), 286–296. https://doi.org/10.3348/kjr.2015.16.2.286

Blum, V. F., Cimerman, S., Hunter, J. R., Tierno, P., Lacerda, A., Soeiro, A., Cardoso, F., Bellei, N. C., Maricato, J., Mantovani, N., Vassao, M., Dias, D., Galinskas, J., Janini, L. M. R., Santos-Oliveira, J. R., Da-Cruz, A. M., & Diaz, R. S. (2021). Nitazoxanide superiority to placebo to treat moderate COVID-19 - A Pilot prove of concept randomized double-blind clinical trial. EClinicalMedicine, 37, 100981. https://doi.org/10.1016/J.ECLINM.2021.100981/ATTACHMENT/40718FF9-B710-453D-8F2D-F9C1B6BE753F/MMC2.DOCX

Brasil. Ministério da Saúde. (2021a). Boletim Epidemiológico Especial - Doença Pelo Coronavírus COVID-19. Semana Epidemiológica 8 (21 a 27/2/2021).

Brasil. Ministério da Saúde. (2021b). Coronavírus. https://covid.saude.gov.br/

Calderón, J. M., Zerón, H. M., & Padmanabhan, S. (2020). Treatment with Hydroxychloroquine vs Hydroxychloroquine + Nitazoxanide in COVID-19 patients with risk factors for poor prognosis: A structured summary of a study protocol for a randomised controlled trial. Trials, 21(1), 504. https://doi.org/10.1186/s13063-020-04448-2

Caly, L., Druce, J. D., Catton, M. G., Jans, D. A., & Wagstaff, K. M. (2020). The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Research, 178, 104787. https://doi.org/10.1016/J.ANTIVIRAL.2020.104787

Campos, D. M. O., Fulco, U. L., de Oliveira, C. B. S., & Oliveira, J. I. N. (2020). SARS-CoV-2 virus infection: Targets and antiviral pharmacological strategies. Journal of Evidence-Based Medicine, 13(4), 255–260. https://doi.org/10.1111/jebm.12414

Campos, D. M. O., Oliveira, C. B. S., Andrade, J. M. A., & Oliveira, J. I. N. (2020). Fighting COVID-19. Brazilian Journal of Biology = Revista Brasleira de Biologia, 80(3), 698–701. https://doi.org/10.1590/1519-6984.238155

Castro-De-Araujo, F. L. S., Agostino, S., Grassi, M. F. R. G., & Teixeira, M. G. (2020). Aspectos clínicos e terapêuticos da infecção da COVID-19. Rede COVIDA.

Chahla, R. E., Medina Ruiz, L., Ortega, E. S., Morales, Rn, M. F., Barreiro, F., George, A., Mancilla, Rn, C., D’Amato, Rn, S., Barrenechea, G., Goroso, D. G., Peral de Bruno, M., Morales Rn, M. F., Barreiro, F., George, A., Mancilla Rn, C., D’Amato Rn, S., Barrenechea, G., Goroso, D. G., & Peral de Bruno, M. (2021). Intensive Treatment With Ivermectin and Iota-Carrageenan as Pre-exposure Prophylaxis for COVID-19 in Health Care Workers From Tucuman, Argentina. American Journal of Therapeutics, 28(5), e601–e604. https://doi.org/10.1097/MJT.0000000000001433

Chérrez-Ojeda, I., Vanegas, E., & Felix, M. (2020). The unusual experience of managing a severe COVID-19 case at home: what can we do and where do we go? BMC Infectious Diseases, 20(1), 862. https://doi.org/10.1186/s12879-020-05608-0

Chitsike, L., & Duerksen-Hughes, P. (2021). Keep out! SARS-CoV-2 entry inhibitors: their role and utility as COVID-19 therapeutics. Virol J, 18(1), 154.

Cicka, D., & Sukhatme, V. P. (2021). Available drugs and supplements for rapid deployment for treatment of COVID-19. Journal of Molecular Cell Biology, 13(3), 232–236. https://doi.org/10.1093/JMCB/MJAB002

Duru, C. E., Umar, H. I. U., Duru, I. A., Enenebeaku, U. E., Ngozi-Olehi, L. C., & Enyoh, C. E. (2021). Blocking the interactions between human ACE2 and coronavirus spike glycoprotein by selected drugs: a computational perspective. Environmental Analysis Health and Toxicology, 36(2), e2021010. https://doi.org/10.5620/eaht.2021010

Elalfy, H., Besheer, T., El-Mesery, A., El-Gilany, A.-H. H., Soliman, M. A.-A. A., Alhawarey, A., Alegezy, M., Elhadidy, T., Hewidy, A. A., Zaghloul, H., Neamatallah, M. A. M., Raafat, D., El-Emshaty, W. M., Abo El Kheir, N. Y., & El-Bendary, M. (2021). Effect of a combination of nitazoxanide, ribavirin, and ivermectin plus zinc supplement (MANS.NRIZ study) on the clearance of mild COVID-19. Journal of Medical Virology, 93(5), 3176–3183. https://doi.org/10.1002/jmv.26880

García-Álvarez, J. L., & García-Vigil, J. L. (2020). Guidelines for clinical management of SARS-CoV-2 infection. Gaceta Medica de Mexico, 156(6), 576–583. https://doi.org/10.24875/GMM.M21000461

Institute of Medicine and National Research Council. (2005). Categories of Scientific Evidence—In Vitro Data. In Dietary Supplements (pp. 217–234).

Kara-Junior, N. (2014). Definition of population and randomization of sample in clinic surveys. Revista Brasileira de Oftalmologia, 73(2), 67–68. https://doi.org/10.5935/0034-7280.20140015

Kelleni, M. T. (2020). Nitazoxanide/azithromycin combination for COVID-19: A suggested new protocol for early management. Pharmacological Research, 157, 104874. https://doi.org/10.1016/J.PHRS.2020.104874

Kelleni, M. T. (2021). NSAIDs/nitazoxanide/azithromycin repurposed for COVID-19: potential mitigation of the cytokine storm interleukin-6 amplifier via immunomodulatory effects. Expert Review of Anti-Infective Therapy, 1–5. https://doi.org/10.1080/14787210.2021.1939683

Lisi, L., Lacal, P. M., Barbaccia, M. L., & Graziani, G. (2020). Approaching coronavirus disease 2019: Mechanisms of action of repurposed drugs with potential activity against SARS-CoV-2. Biochem Pharmacol, 180, 114169. https://doi.org/10.1016/J.BCP.2020.114169

Longo, D. L., Fauci, A. S., Kasper, D. L., Hauser, S. L., Jameson, J. L., & Loscalzo, J. (2013). Medicina de Harrison (18a ed). AMGH Editora.

López, K. Y. E., Calderón, J. M., Ávila, L. de la C., Esquivel, M. Á. L., Figueroa, J. M., Contreras, M. J. V., Herrera, J. A., Martínez, O. R. S., López, J. A. M., Zerón, H. M., Enríquez López, K. Y., Meneses Calderón, J., de la Cruz Ávila, L., López Esquivel, M. Á., Meneses Figueroa, J., Vargas Contreras, M. J., Anaya Herrera, J., Sotelo Martínez, O. R., Mendoza López, J. A., & Mendieta Zerón, H. (2021). Evolution of COVID-19 Pregnancies Treated With Nitazoxanide in a Third-Level Hospital. Cureus, 13(5), e15002. https://doi.org/10.7759/CUREUS.15002

Manja, V., & Lakshminrusimha, S. (2014). Epidemiology and Clinical Research Design, Part 1: Study Types. Neoreviews, 15(12), e558–e569. https://doi.org/10.1542/NEO.15-12-E558

Martins-Filho, P. R., Barreto-Alves, J. A., & Fakhouri, R. (2020). The Pathophysiology of COVID-19 and SARS-CoV-2 Infection: Potential role for nitazoxanide in treating SARS-CoV-2 infection. American Journal of Physiology - Lung Cellular and Molecular Physiology, 319(1), L35. https://doi.org/10.1152/AJPLUNG.00170.2020

Meneses Calderón, J., Figueroa Flores, M. D. R., Paniagua Coria, L., Briones Garduño, J. C., Meneses Figueroa, J., Vargas Contretas, M. J., de la Cruz Ávila, L., Díaz Meza, S., Ramírez Chacón, R., Padmanabhan, S., Mendieta Zerón, H., Calderón, J. M., del Rocío, del R. F., Coria, L. P., Briones Garduño, J. C., Figueroa, J. M., Vargas Contreras, M. J., de la Cruz Ávila, L., Meza, S. D., … Zerón, H. M. (2020). Nitazoxanide against COVID-19 in three explorative scenarios. Journal of Infection in Developing Countries, 14(9), 982–986. https://doi.org/10.3855/jidc.13274

Morgan, C. J. (2018). Reducing bias using propensity score matching. Journal of Nuclear Cardiology, 25(2), 404–406. https://doi.org/10.1007/s12350-017-1012-y

Morgenstern, J., Redondo, J. N., Olavarria, A., Rondon, I., Roca, S., De Leon, A., Canela, J., Tavares, J., Minaya, M., Lopez, O., Castillo, A., Placido, A., Cruz, R., Merette, Y., Toribio, M., Francisco, J., Leon, A. De, Canela, J., Tavares, J., … Francisco, J. (2021). Ivermectin as a SARS-CoV-2 Pre-Exposure Prophylaxis Method in Healthcare Workers: A Propensity Score-Matched Retrospective Cohort Study. Cureus, 13(8), e17455. https://doi.org/10.7759/cureus.17455

Mostafa, A., Kandeil, A., Elshaier, Y. A. M. M., Kutkat, O., Moatasim, Y., Rashad, A. A., Shehata, M., Gomaa, M. R., Mahrous, N., Mahmoud, S. H., GabAllah, M., Abbas, H., Taweel, A. El, Kayed, A. E., Kamel, M. N., Sayes, M. El, Mahmoud, D. B., El-Shesheny, R., Kayali, G., … Ali, M. A. (2020). FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2. Pharmaceuticals, 13(12), 443. https://doi.org/10.3390/ph13120443

Olagunju, A., Fowotade, A., Olagunoye, A., Ojo, T. O., Adefuye, B. O., Fagbamigbe, A. F., Adebiyi, A. O., Olagunju, O. I., Ladipo, O. T., Akinloye, A., Adeagbo, B. A., Onayade, A., Bolaji, O. O., Happi, C., Rannard, S., & Owen, A. (2021). Efficacy and safety of nitazoxanide plus atazanavir/ritonavir for the treatment of moderate to severe COVID-19 (NACOVID): A structured summary of a study protocol for a randomised controlled trial. Trials, 22(1), 3. https://doi.org/10.1186/s13063-020-04987-8

Organização Pan-Americana da Saúde. (n.d.). Folha informativa sobre COVID-19. https://www.paho.org/pt/covid19

Page, M. J., McKenzie, J. E., Bossuyt, P. M., Boutron, I., Hoffmann, T. C., Mulrow, C. D., Shamseer, L., Tetzlaff, J. M., Akl, E. A., Brennan, S. E., Chou, R., Glanville, J., Grimshaw, J. M., Hróbjartsson, A., Lalu, M. M., Li, T., Loder, E. W., Mayo-Wilson, E., McDonald, S., … Moher, D. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. Systematic Reviews, 10(1), 89. https://doi.org/10.1136/bmj.n71

Paumgartten, F. J. R., de Oliveira, A. C. A. X., & Oliveira, A. C. A. X. de. (2020). Off label, compassionate and irrational use of medicines in Covid-19 pandemic, health consequences and ethical issues. Ciencia & Saude Coletiva, 25(9), 3413–3419. https://doi.org/10.1590/1413-81232020259.16792020

Rajoli, R. K. R. K., Pertinez, H., Arshad, U., Box, H., Tatham, L., Curley, P., Neary, M., Sharp, J., Liptrott, N. J., Valentijn, A., David, C., Rannard, S. P., Aljayyoussi, G., Pennington, S. H., Hill, A., Boffito, M., Ward, S. A., Khoo, S. H., Bray, P. G., … Owen, A. (2020). Dose prediction for repurposing nitazoxanide in SARS-CoV-2 treatment or chemoprophylaxis. MedRxiv : The Preprint Server for Health Sciences. https://doi.org/10.1101/2020.05.01.20087130

Ribeiro, T. B., Mazotti, T. A., Silva, N. A. de O., Stein, A. T., Diaz-Quijano, F. A., & de Melo, D. O. (2021). Avaliação da resposta inicial de desenvolvimento de ensaios clínicos para COVID-19 no Brasil. Revista Brasileira de Epidemiologia, 23, 1–13. https://doi.org/10.1590/1980-549720200104

Rocco, P. R. M., Silva, P. L., Cruz, F. F., Melo, M. A. C., Tierno, P. F. G. M. M., Moura, M. A., de Oliveira, L. F. G., Lima, C. C., Dos Santos, E. A., Junior, W. F., Fernandes, A. P. S. M., Franchini, K. G., Magri, E., de Moraes, N. F., Gonçalves, J. M. J., Carbonieri, M. N., Dos Santos, I. S., Paes, N. F., Maciel, P. V. M., … e Silva, J. R. L. (2021). Early use of nitazoxanide in mild COVID-19 disease: randomised, placebo-controlled trial. European Respiratory Journal, 58(1). https://doi.org/10.1183/13993003.03725-2020

Sayed, A. M., Khalaf, A. M., Abdelrahim, M. E. A. A., & Elgendy, M. O. (2021). Repurposing of some anti-infective drugs for COVID-19 treatment: A surveillance study supported by an in silico investigation. International Journal of Clinical Practice, 75(4), e13877. https://doi.org/10.1111/IJCP.13877

Stawicki, S., Jeanmonod, R., Miller, A., Paladino, L., Gaieski, D., Yaffee, A., De Wulf, A., Grover, J., Papadimos, T., Bloem, C., Galwankar, S., Chauhan, V., Firstenberg, M., DI Somma, S., Jeanmonod, D., Garg, S., Tucci, V., Anderson, H., Fatimah, L., … Garg, M. (2020). The 2019–2020 Novel Coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) Pandemic: A Joint American College of Academic International Medicine-World Academic Council of Emergency Medicine Multidisciplinary COVID-19 Working Group Consensus Paper. Journal of Global Infectious Diseases, 12(2), 47. https://doi.org/10.4103/JGID.JGID_86_20

Tura, B. R., Souza e Silva, N. A., Pereira, B. de B., Rangel Tura, B., & Albuquerque de Souza Silva, N. (2003). Avaliação crítica e limitações dos ensaios clínicos. Rev SOCERJ, 16(2), 110–123.

Wang, M., Cao, R., Zhang, L., Yang, X., Liu, J., Xu, M., Shi, Z., Hu, Z., Zhong, W., & Xiao, G. (2020). Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 30(3), 269–271. https://doi.org/10.1038/s41422-020-0282-0

World Health Organization. (2020). Situation Report-51. https://www.who.int/docs/default-source/coronaviruse/situation-reports/20200311-sitrep-51-covid-19.pdf?sfvrsn=1ba62e57_10

Downloads

Published

25/06/2022

How to Cite

SANTOS, C. N.; SILVA NETO, J. G. da; ROCHA, I. C. P.; SANTOS, M. S. dos. Use of ivermectin and nitazoxanide for treatment and prophylaxis of COVID-19: A systematic review. Research, Society and Development, [S. l.], v. 11, n. 8, p. e43511831090, 2022. DOI: 10.33448/rsd-v11i8.31090. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/31090. Acesso em: 19 nov. 2024.

Issue

Vol. 11 No. 8

Section

Review Article

License

Copyright (c) 2022 Camila Neto Santos; João Gomes da Silva Neto; Izabel Cristina Pereira Rocha; Milena Soares dos Santos

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Authors who publish with this journal agree to the following terms:

1) Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.

2) Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.

3) Authors are permitted and encouraged to post their work online (e.g., in institutional repositories or on their website) prior to and during the submission process, as it can lead to productive exchanges, as well as earlier and greater citation of published work.