Reposicionamiento de ivermectina frente a COVID-19: evidencias científicas que avalan su potencial preventivo y terapéutico
DOI:
https://doi.org/10.14409/favecv.v20iSuppl..10819Palabras clave:
COVID-19, Ivermectina, Reposicionamiento terapéutico, DisCoVery, Herramientas terapéuticasResumen
En el presente trabajo se presenta una revisión actualizada y esquemática de la información científica disponible sobre el efecto antiviral del fármaco ivermectina frente al SARS-CoV-2 y las propiedades farmacológicas que avalan este efecto. En el marco del reposicionamiento de fármacos, el efecto antiviral de la ivermectina contra diferentes virus ha sido estudiado en diversos modelos in vitro. Desde el punto de vista farmacodinámico, la ivermectina tendría una respuesta antiviral que podría combinar acciones sobre las células del hospedador (inhibición del transporte a través de la membrana nuclear) y efectos directos sobre blancos moleculares del propio virus. Diferentes esquemas de administración de ivermectina se han evaluado en diversos países del mundo como medida de prevención y como herramienta terapéutica contra SARS-CoV-2. Los resultados muestran efectos de ivermectina en la reducción de la carga viral, en la aceleración de la recuperación clínica y prevención del deterioro de los pacientes tratados en la etapa temprana de la enfermedad y en la disminución de la tasa de hospitalización y mortalidad.
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Afrin LB, Weinstock LB, Molderings GJ. 2020. Covid-19 hyperinflammation and post-Covid-19 illness may be rooted in mast cell activation syndrome. Int. J. Infect. Dis. 100:327-332.
Aref ZF, Bazeed SEES, Hassan MH, Hassan AS, Rashad A, Hassan RG, Abdelmaksoud AA. 2021. Clinical, Biochemical and Molecular Evaluations of Ivermectin Mucoadhesive Nanosuspension Nasal Spray in Reducing Upper Respiratory Symptoms of Mild COVID-19. Int. J. Nanomedicine. 16:4063-4072.
Bazzano AT, Mangione-Smith R, Schonlau M, Suttorp MJ, Brook RH. 2009. Off-label prescribing to children in the United States outpatient setting. Acad Pediatr. 9:81-8.
Behera P, Patro BK, Singh AK, Chandanshive PD, S R R, Pradhan SK, Pentapati SSK, Batmanabane G, Mohapatra PR, Padhy BM, Bal SK, Singh SR, Mohanty RR. 2021. Role of ivermectin in the prevention of SARS-CoV-2 infection among health care workers in India: A matched case-control study. PLoSOne. 16: e0247163. doi: 10.1371/journal.pone.0247163.
Biber A, Mandelboim M, Harmelin G, Lev D, Ram L, Shaham A, Nemet I, Kliker L, Erster O, Schwartz E. 2021 Favorable outcome on viral load and culture viability using ivermectin in early treatment of non-hospitalized patients with mild COVID-19 – A double-blind, randomized placebo-controlled trial. medRxiv 2021.05.31.21258081; doi:https://doi.org/10.1101/2021.05.31.21258081
Bryant A, Lawrie TA, Dowswell T, Fordham EJ, Mitchell S, Hill SR, Tham TC. 2021. Ivermectin for Prevention and Treatment of COVID-19 Infection: A Systematic Review, Meta-analysis, and Trial Sequential Analysis to Inform Clinical Guidelines. Am. J. Ther. doi: 10.1097/MJT.0000000000001402
Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. 2020. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral. Res. 178:104787. doi: 10.1016/j.antiviral.2020.104787.
Carvallo H, Hirsch R, Alkis P, Contreras V. 2020. Study of the Efficacy and Safety of Topical Ivermectin + Iota- Carrageenan in the Prophylaxis against COVID-19 in Health Personnel. Journal of Biomedical Research and Clinical Investigation. Volume 2 Issue 1.1007, DOI: https://doi.org/10.31546/2633-8653.1007
Chahla R, Medina Ruiz L, Mena T, Brepe Y, Terranova P, Ortega E, Barrenechea G, Goroso D, Peral de Bruno M. 2021a. Cluster Randomised Trials – Ivermectin Repurposing For COVID-19 Treatment Of Outpatients With Mild Disease In Primary Health Care Centers, Research Square https://doi.org/10.21203/rs.3.rs-495945/v1.
Chahla, R, Medina Ruiz, L., Ortega, E., Morales, M., Barreiro, F., George, A., Mancilla, C., D’ Amato, S., Barrenechea, G., Goroso, D., Peral de Bruno, M. 2021b. A randomized trial - intensive treatment based in ivermectin and iota-carrageenan as pre-exposure prophylaxis for covid- 19 in healthcare agents. medRxiv 03.26.21254398; doi:https://doi.org/10.1101/2021.03.26.21254398.
Chaccour C, Casellas A, Blanco-Di Matteo A, Pineda I, Fernandez-Montero A, Ruiz-Castillo P, Richardson MA, Rodríguez-Mateos M, Jordán-Iborra C, Brew J, Carmona-Torre F, Giráldez M, Laso E, Gabaldón-Figueira JC, Dobaño C, Moncunill G, Yuste JR, Del Pozo JL, Rabinovich NR, Schöning V, Hammann F, Reina G, Sadaba B,
Fernández-Alonso M. 2021.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. EClinical Medicine. 32:100720. doi: 10.1016/j.eclinm.2020.100720.
Chiu, S, Green, M, Baylis, F, Eline, D, Rosegay, A, Meriwether, H, Jacob. T.1990. Absorption, tissue distribution, and excretion of tritium-labelled ivermectin in cattle, sheep, and rat. J. Agric. Food Chem. 38: 2072-2078.
Chosidow O, Bernigaud C, Guillemot D, Giraudeau B, Lespine A, Changeux JP, Bourhy H, Lecuit M, Amoura Z. 2021. Ivermectin as a potential treatment for COVID-19? PLoS Negl. Trop. Dis. 15:e0009446. doi: 10.1371/journal.pntd.0009446.
Choudhury A, Das NC, Patra R, Bhattacharya M, Ghosh P, Patra BC, Mukherjee S. 2021. Exploring the binding efficacy of ivermectin against the key proteins of SARS-CoV-2 pathogenesis: an in silico approach. Future Virol. 2021;10.2217/fvl-2020-0342 https://doi.org/10.2217/fvl-2020-0342.
Ci X, Li H, Yu Q, Zhang X, Yu L, Chen N, Song Y, Deng X. 2009. Avermectin exerts anti-inflammatory effect by downregulating the nuclear transcription factor kappa-B and mitogen-activated protein kinase activation pathway. Fundam Clin Pharmacol; 23:449-55.
Del Rosso JQ. 2017. Topical Ivermectin: Data Supporting Dual Modes of Action in Rosacea. J Clin Aesthet Dermatol. 10:39-42.
Di Nicolantonio JJ, Barroso-Aranda J, McCarty MF. 2021. Anti-inflammatory activity of ivermectin in late-stage COVID-19 may reflect activation of systemic glycine receptors. Open Heart 8:e001655. doi:10.1136/ openhrt-2021-001655.
Ejere HOD, Schwartz E, Wormald R, Evans JR. 2012. Ivermectin for onchocercal eye disease (river blindness). Cochrane Data base of Systematic Reviews, Issue 8. Art. No.: CD002219. DOI: 10.1002/14651858.CD002219.pub2.
Errecalde J, Lifschitz A, Vecchioli G, Ceballos L, Errecalde F, Ballent M, Marín G, Daniele M, Turic E, Spitzer E,
Toneguzzo F, Gold S, Krolewiecki A, Alvarez L, Lanusse C. 2021. Safety and Pharmacokinetic Assessments of a Novel Ivermectin Nasal Spray Formulation in a Pig Model. J. Pharm. Sci. 110: 2501-2507.
Eweas AF, Alhossary AA, Abdel-Moneim AS. 2021. Molecular docking reveals Ivermectin and Remdesivir as potential repurposed drugs against SARS-CoV-2. Front. Microbiol. 11:592908 https:// doi.org/10.3389/fmicb.2020.592908.
Ghanbari R, Teimoori A, Sadeghi A., Mohamadkhani A, Rezasoltani S, Asadi E, Jouyban A, Sumner SC. 2020. Existing antiviral options against SARS-CoV-2 replication in COVID-19 patients. Future Microbiol.15: 1747–1758.
González Canga A, Sahagún Prieto AM, Diez Liébana MJ, Fernández Martínez N, Sierra Vega M, García Vieitez JJ. 2008. The pharmacokinetics and interactions of ivermectin in humans--a mini-review. AAPS J. 10: 42-6.
Guzzo CA, Furtek CI, Porras AG, Chen C, Tipping R, Clineschmidt CM, Sciberras DG, Hsieh JY, Lasseter KC. 2002. Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adults subjects. J. Clin. Pharmacol. 42:1122-33.
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. 2020. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 181:271-280.e8.
Jermain B, Hanafin PO, Cao Y, Lifschitz A, Lanusse C, Rao GG. 2020. Development of a Minimal Physiologically-Based Pharmacokinetic Model to Simulate Lung Exposure in Humans Following Oral Administration of Ivermectin for COVID-19 Drug Repurposing. J. Pharm. Sci. 109:3574-3578.
Juarez M, Schcolnik-Cabrera A, Dueñas-Gonzalez A. 2018. The multitargeted drug ivermectin: from an antiparasitic agent to a repositioned cancer drug. Am. J. Cancer Res. 8:317-331.
Kern C, Schöning V, Chaccour C, Hammann F. 2021. Modeling of SARS-CoV-2 Treatment Effects for Informed Drug Repurposing. Front. Pharmacol. 10;12:625678. doi: 10.3389/fphar.2021.625678.
Krause RM, Buisson B, Bertrand S, Corringer PJ, Galzi JL, Changeux JP, Bertrand D.1998. Ivermectin: a positive allosteric effector of the alpha7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 53:283-94.
Kory P, Meduri GU, Varon J, Iglesias J, Marik PE. 2021. Review of the Emerging Evidence Demonstrating the Efficacy of Ivermectin in the Prophylaxis and Treatment of COVID-19. Am. J. Ther. 28(3):e299-e318. doi:10.1097/MJT.0000000000001377.
Krolewiecki A, Lifschitz A, Moragas M, Travacio M, Valentini R, Alonso D, Solari R, Tinelli M, Cimino R, Álvarez L, Fleitas P, Ceballos L, Golemba M, Fernández F, Fernández de Oliveira D, Astudillo G, Baeck I, Farina J,. Cardama G, Andrea M, Spitzer E, Gold S, Lanusse C. 2021. Antiviral effect of high-dose ivermectin in adults with COVID-19: a pilot randomised, controlled, open label, multicentre trial. EClinical Medicine, 37, 100959, DOI:https://doi.org/10.1016/j.eclinm.2021.100959.
Lagoumintzis G, Chasapis CT, Alexandris N, Kouretas D, Tzartos S, Eliopoulos E, Farsalinos K, Poulas K. 2021.
Nicotinic cholinergic system and COVID-19: In silico identification of interactions between α7 nicotinic acetylcholine receptor and the cryptic epitopes of SARS-Co-V and SARS-CoV-2 Spike glycoproteins. Food Chem. Toxicol. 149:112009. doi: 10.1016/j.fct.2021.112009.
Lankas G, Gordon R. 1989. Toxicology, pp. 89-112. En Ivermectin and Abamectin, Ed. Campbell, W., Springer-Verlag New York Inc., New York, USA.
Lanusse C, Lifschitz A, Virkel G, Alvarez L, Sánchez S, Sutra JF, Galtier P, Alvinerie M. 1997. Comparative plasma disposition kinetics of ivermectin, moxidectin and doramectin in cattle. J. Vet. Pharmacol. Ther. 20:91-9.
Lifschitz A, Virkel G, Sallovitz J, Sutra JF, Galtier P, Alvinerie M, Lanusse C. 2000. Comparative distribution of ivermectin and doramectin to parasite location tissues in cattle. Vet. Parasitol. 87:327-38.
Lima-Morales R, Méndez-Hernández P, Flores YN, Osorno-Romero P, Sancho-Hernández CR, Cuecuecha-Rugerio E, Nava-Zamora A, Hernández-Galdamez DR, Romo-Dueñas DK, Salmerón J. 2021. Effectiveness of a multidrug therapy consisting of Ivermectin, Azithromycin, Montelukast, and Acetylsalicylic acid to prevent hospitalization and death among ambulatory COVID-19 cases in Tlaxcala, Mexico. Int. J. Infect. Dis. 105:598-605.
López-Medina E, López P, Hurtado IC, Dávalos DM, Ramirez O, Martínez E, Díazgranados JA, Oñate JM,
Chavarriaga H, Herrera S, Parra B, Libreros G, Jaramillo R, Avendaño AC, Toro DF, Torres M, Lesmes MC, Rios CA, Caicedo I. 2021. Effect of Ivermectin on Time to Resolution of Symptoms Among Adults With Mild COVID-19: A Randomized Clinical Trial. JAMA. 325:1426-1435.
Lv C, Liu W, Wang B, Dang R, Qiu L, Ren J, Yan C, Yang Z, Wang X. 2018. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antiviral Res. 159:55-62.
Matamoros G, Sánchez A, Gabrie JA, Juárez M, Ceballos L, Escalada A, Rodríguez C, Martí-Soler H, Rueda MM, Canales M, Lanusse C, Cajal P, Álvarez L, Cimino RO, Krolewiecki A. 2021. Efficacy and safety of albendazole and high-dose ivermectin co-administration in school-aged children infected with Trichuris trichiura in Honduras: A Randomized Controlled Trial. Clin. Infect. Dis. ciab365. doi: 10.1093/cid/ciab365.
Mahmud R, Rahman MM, Alam I, Ahmed KGU, Kabir AKMH, Sayeed SKJB, Rassel MA, Monayem FB, Islam MS, Islam MM, Barshan AD, Hoque MM, Mallik MU, Yusuf MA, Hossain MZ. 2021. Ivermectin in combination with doxycycline for treating COVID-19 symptoms: a randomized trial. J. Int. Med. Res. 49:3000605211013550. doi: 10.1177/03000605211013550.
Matsuyama T, Kubli SP, Yoshinaga SK, Pfeffer K, Mak TW. An aberrant STAT pathway is central to COVID-19. 2020. Cell Death Differ. 27:3209-3225.
Morgenstern J, Redondo J, Olavarría A, Rondon I, Roca S, De León A, Canela J, Tavares J, Minaya M, López, O
Castillo A, Plácido A, Peña Cruz R , Merette Y, Toribio, M, Francisco J. 2021. Retrospective cohort study of Ivermectin as a SARS-CoV-2 pre-exposure prophylaxis method in Healthcare Workers medRxiv 04.10.21255248; doi: https://doi.org/10.1101/2021.04.10.21255248.
Muñoz J, Ballester MR, Antonijoan RM, Gich I, Rodríguez M, Colli E, Gold S, Krolewiecki AJ. 2018. Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers. PLoS Negl. Trop. Dis. 12:e0006020. doi: 10.1371/journal.pntd.0006020.
Naeem Z, Raza S, Afzal S, Sheikh AA, Ali MM, Altaf I. 2021. Antiviral potential of ivermectin against foot-and-mouth disease virus, serotype O, A and Asia-1. Microb Pathog. 155:104914. doi: 10.1016/j.micpath.2021.104914.
Omura S. 2008. Ivermectin: 25 years and still going strong. Int. J. Antimicrob. Agents. 31:91-8.
Paras KL, Kaplan RM. 2020. Motility based assays using cultured fourth stage larvae fail to provide consistent discrimination between known avermectin-resistant and -susceptible isolates of Cooperia spp. Vet. Parasitol. 284:109197. doi: 10.1016/j.vetpar.2020.109197.
Peers, T., 2021. Treating a long COVID cohort of patients. In International Ivermectin for COVID Conference, British Ivermectin Recommendation Development (BIRD) https://bird-group.org/conference-post-event/.
Popp M, Stegemann M, Metzendorf M-I, Gould S, Kranke P, Meybohm P, Skoetz N, Weibel S. 2021. Ivermectin for preventing and treating COVID-19. Cochrane Database of Systematic Reviews, Issue 7. Art. No.: CD015017. DOI: 10.1002/14651858.CD015017.pub2.
Pott-Junior H, Bastos Paoliello MM, Miguel AQC, da Cunha AF, de Melo Freire CC, Neves FF, da Silva de Avó LR,
Roscani MG, Dos Santos SS, Chachá SGF. 2021. Use of ivermectin in the treatment of Covid-19: A pilot trial. Toxicol. Rep. 8:505-510.
Roman Y, Burela A, Pasupuleti V, Piscoya A, Vidal J, Hernandez A. 2019. Ivermectin for the Treatment of Coronavirus Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Clin. Inf. Dis. ciab591,https://doi.org/10.1093/cid/ciab591.
Samaha AA, Mouawia H, Fawaz M, Hassan H, Salami A, Bazzal AA, Saab HB, Al-Wakeel M, Alsaabi A, Chouman M, Moussawi MA, Ayoub H, Raad A, Hajjeh O, Eid AH, Raad H. 2021. Effects of a Single Dose of Ivermectin on Viral and Clinical Outcomes in Asymptomatic SARS-CoV-2 Infected Subjects: A Pilot Clinical Trial in Lebanon. Viruses. 26;13:989.
Schmith VD, Zhou JJ, Lohmer LRL. 2020. The Approved Dose of Ivermectin Alone is not the Ideal Dose for the Treatment of COVID-19. Clin. Pharmacol. Ther. 108:762-765.
Smith MR, Ochomo EO, Aljayyoussi G, Kwambai TK, Abong’o BO, Chen T, Bousema T, Slater HC, Waterhouse D, Bayoh NM, Gimnig JE, Samuels AM, Desai MR, Phillips-Howard PA, Kariuki SK, Wang D, Ward SA, Ter Kuile FO. 2018. Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. Lancet Infect. Dis.;18:615–26.
Tay MY, Fraser JE, Chan WK, Moreland NJ, Rathore AP, Wang C, Vasudevan SG, Jans DA. 2013. Nuclear localizationof dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antiviral Res. 99:301-6.
Thylefors B, Alleman MM, Twum-Danso NA. 2008. Operational lessons from 20 years of the Mectizan Donation Program for the control of onchocerciasis. Trop. Med. Int. Health. 13:689-96.
Vallejos J, Zoni R, Bangher M, Villamandos S, Bobadilla A, Plano F, Campias C, Chaparro Campias E, Medina MF, Achinelli F, Guglielmone HA, Ojeda J, Farizano Salazar D, Andino G, Kawerin P, Dellamea S, Aquino AC, Flores V, Martemucci CN, Martinez SM, Segovia JE, Reynoso PI, Sosa NC, Robledo ME, Guarrochena JM, Vernengo MM, Ruiz Diaz N, Meza E, Aguirre MG. 2021. Ivermectin to prevent hospitalizations in patients with COVID-19 (IVERCOR-COVID19) a randomized, double-blind, placebo-controlled trial. BMC Infect. Dis. 21:635.
Yang SNY, Atkinson SC, Wang C, Lee A, Bogoyevitch MA, Borg NA, Jans DA. 2020. The broad spectrum antiviral ivermectin targets the host nuclear transport importin α/β1 heterodimer. Antiviral Res. 177:104760. doi: 10.1016/j.antiviral.2020.104760.
Yesilbag K, Toker EB, Ates O. 2021. Ivermectin also inhibits the replication of bovine respiratory viruses (BRSV, BPIV-3, BoHV-1, BCoV and BVDV) in vitro. Virus Res. 297:198384. doi: 10.1016/j.virusres.2021.198384.
Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. 2012. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear importable to inhibit replication of HIV-1 and dengue virus. Biochem. J. 443:851-6.
World Health Organization. 2016. Toxicological evaluation of certain veterinary drug residues in food. WHO Food additives series: 72 pp 49-73.
Zhang X, Song Y, Ci X, An N, Ju Y, Li H, Wang X, Han C, Cui J, Deng X. 2008. Ivermectin inhibits LPS-induced production of inflammatory cytokines and improves LPS-induced survival in mice. Inflamm. Res. 57:524-9.
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