Ivermectin: a systematic review from antiviral effects to COVID-19 complementary regimen

Fatemeh Heidary, Reza Gharebaghi, Fatemeh Heidary, Reza Gharebaghi

Abstract

Ivermectin proposes many potentials effects to treat a range of diseases, with its antimicrobial, antiviral, and anti-cancer properties as a wonder drug. It is highly effective against many microorganisms including some viruses. In this comprehensive systematic review, antiviral effects of ivermectin are summarized including in vitro and in vivo studies over the past 50 years. Several studies reported antiviral effects of ivermectin on RNA viruses such as Zika, dengue, yellow fever, West Nile, Hendra, Newcastle, Venezuelan equine encephalitis, chikungunya, Semliki Forest, Sindbis, Avian influenza A, Porcine Reproductive and Respiratory Syndrome, Human immunodeficiency virus type 1, and severe acute respiratory syndrome coronavirus 2. Furthermore, there are some studies showing antiviral effects of ivermectin against DNA viruses such as Equine herpes type 1, BK polyomavirus, pseudorabies, porcine circovirus 2, and bovine herpesvirus 1. Ivermectin plays a role in several biological mechanisms, therefore it could serve as a potential candidate in the treatment of a wide range of viruses including COVID-19 as well as other types of positive-sense single-stranded RNA viruses. In vivo studies of animal models revealed a broad range of antiviral effects of ivermectin, however, clinical trials are necessary to appraise the potential efficacy of ivermectin in clinical setting.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1
The molecular structure of avermectin, which then underwent chemical alteration to make ivermectin [45]

References

    1. Crump A, Ōmura S. Ivermectin, ‘wonder drug’ from Japan: the human use perspective. Proc Jpn Acad Ser B Phys Biol Sci. 2011;87:13–28. doi: 10.2183/pjab.87.13.
    1. Kircik LH, Del Rosso JQ, Layton AM, Schauber J. Over 25 years of clinical experience with ivermectin: an overview of safety for an increasing number of indications. J Drugs Dermatol. 2016;15:325–32.
    1. Gonzalez Canga A, Sahagun Prieto AM, Diez Liebana MJ, Fernandez Martinez N, Sierra Vega M, Garcia Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans–a mini-review. AAPS J. 2008;10:42–6. doi: 10.1208/s12248-007-9000-9..
    1. Laing R, Gillan V, Devaney E. Ivermectin—old drug, new tricks? Trends Parasitol. 2017;33:463–72. doi: 10.1016/j.pt.2017.02.004..
    1. Sohrabi C, Alsafi Z, O’Neill N, et al. World Health Organization declares global emergency: a review of the 2019 novel coronavirus (COVID-19) Int J Surg. 2020;76:71–6. doi: 10.1016/j.ijsu.2020.02.034..
    1. Lu H, Stratton CW, Tang Y-W. Outbreak of pneumonia of unknown etiology in Wuhan, China: the mystery and the miracle. J Med Virol. 2020;92:401–2. doi: 10.1002/jmv.25678..
    1. Ge X-Y, Li J-L, Yang X-L, et al. Isolation and characterization of a bat SARS-like coronavirus that uses the ACE2 receptor. Nature. 2013;503:535–8. doi: 10.1038/nature12711..
    1. Yang X-L, Hu B, Wang B, et al. Isolation and characterization of a novel bat coronavirus closely related to the direct progenitor of severe acute respiratory syndrome coronavirus. J Virol. 2015;90:3253–6. doi: 10.1128/JVI.02582-15..
    1. Lu C-C, Chen M-Y, Chang Y-L. Potential therapeutic agents against COVID-19: what we know so far. J Chin Med Assoc. 2020. 10.1097/JCMA.0000000000000318.
    1. Ang L, Lee HW, Choi JY, Zhang J, Soo Lee M. Herbal medicine and pattern identification for treating COVID-19: a rapid review of guidelines. Integr Med Res. 2020;9:100407.. doi: 10.1016/j.imr.2020.100407..
    1. Gharebaghi R, Heidary F, Moradi M, Parvizi M. Metronidazole; a potential novel addition to the COVID-19 treatment regimen. Arch Academic Emerg Med. 2020;8:e40.
    1. Baron SA, Devaux C, Colson P, Raoult D, Rolain J-M. Teicoplanin: an alternative drug for the treatment of COVID-19? Int J Antimicrob Agents. 2020:105944. 10.1016/j.ijantimicag.2020.105944.
    1. Gharebaghi R, Heidary F. COVID-19 and Iran: swimming with hands tied! Swiss Med Wkly. 2020;150:w20242.. doi: 10.4414/smw.2020.20242..
    1. Reviglio VE, Osaba M, Reviglio V, Chiaradia P, Kuo IC. COVID-19 and ophthalmology: a new chapter in an old story. Med Hypothesis Disco Innov Ophthalmol. 2020;9:71–3.
    1. Caly L, Druce JD, Catton MG, Jans DA, Wagstaff KM. The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antiviral Res. 2020:104787. 10.1016/j.antiviral.2020.104787.
    1. Barrows NJ, Campos RK, Powell ST, et al. A screen of FDA-approved drugs for inhibitors of Zika virus infection. Cell Host Microbe. 2016;20:259–70. doi: 10.1016/j.chom.2016.07.004..
    1. Ketkar H, Yang L, Wormser GP, Wang P. Lack of efficacy of ivermectin for prevention of a lethal Zika virus infection in a murine system. Diagn Microbiol Infect Dis. 2019;95:38–40. doi: 10.1016/j.diagmicrobio.2019.03.012..
    1. Khalil AM, Abu Samrah HM. In vivo combined treatment of rats with ivermectin and aged garlic extract attenuates ivermectin-induced cytogenotoxicity in bone marrow cells. Res Vet Sci. 2018;120:94–100. doi: 10.1016/j.rvsc.2018.09.005..
    1. Ji W, Luo G. Zika virus NS5 nuclear accumulation is protective of protein degradation and is required for viral RNA replication. Virology. 2020;541:124–35. doi: 10.1016/j.virol.2019.10.010..
    1. Tay MYF, Fraser JE, Chan WKK, et al. Nuclear localization of dengue virus (DENV) 1-4 non-structural protein 5; protection against all 4 DENV serotypes by the inhibitor Ivermectin. Antivir Res. 2013;99:301–6. doi: 10.1016/j.antiviral.2013.06.002..
    1. Wagstaff KM, Sivakumaran H, Heaton SM, Harrich D, Jans DA. Ivermectin is a specific inhibitor of importin alpha/beta-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem J. 2012;443:851–6. doi: 10.1042/BJ20120150..
    1. Surnar B, Kamran MZ, Shah AS, et al. Orally administrable therapeutic synthetic nanoparticle for Zika virus. ACS Nano. 2019;13:11034–48. doi: 10.1021/acsnano.9b02807..
    1. Yang SNY, Atkinson SC, Wang C, et al. The broad spectrum antiviral ivermectin targets the host nuclear transport importin alpha/beta1 heterodimer. Antivir Res. 2020;177:104760. doi: 10.1016/j.antiviral.2020.104760..
    1. Kosyna FK, Nagel M, Kluxen L, Kraushaar K, Depping R. The importin alpha/beta-specific inhibitor Ivermectin affects HIF-dependent hypoxia response pathways. Biol Chem. 2015;396:1357–67. doi: 10.1515/hsz-2015-0171..
    1. Mastrangelo E, Pezzullo M, De Burghgraeve T, et al. Ivermectin is a potent inhibitor of flavivirus replication specifically targeting NS3 helicase activity: new prospects for an old drug. J Antimicrob Chemother. 2012;67:1884–94. doi: 10.1093/jac/dks147..
    1. Fraser JE, Rawlinson SM, Wang C, Jans DA, Wagstaff KM. Investigating dengue virus nonstructural protein 5 (NS5) nuclear import. Methods Mol Biol. 2014;1138:301–28. doi: 10.1007/978-1-4939-0348-1_19..
    1. Croci R, Bottaro E, Chan KWK, et al. Liposomal systems as nanocarriers for the antiviral agent ivermectin. Int J Biomater. 2016;2016:8043983.. doi: 10.1155/2016/8043983..
    1. Atkinson SC, Audsley MD, Lieu KG, et al. Recognition by host nuclear transport proteins drives disorder-to-order transition in Hendra virus V. Sci Rep. 2018;8:358.. doi: 10.1038/s41598-017-18742-8.
    1. Azeem S, Ashraf M, Rasheed MA, Anjum AA, Hameed R. Evaluation of cytotoxicity and antiviral activity of ivermectin against Newcastle disease virus. Pak J Pharm Sci. 2015;28:597–602.
    1. Lundberg L, Pinkham C, Baer A, et al. Nuclear import and export inhibitors alter capsid protein distribution in mammalian cells and reduce Venezuelan equine encephalitis virus replication. Antivir Res. 2013;100:662–72. doi: 10.1016/j.antiviral.2013.10.004..
    1. Shechter S, Thomas DR, Lundberg L, et al. Novel inhibitors targeting Venezuelan equine encephalitis virus capsid protein identified using in silico structure-based-drug-design. Sci Rep. 2017;7:17705.. doi: 10.1038/s41598-017-17672-9..
    1. Varghese FS, Kaukinen P, Glasker S, et al. Discovery of berberine, abamectin and ivermectin as antivirals against chikungunya and other alphaviruses. Antivir Res. 2016;126:117–24. doi: 10.1016/j.antiviral.2015.12.012..
    1. Gotz V, Magar L, Dornfeld D, et al. Influenza A viruses escape from MxA restriction at the expense of efficient nuclear vRNP import. Sci Rep. 2016;6:23138. doi: 10.1038/srep23138..
    1. Lee YJ, Lee C. Ivermectin inhibits porcine reproductive and respiratory syndrome virus in cultured porcine alveolar macrophages. Arch Virol. 2016;161:257–68. doi: 10.1007/s00705-015-2653-2..
    1. Wagstaff KM, Rawlinson SM, Hearps AC, Jans DA. An AlphaScreen(R)-based assay for high-throughput screening for specific inhibitors of nuclear import. J Biomol Screen. 2011;16:192–200. doi: 10.1177/1087057110390360..
    1. Slonska A, Cymerys J, Skwarska J, Golke A, Banbura MW. Influence of importin alpha/beta and exportin 1 on equine herpesvirus type 1 (EHV-1) replication in primary murine neurons. Pol J Vet Sci. 2013;16:749–51. doi: 10.2478/pjvs-2013-0106..
    1. Lv C, Liu W, Wang B, et al. Ivermectin inhibits DNA polymerase UL42 of pseudorabies virus entrance into the nucleus and proliferation of the virus in vitro and vivo. Antivir Res. 2018;159:55–62. doi: 10.1016/j.antiviral.2018.09.010..
    1. Berthomme H, Monahan SJ, Parris DS, Jacquemont B, Epstein AL. Cloning, sequencing, and functional characterization of the two subunits of the pseudorabies virus DNA polymerase holoenzyme: evidence for specificity of interaction. J Virol. 1995 May;69(5):2811-8. PubMed PMID: 7707503; PubMed Central PMCID: PMC188975
    1. Wang Y-P, Du W-J, Huang L-P, et al. The pseudorabies virus DNA polymerase accessory subunit UL42 directs nuclear transport of the holoenzyme. Front Microbiol. 2016;7:124.. doi: 10.3389/fmicb.2016.00124..
    1. Bennett SM, Zhao L, Bosard C, Imperiale MJ. Role of a nuclear localization signal on the minor capsid proteins VP2 and VP3 in BKPyV nuclear entry. Virology. 2015;474:110–6. doi: 10.1016/j.virol.2014.10.013..
    1. Wang X, Lv C, Ji X, Wang B, Qiu L, Yang Z. Ivermectin treatment inhibits the replication of Porcine circovirus 2 (PCV2) in vitro and mitigates the impact of viral infection in piglets. Virus Res. 2019;263:80–6. doi: 10.1016/j.virusres.2019.01.010..
    1. Raza S, Shahin F, Zhai W, et al. Ivermectin inhibits bovine herpesvirus 1 DNA polymerase nuclear import and interferes with viral replication. Microorganisms. 2020;8. 10.3390/microorganisms8030409.
    1. The FDA’s Center for Veterinary Medicine, . Accessed 5 May 2020.
    1. Canga AG, Prieto AM, Liébana MJ, Martínez NF, Vega MS, Vieitez JJ. The pharmacokinetics and interactions of ivermectin in humans—a mini-review. AAPS J. 2008;10:42–6. doi: 10.1208/s12248-007-9000-9.
    1. Crump A. Ivermectin: enigmatic multifaceted ‘wonder’ drug continues to surprise and exceed expectations. J Antibiot. 2017;70:495–505. doi: 10.1038/ja.2017.11.

Source: PubMed

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