brazjinfectdis2020;24(4):369–371
w w w . e l s e v i e r . c o m / l o c a t e / b j i d
The
Brazilian
Journal
of
INFECTIOUS
DISEASES
Letter
to
the
editor
Ivermectin:
potential
candidate
for
the
treatment
of
Covid
19
DearEditor:
Ivermectin,awell-knownanti-helminticagentfromthe
late-1970s, causes stimulation of gamma amino butyric acid
(GABA)-gated-Cl−channels,leadingtohyperpolarization,and resulting in paralysis of the infesting organism. Another mechanismthathasbeen postulatedforthesame effectis
the immunomodulation of host response. This isattained
by the activation of neutrophils, increase in the levels of C-reactive protein and interleukin-6.1 In recent times, the antiviralfunctionofivermectinhasbeendiscovered,which appears to be intriguing. Already its effectiveness against certain flavivirus (dengue fever, Japanese encephalitis and tick-borneencephalitisvirus)andchikungunyavirushasbeen demonstrated in vitro.2,3 Since then the same activity has beenassessedinnumerousotherviralinfections.Offlately itspotencyhasbeenrecognizedineliminatingcoronavirus
in vitro. Theexact mechanism towhich this effect can be attributedtoisyettobevalidated,butthespeculatedmethod is inhibition of importin ␣/1 mediated transport of viral proteinsinandoutofthenucleus.4Importins,atypeof karyo-pherins,exemplifyamajorclassofsolubletransportreceptors whichareinvolvedinnucleo-cytoplasmictransitofvarious substrates(Fig.1).5Thespeculatedinhibitoryactionof iver-mectinonimportin␣/mediatedtransportsystem,Basedon thisconjecture,theroleofivermectinineliminatingCovid-19 canbeassumed.
Untilnow,inonlysingleinvitrostudy,theefficacyof iver-mectinagainstcoronavirushasbeendemonstrated.Calyetal. testedfortheviralRNAlevelsinbothsupernatantandcell pellets of the Vero/hSLAMcells which were infected with SARS-CoV-2 (isolate Australia/VIC01/2020), and were then treatedwith5Mivermectintwohourslater.After24h,they observedadeclineofabout93%and98%inviralRNAlevels andcell-associatedviralRNA,respectively.Laterat48h,they detectedfurtherreduction(∼5000fold)intheviralRNAload only.Toascertainthisfinding,theinfectedcellsweretreated withserialdilutionsofivermectin,andwerethentestedfor viralRNAloadbyRT-PCR.Withthisresearch,theinvestigators couldcommentabouttheinhibitoryconcentration50(IC50) whichwasestimatedtobe∼2M,andalsothatnotoxicities
Protein in cytoplasm Marked with cNLS Identified by importin a (adaptor protein) Links the labelled protein to importin b
(nuclear transport protein
The cargo protein is transited to nucleus Mimics the cNLS Ivermectin Binds directly to importinb
Fig.1–Mechanismofivermectininducedinhibitionof
importin␣/mediatedcoronavirusproteinstransport.
cNLS:classicalNuclearLocalizationSignal.*Image
courtesy:CDC/AlissaEckert,MS;DanHiggins,MAMSA.
were noticed forthe various concentrations atwhich iver-mectinwastested.6Basedontheefficacyevidencedininvitro study,variousclinicalstudieshavebeenplannedandstarted, thoughnoneofthemhaveyetbeencompleted(Table1).
TheinvitropotencyofivermectinagainstCovid-19virus isatestimonythatthisdrugcanbeutilizedtomanagethose patientswhohavebeeninfectedwithSARS-CoV-2.Sincethe conditionsinwhichthevirusreplicatesandinfectsthecells
in vivo and in vitro differs, adecisive comment about how ivermectinmayprovetobebeneficialtothepatientscannot beconstructed yet.Similarly, anydisparity inthe pharma-cokinetic properties ofthisdrug and the unidentifieddrug interactionswhichmayoccurundersuchconditionsareyet
to be recognized and remarked on. Nevertheless if
com-pared withthe other pharmacotherapeutic options for the managementofCovid-19infection,ivermectinmayproveto haveleverage over them.Inadditiontoadifferent mecha-nismofaction,thereare otherfacetsaswell inwhichthis
370
braz j infect dis.2020;24(4):369–371Table1–SalientfeaturesofongoingclinicaltrialsofivermectinforCOVID-19.
S.No Intervention Phase No.ofParticipants PrimaryEndPoint(s) ClinicalTrial
Identifier
1 Ivermectin0.2mg/kg(singledose
atonce=2tabletsof6mg/weekly) Hydroxychloroquine400mg/daily Azithromycincapsules500mg daily
Placebo
I 50 Numberofpatientscured
assessedby
Nasopharyngealswab, oropharyngealswab,and bloodaspirationforcovid19 (PCR)inadditiontochest x-rayin14days
NCT04343092
2 Ivermectin600g/kgoncedaily
plusstandardcare. Control:StandardCare
II 45 Numberofpatientsin
whomtheSARS-CoV-2viral loaddecreasesafter ivermectintreatmentin 1−5days
NCT04381884
3 Bicalutamide150mgbymouth
dailyfor7days
Ivermectin600g/kg(uptoa maximumdoseof60mg)by mouthdailyfor3days
II 60 Numberofparticipants
whohaveclinical improvementatday7after randomization
NCT04374279
4 Hydroxychloroquine:
Days1−14:3tabs(600mgtotal dailydose)
Azithromycin:
Day1:2tabs(500mgtotaldaily dose)Days2−5:1tab(250mgtotal dailydose)
Ivermectin:
Days1−2:Weight<75kg:4tabs (12mgtotaldailydose)Days1−2: Weight>75kg:5tabs(15mgtotal dailydose)
CamostatMesilate
Days1−14:2tabTIDafterameal (600mgtotaldailydose)
II 240 Proportionofpatients
experiencingclinical deteriorationin14days
NCT04374019
5 Ivermectin200g/kgonceorally
plusNitazoxanide500mgtwice dailyorallywithmealfor6days Control:StandardCare
II/III 100 NumberofPatientswith
COVID-19-negativePCRin 10days
NCT04360356
6a Chloroquine
ChloroquinewithNitazoxanide Chloroquinewithivermectin
II III
60 Numberofpatientswith
virologicalcureinsix months NCT04351347 7a Chloroquine Favipiravir Nitazoxanide Ivermectin Niclosamide
Otherdrugs(oselatamiviror combinationofanyofabove treatment)
II/III 120 Numberofpatientswith
decreasedviralloadinsix months NCT04345419 8a Nitazoxanide Ivermectin Chloroquine Azithromycin
III 80 Numberofpatientswith
virologicalcureinsix months
NCT04382846
9 Ivermectin200–400gperkgbody weight
Control:StandardCare
N/A 50 Testforvirusat1,3&5
daysfrombeginningoftrial drugstartedforthepatient inthehospitalin03months
NCT04373824
Allthedetailsmentioned,havebeenobtainedfromhttps://clinicaltrials.gov/. a Doseofthedrugsnotavailable.
effectsassociatedwithhydroxychloroquine(irreversible reti-naldamage,prolongQTinterval,myopathy, neuropathy)or withlopinavir+ritonavircombination(hypertriglyceridemia, hypercholesterolemia)are notseen inpatients whoare on
ivermectin. Furthermore,the treatment regimenwith iver-mectinmayturnouttobemorecost-effective.Thetherapeutic
regimenwithhydroxychloroquineandazithromycin
brazj infect dis.2020;24(4):369–371
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onewithivermectin.Thesamecanbecommentedaboutthe patentantiviralswhicharepricedatexorbitantrates.Another worthwhileissue tobe addressedisthe over-utilization of hydroxychloroquineinmanagingtheCovid-19patients,may createanapparentshortageofthisdrugwhichisastandard treatmentforpatientswithauto-immunediseases.
Takingintoaccounttheselacunaeandmerits,itbecomes imperativethatclinicaltrialswithivermectinbeconducted inpatientsofCovid-19,tocomprehendwhetherthisdrugcan providebeneficialeffecttothosepatientswhohavealready developedcomplicationsduetothisinfection.
Funding
Nofundingreceived.
Conflict
of
interest
Theauthorsdeclarenoconflictsofinterest.
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1.NjooFL,HackCE,OostingJ,LuyendijkL,StilmaJS,KijlstraA. C-reactiveproteinandinterleukin-6areelevatedin onchocerciasispatientsafterivermectintreatment.JInfect Dis.1994;170:663–8,http://dx.doi.org/10.1093/infdis/170.3.663. 2.MastrangeloE,PezzulloM,BurghgraeveTD,etal.Ivermectinia
apotentinhibitorofflavivirusreplicationspecificallytargeting NS3helicaseactivity:newprospectsforanolddrug.J AntimicrobChemother.2012;67:1884–94.
3.VargheseFS,KaukinenP,GläskerS,etal.Discoveryof berberine,abamectinandivermectinasantiviralsagainst chikungunyaandotheralphaviruses.AntiviralRes. 2016;126:117–24,
http://dx.doi.org/10.1016/j.antiviral.2015.12.012.
4.TessierTM,DodgeMJ,etal.Viralappropriation:layingclaimto hostnucleartransportmachinery.Cells.2019;8:1–23.
5.OkaM,YonedaY.Importin␣:functionsasanucleartransport factorandbeyond.ProcJpnAcadSerB:PhysBioSci.
2018;94:259–74,http://dx.doi.org/10.2183/pjab.94.018. 6.CalyL,DruceJD,etal.TheFDA-approveddrugivermectin
inhibitsthereplicationofSARS-CoV-2invitro.AntiviralRes. 2020;178:104787.
DhyutiGupta1,AjayaKumarSahoo1, AlokSingh ∗,1
DepartmentofPharmacology,AllIndiaInstituteofMedicalSciences, Raipur,Chhattisgarh,India
∗Correspondingauthor.
E-mailaddress:draloksingh@aiimsraipur.edu.in(A.Singh). 1Allauthorscontributedequally.
Received21May2020 Accepted14June2020 Availableonline28June2020 1413-8670/
©2020SociedadeBrasileiradeInfectologia.Publishedby ElsevierEspa ˜na,S.L.U.Thisisanopenaccessarticleunder theCCBY-NC-NDlicense(http://creativecommons.org/ licenses/by-nc-nd/4.0/).
