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RESEARCHOpenAccessTherelativeplasmaavailabilitiesofivermectininreindeer(Rangifertarandustarandus)followingsubcutaneousandtwodifferentoralformulationapplicationsAnttiOksanen1*,Kjetilsbakk2,MarjaRaekallio3andMauriNieminen4AbstractBackground:Overwintering(breeding)reindeer(Rangifertarandustarandus)arecommonlytreatedwithivermectinagainstparasiticinfestationsonceyearlyinautumn-winterroundups.
Theonlypreparationsregisteredtoreindeerarethoseforsubcutaneousinjection.
However,alsooralextra-labelivermectinadministrationisused.
Twenty-six,8-month-oldreindeercalveswererandomlyallocatedintothreegroups.
Group1(n=9)receivedoralivermectinmixture(Ivomecvetmixt.
0.
8mg/ml,oralovineliquiddrenchformulation),Group2(n=9)oralivermectinpaste(Ivomecvet18.
7mg/gequinepaste),andGroup3(n=8)subcutaneousinjectionofivermectin(Ivomec10mg/mlvetinj.
),eachgroupatadoseof200μg/kgbodyweight.
Bloodsampleswerecollectedattreatmentandatdays1,2,3,6,9and16posttreatment.
Plasmaconcentrationsofivermectinweredeterminedbyhigh-pressureliquidchromatography(HPLC)withfluorescencedetection.
Results:Thepeakplasmaconcentration(Cmax)wasreachedby2daysaftereachtreatment.
TheCmaxandAreaUnderCurve(AUC)differedsignificantlybetweenthegroups:Cmaxwas30.
2±3.
9,14.
9±5.
7and63.
1±13.
1ng/ml,andAUC∞was2881±462,1299±342and6718±1620ng*h/mlforgroups1,2and3,respectively(mean±standarddeviation).
Conclusions:Thedifferencesinplasmaconcentrationsofivermectinareconcomitantwithearlierobserveddifferencesinantiparasiticefficacy,whichdiscountstheuseoftheequinepasteinreindeerinfavouroftheoralovineliquiddrenchformulation,orpreferably,thereindeer-registeredsubcutaneousinjectionformulation.
Keywords:Reindeer,Ivermectin,Injection,Drench,Paste,AUCBackgroundSincethelaunchattheproductionanimalmarket,iver-mectinhasbeenwidelyusedtotreatdifferentendo-parasiteandectoparasite(nematodesandarthropods)infectionsinthemainproductionanimalspecies[1],andalsoin"minor"ruminantspeciessuchasgoats,deer,buffaloes,antelopes,andalsocamelids.
Inareviewofextra-labeluseinminorspecies[2],itwasconcludedthatthereisahighinter-speciesvariabilityinivermectinpharmacokineticsandefficacyandaneedforextendedpharmacokineticdatainvariousanimalspeciestoavoidmisuseofdoseratesextrapolatedfromotherspecies.
Ivermectinhasbeenusedtotreatbotharthropodandnematodeparasitesofreindeer(Rangifertarandustarandus)sincetheearly1980s[3,4]withasmanyas80%oftheoverwinteringreindeerinFinlandtreatedonceyearly[5].
TheonlyivermectinpreparationregisteredforadministrationtoreindeerinanyFennoscandiancountryisinjectable(e.
g.
Ivomec10mg/mlvetinj.
,Merial),at200μg/kgsubcutaneously(s.
c.
).
Theequineoralpaste(Ivomecvet18.
7mg/gpaste,Merial)isnotintendedby*Correspondence:Antti.
Oksanen@evira.
fi1FinnishFoodSafetyAuthorityEvira,ProductionAnimalandWildlifeHealthResearchUnit(FINPAR),Elektroniikkatie3,FI-90590Oulu,FinlandFulllistofauthorinformationisavailableattheendofthearticle2014Oksanenetal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/4.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycredited.
TheCreativeCommonsPublicDomainDedicationwaiver(http://creativecommons.
org/publicdomain/zero/1.
0/)appliestothedatamadeavailableinthisarticle,unlessotherwisestated.
Oksanenetal.
ActaVeterinariaScandinavica2014,56:76http://www.
actavetscand.
com/content/56/1/76themanufacturerforuseinruminants.
Itwas,however,adoptedtothetreatmentofreindeerinFinlandafterrein-deerherdershadseenthatadministrationat200μg/kghadhighefficacyagainstreindeerwarbles(Hypodermatarandi)andthroatbots(Cephenemyiatrompe),whicheffectwaslaterdemonstratedexperimentally[6].
Theoralovineliquiddrenchformulation(Ivomecvetmixt.
,0.
8mg/ml,Merial)isoccasionallyusedonreindeerinNorway(Aamot,HerdisG.
,pers.
comm.
,2013).
Thisstudycomparestheplasmaconcentrationsofivermectininreindeerafteradministrationoftheoralovineliquiddrenchandequinepasteformulations,andthesubcuta-neousinjection,anddiscussestheconsequencesoftheobserveddifferencestoantiparasiticeffectandresistance.
MaterialandmethodsTwenty-six(13femalesand13males)individuallyear-tagged8-month-oldreindeercalvesoftheKaamanenEx-perimentalReindeerHerd,Kaamanen,FinnishLapland,werecorralledattheFinnishGameandFisheriesResearchInstitute'sReindeerResearchStationanimalexperimentfacilitiesandfedlichenandcommercialreindeerfeedpellets(Poron-Herkku,Rehu-Raisio,Finland)adlib.
Theanimalswereweighed(medianbodyweight46kg,range42to53kg)andallocatedbysexandweightintothreetreatmentgroups:1)ovineIvomecvetmixt.
0.
8mg/ml,n=9;2)equineIvomecvet18.
7mg/gpaste,n=9;and3)Ivomec10mg/mlvetinj.
,n=8.
Thetreatmentswereperformedafterpelletedfodderhadbeenaddedtotheirfeedtroughsinthemorning.
Allanimalsweredosedat200μg/kgbodyweight.
ThoseinGroups1and2weretreatedbyemptyinganindividuallyfilledsyringeonthebaseofthetongue,0.
25ml/kgand10.
7mg/kg,respect-ively.
Subcutaneousinjections(Group3)weregiveninfrontoftheleftshoulder(lateralmidlineoftheneck)at0.
02ml/kg.
Bloodsampleswerecollectedintoevacuatedsodiumheparinised10mltubes(Venoject)immediatelypriortotreatment(day0)andatthesametimeofdayondays1,2,3,6,9and16posttreatment.
Plasmawassepa-ratedbycentrifugation,storedat-20°C,andonlythawedonceforanalysis.
TheexperimentwasperformedwiththepermissionfromFinnishGameandFisheriesResearchInstitute'sAnimalCareCommittee.
Ivermectinconcentrationinplasmawasdeterminedbyhigh-pressureliquidchromatography(HPLC)withfluorescencedetectionfollowingamodificationofthemethoddescribedforivermectininreindeerfaeces[7,8].
Themodificationsincludedthatthe1.
0mlplasmasamplewassupplementedwith10ngofabamectinin-ternalstandard,mixedwith5mlof30%acetone,andtheiso-octaneextractionstepwasperformedwith5mlportionsofiso-octane.
Asinglecalibrationlinebasedontheleast-squaresmethodwasusedforthequantificationofivermectin.
Concentrationswerecalculatedaccordingtotheequation:CsRf1HiHaRf2WaWsDfwhereCsistheplasmaconcentration(ng/ml);Rf1andRf2aretheresponsefactorsrepresentingthecalibrationlineused,1.
1777and0,respectively;HiandHaaretheHPLCsoftware-generatedheightsoftheivermectinB1aandabamectinBlapeaks,respectively;Waistheinternalstandardweight(ng);Ws,thesamplevolume(ml);Df,thedilutionfactorforsampleinjected.
Forrecoverycalculation,1.
0mlplasmaportionsfromuntreatedanimalsfortifiedwithconcentrationsofivermectinrangingfrom1to100ng/mlwereanalysed,andrecoverywascalculatedaccordingtoequationpublishedbefore[7].
Theplasmaivermectinconcentration-timeprofileswereexaminedusingWinNonLin6.
3(StatisticalConsultingInc.
PharsightCorporation,Cary,NC,USA)softwarewithnon-compartmentalanalysis,lineartrapezoidallinear/loginterpolation,uniformweighting.
Appropriatebasicphar-macokineticparameters,meanandstandarddeviation,weregenerated.
Forcalculation,thefirstivermectincon-centrationfromananimalbelowthelevelthatcouldberecoveredanddetermined(1ng/ml)wasreplacedwith0.
5ng/ml.
Therelativeplasmaavailabilityofivermectin(Frel)wasapproximatedbyusingthemeanAUCsofeachgroupandcalculating(AUCoral/AUCsc)*100%,wheres.
c.
routewasusedasareference.
Differencesinmaximumconcentration(Cmax)andAreaUndertheplasmaivermec-tinconcentration-timeCurve(AUC∞)betweentreatmentswereanalyzedwithanalysisofvariancesbyJMPstatisticalsoftware(ver.
11,SASInstituteInc.
,www.
jmp.
com).
Thenullhypothesiswasrejectedatanα-levelof0.
05.
ResultsChromatographyof1.
0mlplasmasamplesfromanuntreatedreindeerfortifiedwithvariousamountsofivermectindemonstratedthatfortificationlevelsdownto1ng/mlcouldeasilybedetectedandmeasuredbyHPLC.
RetentiontimesfortheBlacomponentsofabamectinandivermectinwereapproximately5.
1and7.
5min,respect-ively,withtheBlbcomponentselutingalittlelessthan1minearlier(Figure1).
Theindividualpeakswerewellre-solvedatallfortificationlevels,andnoextraneouspeaksin-terferedwiththeBlacomponents,asdemonstratedbyanalysisofnon-fortifiedplasmafromuntreatedanimals.
Therelativerecoveryraterangedfrom~99to~116%forthewholeconcentrationrange(1-100ng/ml),andreproduc-ibilitywasgood(standarddeviationlessthan5.
2%forcon-centrationdeterminedfor5identicallypreparedsamples).
OneanimalofGroup3gaveanalysisresultsshowingcompleteabsenceofivermectininallsamplesandwasOksanenetal.
ActaVeterinariaScandinavica2014,56:76Page2of7http://www.
actavetscand.
com/content/56/1/76excludedasanuntreatedanimal.
Inaddition,ofthe175samplesofotheranimals,17weremissingfromanalysisforvariousreasons.
MeanplasmaivermectinconcentrationsbytimeposttreatmentforeachgroupareshowninFigure2.
Thema-ximummeasuredivermectinconcentration(Cmax)wasreachedbyday2posttreatment(Tmax).
OneanimalinGroup2exhibitedanexceptionallyhighplasmaivermec-tinconcentrationonday1(29ng/ml,comparedtothemeanof11.
8ng/mlfortheothereightofthegroup)andcausedthemeanconcentrationinthatgroupinFigure2topeakonday1(mean=13.
7,day2mean=12.
2ng/ml).
Figure1AnexampleHPLCchromatogramforanactualplasmasamplefromareindeertreatedwithivermectinbyoraladministrationofequinepaste(Group2)atthedoseof200μg/kg.
Samplefromday2posttreatment,concentrationdeterminedto9ng/ml.
HPLCdetectorattenuation:3.
Eachplasmasampleforanalysis(1.
0ml)wassupplementedwith10ngabamectin(internalstandard)beforeextractionandsamplepreparation.
TheplasmaconcentrationcalculationwasbasedontheHPLCsoftware-generatedheightsoftheivermectinB1aandabamectinBlapeaksusingtheequationgivenabove.
Figure2Mean(+standarddeviation)plasmaivermectinconcentration(ng/ml)inthreegroupsofreindeertreatedwithivermectin(x-axis:daysaftertreatment),1)brokenline,Ivomecvetmixt.
0.
8mg/mlorallyn=9;2)dottedline,Ivomecvet18.
7mg/gpasteorallyn=9;3)solidline,Ivomec10mg/mlvetinj.
subcutaneouslyn=8.
Alltreatmentsatadoseof200μg/kg.
Oksanenetal.
ActaVeterinariaScandinavica2014,56:76Page3of7http://www.
actavetscand.
com/content/56/1/76TheCmaxandAUCdifferedsignificantlybetweenthegroups(Table1),andthemeanCmaxandAUCweresignificantlylowerforGroup2comparedtoGroups1and3,andsignificantlyhigherforGroup3comparedtoGroups1and2(onewayANOVA,Tukeytest,P<0.
007).
Noivermectincouldbedetectedonday16posttreatmentinanyanimalindicatingthattheplasmaconcentrationswerebelowthedetectionlimit(1ng/ml).
Theapproxi-matedFrelwere43%and19%fortheoralmixtureandpaste,respectively.
DiscussionThemaximumivermectinplasmaconcentrationsmea-suredinthesubcutaneouslyinjectedreindeerwerehigherinthisstudythaninapreviousonewithsimilaranimals[9].
Inthatearlierexperiment,nosamplingwasdoneonday2aftertreatment,butonlyondays1and3,andthusCmaxwasprobablymissed.
Otherwise,theresultsfromthesetwoexperimentsweresimilar,suggestingthesupe-riorplasmaavailabilityofivermectinaftersubcutaneousinjectioncomparedtooraladministration.
MaybeCmaxwerenotseeninthecurrentstudyeither,becausetheymaybeanywherebetweendays1and2,orbetweendays2and3.
TheTmaxofivermectininreindeerisinanycaselongerthaninsomeothercervidspecieswhereithasbeenlessthan1day(seebelow)butshorterthanorsimilartocattle,sheepandgoats(reviewedin[2]).
TheCmaxfollowingsubcutaneousadministrationat200μg/kgwasconsiderablyhigherinourstudythanobservedincattle[10-12].
Itismostinterestingtocomparethefindingswithre-sultsfromothercervidspecies.
Afters.
c.
injectionofivermectininreddeer(Cervuselaphus)at200μg/kg,Cmaxwasonly15.
8ng/ml[13],aboutonefourthofthatmeasuredinthecurrentstudy.
InreddeertheTmaxwas20hours.
Similarvalueswereobtainedinanotherstudyinreddeer[14].
Inwhite-taileddeer(Odocoileusvirginianus)sampleddays3,7,14,and21postinjection,Cmaxwasobservedinthefirstsampling,onday3postinjection;theserumconcentrationwasabout30ng/ml,al-mostdoubletheCmaxinreddeer[15].
Theeliminationtonon-detectableserumconcentration(<2ppb~2ng/ml)lastednotmorethan21daysafterinjection[15].
However,thesefindingsarenotfullycomparable,asthesamplingintervalsdifferedbetweenstudiesandthepeakconcen-trationsmaynothavebeenmeasuredduetoinfrequentsampling.
Infallowdeer(Cervusdamadama),injectableabamectin(200μg/kg,s.
c.
),chemicallyacloselyrelatedandpharmacologicallyrathersimilardrug,producedaCmaxof120ng/mlat19hpostinjection[16].
Inspiteofthesimilarities,ivermectinisregardedastheleastlipo-philicofthemacrocycliclactoneantiparasitics[17],whichprobablycausesdifferencesbetweenthepharmacokineticsofthesetwocompounds.
Asstated[2],erroneousdosagesmayemergewhenextrapolatingrecommendedtreatmentsfromoneanimalspeciestoanother.
ThisappearsveryclearlyevidentalsowithintheCervidaefamily.
Inthepresentstudy,theeliminationhalf-timeandmeanresidencetimecouldnotbecalculatedaccurately,astheslowabsorptionwasprobablyalimitingfactorfortheeliminationcausingthesocalledflip-floppharmacoki-netics.
Thusthemain,andclinicallymostimportant,differencesbetweenthegroupswereinCmaxandAUC.
Plasmaconcentration,orspecificallyAUC,ofamacrocyc-liclactoneinagivenanimalspecieshasbeensuggestedtoindicatethelevelofantiparasiticefficacy[18].
Itwassuggestedthattheremaybeaminimumplasmadrugconcentration(between0.
5and1ng/ml[19]foroptimalanthelminticactivityagainstsusceptiblegastrointestinalorlungnematodes.
However,theexistenceofsuchamini-mumeffectiveconcentrationhasnotbeenconfirmed.
Inanycase,theefficacyconcentrationanddurationrequire-mentsareaffectedbyphysiologicalandbiochemicaldif-ferencesbetweenbothhostandparasitespeciesandstrains.
Eventhoughmoresensitiveanalyticalmethodsdoexist[20],weconsiderourmethodappropriateforthefocusofthepresentwork,thecomparisonbetweenthepracticaloutcomesofthethreeadministrationregimesinquestion,particularlywhenlaboratorycost-effectivenessandlabour-intensityalsoaretakenintoaccount.
Animportantproblemwiththerelativelylowanalyticalsensitivityofthemethodisthatitwasnotpossibletodetecttheprolongedlowconcentrationswhichmaybeimportantinanthelmin-ticresistancebuild-upinnematodepopulations.
Further-more,theeliminationparameterscouldnotbecalculated.
Theefficacyofivermectinformulationsagainstgastro-intestinaltrichostrongylidnematodesinreindeerhasbeenassessedinseveralpreviousstudiesbasedonthereductioninfaecaleggoutputintheKaamanenHerd.
Thes.
c.
injec-tiontreatmentreducedthefaecaleggcountmean(basedonseveralrepeatedsamplingsofindividualanimals2to6monthsposttreatment)by80-95%[21,22];theequineTable1Basicpharmacokineticparametersofivermectinadministeredorally(asmixtureorpaste),orsubcutaneouslytoreindeercalvesat200μg/kg,meanandstandarddeviationParameterGroup1,mixtureGroup2,pasteGroup3,injectionTmax(days)212Cmax(ng/ml)30.
2±3.
9a14.
9±5.
7b63.
1±13.
1cAUC∞(ng*h/ml)2881±462a1299±342b6718±1620cFrel0.
430.
191Meansofthegroupsmarkedwithdifferentletters(a,b,c)differsignificantly(P<0.
05).
Oksanenetal.
ActaVeterinariaScandinavica2014,56:76Page4of7http://www.
actavetscand.
com/content/56/1/76pasteby39%[21],andtheovinemixtureby62to74%[23].
TheseefficacyfigureswereconsistentbothwiththeCmaxandAUCdifferencesdetectedinthepresentstudy.
BasedonCmaxandAUCcomparisonsbetweenthedif-ferentpreparationsandadministrations,theequineiver-mectinpastemayhavesimilarantiparasiticefficacy,atleastagainstextra-intestinalparasites,toalowerdoseoftheovinemixture,ortoanevenlowerdoseinjectedsub-cutaneously,whichlowinjectiondosewouldnaturallyberegardedasevidentunderdosage.
Thereasonfortheobviouslybetterabsorptiontothecirculationofivermectinfromtheovinemixturecom-paredtotheequinepastemaybeinthechemicalcom-positionofthebasematerialoftheproducts,butonepossibleexplanationisintheconsistenceandvolumeofthedrench.
Theequinepastedosecontaining200μg/kgofivermectinandgiventoa50kgreindeercalfis0.
535gofviscouspaste,whilethatoftheovinemixtureis12.
5mlofliquid.
Ifsomeofthemixturebypassestherumentoendupdirectlyintheabomasum,theabsorp-tiontothebodymightbegreatlyenhanced.
Inanearlystudyinsheep,thebioavailabilityofintra-abomasallyadministeredivermectinwas100%,whilethatofiver-mectinadministeredintraruminallywasonly25%[24].
Itwassuggestedthatorallyadministeredivermectinisadsorbedtotheruminalingesta[24,25],whichlimitsitsavailabilityforabsorption.
Accordingly,alsothesystemicavailabilityofintraruminallyadministereddoramectininsheepislow,35%[26].
Inourstudy,theapproximatedrelativeplasmaavailabilitywaslowerforthepasteandhigherforthemixtureinreindeerthanthesevaluesre-portedforintraruminaladministrationinsheep[24].
Ruminalbypasscouldbeexplainedbytheoesophagealgrooveclosuredirectingthedrugmixturedirectlytotheabomasum.
Thisexplanationlosessomecredibilitybe-causeruminalbypasswasfoundnottotakeplaceinadultreindeer[27].
The8-month-oldreindeercalvesinthepresentstudyhadrecentlybeenweaned;theendoflactationtakesplacetypically24to26weeksafterbirth[28].
Possiblytheanimals'raisedheadpostureduringadministrationanyhowdirectsivermectinmixturetotheabomasum.
Itcanalsobedifficulttomakesurethatthereindeerswallowthesmallvolumeofpaste.
Inthisstudy,properrestraintoftheanimalsensuredswallowing.
Wearenotawareofanyreportsofmacrocycliclactoneresistanceinanyoestridflyspecies,suchasreindeerwarbleandthroatbotflies,butresistanceingastrointestinalnematodeparasitesisamajorprobleminmanyareaswheree.
g.
sheepareintensivelytreated[29,30].
Wedonotknowofanyreportofivermectinre-sistanceinanyreindeerparasites.
However,aftertwode-cadesofmoxidectinpour-onuseonaNewZealanddeerfarm,significantresistancetomoxidectinandabamectininabomasalnematodeswasseen[31].
Moxidectinisapparentlynotusedinreindeer,asitwasfoundnottohavesatisfactoryefficacyagainsttheimportantinsectparasites,warblesandthroatbots[22].
Pour-onivermec-tinpreparationwasfoundtohaveverylowabsorptionintothereindeerbody,especiallyinmidwinter[9].
Asunderdosageisregardedasadriverofresistance[32],itshoulddefinitelybeavoided.
Ontheotherhand,persistentactivityofmacrocycliclactonescreatessitua-tionsinwhichtreatedanimalshaveprolongedlowcon-centrationofthedruginthebody,whichmayallow(re)infectionbythefittestofparasitelarvae[33].
Fromthatpointofview,rapiddisappearanceofthedrugwouldbepreferable,andthereoraladministrationsprobablyscorehighest.
Ivermectinismostlyexcretedunalteredinthefaeces[34],andtheenvironmentalcontamination[8]willbesimilarinsize,butnotintime,regardlesstheapplicationroute.
However,systemicplasmaavailabilityisprobablynotessentialasameasureofantiparasiticactivity;itistheavailabilityofthetoxicsubstancetotheparasitesthatreallycounts.
Whileplasmaconcentrationvirtuallycer-tainlydeterminestheavailabilityofivermectintoparen-teralnematodes(suchase.
g.
Dictyocauluseckerti,SetariatundraandRumenfilariaandersoni)andwarbleandthroatbotflylarvae,thesituationregardinggastrointes-tinalnematodesissomewhatconfusing.
Inrecentstudiesinsheepandcattle,oralmacrocycliclactoneshavebeenshowntohavehigherefficacyagainstgastrointestinalnematodesthansubcutaneousinjection[35,36],evenagainstHaemonchuscontortus,whichisknowntofeedonblood.
Oneprobableexplanationtotheobserveddifferenceineffectagainstreindeerabomasalnematodes(Ostertagiagruehneri)[37]andthoseofsheepandcattle,isthatduringthetimeoftreatment,reindeernematodesmostlyresideintheabomasalmucosaasinhibitedlarvae[37,38],andcannotgetincontactwithdruginingesta;thus,ivermectinisonlyavailabletothemviabloodcirculation.
ConclusionsThisstudyhasdefinedtheplasmaconcentrationsofivermectininreindeerusingthreeformulations,andtheresultsagreewellwithpreviouslyacquiredanthelminticefficacydata.
Withthisinformation,somedirectionsforthebestuseofdrugcanbemade.
Specifically,ifaninjec-tionisimpracticaltoadministere.
g.
duetolackofcapablepersonnell,andivermectintreatmentisstillrequired,thehigherrelativeplasmaavailabilityofivermectininthemixtureformulation,designedtobeusedinaruminantspecies,suggeststhatitwouldbeabettersubstitutethanthepastedesignedforamonogastricspecies.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Oksanenetal.
ActaVeterinariaScandinavica2014,56:76Page5of7http://www.
actavetscand.
com/content/56/1/76Authors'contributionsK,MNandAOplannedandperformedthetreatment,keepingandsamplingoftheexperimentalreindeer.
Kperformedallivermectinanalyses.
MRmadeallthepharmacokineticcalculations.
Allauthorsparticipatedinwritingthemanuscript,andtheyhavereadandapprovedthefinalversionofthemanuscript.
AcknowledgmentsWearegratefultotheKaamanenExperimentalReindeerHerdandReindeerResearchStationandtheirpersonnelfortheuseofanimalsandfacilities,andtoHeidiR.
Bendiksenforlaboratoryassistance.
WearedeeplygratefultothelateDr.
DesHennessy,whomadesubstantialcontributiontostudydesignandinterpretationofdata,anddraftingasanauthorofthefirstmanuscriptsubmittedin2000.
Unfortunately,therevisedmanuscripttooksomuchtimethathewasnotheretoseetheupdateddiscussionbasedonthescientificprogressofthelastyears.
WethanktheanonymousReviewers1and2fortheirkindwordsandconstructivecriticismthatledtoclearimprovementofthemanuscript.
Authordetails1FinnishFoodSafetyAuthorityEvira,ProductionAnimalandWildlifeHealthResearchUnit(FINPAR),Elektroniikkatie3,FI-90590Oulu,Finland.
2DepartmentofArcticandMarineBiology,ResearchGroupofArcticInfectionBiology,UniversityofTroms,P.
O.
Box6050,Langnes,NO-9037Troms,Norway.
3FacultyofVeterinaryMedicine,DepartmentofEquineandSmallAnimalMedicine,PharmacologyandToxicologySection,UniversityofHelsinki,P.
O.
Box57,FI-00014Helsinki,Finland.
4FinnishGameandFisheriesResearchInstitute,ReindeerResearchStation,FI-99910Kaamanen,Finland.
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