实验动物给药和样品处理知道手册

EFPIA(theEuropeanFederationofPharmaceuticalIndustriesAssociations)andECVAM(theEuropeanCenterfortheValidationofAlternativeMethods).Feb2000DraftDocumentAGoodPracticeGuidetotheAdministrationofSubstancesandRemovalofBlood,IncludingRoutesandVolumesESLAVHomepageNOTETHISISANINITIALDRAFTOFTHEPAPERWHICHHASNOWBEENPUBLISHEDINTHEFOLLOWINGJOURNALEFPIA/ECVAMpaperongoodpracticeinadministrationofsubstancesandremovalofblood,JApplToxicol2115-23,2001.PrefaceThispublicationistheresultofaninitiativebetweenEFPIA(theEuropeanFederationofPharmaceuticalIndustriesAssociations)andECVAM(theEuropeanCenterfortheValidationofAlternativeMethods).Itsobjectivesaretoprovidetheresearcherinthesafetyevaluationlaboratorywithanup-to-date,easytousesetofdatasheetstoaidinthestudydesignprocesswhilstatthesametimeaffordingmaximumwelfareconsiderationstotheexperimentalanimals.AlthoughthispublicationistargetedatresearchersintheEuropeanPharmaceuticalIndustryitisconsideredthattheprinciplesunderpinningthedatasetsandrefinementproposalsareequallyapplicabletoallthosewhousethesetechniquesonanimalsintheirresearchwhetherinResearchInstitutes,Universitiesorothersectorsofindustry.TheimplicationsofthisdocumentmayleadtodiscussionwithRegulatorssuchasthoseresponsibleforPharmacopoeialtesting.Therearenumerouspublicationsdealingwiththeadministrationoftestsubstancesandremovalofbloodsamplesand,additionally,manylaboratoriesalsohavetheirown‘in-house’guidelineswhichhavebeendevelopedbycustomandpracticeovermanyyears.WithintheEuropeanUnionDirective86/609EEC(EU,1986)wehaveanobligationtorefineexperimentstocausetheminimumamountofstress.Wehopethisguidewillprovidebackgrounddatausefultothoseresponsibleforprotocoldesignandreview.Thisdocumentisbasedonpeerreviewedpublicationswheneverpossible,but,wherethatisnotpossible,wehaveused‘in-house’dataandtheexperienceofthoseontheworkingparty(aswellashelpfulcommentssubmittedbytheindustry)forafinalopinion.Thedocumentalsoaddressesthecontinuingneedtorefinethetechniquesassociatedwithadministrationofsubstancesandwithdrawalofbloodandsuggestswaysofdoingso.Datasharingbetweenlaboratoriesshouldbeencouragedtoavoidduplicationofanimalwork,aswellassharingpracticalskillsconcerninganimalwelfareandscientificproblemscausedby‘overdosing’somewayoranother.Therecommendationsinthisdocumentrefertothe‘normal’animalandspecialconsiderationisneeded,forinstance,duringpregnancyandlactation.Interpretationofstudiesmaybeconfoundedwhenlargevolumesareadministeredorexcessivesamplingemployed,particularlyifanaestheticsareused.GoodPracticeGuideforAdministrationofSubstancesIntroductionDosingofexperimentalanimalsisnecessaryforavarietyofscientificinvestigationsandtomeetregulatorydemands.Thepharmaceuticalindustry,inparticular,hasinvestigatedthelevelsofdosingcompatiblewithanimalwelfareandvalidscience(Hull1995).Inthepreclinicalstageofthesafetyevaluationofnewdrugsitisnormalpracticetousemultiplesofthe‘effectivedose’inordertoattempttoestablishthenecessarysafetymargins.Wherechemicalsareoflowtoxicityorareonlypoorlysolubleinacceptableformulations,alargevolumemayberequiredtobegiventoindividualanimalstosatisfybothscientificandregulatoryrequirements.Theintendedclinicalusemayalsoimpactontheacceptabilityoflargerthanusualdosevolumes,egimagingagentsorplasmaexpandersforintravenousapplication.TheobjectivesoftheWorkingGroupwereasfollows:Toprovideaguideonadministrationvolumesforuseincommonlaboratoryspeciesusedintoxicitystudiesrequiredbyregulatoryauthorities.Toprovideconsensusdosagelevelsforroutineusewhichrepresentgoodpracticeintermsofanimalwelfareandpracticality.Toproduceaguidetodosagelevelsrepresentingtheupperlimitofcommonpractice.Thisleavesscopetomakethecaseforspecialinvestigations.AdministrationvolumesTable1presentsadministrationvolumesforthecommonlyemployedroutesinthemostfrequentlyusedspecies.Theyareconsensusfiguresbasedonpublishedliteratureandinternalguidelines.ThemarmosetandminipigarenowconsideredwithinthiscategorysincetheyarebeingusedincreasinglyinEurope.Table1AdministrationVolumesConsideredGoodPractice(andpossiblemaximaldosevolumes)SpeciesRouteandVolumes(ml/kgexcept*ml/site)Oralscipimivbolusiv(slowinj)Mouse10(50)10(40)20(80)0.05*(0.1)*5(25)Rat10(40)5(10)10(20)0.1*(0.2)*5(20)Rabbit10(15)1(2)5(20)0.25(0.5)2(10)Dog5(15)1(2)1(20)0.25(0.5)2.5(5)Macaque5(15)2(5)-(10)0.25(0.5)2(-)Marmoset10(15)2(5)-(20)0.25(0.5)2.5(10)Minipig10(15)1(2)1(20)0.25(0.5)2.5(5)Notestobeusedinconjunctionwithtable:(-)datanotavailableFornon-aqueousinjectatesconsiderationmustbegiventotimeofabsorptionbeforere-dosing.Nomorethan2intramuscularsitesshouldbeusedperday.Subcutaneoussitesshouldbelimitedto2to3sitesperday.ThesubcutaneoussitedoesnotincludeFreund’sadjuvantadministrationTwosetsoffiguresareshownineachcolumn.Figuresintheleftsideofcolumnsareintendedasaguideto‘goodpractice’dosevolumesforsingleormultipledosing.Thesecondbracketedsetoffigures,wheregiven,arethepossiblemaximalvalues.Ifexceeded,animalwelfareorscientificimplicationsmayresultandreferencetotheresponsibleveterinarysurgeonshouldbemade.InsomeinstancesfiguresaretheretoaccommodatePharmaco