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JOURNALOFAPPLIEDTOXICOLOGY
J.Appl.Toxicol.
21,15±23(2001)
AGoodPracticeGuidetotheAdministration
ofSubstancesandRemovalofBlood,
IncludingRoutesandVolumes
Karl-HeinzDiehl
1,RobinHull
2,DavidMorton
3,RudolfP®ster
4,YvonRabemampianina
5,DavidSmith
6,*,Jean-MarcVidal
7andCorvandeVorstenbosch
81Aventis,POBox1140,D35001Marburg,Germany
2NIBSC,BlanchLane,SouthMiimms,PottersBar,HertfordshireEN63QG
3TheUniversityofBirmingham,MedicalSchool,Edgbaston,BirminghamB152TT
4NovartisPharmaAG,CH-4002Basel,Switzerland
5CentredeRechercheP®zer,Etablissementd’Amboise,Z1Poce
Â-sur-Cisse-BP15937401AmboiseCedex,France
6AstraZenecaR&DCharnwood,BakewellRoad,Loughborough,LeicsLE115RH
7Aventis,102RoutedeNoisy,95235RomainvilleCe
Âdex,France
8NVOrganon,POBox20,5340BHOss,Netherlands
Keywords:bloodvolumes;bloodremoval;administrationsubstances;laboratoryanimals;re®nement.
ThisarticleistheresultofaninitiativebetweentheEuropeanFederationofPharmaceuticalIndustries
Associations(EFPIA)andtheEuropeanCentrefortheValidationofAlternativeMethods(ECVAM).
Itsobjectivesaretoprovidetheresearcherinthesafetyevaluationlaboratorywithanup-to-date,easy-
to-usesetofdatasheetstoaidinthestudydesignprocesswhilstatthesametimeaffordingmaximum
welfareconsiderationstotheexperimentalanimals.
AlthoughthisarticleistargetedatresearchersintheEuropeanPharmaceuticalIndustry,itis
consideredthattheprinciplesunderpinningthedatasetsandre®nementproposalsareequallyapplicable
toallthosewhousethesetechniquesonanimalsintheirresearch,whetherinresearchinstitutes,
universitiesorothersectorsofindustry.Theimplicationsofthisarticlemayleadtodiscussionwith
regulators,suchasthoseresponsibleforpharmacopoeialtesting.
Therearenumerouspublicationsdealingwiththeadministrationoftestsubstancesandtheremoval
ofbloodsamples,andmanylaboratoriesalsohavetheirown`in-house’guidelinesthathavebeen
developedbycustomandpracticeovermanyyears.WithinEuropeanUnionDirective86/609EEC
1wehaveanobligationtore®neexperimentstocausetheminimumamountofstress.Wehopethatthis
articlewillprovidebackgrounddatausefultothoseresponsibleforprotocoldesignandreview.
Thisguideisbasedonpeer-reviewedpublicationswheneverpossible,butwherethisisnotpossible
wehaveused`in-house’dataandtheexperienceofthoseontheworkingparty(aswellashelpful
commentssubmittedbytheindustry)fora®nalopinion.Theguidealsoaddressesthecontinuingneed
tore®nethetechniquesassociatedwiththeadministrationofsubstancesandthewithdrawalofblood,
andsuggestswaysofdoingso.Data-sharingbetweenlaboratoriesshouldbeencouragedtoavoid
duplicationofanimalwork,aswellassharingpracticalskillsconcerninganimalwelfareandscienti®c
problemscausedby`overdosing’insomewayoranother.Therecommendationsinthisguidereferto
the`normal’animal,andspecialconsiderationisneeded,forinstance,duringpregnancyandlactation.
Interpretationofstudiesmaybeconfoundedwhenlargevolumesareadministeredorexcessivesampling
employed,particularlyifanaestheticsareused.Copyright
ã2001JohnWiley&Sons,Ltd.
GOODPRACTICEGUIDEFOR
ADMINISTRATIONOFSUBSTANCES
IntroductionDosingofexperimentalanimalsisnecessaryfora
varietyofscienti®cinvestigationsandtomeetregulat-
*Correspondenceto:DrDavidSmith,SeniorDirector,Toxi-
cology,AstraZeneca,R&DCharnwood,BakewellRoad,Lough-
boroughLE115RH
Received6February2000
CopyrightÓ2001JohnWiley&Sons,Ltd.
Accepted27September2000
orydemands.Thepharmaceuticalindustry,inparti-
cular,hasinvestigatedthelevelsofdosingcompatible
withanimalwelfareandvalidscience.
2Inthepreclini-
calstageofthesafetyevaluationofnewdrugsitis
normalpracticetousemultiplesofthe`effectivedose’
inordertoattempttoestablishthenecessarysafety
margins.Wherechemicalsareoflowtoxicityorare
onlypoorlysolubleinacceptableformulations,alarge
volumemayberequiredtobegiventoindividual
animalstosatisfybothscienti®candregulatoryrequire-
ments.Theintendedclinicalusemayalsohavean
impactontheacceptabilityoflargerthanusualdose
volumes,e.g.imagingagentsorplasmaexpandersfor
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