抗癌藥英文課件

抗癌藥（Antineoplasticagents）

抗癌藥（Antineoplasticagents）1Overview

IntroductionMalignantdiseaseaccountsforahighproportionofdeathsinindustrialisedcountries.Thetreatmentofanticancerdrugistogivepalliation,induceremissionand,ifpossible,cure.OverviewIntroduction2OverviewIntroductionCanceroccursafternormalcellshavebeentransformedintoneoplasticcellsthroughalterationoftheirgeneticmaterialandtheabnormalexpressionofcertaingenes.Neoplasticcellsusuallyexhibitchromosomalabnormalitiesandthelossoftheirdifferentiatedproperties.Thesechangesleadtouncontrolledcelldivisionandmanyresultintheinvasionofpreviouslyunaffectedorgans,aprocesscalledmetastasis.OverviewIntroduction3

AdvancesinCancerChemotherapy

Treatmentoptionsofcancer:Surgery:before1955Radiotherapy:1955~1965Chemotherapy:after1965ImmunotherapyandGenetherapy

AdvancesinCancerChemothera4AdvancesinCancerChemotherapyThetreatmentofapatientwithcancermayaimto:givepalliation,forexamplepromptreliefofunpleasantsymptomssuchassuperiorvenacavaobstructionfromamediastinaltumorinduce‘remission’sothatallmacroscopicandmicroscopicfeaturesofthecancerdisappear,thoughdiseaseisknowntopersistcure,forwhichallthecellsoftheclonemustbedestroyed.AdvancesinCancerChemotherap5CancerChemotherapy

DiseaseName5YearsSurvivalRateChildhoodAcuteLymphoblasticLeukemia50~80%AdultAcuteLymphoblasticLeukemia20~60%ChildhoodAcuteMyeloblasticLeukemia20~60%AdultAcuteMyeloblasticLeukemia 10~20%BreastCancer（Premenopausal） 10~20%BreastCancer（Postmenopausal） 0~15%Hodgkin’slymphoma* 40~80%CancerChemotherapyDisea6CancerChemotherapyDiseaseName5YearsSurvivalRateSmallCellLungCancer（LimitedStage） 10~20% （ExtensiveStage）0~5%Non-Hodgkin’slymphoma* 40~65%OvarianCancer 40~60%ChildrenSolidTumor(Nephroblastoma,Rhabdomyosarcoma,Lymphoma，Osteosarcoma）* 60~90%Trophoblastoma（ChorionEpithelioma）**80~90%SeminomaofTestis** 60~90%EmbryonicCarcinomaofTestis 60~80%Note：*Combinationwithothertherapeutics **ChemotherapyLevelofourcountryishighCancerChemotherapyDiseaseNam7TheClassificationofAnticancerDrugsAccordingtochemicalstructureandresourceofthedrug;Accordingtobiochemistrymechanismsofanticanceraction;Accordingtothecycleorphasespecificityofthedrug

TheClassificationofAnticanc8TheClassificationofAnticancerDrugsAccordingtochemicalstructureandresourceofthedrug:

AlkylatingAgents,Antimetabolite,Antibiotics,PlantExtracts，Hormones，Others.TheClassificationofAnticanc9TheClassificationofAnticancerDrugsAccordingtobiochemistrymechanismsofanticanceraction:BlocknucleicacidbiosynthesisDirectinfluencethestructureandfunctionofDNAInterferetranscriptionandblockRNAsynthesis

InterfereproteinsynthesisandfunctionInfluencehormonehomeostasisOthersTheClassificationofAnticanc10TheClassificationofAnticancerDrugsAccordingtothecycleorphasespecificityofthedrug:

Cellcyclenonspecificagents(CCNSA)Cellcyclespecificagents(CCSA)TheClassificationofAnticanc11TheBasicConceptof

CellGenerationCycleThecycleofcellreplicationincludes:M（Mitosis）phaseG1（Gap1,periodbeforeS）phaseS（DNAsynthesis）phaseG2（Gap2,periodafterS）phase

GrowthFraction(GF）TheBasicConceptof

CellGen12抗癌藥英文課件13GrowthFraction(GF)GF＝ProliferatingcellgroupTotaltumorcellgroupCCNSA：drugsthatareactivethroughoutthecellcycle.CCSA:

drugsthatactduringaspecificphaseofthecellcycle.GrowthFraction(GF)GF＝Prolife14CCSAandCCNSACellCycleNonspecificAgents(CCNSA)

drugsthatareactivethroughoutthecellcycle

AlkylatingAgentsPlatinumCompoundsAntibiotics

CCSAandCCNSACellCycleNonsp15CellCycleSpecificAgents(CCSA)

drugsthatactduringaspecificphaseofthecellcycle

SPhaseSpecificDrug:

Aantimetabolites,TopoisomeraseInhabitors

MPhaseSpecificDrug:

VincaAlkaloids,Taxanes

G2PhaseSpecificDrug:

BbleomycinCCSAandCCNSACellCycleSpecificAgents(CC16MechanismofAnticancerDrugsBlocknucleicacid(DNA,RNA)biosynthesisDirectlydestroyDNAandinhibitDNAreproductionInterferetranscriptionandblockRNAsynthesisInterfereproteinsynthesisandfunctionInfluencehormonehomeostasisMechanismofAnticancerDrugsB17BlockNucleicAcid(DNA,RNA)BiosynthesisAntimetabolites:FolicAcidAntagonist:

inhibitdihydrofolatereductase(methotrexate)PyrimidineAntagonist:

inhibitthymidylatesynthetase(fluorouracil);inhibitDNApolymerase(cytarabine)PurineAntagonist:

inhibitinterconversionofpurinenucleotide(mercaptopurine)RibonucleosideDiphosphateReductaseAntagonist:

(hydroxyurea)

BlockNucleicAcid(DNA,RNA)18InterfereProteinSynthesis

Antitubulin:

vincaalkaloids

and

taxanes;Interferethefunctionofribosome:

harringtonines；Influenceaminoacidsupply:

L-asparaginase

Bindtubulin,destroyspindletoproducemitoticarrest.InterfereProteinSynthesisAn19InterfereTranscriptionandBlockRNASynthesisBindwithDNAtoblockRNAproduction.

doxorubicinInterfereTranscriptionandBl20InfluencetheStructureandFunctionofDNAAlkylatingAgent:

mechlorethamine,cyclophosphamideandthiotepaPlatinum:

cis-platiniumAntibiotic:

bleomycinandmitomycinCTopoismeraseinhibitor:

camptothecineand

podophyllotoxin

InfluencetheStructureandFu21InfluenceHormoneHomeostasis

Thesedrugsbindtohormonereceptorstoblocktheactionsofthesexhormoneswhichresultsininhibitionoftumorgrowth.EstrogensandestrogenantagonisticdrugAndrogensandandrogenantagonisticdrugProgestogendrugGlucocorticoiddruggonadotropin-releasinghormoneinhibitor:

leuprolide,goserelinaromataseinhibitor:

aminoglutethimide,anastrazoleInfluenceHormoneHomeostasis22TheLongRoadofaNewMedicineTheLongRoadofaNewMedicin23TheMainStepofAnticancerDrugResearch

Non-clinicalResearch：1.AnticancerDrugScreen:

invitro：tumorcellculture,tumorinhibitor/killtest

invivo：animalxenograftmodele.g.Ehrlichascitestumor,S180lymphosarcoma2.Pharmacodynamics,pharmacokineticsandtoxicologytestTheMainStepofAnticancerDr24TheMainStepofAnticancerDrugResearchClinicalResearch:

Phase1clinicaltrialPhase2clinicaltrialPhase3clinicaltrialPhase4clinicaltrialTheMainStepofAnticancerDr25TheMainStepofAnticancerDrugResearchPhase1clinicaltrial

InPhase1clinicaltrials,researcherstestanewdrugortreatmentinasmallgroupofpeople(20-80)forthefirsttimetoevaluateitssafety,determineasafedosagerange,andidentifysideeffects.TOLERANCEPHARMACOKINETICSTheMainStepofAnticancerDr26TheMainStepofAnticancerDrugResearchPhase2clinicaltrial

InPhase2clinicaltrials,thestudydrugortreatmentisgiventoalargergroupofpeople(40-100)toseeifitiseffectiveandtofurtherevaluateitssafety.

TheMainStepofAnticancerDr27TheMainStepofAnticancerDrugResearchPhase3clinicaltrial

InPhase3studies,thestudydrugortreatmentisgiventolargegroupsofpeople(morethan200)tofurtherdetermineitseffectiveness,monitorsideeffects,compareittocommonlyusedtreatments,andcollectinformationthatwillallowthedrugortreatmenttobeusedsafely.TheMainStepofAnticancerDr28TheMainStepofAnticancerDrugResearchPhase4clinicaltrial

Phase4studiesaredoneafterthedrugortreatmenthasbeenmarketed.Thesestudiescontinuetestingthestudydrugortreatmenttocollectinformationabouttheireffectinvariouspopulationsandanysideeffectsassociatedwithlong-termuse.

TheMainStepofAnticancerDr29AnticancerDrugsAlkylatingAgentAntimetaboliteAntibioticsAlkaloid

HormonesOthers（cis-platinum，carboplatin，lobaplatin）AnticancerDrugsAlkylatingAge30AlkylatingAgentsOneofthefrighteningdevelopmentsofWorldWarIwastheintroductionofchemicalwarfare.Thesecompoundswereknownasthenitrogenmustardgases.Thenitrogenmustardswereobservedtoinhibitcellgrowth,especiallyofbonemarrow.Shortlyafterthewar,thesecompoundswereinvestigatedandshowntoinhibitthegrowthofcancercells.AlkylatingAgentsOneofthefr31AlkylatingAgentsMechanismofActionNitrogenmustardsinhibitcellreproductionbybindingirreversiblywiththenucleicacids(DNA).Thespecifictypeofchemicalbondinginvolvedis

alkylation.Afteralkylation,DNAisunabletoreplicateandthereforecannolongersynthesizeproteinsandotheressentialcellmetabolites.Consequently,cellreproductionisinhibitedandthecelleventuallydiesfromtheinabilitytomaintainitsmetabolicfunctions.AlkylatingAgentsMechanismof32ClassificationofAlkylatingAgentsBisChloroethylAmines：Cyclophosphamide,Chlormethine,Chlorambucil,SarcolysineNithrosoureas：Carmustine，LomustineEthyeneammoniumorAziridines：Thiotepa，triethylenemelamineAlkysulfonates：BusulfanClassificationofAlkylatingA33ResistanceofAlkylatingAgents

Resistancetoalkylatingagentshasseveralcauses:

Membranetransportmaybedecreased.Thedrugmaybeboundbyglutathione(GSH)viaGSH-S-transferaseormetallothioneinsinthecytoplasmandinactivated.Thedrugmaybemetabolizedtoinactivespecies.ResistanceofAlkylatingAgent34AdverseEffectsofAlkylatingAgentsMyelosuppressionisthedose-limitingadverseeffectforalkylatingagents.Nauseaandvomitingarecommonasareteratogenesisandgonadalatrophy,althoughinthelattercasesthesearevariable,accordingtothedrug,itsschedule,androuteofadministration.Treatmentalsocarriesamajorriskofleukemogenesisandcarcinogenesis.AdverseEffectsofAlkylating35AlkylatingAgents——MustineMustinemustbeinjectedintravenouslybecauseitishighlyreactive.Itdisappearsveryrapidlyfromtheblood,theactivityofMustinelastsonlyafewminutes.ThemainindicationforMustineisintreatmentofHodgkinsdiseaseandlymphomas,butitmayalsobeusefulinothermalignancies.AlkylatingAgents——MustineMust36AlkylatingAgents——CyclophosphamideCyclophosphamidecanalsobegivenorally.Indications：Itisusedinthetreatmentofchroniclymphocycticleukemia,non-Hodgkin’slymphomas,breastandovariancancer,andavarietyofothercancers.Itisalsoapotentimmunosuppressant,itisusedinthemanagementofrheumatoiddisordersandautoimmunenephritis.AdverseEffects:Alopecia,nausea,vomiting,myelosuppression,andhemorrhagiccystitis.AlkylatingAgents——Cycloph37AlkylatingAgents——NitrosoureasCarmustine,Lomustine,SemustinePharmacokinetics:Nitrosoureasarehighlylipophilicandreachcerebrospinalfluidconcentrationsthatareabout30%ofplasmaconcentrations.Indications:BecauseoftheirexcellentCNSpenetration,carmustineandlomustinehavebeenusedtotreatbraintumors.AlkylatingAgents——Nitrosourea38AlkylatingAgents——

PhenylalanineNitrogenMustardMelphalanisanitrogenmustardthatisprimarilyusedtotreatmultiplemyeloma(plasmacellmyeloma),breastcancer,andovariancancer.AlkylatingAgents——

Phenylala39AlkylatingAgents——

AlkysulfonatesBusulfan[Myleran]Indications:Busulfanisadministeredorallytotreatchroicgranulocyticleukemiaandothermyeloproliferativedisorders.AdverseEffects:Busulfanproducesadverseffectsrelatedtomyelosuppression.Itonlyoccasionallyproducesnauseaandvomitting.Inhighdoses,itproducesararebutsometimesfatalpulmonaryfibrosis,”busulfanlung”.AlkylatingAgents——

Alkysulfo40AlkylatingAgents——Thiotepa

Thiotepaisconvertedrapidlybylivermixed-functionoxidasestoitsactivemetabolitetriethylenephosphoramide(TEPA);itisactiveinbladdercancer.AlkylatingAgents——Thiotepa41AntimetabolitesGeneralCharacteristics：AntimetabolitesareSphase-specificdrugsthatarestructuralanaloguesofessentialmetabolitesandthatinterferewithDNAsynthesis.Myelosuppressionisthedose-limitingtoxicityforalldrugsinthisclass.AntimetabolitesGeneralCharact42ClassificationofAntimetabolitesFolicacid

Antagonists:MTX

PurineAntagonists:6MP6TG

PyrimidineAntagonists：5FUaraCHUClassificationofAntimetaboli43Antimetabolites——

FolicAcidAntagonistMethotrexate（MTX）MechanismofAction：

ThestructuresofMTXandfolicacidaresimilar.MTXisactivelytransportedintomammaliancellsandinhibitsdihydrofolatereductase,theenzymethatnormallyconvertsdietaryfolatetothetetrahydrofolateformrequiredforthymidineandpurinesynthesis.Antimetabolites——

FolicAcidA44Antimetabolites——

FolicAcidAntagonistMethotrexate（MTX）Indications：TheuseofMTXinthetreatmentofchoriocarinoma,atrophoblastictumor,wasthefirstdemonstrationofcurativechemotherapy.Itisespeciallyeffectivefortreatingacutelymphocyticleukemiaandfortreatingthemeningealmetastasesofawiderangeoftumors.Antimetabolites——

FolicAcidA45Antimetabolites——

FolicAcidAntagonist

Methotrexate（MTX）AdverseEffects：MTXismyelosuppressive,producingsevereleukopenia,bonemarrowaplasia,andthrombocytopenia.Thisagentmayproduceseveregastrointestinaldisturbances.Renaltoxicitymayoccurbecauseofprecipitation(crystalluria)ofthe7-OHmetaboliteofMTX.Antimetabolites——

FolicAcidA46Antimetabolites——

PurineAntagonists6-Mercapapurine（6-MP）

Thedrugsarebelievedtoactsimilarlytoinhibitpurinebasesynthesis,althoughtheirexactmechanismsofactionarestilluncertain.Indications:MercaptopurineisusedprimarilyforthemaintenanceofremissioninpatientswithacutelymphocyticleukemiaandisgivenincombinationwithMTXforthispurpose.AdverseEffects:Welltolerate.Myelosuppressionisgenerallymildwiththioguanine.Long-termmercaptopurineusemaycausehepatotoxicity.Antimetabolites——

PurineAntag47Antimetabolites——

PyrimidineAntagonists5-Fluorouracil(5-FU)MechanismofAction：Fluorouracilisananalogueofthymineinwhichthemethylgroupisreplacedbyafluorineatom.Ithastwoactivemetabolites:5-FdUMPand5-FdUTP.5-FdUMPinhibitsthymidylatesynthetasesandpreventsthesynthesisofthymidine,amajorbuildingblockofDNA.5-FdUTPisincorporatedintoRNAbyRNApolymeraseandinterfereswithRNAfunction.Antimetabolites——

PyrimidineA48Antimetabolites——

PyrimidineAntagonists5-Fluorouracil(5-FU)Indications：Fluorouracilisexclusivelyusedtotreatsolidtumors,especiallybreast,colorectal,andgastrictumorsandsquamouscelltumorsoftheheadandneck.Antimetabolites——

PyrimidineA49Antimetabolites——

PyrimidineAntagonists5-Fluorouracil(5-FU)AdverseEffects：Fluorouracilmaycausenauseaandvomiting,myelosuppression,andoralandgastrointestinalulceration.Nauseaandvomittingareusuallymild.Withfluorouracil,myelosuppressionismoreproblematicafterbolusinjections,whereasmucosaldamageisdose-limitingwithcontinuousinfusions.Antimetabolites——

PyrimidineA50Antimetabolites——

PyrimidineAntagonistsCytarabineIndications：Cytarabinehasanarrowclinicalspectrumandisprimarilyusedincombinationwithdaunorubicinorthioguanineforthetreatmentofacutenonlymphocyticleukemia.AdverseEffects:Highdosesofcytarabinecandamagetheliver,heart,andotherorgans.

Antimetabolites——

PyrimidineA51AntibioticsClassificationofAntibiotics:Adriamycin(AnthracyalineAntibiotics)MitomycinCBleomycinActinomycinDAntibioticsClassificationofA52AntibioticsAdriamycinandDaunorubicin：Properties:AdriamycinandDaunorubicinaretetracyclineringswiththesugardaunosamine.TheyareDNAintercalatingagentsthatblockthesynthesisofDNAandRNA.TheseagentsareprimarilytoxicduringtheSphaseofcellcycle.Theseagentsimpartsaredtingetotheurine.Adramycinisusedtotreatacuteleukemias,lymphoma,andanumberofsolidtumors.AntibioticsAdriamycinandDaun53AntibioticsMitomycinC:Mechanism:MitomycinCisanantineoplasticantibioticthatalkylatesDNAandtherebycausesstrandbreakageandinhibitionofDNAsynthesis.Indications:Itisprimarilyusedincombinationwithvinvristineassalvagetherapyforbreastcancer.AdverseEffects:Mitomycinproducesdelaysandprolongedmyelosuppressionthatpreferentiallyaffectsplateletsandleukocytes.AntibioticsMitomycinC:54AntibioticsActinomycinD:ActinomycinDintercalatesDNAandtherebypreventsDNAtranscriptionandmessengerRNAsynthesis.Thedrugisgivenintravenously,anditsclinicaluseislimitedtothetreatmentoftrophoblastic(gestational)tumorsandthetreatmentofpediatrictumors,suchasWilms’tumorandEwing’ssarcoma.AntibioticsActinomycinD:55AntibioticsBleomycin:Mechanism:ThedrughasitsgreatesteffectonneoplasticcellintheG2phaseofthecellreplicationcycle.AlthoughbleomycinintercalatesDNA,themajorcytotoxicityisbelievedtoresultfromironcatalyzedfreeradicalformationandDNAstrandbreakage.Indications:ItisusefulinHodgkin’sandnon-Hodgkin’slymphomas,testicularcancer,andseveralothersolidtumors.AdverseEffects:Bleomycinproducesverylittlemyelosuppression.ThemostserioustoxicitiesofBleomycinarepulmonaryandmucocutaneousreactions.AntibioticsBleomycin:56Anti-CancerPlantAllaloidsTubulin-BindingAgents

VincaAlkaloids:Thecellularmechanismofactionofvincaalkaloidsisthepreventionofmicrotubuleassembly,causingcellstoarrestinthelateG2phasebypreventingformationofmitoticfilamentsfornuclearandcelldivision.Anti-CancerPlantAllaloidsTub57Anti-CancerPlantAllaloidsTubulin-BindingAgentsVincaalkaloids:

Vinblastine,vincristin,vindesineandvinorelbineareallalkaloidsderivedfromtheperiwinkleplant(Vincarosea).Indications:VinblastineisusedincombinationwithBleomycinandCisplatinformetastatictesticulartumors.Vincristineisusedincombinationwithprednisonetoinduceremissioninchildhoodleukemia.Vinorelbineisusedtotreatnon-small-celllungcancerandbreastcancer.Anti-CancerPlantAllaloidsTub58Anti-CancerPlantAllaloidsTubulin-BindingAgentsPaclitaxel:

Taxanesenhanceallaspectsoftubulinpolymerization,anactionthatistheoppositetothatofvincaalkaloids,buttheyarealsocytotoxic,emphasizingthedynamicimportanceoftubulinpolymerizationasatargetforcytotoxicdrugs.

Paclitaxel,TaxotereAnti-CancerPlantAllaloidsTub59InterferetheFunctionofRibosome:CephalotaxusAlkaloids:

HarringtonineHomoharringtonineAnti-CancerPlantAllaloidsInterferetheFunctionofRibo60PlatinumCompoundCisplatin:MechanismofAction:CisplatinbindstoguanineinDNAandRNA,andtheinteractionisstabilizedbyhydrogenbonding.ThemolecularmechanismofactionisunwindingandshorteningoftheDNAhelix.PlatinumCompoundCisplatin:61PlatinumCompoundCisplatin:Indications:Cisplatinhasefficacyagainstawiderangeofneoplasms.Itisgivenintravenouslyasafirst-linedrugfortesticular,ovarian,andbladdercancer,anditisalsousefulinthetreatmentofmelanomaandanumberofothersoildtumors.AdverseEffect:Cisplatinproducesrelativelylittlemyelosuppressionbutcancauseseverenausea,vomiting,andnephrotoxicity.PlatinumCompoundCisplatin:62PlatinumCompoundCarboplatin:Indication:Carboplatinhasasimilarspectrumofactivity,butitisapprovedonlyasasecond-linedrugforovariancancer.PlatinumCompoundCarboplatin:63HormonesSeveraltypesofhormone-dependentcancer(especiallybreast,prostate,andendometrialcancer)respondtotreatmentwiththeircorrespondinghormoneantagonists.Estrogenantagonistsareprimarilyusedinthetreatmentofbreastcancer,whereasandrogenantagonistsareusedinthetreatmentofprostatecancer.Corticosteroidsareparticularlyusefulintreatinglymphocyticleukemiasandlymphomas.HormonesSeveraltypesofhormo64HormonesEstrogens:Estrogensinhibittheeffectsofendogenousandrogensandandrogen-dependentmetastaticprostaticcarcinoma.Diethylstilbestrolisusuallytheagentofchoice.Cardiacandcerebrovascularcomplicationsandcarcinomaofthemalebreastarepotentialadverseeffects.HormonesEstrogens:65HormonesProgenstins:Progestinsareusefulinthemanagementofendometrialcarcinomaandback-uptherapyformetastatichormone-dependentbreastcancer.

HormonesProgenstins:66HormonesAntiestrogen:

TamoxifenTamoxifenisthedrugofchoiceinpostmenopausalwomenwithorrecoveringfrommetastaticbreastcancer.Itismosteffectiveinpatientswhohaveestrogenreceptor-positivetumors.Tamoxifenisalsousedasadjunvctivetherapytooophorectomytoleuprolideorgoserelininpremenopausalwomenwithestrogenreceptor-positivetumors.HormonesAntiestrogen:Tamoxife67HormonesAndrogens:Androgenactivityinbreastcancerissimilartothatofestrogens,perhapsforthesamemechanisticreasons.Virilizingeffectsandhepatictoxicitymakethemunacceptabletomostpatients.Fluoxymesteroneisthemostwidelyusedagent.Danazolhasuseinhematologyinaplasticanemiaandcongenitalanemias.HormonesAndrogens:68HormonesGlucocorticoids:Theyareintegralcomponentsofcurativetherapyforacutelymphoblasticleukemia,non-Hodgkin’slymphoma,andHodgkin’sdisease.Glucocorticoidshaveessentialrolesinthepreventionofallergicreaction,emesiscontrol,reliefofintracranialhypertensionorspinalcordcompressioninneurologiccomplications,andpainrelief.HormonesGlucocorticoids:69ProblemsWithCancerChemotherapy

DrugResistance

DrugToxicityProblemsWithCancerChemother70DrugResistance

DenovoResistanceAcquiredResistanceMultidrugResistance(MDR)DrugResistanceDenovoResist71DrugResistance

Denovoresistance:Denovoresistancecanbedenovogenetic(i.e.thecellsareinitiallyinherentlyresistant),orcanarisebecausedrugsareunabletoreachthetargetcellsbecauseofpermeabilitybarrierssuchastheblood-brainbarrier.DrugResistanceDenovoresist72DrugResistance

AcquiredResistance:Acquireddrugresistancemayresultfromgenomicmutations,suchastheinductionordeletionofenzymesinvolvedindrugina