多发性硬化英文 ppt课件

MultipleSclerosisandCurrentlyAvailableTreatmentsintheUSMichelleRainka Pharm D CCRPDentInstituteUniversityatBuffalomrainka mmrainka buffalo eduCopyright Reproductionoftheseslidesisprohibitedwithoutpermissionoftheauthor Multiple multipleareasoflostmyelin Sclerosis ScarringMSisachronicautoimmuneinflammatorydiseaseAffectsCentralNervousSystem brain spinalchordandopticnerves MultipleSclerosis InternationalJournalofMSCare MultipleSclerosis MultipleSclerosis Achronic autoimmunediseaseAffectscentralnervoussystem themyelinsheathcoveringofnervefibersinthebrainandspinalcordImpairsthenervesabilitytosendelectricalimpulses MSStatistics Approximately400 000AmericansarediagnosedwithMSAffects2 5millionpeopleworldwideSymptomonsetanddiagnosisoccurtypicallybetweentheagesof20 502 5 1women manratioPeopleofNorthernEuropeandescentareafflictedmostcommonlyMorecommonabove40 latitudeinareaslikewesternNewYork Womenare2timesmorelikelytogetthedisease i e 2womenforevery1men MorecommoninNorthernEuropeandescendantsthananyotherraceFoundinpeoplewholiveintemperateclimatesOnsetoccursbetweenagesof20and40 SymptomsofMS MuscleweaknessVisualsymptomsBlurryvisionDoublevisionUnsteadygait balanceissuesPain ParesthesiasEmotional CognitivedisturbancesShorttermmemorylossInabilitytoconcentrate FatigueSexualDysfunctionSpeechSwallowingAbnormalsensationsTinglingNumbnessSensitivitytoheatBladderandbowelproblemsFrequencyLossofcontrol MultipleSclerosisKurtzkedisabilitystatusscale1Nodisability minimalneurologicsign2Minimaldisability slightweaknessorstiffness milddisturbanceofgaitormildvisualdisturbance3Moderatedisability monoparesis partialorincompleteparalysisaffectingoneorpartofoneextremity mildhemiparesis slightparalysisaffectingonesideofbody moderateataxia disturbingsensoryloss prominenturinaryoreyesymptom oracombinationoflesserdysfunction4Relativelyseveredisability butfullyambulatorywithoutaid selfsufficientandabletobeupandabout12hoursaday doesnotpreventtheabilitytoworkorcarryonnormallivingactivities excludingsexualdysfunction5Disabilityissevereenoughtoprecludeworking maximalmotorfunctioninvolveswalkingunaidedupto500meters6Needsassistancewalking forexampleacane crutches orbraces7Essentiallyrestrictedtoawheelchairbutabletowheeloneselfandenterandleavethechairwithoutassistance8Essentiallyrestrictedtobedorachair retainsmanyselfcarefunctionsandhaseffectiveuseofarms9Helplessandbedridden10DeathduetoMS resultsfromrespiratoryparalysis comaofuncertainorigin orfollowingrepeatedorprolongedepilepticseizures DiagnosingMS Adiagnosisbyexclusion eliminateotherdiseasestatesthatmayexplainsymptomsbeforesuggestingMSPatientsundergoclinical laboratory hematologyandCSFpanels andimagingstudiestoconfirmdiagnosis DiagnosisbyPoserCriteriaClinicallydefiniteMS2attacksandclinicalevidenceof2separatelesionsLaboratorysupportedDefiniteMS2attacks eitherclinicalorparaclinicalevidenceof1lesion andCSFimmunologicabnormalities1attack clinicalevidenceof2separatelesions CSFabnormalities1attack clinicalevidenceof1andparaclinicalevidenceofanotherseparatelesion CSFabnormalities MRIMRIfindingsthatstronglysuggestiveofMS4ormorewhitematterlesions each 3mm 3whitematterlesions 1periventricularLesions6mmdiameterorgreaterOvoidlesions orientedperpendiculartoventriclesCorpuscallosumlesionsBrainstemlesionsOpenringappearanceofgadoliniumenhancement TheaxialT2WIshowsperi ventricularflame shapedhyperintenseareas MRIImaging NormalBrain PatientwithMS MSLesions Dawson sFingers MSLesionsinSpine CerebralSpinalFluidStudiesStronglysuggestiveofMSNormalRedBloodCellsandglucoseNormalormildlyelevatedprotein5 20mononuclearcells ulIntrathecalIgGsynthesisIncreasedIgGindexor24hoursynthesisrateIncreasedfreekappalightchainsOligoclonalbands Relapsing RemittingMS RRMS Mostcommon affecting85 ofpatients Patientsexperienceworseningofpre existingsymptomsoronsetofnewsymptomsforperiodsofgreaterthan48hourswithoutconcomitantfever knownasrelapses flare ups orexacerbations ofMS Contrastedbysymptom freeperiods knownasremissions wherethepatient ssymptomspartiallyorcompletelydisappear Secondary ProgressiveMS SPMS AprogressionofRRMSMorecommonbeforeadventofdisease modifyingmedicationsApproximately50 ofpatientsprogressedtoSPMSafter10 15yearswithRRMSIncidencehassincedecreasedThisdiseasecourseissteadilyprogressing Canpresentwithorwithoutclear cutrelapses Primary ProgressiveMS PPMS Relativelyrare affecting10 ofpatients Diseasecourseischaracterizedbysteadydecline withoutclear cutrelapses Medicationsaregenerallynoteffectiveattreatingthistypeofdisease Progressive RelapsingMS PRMS Relativelyrare affecting5 ofpatients Steadydiseaseprogression inadditiontoclear cutperiodsofexacerbationsofMS Patientscanbetreatedforrelapseswithsteroids howeverdiseasewillprogressregardlessoftherapy Treatment NotaknowncureTreatmentaimedatcontrollingsymptomsandmaintainingfunctionDiseasemodifyingtherapyTreatmentofRelapsesMedicationsdependingonthesymptomsPhysicaltherapySpeechtherapyPlannedexerciseprogramsinearlycourseofdisease TreatmentforAcuteExacerbation AcutesevereattackCorticosteroidsAhormonethatstimulatesthebodytomakeitsownhormoneandimproveitsimmunesystem Decreasesinflammationbysuppressionofmigrationofpolymorphonuclearleukocytesandreversalofincreasedcapillarypermeability Methylprednisone Solumedrol 1gramivinfusionperdayx3to5days maybefollowedbyoralPrednisonetaper60mgqdx7days then60mgqodx7days then40mgqodx7days then20mgqodx7days thenstopH2blocker PPIforulcerprophylaxisMonitorbloodglucoseWatchforinfection TreatmentforAcuteExacerbation AcutesevereattackCorticotropinActhargel Adrenocorticotropichormonestimulatestheadrenalcortextosecreteadrenalsteroids includingcortisol weaklyandrogenicsubstances andaldosteroneIntramuscularorSubcutaneously 80to120units dayfor2to3weeks CurrentlyAvailableDiseaseModifyingTreatments KM Gawronskietal TreatmentOptionsforMultipleSclerosis CurrentandEmergingTherapiesPharmacotherapy 2010 30 9 916 927 Dipiroetal Pharmacotherapy APathophysiologicA Interferonbeta MechanismofAction Specificinterferon inducedproteinsandmechanismsbywhichinterferonbetaexertsitseffectsinMShavenotbeenfullydefined ItmayaugmentsuppressorT cellfunction maydecreaseinterferongammasecretionbyactivatedlymphocytes maydecreasemacrophageactivatingeffect maydown regulateexpressionofmajorhistocompatibilitycomplexgeneproductiononantigenpresentingglialcells MayalsosuppressTcellproliferationanddecreasebloodbrainbarrierpermeability IntramuscularinjectiongivenonceweeklyDose 30mcgPregnancyCategoryC SubcutaneousinjectiongiventhreetimesaweekDose 22or44mcgPregnancyCategoryC Interferonbeta 1b SubcutaneousinjectiongiveneveryotherdayDose 250mcgachievedovera6weektitrationPregnancyCategoryC Betaseron Rebif Avonex Interferonbeta 1aAvailableinthreeforms Interferonbeta SideEffects FLULIKESYMPTOMS Upto60 ofpatients Pre medicatebeforeinjectionandthedayfollowingwithIbuprofenorAcetaminophentodecreasethesesymptoms Willdissipatewithcontinueduse Generallyworseinfemalesandthosewithlowerbodyweight FeverChillsHeadacheChestpain InjectionsitereactionsErythemaInflammationPainSkindiscoloration swellingDepressionMyalgiaArthralgiaAstheniaMalaiseDiaphoresisMyastheniaAbdominalpain Glatirameracetate MechanismofAction Notfullyknown thoughttoberelatedtoalterationofT cellactivationanddifferentiation Studiesinanimalsandinvitrosystemssuggestthatuponitsadministration glatirameracetate specificsuppressorT cellsareinducedandactivatedintheperiphery Maymimicantigenicpropertiesofmyelinbasicprotein MaybindtoMajorhistocompatibilitycomplexclassIIreceptorsandinhibitbindingofmyelinbasicproteinpeptidestoTcellreceptorcomplexes MayinduceTh2antiinflammatorylymphocytesanddecreaseinflammation demyelination andaxondamage AvailableasCopaxone SubcutaneousinjectiongivenoncedailyDose 20mgPregnancyCategoryB Glatirameracetate SideEffects INJECTIONSITEREACTION Indurations masses andweltsfrominjectionsmaylastfordaysafteradministration PainErythemaInflammationUrticariaTransientflushingVasodilitation Chesttightnessand orchestpainAstheniaNausea vomitingPainArthralgiaAnxietyPalpitationsDyspneaConstrictionofthethroat Natalizumab MechanismofAction Antagonizes 4 integrinoftheadhesionmoleculeverylateactivatingantigen VLA 4onleukocytes bindstothe 4 subunitof 4 1and 4 7integrinsexpressedonthesurfaceofallleukocytesexceptneutrophils andinhibitsthe 4 mediatedadhesionofleukocytestotheircounter receptor s preventstransmigrationofleukocytesacrosstheendotheliumintoinflamedparenchymaltissueAvailableasTysabri Ahumanizedmonoclonalantibody Intravenousinfusiongivenonceevery4weeksDose 300mgPregnancyCategoryC Tysabri Inmultiplesclerosis lesionsarebelievedtooccurwhenactivatedinflammatorycells includingTlymphocytes crosstheblood brainbarrier BBB LeukocytemigrationacrosstheBBBinvolvesinteractionbetweenadhesionmoleculesoninflammatorycellsandtheircounter receptorspresentonendothelialcellsofthevesselwall Theclinicaleffectofnatalizumabinmultiplesclerosismaybesecondarytoblockadeofthemolecularinteractionof 4 1 integrinexpressedbyinflammatorycellswithVCAM 1onvascularendothelialcells andwithconnectingsegment1and orosteopontinexpressedbyparenchymalcellsinthebrain Datafromanexperimentalautoimmuneencephalitisanimalmodelofmultiplesclerosisdemonstratereductionofleukocytemigrationintobrainparenchymaandreductionofplaqueformation detectedbyMRIfollowingrepeatedadministrationofnatalizumab Natalizumab PML ProgressiveMultifocalLeukoencephalopathy PML isasometimesfatalviralopportunisticinfectionthathasbeenobservedinpatientsreceivingnatalizumab ResultsfromactivationofthelatentJohnCunninghampolyomavirusinimmunocompromisedpatients PMLisademyelinatingdiseasesimilartoMS causingimpairmentofthetransmissionofnerveimpulses howeveroncemyelinislostinPML itcannotberegained DuetoPML thereisaTOUCHPrescribingProgramwherepatients prescribers andinfusioncentersmustberegisteredtomonitorforthedevelopmentofthiscondition Note PMLhasnowalsobeenseeninpatientstreatedwithFingolimodandDimethylFumarate Natalizumab SideEffects InfusionreactionincludinghypersensitivityreactionsRespiratorytractinfectionUrinarytractinfectionDepressionHeadacheFatigueDiarrheaCholelithiasisArthralgiaPML Mitoxantrone MechanismofAction IntercalateswithDNAstrandscausingbreaks andinhibitsDNArepairthroughtopoisomeraseII Affectsrapidlydividingcells secondaryeffectsontheimmunesystemAntigenpresentationPro inflammatorycytokineexpressionDecreasedleukocytemigrationAvailableasNovantrone AnimmunosuppressiveagentchemicallyrelatedtodoxorubicinanddaunorubicinIntravenousinfusiongivenonceevery3monthsDose 12mg m2 Cumulativelifetimedoseof100mg m2PregnancyCategoryD Mitoxantrone SideEffects CardiotoxicityBonemarrowsuppressionHemoglobinlevels whitebloodcellcount andplateletcountsmustbemeasuredbeforeeachinfusionStomatitis esophagitis oralulcerationNausea vomitingAlopeciaHeadacheFatigueHepaticdysfunction Fingolimod Gilenya MechanismofAction Actsonthesphingosine 1 phosphate S1P receptorsS1P1andS1P3 5onthesurfaceoflymphocytesDepletesbothCD4 andCD8 Tlymphocytesinthebloodstream upto75 belowbaseline CD4 cellsaredecreasedtoagreaterextentthanCD8 cells Inhibitslymphocytereleasefromlymphaticorgansdecreasingoverallnumbersincirculation Fingolimod FingolimodhasbeenassessedasanoraltherapyforRRMSandSPMSDose 0 5mgQDsignificantlyreducedgadolinium enhancinglesions relapseratecomparedtobothplaceboandAvonex anddemonstratedsignificantlylesslossinbrainvolume 36 ClinicalPharmacology 800patientsinPharmacologystudiesusing0 125to40mgdoseHighoralbioavailabilitywithnofoodeffectMetabolizedbycytochromeCyP450 4F2 noDDI notoxicmetabolitesT1 2of6 9daysNodoseadjustment renal hepaticdysfunction age gender race Reducedlymphocytecount 70 reductionat0 5mgsteadystateHeartratedecreaseonday1 attenuatesovertimeMild moderatedecreaseinFEV1athighdose 5 0mg FirstDoseMonitoring ECGneededbeforeinitiatingMonitorhourlyfor6hrspost1stdoseforbradycardia takeHRandBPContinueobservingifbpm 45orifHRisstillatlowestpointpostdoseat6hoursRepeat1stdosemonitoringifpatientmisses1dayinfirst2weeks 7daysin3rdand4thweeks or14daysafter1month Fingolimod SideEffects NasopharyngitisHeadacheInfluenzaLymphopeniaLeukopeniaUpperrespiratorytractinfectionMacularedemaChangesinFEV1IncreaseinBPHypertensionElevationinLFTsDose dependenteffectsincludetransientheartratereductionontreatmentinitiation smallincreaseinbloodpressure liverenzymeelevations macularedema Teriflunomide Aubagio MechanismofAction Blockspyrimidinesynthesisinrapidlydividingcells inhibitsproteintyrosine kinaseandcyclo oxygenase 2activity anddecreasestheabilityofantigenpresentingcellstoactivateT cells activemetaboliteofleflunomidethathasantiproliferativeandanti inflammatoryactivity inhibitsthemitochondrialenzymaticactivityofdihydroorotatedehydrogenase Dihydroorotatedehydrogenasefunctionsastherate limitingenzymeindenovopyrimidinesynthesis InhibitionofpyrimidinesynthesisselectivelyproducesacytostaticeffectonproliferatingTandBlymphocytesintheperiphery whileavoidingunduecytotoxicitytoothercelltypes 5 6TeriflunomideeffectivelyreducesB lymphocyteproliferationbydirectsuppressionofdihydroorotatedehydrogenaseandreductionoflipopolysaccharide inducedproliferationviathesecretionofimmunoglobulinMfromBcells Additionally independentofteriflunomideactivity B cellproliferationissuppressedbyaninterleukin4classswitchintoimmunoglobulinG1 TheinteractionbetweenBandTlymphocytesiseffectivelyinhibitedbyteriflunomide thus blockadeofTlymphocytedependentantibodyproductionoccurs HasbeenstudiedasanoraltherapyforRRMSandSPMS Doses 7and14mg Teriflunomide Aubagio StudyResults Bothdosesreducedgadolinium enhancingMRIlesionsby61 Theannualizedrelapserateofteriflunomidepatientswas0 56comparedto0 81intheplacebogroup 77 ofpatientsinthe14mgteriflunomidegroupwerefreefromrelapsesduringthestudyperiod comparedtoonly62 intheplacebogroup Teriflunomide Aubagio ThePObioavailabilitysingledosehealthy fastedpatientsis100 peak1to2hours fooddelayedabsorptionbyapproximately6hours7or14mgqdwithorwithoutfoodhalf lifeofteriflunomideis10to12days enterohepaticrecirculationresultsinthetotalplasmaclearanceofapproximately0 5L h 15includingoxidation hydrolysis sulfateconjugation cytochromeP450enzyme3A4 CYP3A4 CYP2C9 andN cetyltransferase substrateofBCRP inhibitorsarecyclosporine eltrombopag gefitnib inhibits2C8 repaglinide paclitaxel pioglitizone rosiglitazone mayincreaseEthinylestradiolandlevonorgestrel maydecreaseINRmayinduce1A2 duloxetine alosetron theophylline caffeine tizanidine inhibitsBCRP hepaticuptaketransporter OATP1B1 renaluptaketransporter OAT3 Teriflunomide SideEffects HeadacheNasopharyngitisUpperrespiratorytractinfectionAlopeciaSensorydisturbancesNauseaParasthesias InsomniaFatigueUrinarytractinfectionIncreasesinLFTsBackpainLimbpainDiarrheaArthralgia Teriflunomide Aubagio Commonadversereactionsobservedinclinicaltrialsatarategreaterthan10 andatincreasedincidencecomparedwithplaceboincludediarrhea elevatedALT nausea influenza hypersensitivityreactionorskindisorder paresthesia andhairthinningneuropathy kidneyproblems hyperkalemia seriousskinproblems breathingproblemsinterstitiallungdisease neworworsening HTN Teriflunomide Aubagio Monitoring MaydecreaseWBC CBCwithin6monthsbeforestarting notduringactiveinfectionsLiverfunctiontestsandbiliwithin6monthsandeverymonthforatleast6monthsafterScreenforlatentTB Teriflunomide Aubagio Blackbox Hepatotoxicity teratogenicity CategoryX registryavailable levelslessthan0 02mg lDetectedinsemen contraceptionformen DecreasedspermcountinmenDetectedinratmilk donotbreastfeed Accelerateeliminationwithcholestyramine8or4gq8hx11dor50gactivatedcharcoalq12hx11dDecreaseconcby98 Without8mo 2years Dimethylfumarate Tecfidera MechanismofAction InducesT helper2 likecytokinescausingApoptosisinactivatedTcellsandDown regulationofintracellularadhesionmolecules leadingtoreducedmigrationoflymphocytes ApprovedasanoraltherapyforRRMSDose 120mgPOBIDfor7days then240mgPOBIDDelayedrelease donotcrush Dimethylfumarate StudyResults DimethylfumaratetreatmentdecreasednumberofnewT1 newT2 andGd lesionsonMRIDecreasedproportionofpatientsrelapsingTrendedtowardsslowingdiseaseprogressionTIDdosingshowednoaddedbenefits Dimethylfumarate SideEffects GISYMPTOMS DiarrheaNauseaCrampingFlushingTransientincreasesinLFTsTransienteosinopheliaLymphopeniaRecentCBC within6months neededbeforetreatment Alemtuzumab Lemtrada MechanismofAction TargetsCD52onlymphocytesandmonocytes causinglong termreductionofcirculatingT cellsEvaluatedasanintravenousinfusionforRRMSandSPMSDose 12mginfusedIVdailyover4hoursfor5days thena3daycourseatmonth12 patientsareobserved2hoursafterinfusionPremedicatewithcorticosteroids methylprednisolone1 000mgorequivalent immediatelypriortoalemtuzumabforthefirst3daysofeachtreatmentcourse Antihistaminesand orantipyreticsmayalsobeconsidered Administerantiviralprophylaxis forherpeticviralinfections beginningonthefirstdayoftreatmentandcontinueforatleast2monthsaftercompletionofalemtuzumabanduntilCD4 lymphocytecountis 200 mm3 Insomeclinicaltrialspatientsreceivedanadditional12mgdailyfor3consecutivedays12monthslaterPregnancycategory C Alemtuzumab StudyResults InSPMS alemtuzumabdidnothindertheformationofnewlesionsonMRI EvaluatingRRMS 12and24mg ImprovedEDSSscore whileEDSSscoreworsenedwithinterferon 1a Decreasedannualizedrelapserate 0 11and0 08respectively 80 ofpatientswerefreefromrelapse comparedto52 treatedwithinterferon 1a Alemtuzumab SideEffects DEVELOPMENTOFAutoimmuneTHYROIDDISORDERSIncludingGRAVES DISEASErequiringthyroidablationIn1 3ofpatientsForMS monitorTSHatbaselineandevery3monthsuntil48monthsafterlastinfusionorlongeroratanytimeduringtherapyifclinicallyindicated Rashin90 ofpatientsHeadachePyrexiaFatiguePruritis NauseaNeurologicproblemsChillsInsomniaChestdiscomfort dusgeusiaDyspneaMusculoskeletalpain discomfortDyspepsiaVomitingFlushing Alemtuzumab SideEffects BlackBoxWarning Alemtuzumabcausesserious sometimesfatal autoimmuneconditions suchasimmunethrombocytopeniaandanti glomerularbasementmembranedisease Monitorcompletebloodcountswithdifferential serumcreatininelevels andurinalysiswithurinecellcountsatperiodicintervalsfor48monthsafterthelastdoseofalemtuzumab Infusionreactions Lemtrada Alemtuzumabcausesseriousandlife thre