多发性硬化--英文

MultipleSclerosisandCurrentlyAvailableTreatmentsintheUSMichelleRainka,Pharm.D.,CCRPDentInstituteUniversityatBCopyright:Reproductionoftheseslidesisprohibitedwithoutpermissionoftheauthor,“Multiple”-multipleareasoflostmyelin“Sclerosis”-ScarringMSisachronicautoimmuneinflammatorydiseaseAffectsCentralNervousSystem(brain,spinalchordandopticnerves),MultipleSclerosis,InternationalJournalofMSCare,MultipleSclerosis,MultipleSclerosis,Achronic,autoimmunediseaseAffectscentralnervoussystemthemyelinsheathcoveringofnervefibersinthebrainandspinalcordImpairsthenervesabilitytosendelectricalimpulses,MSStatistics,Approximately400,000AmericansarediagnosedwithMSAffects2.5millionpeopleworldwideSymptomonsetanddiagnosisoccurtypicallybetweentheagesof20-502.5:1women:manratioPeopleofNorthernEuropeandescentareafflictedmostcommonlyMorecommonabove40latitudeinareaslikewesternNewYork.Womenare2timesmorelikelytogetthedisease(i.e.2womenforevery1men)MorecommoninNorthernEuropeandescendantsthananyotherraceFoundinpeoplewholiveintemperateclimatesOnsetoccursbetweenagesof20and40,SymptomsofMS,MuscleweaknessVisualsymptomsBlurryvisionDoublevisionUnsteadygait/balanceissuesPain/ParesthesiasEmotional/CognitivedisturbancesShorttermmemorylossInabilitytoconcentrate,FatigueSexualDysfunctionSpeechSwallowingAbnormalsensationsTinglingNumbnessSensitivitytoheatBladderandbowelproblemsFrequencyLossofcontrol,MultipleSclerosisKurtzkedisabilitystatusscale1NodisabilityDecreasesinflammationbysuppressionofmigrationofpolymorphonuclearleukocytesandreversalofincreasedcapillarypermeability.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:,InterferonbetaSideEffects,FLULIKESYMPTOMS!Upto60%ofpatients.Pre-medicatebeforeinjectionandthedayfollowingwithIbuprofenorAcetaminophentodecreasethesesymptoms.Willdissipatewithcontinueduse.Generallyworseinfemalesandthosewithlowerbodyweight.FeverChillsHeadacheChestpain,InjectionsitereactionsErythemaInflammationPainSkindiscoloration/swellingDepressionMyalgiaArthralgiaAstheniaMalaiseDiaphoresisMyastheniaAbdominalpain,Glatirameracetate,MechanismofAction=Notfullyknown,thoughttoberelatedtoalterationofT-cellactivationanddifferentiation.Studiesinanimalsandinvitrosystemssuggestthatuponitsadministration,glatirameracetate-specificsuppressorT-cellsareinducedandactivatedintheperiphery.Maymimicantigenicpropertiesofmyelinbasicprotein;MaybindtoMajorhistocompatibilitycomplexclassIIreceptorsandinhibitbindingofmyelinbasicproteinpeptidestoTcellreceptorcomplexes;MayinduceTh2antiinflammatorylymphocytesanddecreaseinflammation,demyelination,andaxondamage.AvailableasCopaxoneSubcutaneousinjectiongivenoncedailyDose=20mgPregnancyCategoryB,GlatirameracetateSideEffects,INJECTIONSITEREACTION!Indurations,masses,andweltsfrominjectionsmaylastfordaysafteradministration.PainErythemaInflammationUrticariaTransientflushingVasodilitation,Chesttightnessand/orchestpainAstheniaNausea/vomitingPainArthralgiaAnxietyPalpitationsDyspneaConstrictionofthethroat,Natalizumab,MechanismofAction=Antagonizes4-integrinoftheadhesionmoleculeverylateactivatingantigen(VLA)-4onleukocytes.bindstothe4-subunitof41and47integrinsexpressedonthesurfaceofallleukocytesexceptneutrophils,andinhibitsthe4-mediatedadhesionofleukocytestotheircounter-receptor(s).preventstransmigrationofleukocytesacrosstheendotheliumintoinflamedparenchymaltissueAvailableasTysabriAhumanizedmonoclonalantibody.Intravenousinfusiongivenonceevery4weeksDose=300mgPregnancyCategoryC,Tysabri,Inmultiplesclerosis,lesionsarebelievedtooccurwhenactivatedinflammatorycells,includingTlymphocytes,crosstheblood-brainbarrier(BBB).LeukocytemigrationacrosstheBBBinvolvesinteractionbetweenadhesionmoleculesoninflammatorycellsandtheircounter-receptorspresentonendothelialcellsofthevesselwall.Theclinicaleffectofnatalizumabinmultiplesclerosismaybesecondarytoblockadeofthemolecularinteractionof41-integrinexpressedbyinflammatorycellswithVCAM-1onvascularendothelialcells,andwithconnectingsegment1and/orosteopontinexpressedbyparenchymalcellsinthebrain.Datafromanexperimentalautoimmuneencephalitisanimalmodelofmultiplesclerosisdemonstratereductionofleukocytemigrationintobrainparenchymaandreductionofplaqueformation,detectedbyMRIfollowingrepeatedadministrationofnatalizumab.,NatalizumabPML,ProgressiveMultifocalLeukoencephalopathy(PML)isasometimesfatalviralopportunisticinfectionthathasbeenobservedinpatientsreceivingnatalizumab.ResultsfromactivationofthelatentJohnCunninghampolyomavirusinimmunocompromisedpatients.PMLisademyelinatingdiseasesimilartoMS,causingimpairmentofthetransmissionofnerveimpulses,howeveroncemyelinislostinPML,itcannotberegained.DuetoPML,thereisaTOUCHPrescribingProgramwherepatients,prescribers,andinfusioncentersmustberegisteredtomonitorforthedevelopmentofthiscondition.Note:PMLhasnowalsobeenseeninpatientstreatedwithFingolimodandDimethylFumarate,NatalizumabSideEffects,InfusionreactionincludinghypersensitivityreactionsRespiratorytractinfectionUrinarytractinfectionDepressionHeadacheFatigueDiarrheaCholelithiasisArthralgiaPML,Mitoxantrone,MechanismofAction=IntercalateswithDNAstrandscausingbreaks,andinhibitsDNArepairthroughtopoisomeraseII.AffectsrapidlydividingcellssecondaryeffectsontheimmunesystemAntigenpresentationPro-inflammatorycytokineexpressionDecreasedleukocytemigrationAvailableasNovantroneAnimmunosuppressiveagentchemicallyrelatedtodoxorubicinanddaunorubicinIntravenousinfusiongivenonceevery3monthsDose=12mg/m2Cumulativelifetimedoseof100mg/m2PregnancyCategoryD,MitoxantroneSideEffects,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,800patientsinP