药学专业英语视听说教程 课件全套 史志祥 lecture1 Target Identification and Lead Discovery -Lecture 9 Natural Products

Lecture1TargetIdentificationandLeadDiscovery[,saikləu'ɔksidʒə,neis]efficacyselectivitypathwaypotencyprodrugaffinityantagonistchromatographyhydrophobiccombinatorialchemistrybiologicalscreenbindingdenaturationagonistantagonistfunctionalabsorbedmetabolizeddrugcandidateoptimizedOralpracticeActive/Whatareactives,hits,leadsandcandidatedrugsintheprocessofnewdrugdevelopment?ItshouldhavedesiredpharmacologicalpropertiesandproducetherighteffectinthescreensthiscanpreventuptakeofthedrugintothebodyItshouldnotcontaintoxicgroupsorgroupsknowntoproducetoxicmetabolitesthecompoundshouldinteractreversiblywiththetargettestinginascreeningcascadesharingthemforapriceinanacademiclaboratorybycombinatorialchemistrynaturalproductsbiologicalagents.1.Whatisadruginchemicalterm?Chemicallyspeaking,adrugisamoleculethatbindstoanothermoleculartargetinordertoalteritsfunctionandusuallythattargetisanenzyme.2.What’sthedifferencebetweencompetitiveandnon-competitiveinhibition?3.Whatarethedifferentlevelsofproteinstructure?4.Whatisstructure-baseddrugdesign?Withtheknowledgeofthestructuresofachemicalcompoundandatargetenzymeaswellastheinteractionsbetweenthem,scientistscanmakechangesthatwouldimprovethebindingofthatsubstrateinthepocketandmakeitamoreeffectivedrug.Inthisway,scientistscandesignbetterdrugs.5.Whatareaffinityandselectivity?Andwhyaretheydesirablepropertiesforagooddrug?----Affinityishowtightlyadrugbindstoitsmoleculartarget.Thetighterthedrugbinds,themoreeffectiveit’sgoingtobebecauselessofitwillbeneededtobindjustasmuchofthetarget.----Selectivityishowwelladrugbindstotheintendedtargetandnottoothertargets.Ahigherselectivitywillleadtolessbindingwithunintendedtargetsandsubsequentlylesssideeffects.----Agooddrugshouldhavehighaffinityandhighselectivity.1.HowisRASproteinswitchedonandswitchedoff?----WhenRASisGDP-bound,itisintheinactivestate;----GEFcatalyzesthereleaseofGDP;----GTPbindstoRAStoswitchiton;----GAPproteinhydrolyzesGTPbybreakingaphosphatebondtomakeGDP.Throughthismechanism,RASisswitchedoffagain.1.WhyisKRAScalled“thekingofRASgenes”?----KRASisthemostcommonlymutatedofthethreeRASgenesincancer;----Ithasthehighestmutationfrequency,coveringabout80%ofallcancer;----AsthefirstthreemajorcausesofcancerdeathintheUS,lung,colonandpancreaticcancerhavethehighestfrequencyofKRASmutations.2.Whydoesthespeakeruse“alongandwindingroad”todescribedrugdiscoveryprocess?----Therearemanystepstogothroughinthewholeprocess;----Ittakesatleasttenyearstocompletethejourneyfromtheinitialdiscoverytothemarketplace.----Theoddsofsuccessarevery,verylow.3.WhydidKRASdevelopareputationasanundruggabletarget?Comparedwithotherproteins,therelativelysmoothproteinstructuremeantthatdesigninginhibitorstobindtosurfacegrooveswasdifficult,stallingprogressindrugdevelopmentformanyyears.4.WhatbreakthroughsindruggingKRASarementionedinthislecture?Doyouknowanyotheradvancementsinthisfield?----In2013,thefirstsmallmoleculethatcanbindintoRASandblockRASfunctionwasidentified;----In2021,thefirstKRASinhibitortargetingmutationG12Cwasfinallyapprovedforthetreatmentoflungcancerpatientswiththismutation;----AdditionalKRASG12Cinhibitorsthatarenowbeingevaluatedintheclinic.Sotorasib(索托拉西布)bindstothecysteineresidueinKRASG12Cmutations,holdingtheproteininitsinactiveform.ThecysteineresiduethatsotorasibtargetsisnotpresentinthewildtypeKRAS,whichpreventsoff-targeteffects.Thismutationispresentin13%ofnonsmallcelllungcancer,3%ofcolorectalandappendixcancer,and1-3%ofsolidtumors.Lecture3Chemistry,ManufacturingandControlreconciliationvariabilityfriabilitypassagefreeze-dryingassayfermentercentrifugationstartingmaterialgranulationlotefficacyspecificationconsistencystabilityshelflifecompositionlicensesThemanufacturingprocessiswellcontrolledThespecificationsandtestproceduresareadequatelydefinedmarketingthesamefundamentalmanufacturingprocessesandthetestproceduresthesamequalityproductismanufacturedequivalencebeforeandaftertheCMCchangeThequalityofrawmaterialsincludingthestartingmaterialsisnotalwaysthesameThemanufacturingconditionsarenotalwaysstableTheCMCreviewersshareinformationabouttheirreviewprocessmethodsformanufacturingprocesschangeswiththeGMPinspectorsTheGMPinspectorsinformtheCMCreviewersoftheresultsoftheGMPinspectionsTheCMCreviewersmayalsojoininwithGMPinspectionsFFFTFT1.Whatfactorsshouldbeconsideredformanufacturingtablets?Severalfactorsshouldbeconsideredformanufacturingtablets,includingthemanufacturingprocess,thephysiochemicalpropertiesofAPI,thetypesandconcentrationofexcipientsintheformulation,thecompressionforceofthetabletpunch,thetablet’sfriabilityandhardness,andthecosts,etc.2.Whatarethemostcommontabletmanufacturingprocesses?Thethreemostcommontabletsmanufacturingprocessesaredirectcompression,wetgranulation,androllercompaction,alsocalleddrygranulation.3.Howtodeterminetheflowpropertiesofpowders?Theflowpropertiesofpowdersaremeasuredbytheangleofrepose.Asmallangleindicatesgoodflowability.4.Whyisgranulationnecessaryfortabletmanufacturing?Granulationistheprocessofforminggrainsorgranulesfromapowderyorsolidsubstance,producingagranularmaterial.Granulationproducesfree-flowing,dust-freegranulesthatareeasytocompress.5.Whatarethebasicstepsofwetgranulation?Additionofgranulatingfluid→Granulation→Milling→Drying→Sieving→Blendingwithfunctionalexcipients→Readyforcompression

6.Whatarethebasicstepsofdrygranulation?Premixingexcipients→Rollercompaction→Grinding→Sieving→BlendingwithAPI→Compression1.Whatarethekeymanufacturingstepsinvolvedinmanufacturingvaccineonalargescale?----AntigenproductionThefirststeptypicallyinvolvesgrowingvirusesorbacteriaincomplexmediacontainingnutrientslikecarbohydrates,proteins,andvitamins.Bacterialantigensareproducedinlargefermenters,withmultiplegrowthpassagesunderstrictlyasepticconditionstoavoidcontamination.Afterfermentation,thesuspensionundergoesdownstreamprocessing,whichmayincludeconcentration,centrifugation,filtration,orinactivationsteps.Theantigenharvestmaterialisthenstoreduntiltestedandreleasedforfurtherprocessinginthefinalvaccinebatch.Viralantigenproductioninvolvesgrowingvirusesinhostcellssuchasmammalianorinsectcells.Oncethecellsareinfectedwithvirusseeds,thevirusesreplicatewithinthecellsandareharvested.Thebioreactorsareautomatedandmanagedbyspeciallytrainedtechnicians,withdownstreamactivitiessimilartobacterialprocesses.----FinalvaccineproductionTherearetwomajorkindsofvaccines:modifiedlivevaccineswithliveorganismsandinactivatedvaccineswithchemicallyinactivatedorganisms.Duringformulation,antigensarecombinedwithnecessarycomponentsandtransferredtothefillingroominsterilizedlines.Livevaccinesrequirepreservationofactiveorganisms.Sterilizedvialsarefilledwithvaccineunderstrictlycontrolled,asepticconditionsandthenfreeze-driedforlong-termstorage.Inactivatedvaccineshaveasimilarfillingprocessbutaretypicallyfilledinplasticbottlespre-sterilizedbyirradiation.Somevaccinesarealsofilleddirectlyintopre-sterilizedsyringes.----FinalvaccineproductionTherearetwomajorkindsofvaccines:modifiedlivevaccineswithliveorganismsandinactivatedvaccineswithchemicallyinactivatedorganisms.Duringformulation,antigensarecombinedwithnecessarycomponentsandtransferredtothefillingroominsterilizedlines.Livevaccinesrequirepreservationofactiveorganisms.Sterilizedvialsarefilledwithvaccineunderstrictlycontrolled,asepticconditionsandthenfreeze-driedforlong-termstorage.Inactivatedvaccineshaveasimilarfillingprocessbutaretypicallyfilledinplasticbottlespre-sterilizedbyirradiation.Somevaccinesarealsofilleddirectlyintopre-sterilizedsyringes.----PackagingandLabeling:Eachoftheeighteenpackagingcentersisdesignedforspecificoperationsthatincludelabeling,cartoning,bagging,trayloading,flowwrapping,auto-cartoningandmanualpackagingprocessing.2.Whatistraceabilityandwhyisitsoimportant?Howistraceabilityimplementedinmanufacturing?Traceabilityreferstotheabilitytotrackaproductorcomponentthroughallstagesofproduction,distribution,anduse.Itiscrucialbecauseitallowsfortheidentificationandrecallofproductsintheeventofasafetyissueorqualitydefect,ensuringconsumersafetyandregulatorycompliance.Inmanufacturing,traceabilityisensuredbytrackingbatchandlotnumbersthroughlabels,inspections,andadvancedsystems.Uponpackaging,recordsandcomponentsarereconciled,revieweddepartmentally,andfinallyapprovedbyqualityassurancebeforedistribution.3.Whatdoyouknowaboutvaccinesandtheirimpactonhumanhealth?Vaccinesarebiologicalpreparationsdesignedtostimulatetheimmunesystemandprovideprotectionagainstspecificinfectiousdiseases.Theyhaveaprofoundimpactonhumanhealthbyreducingtheincidenceandseverityofdiseases,leadingtodecreasedmortalityandmorbidity.Byensuringwidespreadvaccination,communitiescanachieveherdimmunity,protectingvulnerablepopulationsandpreventingoutbreaks.Vaccinesarecrucialforpublichealthandglobaldiseaseprevention.Forexample,COVID-19vaccinespreventsevereillnessanddeathfromCOVID-19,reducehospitalizations,andhelpcontrolthepandemicbylimitingvirustransmission.Bystimulatingtheimmunesystem,thesevaccinesprovideprotectionagainstSARS-CoV-2,thevirusthatcausesCOVID-19,therebysafeguardingpublichealthandenablingsocialandeconomicrecovery.FTFTTTF1.Whatisacleanroom?Whyarecleanroomsimportantinpharmaceuticalindustry?Acleanroomisanenvironmentwithcontrolledlevelsofcontamination,typicallyachievedbylimitingthenumberandsizeofparticlesintheair.Cleanroomsarecrucialinthepharmaceuticalindustrybecausetheyplayavitalroleintheresearchandmanufacturingofmedicines,vaccines,andothersterilemedicalproducts.Bymaintainingstrictcleanroomrequirements,theUnitedStatesFoodandDrugAdministrationensuresthattheproductsproducedaresafeforhumanuseanddonotposeanydangerousrisks.Cleanroomshelppreventcontaminationandensurethequalityandefficacyofpharmaceuticalproducts,therebysafeguardingpublichealth.2.Whatarethemajorconsiderationsforbuildingacleanroom?----LayoutorderCleanroomsmustbelaidoutintheorderofpeople'sentryfromtheoutside,withthecleanlinesslevelgraduallyincreasing.----AirlocksandtransitionroomsBufferzonescreatedusingairlocksandtransitionroomstomaintaindifferentcleanlinesslevels.----Separateentranceandexitroutes:Topreventcross-contamination.----FlooringselectionResistanttochemicalsandsolvents.Freeofcrackstopreventbacterialaccumulation.Righttexturetoreduceslippingandfallingrisks.----FlowofpeopleandmaterialsImportanttoconsiderwhenplanningthelayout.----CompliancewithregulationsDeterminingapplicablegovernmentregulationsandrequiredclassesfortheprocess.----CostsPotentialcostsofthecleanroomshouldbemodeledandconsidered.3.Whatarethedosanddon’tsinacleanroomenvironment?Pleasecreatealist.DosinaCleanroomEnvironment----Wearappropriateprotectiveclothing:Thisincludesgowns,gloves,headcoverings,andfootweardesignedtopreventcontamination.----Avoidwearingjewelryorcosmetics----UsedesignatedentranceandexitRoutes:Thishelpspreventcross-contamination.----Keepequipmentandworkspacesclean:Regularlycleananddisinfectsurfacesandtools.----Useairlocksandtransitionrooms:Thesehelpcreatebufferzonesandmaintaincleanlinesslevels.----Reportanycontaminationorissues:Promptlyreportanyincidentstomaintaintheintegrityofthecleanroom.Don'tsinaCleanroomEnvironment----Donotwearunauthorizedclothing:Avoidstreetclothes,jewelry,orotherpersonalitemsthatcouldcontaminatetheenvironment.----Donoteat,drink,orusetobaccoproducts:Theseactivitiescanintroducecontaminantsintothecleanroom.----Donottouchunnecessarysurfaces:Avoidunnecessarycontactwithwalls,floors,orothersurfacesthatcouldharborcontaminants.----Donotuseunapprovedcleaningproducts:Sticktocleaningsuppliesandmethodsapprovedforcleanroomuse.----Donotignoresignsorprocedures:Alwaysfollowpostedsignsandprocedurestomaintaincleanlinessandsafety.Lecture5Newdrugapplicationanddrugapprovalinformedconsentstrengthgenericdrugthalidomidemislabelingsponsordesignationcompliancerevokeadulteration1.FDA’scurrentresponsibilities—reviewing____________________________________________;—inspecting____________________________________________;—monitoring___________________________________________________________________________________________________________________________________________________;—issuing__________________________________________________________________________________________________.individualapplicationstomarketspecificdrugsmanufacturingfacilitiesItalsomonitorsadvertisements,websitesandotherpromotionalmaterialsbydrugdevicecompaniesotherhelpfulinformationtotheindustryimportsofoverseas,esp.foodanddrugproducts.summariesofdrugapprovaldataforthepublicandprovides2.FDAprotectsthepublichealthby—reviewing____________________________________________;—takingappropriateactionon_____________________________;—ensuring_____________________________________________;—participating__________________________________________________________________________________________________________________________________________________.—servingas________________________________________________________________________________________________.theclinicalresearchthemarketofregulatedproductshumandrugsaresafeandeffectiveharmonizingregulatoryrequirementsacrossbordersthroughtheappropriateprocesswithrepresentativesinothercountriestoreducetheburdenofregulation,anddeliverymarketplaceacriticalguidepostforinnovationinhealthcareunmetbiologicslife-threateningpreliminarymagnitudesurrogateoncologydiagnosisMakeacomparisonbetweenthefourexpeditedapprovalpathways.()1.Regulatorsrequirethreecategoriesofregulatorysubmissions,INDA,NDAorBLA,andANDAbeforeclinicaltrialscanbestarted.()2.INDAisarequestfromaclinicaltrialsponsortotheFDA,inwhichprotocolsofanimalpharmacologyandtoxicologystudies,manufacturinginformationandinvestigatorinformationaretypicallyincluded.()3.NDAistheformalprocessbywhichadrugsponsorseeksFDAapprovalformarketinganewpharmaceuticalintheUnitedStates.TFT()4.Genericdrugapplicationsaretermedabbreviatedbecausesomestepshavebeensimplified,likepreclinicalstudiesandclinicalstudies.()5.Thegenericdrugproductisanalternativetotheinnovatordrugproductitreferencesiningredients,dosageform,strength,routeofadministration,quality,performancecharacteristicsandintendeduse.FFTrytobrieflydescribethedifferencesbetweenNDAprocessandANDAprocess.1.Howaregenericdrugsthesameasbrand-namedrugs?Theyhavethesameactiveingredient.TheFDArequiresgenericdrugmanufacturerstomanufacturegenericdrugsandmeetthesamestandardsasbrand-namedrugs.Theyhaveequalquality,safety,andeffectiveness.2.Howdogenericsdifferfrombrand-namedrugs?Theymaylookdifferent.TheFDAallowsthemtohavedifferentinactiveingredients,likethebinders,theflavoring.Thecolorsofthemmightbedifferent.Thepackagingofthegenericdrugsisdifferentinlabeling.3.Whyaregenericdrugscheaperthanbrand-namedrugs?----Thedirectmanufacturingcostsarejustasmallpartofthecostofdevelopingadrug.Alotofmoneyisspentonnewdrugresearchanddevelopment,marketingandadvertising.----FDAgivesmanufacturers20yearsofpatentprotectiontorecouptheircostsofdevelopment.Oncethat20yearspass,otherdrugcompaniesmanufacturegenericdrugs.Andthenthecostforthegenericsismuchcheaper.4.Shouldpatientsbetakinggenericmedicationiftheyfindoutthatit’scheaperthanthebrandnamedrugs?Itdepends.Generally,theanswerisyes.Ifthegenericisequivalentforthepatientsasthebrand-namedrug,theyareencouragedtogetgenericstosavemoneyandkeeptheirhealthcostdown.Ifthegenericisnot,patientsarenotrecommendedtoswapthebranddrugstheyaretaking.1.Howwassulfanilamidedeveloped?Sulfanilamidewasdevelopedfromanearlierdrugcalledprontosil,whichwasactuallydevelopedbythedyeindustry.Furtherresearchshowedthatprontosilhadtwoparts:onewasthedye,andtheotherwastheantibiotic.Theantibiotichalfwassulfanilamide,whichresearchersfoundcouldbeusedonitsown.2.Pleasediscusstheprocessofsulfanilamideelixirdisaster.DiscoveryofProntosilGerhardDomagkdiscoversprontosil,adrugwithavividredcolordevelopedbythedyeindustry.DevelopmentofSulfanilamideResearchersfindthatprontosilhastwoparts:oneisthedye,andtheotheristheantibioticsulfanilamide,thelatterisidentifiedasapotentialstandaloneantibiotic.FormulationofElixirMassengillcompanyuseddiethyleneglycoltoformulatesulfanilamideintoanelixirandmarketedthenewproductwithoutanysafetytesting.ConsumptionandDeathPatientsconsumedthesulfanilamideelixirasprescribedbytheirhealthcareprovidersandstaredexperiencingsevereadversereactions,includingdeath,duetothepresenceofthetoxicsolvent.InvestigationandRecallofProductAninvestigationislaunchedtodeterminethecauseoftheadversereactionsandtheelixirwasrecalledfromthemarket.3.Itwasthesolventofthesulfanilamideelixir,diethyleneglycol,thattriggeredthetragedy.Pleasemakeacommentontheresponsibilitythatthepharmaceuticalcompany,theFDA,andthelegislaturesshouldtake.PharmaceuticalCompany:Thepharmaceuticalcompanybearsasignificantresponsibilityinthiscase.Theywereresponsibleforformulatingthesulfanilamideelixirandselectingthesolvent,diethyleneglycol.Theyshouldhaveconductedthoroughtestingtoensurethesafetyandefficacyoftheirproductbeforereleasingittothemarket.Theuseofdiethyleneglycolasasolvent,despiteitsknowntoxicity,indicatesalackofproperresearchandregardforpatientsafety.Thecompanyshouldhavebeenawareofthepotentialrisksassociatedwiththissolventandtakenstepstoavoidusingitortoensurethatitwasusedinasafemanner.FDA:TheFDA,astheregulatorybodyresponsibleforoverseeingthesafetyandefficacyofdrugsintheUnitedStates,alsohasaresponsibilityinthiscase.WhiletheFDAdidnotdirectlyapprovethesulfanilamideelixir,theywereresponsibleforsettingstandardsandguidelinesfordrugmanufacturingandtesting.Theagencyshouldhavehadstricterregulationsinplacetopreventtheuseoftoxicsolventsinmedications.Additionally,theFDAshouldhaveconductedmorerigorousinspectionsandauditsofpharmaceuticalcompaniestoensurecompliancewithsafetystandards.Legislatures:Legislaturesplayacrucialroleinsettingthelegalframeworkfordrugregulationandsafety.Theyshouldenactlawsthatprovideclearguidelinesandpenaltiesfornon-compliancewithsafetystandards.Inthiscase,thelegislaturecouldhaveimposedstricterpenaltiesforusingunsafesolventsinmedicationsandprovidedmorefundingforregulatorybodiestoconductinspectionsandaudits.Additionally,theycouldhaveencouragedpublicawarenesscampaignstoeducateconsumersaboutthepotentialrisksassociatedwithcertainmedications.FTTFTF1.WhydidtheFDAstillapproveAduhelm(aducanumab)despitethedisagreementovertheeffectivenessofthedrug?WhatdidtheFDAbaseitsapprovalon?TheFDAstillapprovedAduhelm(aducanumab)becauseitattacksakeyproteininAlzheimer'sdisease,amyloid,whichclumpsintoplaquesinthebrainsofpatientswithAlzheimer's.TheFDAacknowledgedthattherewasnotclearevidenceofclinicalbenefitandsomemurkinessintheevidenceregardingwhetherthedrugwouldactuallyhelppatientsslowdowntheirmemoryandthinkingproblems.FDAbaseditsapprovalonthesuggestionthatthedrugmightoffersomebenefitforpatientsymptomsandtheneedfornewtreatmentsforAlzheimer's,giventhatthelasttreatmentcameonthemarket18yearsago.Additionally,theFDArequiredthecompanytoconductanotherclinicaltrial,andiftheresultsofthattrialdonotshowbenefit,theFDAmightrevoketheapproval.2.WhatarethebenefitsandrisksofAduhelm?ThebenefitsofAduhelm,basedonthetrialsconducted,arerelativelyuncertainandmild.Onlyoneofthetrialsshowedanypotentialbenefit,andeventhen,theimprovementwasquiteslight.However,itisworthnotingthatthedrugisintendedtotargettheamyloidprotein,whichisbelievedtoplayaroleinthebiologyofAlzheimer'sdisease.RegardingtherisksofAduhelm,therearesomeseriousconcerns.Thedrughasbeenshowntocausebrainswellingandbrainbleedinginabout40%ofpatientsinthetrials,althoughmostofthesecasesdidnotproduceanysymptoms.However,asignificantnumberofpatientsdidexperiencesymptoms,andabout6%hadtoquitthetrialsduetothesesideeffects.Asaresult,anyonetakingAduhelmwillneedtoundergoregularbrainMRIstomonitorforpotentialcomplications.3.AlthoughAduhelmgainedtheapprovalfromtheFDA,theeffectivenessseemsnotsoclear.So,whatisFDA’sroleinthisprocess?----Inthisprocess,theFDA'sroleistoevaluatethesafety,efficacy,andoverallbenefit-riskprofileofthedrugbasedontheavailablescientificevidenceandclinicaltrialdata.TheFDAconsiderstheseriousnessofthedisease,theunmetmedicalneed,andthepotentialbenefitsthedrugmayoffertopatients.----Inthiscase,despitetheuncertaineffectivenessandthehistoryoffailedanti-amyloiddrugs,theFDAmayhavedecidedtoapproveAduhelmbasedonitshintofbenefitanditsabilitytotargetthekeyproteinimplicatedinAlzheimer'sdisease.----However,itisimportanttonotethattheFDA'sapprovaldoesnotguaranteethedrug'seffectivenessorsafetyinallpatients,andongoingmonitoringandresearcharenecessarytofurtherassessitsbenefitsandrisks4.ThereisgreatcontroversyovertheapprovalofthisnewAlzheimer’sdrug,Aduhelm.Doyouthinksuchadrugshouldbeapproved?Pleasemakeacommentonit.SupportingArguments----AddressinganUnmetMedicalNeedAlzheimer'sdiseaseisadevastatingconditionthataffectsmillionsofpeopleworldwideandhasasignificantimpactonpatientsandtheirfamilies.Thereisapressingneedfornewtreatmentsthatcanslowtheprogressionofthediseaseandimprovethequalityoflifeforpatients.AduhelmrepresentsapotentialbreakthroughinAlzheimer'streatmentbytargetingtheamyloidprotein,whichisimplicatedinthediseaseprocess.----PotentialforClinicalBenefit:AlthoughtheevidenceforAduhelm'seffectivenessisnotconclusive,someclinicaltrialshaveshownahintofbenefitinreducingcognitivedecline.TheFDA'sapprovalofAduhelmwasbasedonitsabilitytoclearamyloidplaquesfromthebrain,whichisabiologicallyplausiblemechanismofaction.----EncouragingDrugDevelopment:ApprovingAduhelmmayencouragefurtherresearchanddevelopmentinthefieldofAlzheimer'streatment.Thiscouldleadtothediscoveryofmoreeffectiveandsafertreatmentsinthefuture.OpposingArguments----UncertaintyofEffectiveness:TheclinicaltrialsforAduhelmhaveyieldedmixedresults,withsomeshowingnosignificantbenefitincognitivefunction.Theeffectivenessofthedruginreducingcognitivedeclineremainsuncertain,andthereisariskthatitmaynotprovideameaningfulbenefittopatients.----PotentialSafetyRisks:Aduhelmhasbeenassociatedwithpotentialsafetyrisks,includingbrainswellingandbleeding.Theserisksmustbecarefullyweighedagainstthepotentialbenefitsofthedrug.----EthicalConsiderations:Approvingadrugwithuncertaineffectivenessandpotentialsafetyrisksraisesethicalconcernsaboutexposingpatientstounnecessaryharm.Thereisaneedforabalancebetweenprovidingpatientswithaccesstopotentiallybeneficialtreatmentsandprotectingthemfrompotentialharms.Lecture6DrugcommercializationprocurementcopayrebateformularyportfoliotendersubsidiaryreimbursementblockbusterrevenueTFTFFTTFPepsiCo.manufacturesthesodaandsendsittoaretailer,whosellsittoacustomer.ThecustomerpaystheretailerandtheretailerpaysPepsiCo.developadrugandsetapriceknownasthelistpricetransportthedrugsandsellthemtothepharmaciespaysthecopaysendsoutabillthatgetspaidbytheinsurancecompanyworkforinsurancecompanies,bigemployersandgovernmentagencies.Andabigpartoftheirjobistobringdownthecostofdrugsfortheiremployersnegotiatingwithpharmaceuticalcompaniesforrebates.ThePBMssometimespocketaportionandpassesanotherportionontotheinsurancecompanyoremployerthattheinsurancecompanycovers,andit’sgroupedintiersrepresentswhatportionofthelistpricethepatientpaysandwhatporti