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1新药研发医学知识培训2Newwordsandexpression◼acute:acuteinfection（急性感染）,acuteleukemia（急性白血病）chronic:chronicgastr

itis（慢性胃炎）◼agonist:stimulatorantagonist:blocker◼adversereaction（不良反应）:anybadeffectorundesirableeffectcaused

bydruguseatnormaldose（正常剂量）新药研发医学知识培训23◼newchemicalentity(新化学实体):newcompoundshowspharmacologicalactivityagainstcertaindisease,whichis

alsocalledleadcompound(先导化合物)ordrugcandidate(候选药物)◼in-vitro（体外）:outsideoforganismsinvivo（体内）:withinawholelivingorganism新药研发医学知识培训341.Wh

atisanewdrug?Chemicalstructure（化学成分）Dosageform(剂型）Routeofadministration（给药途径）Indication（适应症）Newdrug新药研发医学知识培训452.Whyd

oweneednewdrugs?◼manyincurablediseasesstillawaitconquest◼toproducenewdrugsthataresuperiorthanexistingmedications◼theultimategoal:toprovideeffective

,accessibleandaffordablemedicinesforall新药研发医学知识培训56①Inthepast,drugswereextractedfromplantandanimalsources,butthe

purityofdrugswasverylimited.quinine（奎宁）:extractedfromthebarkofcinchona（金鸡纳树皮）,itsantimalarial（抗疟疾）functi

onwasdiscoveredbytheIndiansinNorthAmerica3.Evolutionofnewdrug新药研发医学知识培训67②From1900chemicallysynthesizeddrugsbecameavailable,t

hepurityofdrugswereremarkablypromotedwhichincreasedthespecificityofaction.e.g.quininecanbeartificiallysynthesizedin1945Nowada

ysmostwesternmedicinesaretotallysynthesizedorsemi-synthesized新药研发医学知识培训78③Withthedevelopmentofgeneticengineer

ing（基因工程）moredrugswillbeproducedartificially.e.g.thefirstgeneticallyengineereddrugisrh-insulin(forthetre

atmentofdiabetes)andwasfirstmarketedinAmericain1982.新药研发医学知识培训894.RegulationofdrugdevelopmentTherangeofnovelchemicalentitiesdevelopedhasoccasionally

ledtounexpectedtoxicity.Inordertoensurethesafetyandefficacyofnewdrugs,theirdevelopmentmustfollowstatutoryprocedures（法定程序）.新药研发医学知识培训910Th

alidomide--------abigtragedy!ThalidomidewasdevelopedbyaGermanpharmaceuticalcompany.Itwassoldfrom1957to1961inalmost50coun

triesunderatleast40brandnames.Thalidomidewaschieflysoldandprescribedtopregnantwomen,asanantiemetic(止吐药)t

ocombatmorningsicknessandasanaidtohelpthemsleep。In1961whenthalidomidewaswithdrawnfromthemarket,morethantenthous

anddeformedbabieswereborn.Theysufferedfromphocomelia(海豹肢).新药研发医学知识培训1011Developinganewdrugisahighlycomplex,

time-consuming,riskyandcostlyprocess.5.Anoverviewofnewdrugdevelopment新药研发医学知识培训1112◼complexandtime-consumingNewdrugdevelopmentrequiresmultidiscipl

inaryeffortsformanyyears,involvingnumerousstepsandmanysophisticatedtechniques0.5-1year3-4years6-8years2-3years新药研

发医学知识培训1213⚫risky:OnlyaverysmallportionofNCEscanbefinallymarketedasdrugproduct新药研发医学知识培训1314◼costly:Onebillion新药研发医学知识培训14156.Developm

entofnewdrugs6.1Strategiesfordiscoveringnewchemicalentities①Serendipity:Thenewtherapeuticagentisdiscoveredbychance.e.g.the

discoveryofpenicillinAlexanderFlemingpenicillum新药研发医学知识培训1516②Molecularroulette（分子的轮盘赌）Agreatmanyofnewchemicalstructureswere

synthesizedrandomlyandscreenedbyanimalorin-vitromodelsofhumandiseasetoseeifanyofthenewlyobtainedstructuresprovec

ertaineffect.Disadvantage:wasteful,dependentonsensitivemodelsforscreening新药研发医学知识培训161718Disadvantagesofpenic

illin:◼unstabletoacid◼unstabletoβ-lactamase(内酰胺酶)◼littleeffectonGramnegativebacteria（革兰氏阴性菌）新药研发医学知识培训1819④Programmedbasicresearchwithsynthesiso

fspecificchemicalse.g.1Histamie(H2)receptorantagonist(suchasCimetidine西米替丁)forpepticulcerHistaminereceptorscanbeclassifie

dintothreeclasses,H1,H2andH3,theydistributeindifferenttissues,andcausedifferenteffectswhenagitated.H2receptore

xistsingastricwallcells,whenagitatedbyhistaminethesecretionofgastricacidisenhanced,causingpepticulcer.H2receptorantagonis

tcanspecificallybindwithH2receptorbutwithoutagitation.新药研发医学知识培训1920e.g.2angiotensin-convertingenzymeinhibitor(血管紧张素转化酶抑制剂)for

hypertensionangiotensinⅠisconvertedtoangiotensinⅡbyangiotensin-convertingenzyme.angiotensinⅡcanbindwithangiotensinreceptor(AT,exis

tinginvascularsmoothmuscle),leadingtovasoconstrictionandriseofbloodpressure.angiotensin-convertingenzymeinhibitorsuchasCaptopril（卡托普利）canbindw

iththeconvertingenzymes,thusangiotensinⅠcouldn'tbindtotheconvertingenzymesandwon’tbeconvertedtoangiotensinⅡ.新药研发医学知识培训2021⑤Clin

icalobservationofdrugactioninpracticeNewpharmacologicalactionwhichisnotdetectedinanimalmodelsmaybediscoveredinclinicalapp

lication.thiazidediuretics(噻嗪类利尿剂)areusedforthetreatmentofedema(水肿),theirantihypertensiveeffectswasnotpredictedfromanimalscreeningtest,butiden

tifiedafterthedrugsweremarketedandbeingusedinpractice.新药研发医学知识培训21226.2Pre-clinicalstudies①medicinalchemistrystudies:technologyforproductio

n,chemicalandphysicalproperties,stability,dosageform,standardsforqualitycontrol新药研发医学知识培训2223②pharmacologicaland

toxicologicalstudiesinclude:pharmacodynamic（药物效应动力学）studies:drugaction(therapeuticeffectandadverseeff

ect)dose-effectrelationship(minimaleffectivedose,maximaleffect,medianeffectivedose,medianlethaldose)mechanismofaction（作用机制）:interactionwit

hitstargetpharmacokinetic（药物代谢动力学）studies:absorption,distribution,metabolismandexcretionofthedrugtoxicityinanimals：acutetoxicity,chronictoxicit

yspecialtoxicity新药研发医学知识培训2324SomeimportantdefinitionsintoxicologicalassessmentAcutetoxicitytesting:acutet

oxicreactionswithin24hoursaftersingledosingChronictoxicitytesting:toxicreactionswhichresultfromrepeateddoses,usuallyforthreemo

nthsLD50(medianlethaldose):thedosethatkills50%ofanimalsED50(medianeffectivedose):thedosecausingtherapeutic

effectsin50%ofexperimentalanimalstherapeuticindex=LD50/ED50新药研发医学知识培训2425新药研发医学知识培训2526Significanceofpreclin

icalstudy◼determinethepossibilityofconductingclinicaltrials◼predictpossibletoxicityandsafetyrangeinman◼providereferenc

eforselectionofinitialdoseinclinicaltrials新药研发医学知识培训26276.3Clinicaltrails:PhaseⅠ:smallscalestudieson20-30volunteerstoprovethesafetyinmanaswellast

hetolerability,thewholeprocesslast6to9months.dose-rangingstudy(剂量递增试验)：todetermineappropriatedosesfortherapeuticuseandtolerabili

ty(maximumtolerateddose最大耐受剂量)inman.informedconsent(知情同意书)：informationaboutaparticulartreatmentortestforsubjectstodecide

whetherornottoundergosuchtreatmentortest.新药研发医学知识培训2728PhaseⅡ:randomized,controlledandblindstudyareusedtodeterminethetherapeuticeffect,indica

tionandadversereactionofthenewtherapeuticagentonpatients,thetestsubjectsshouldbenolessthan100pairs.PhaseⅢ:largescalestudy(usuallyinm

ulti-centerstudyworldwide)tofurtherevaluateefficacyandsafetyofthenewdrug.thetestsubjectsshouldbenolessthan300.Afterphase3studies,anew

drugapplication(新药申请)issubmittedtotheregulatoryauthoritieswitharequestforproductlicense.新药研发医学知识培训2829PhaseⅣ:post-marketingstudyunderwideap

plicationofthenewdrugtoexaminethetherapeuticeffectsandadversereactionsofthenewdrugaswellastodiscovernewindicationsandadversereactionsthatwer

enotuncoveredbefore.Thetestsubjectsshouldbenolessthan2000.新药研发医学知识培训2930Withdrawalofcerivastatin(西立伐他汀)formthe

market:Cerivastatinisasyntheticmemberoftheclassofstatinsusedtolowercholesterolandpreventcardiovasculardisease.Itwasmarketedint

helate1990s.Duringpost-marketingsurveillance,52deathswerereportedinpatientsusingcerivastatin,mainlyfromrhabdomyolysis(横纹肌溶解)anditsresu

ltantrenalfailure(肾衰竭).Cerivastatinwaswithdrawnfromthemarketworldwidein2001.新药研发医学知识培训3031Translation1.新药的人体评价可分为四个阶段，每个阶段都应在严格的监管

下进行。2.以前，药物都是从天然植物和动物提取的，治疗方法以传统经验为基础。3.新药只有在经过广泛的正规毒理学试验之后才可用于患者。4.新药的临床评价必须在动物试验证明有效之后方可进行。新药研发医学知识培训31325.Sy

nthetictechniqueshaveproducedpuresubstances.Thishasledtoincreasedspecificityofactionand,insomecases,greaterefficacyandreducedtoxicity.

6.Whendrugswithspecificactionsonenzymesorreceptorsarebeingstudied,relativelysimplecellfreesystemsorisolatedtissuepreparationscanbe

used.7.ThesafetysurveillanceinPhaseIVtrialisdesignedtodetectanyrareorlong-termadverseeffectsoveramuchlargerpatientpopulationandlongertimepe

riodthanwaspossibleduringthePhaseI-IIIclinicaltrials.8.PhaseItrialsnormallyincludedoseescalation,sothat

theappropriatedosefortherapeuticusecanbefound.新药研发医学知识培训32