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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:chronicgastritis（慢性胃炎）◼agonist:stimulatorant

agonist:blocker◼adversereaction（不良反应）:anybadeffectorundesirableeffectcausedbydruguseatnormaldose（正常剂量）新药研发医学知识培训23◼newchemicalentity(新化学实

体):newcompoundshowspharmacologicalactivityagainstcertaindisease,whichisalsocalledleadcompound(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.Whatisanewdrug?Chemicalstructure（化学成分）Dosageform(剂型）Routeo

fadministration（给药途径）Indication（适应症）Newdrug新药研发医学知识培训452.Whydoweneednewdrugs?◼manyincurablediseasesstillawaitconquest◼

toproducenewdrugsthataresuperiorthanexistingmedications◼theultimategoal:toprovideeffective,accessibleandaffordablemedicinesforall新药研发医学知识培

训56①Inthepast,drugswereextractedfromplantandanimalsources,butthepurityofdrugswasverylimited.quinine（奎宁）:extractedfromthebarkofcinchona（金鸡纳树皮）,it

santimalarial（抗疟疾）functionwasdiscoveredbytheIndiansinNorthAmerica3.Evolutionofnewdrug新药研发医学知识培训67②From1900chemicallysy

nthesizeddrugsbecameavailable,thepurityofdrugswereremarkablypromotedwhichincreasedthespecificityofaction.e.g.quininecanbeartificiallysynt

hesizedin1945Nowadaysmostwesternmedicinesaretotallysynthesizedorsemi-synthesized新药研发医学知识培训78③Withthedeve

lopmentofgeneticengineering（基因工程）moredrugswillbeproducedartificially.e.g.thefirstgeneticallyengineereddrugisrh-in

sulin(forthetreatmentofdiabetes)andwasfirstmarketedinAmericain1982.新药研发医学知识培训894.Regulationofdrugdeve

lopmentTherangeofnovelchemicalentitiesdevelopedhasoccasionallyledtounexpectedtoxicity.Inordertoensurethesafetyandefficacyof

newdrugs,theirdevelopmentmustfollowstatutoryprocedures（法定程序）.新药研发医学知识培训910Thalidomide--------abigtragedy!Thalidomidewasdeve

lopedbyaGermanpharmaceuticalcompany.Itwassoldfrom1957to1961inalmost50countriesunderatleast40brandnames

.Thalidomidewaschieflysoldandprescribedtopregnantwomen,asanantiemetic(止吐药)tocombatmorningsicknessandasanaidtohelpthemsleep。In1961whenthalidomidewas

withdrawnfromthemarket,morethantenthousanddeformedbabieswereborn.Theysufferedfromphocomelia(海豹肢).新药研发医学知识培训1011Develo

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

omplexandtime-consumingNewdrugdevelopmentrequiresmultidisciplinaryeffortsformanyyears,involvingnumero

usstepsandmanysophisticatedtechniques0.5-1year3-4years6-8years2-3years新药研发医学知识培训1213⚫risky:OnlyaverysmallportionofNCEscanbefinallymarketedasdrugpro

duct新药研发医学知识培训1314◼costly:Onebillion新药研发医学知识培训14156.Developmentofnewdrugs6.1Strategiesfordiscoveringnewchemicalentities①Ser

endipity:Thenewtherapeuticagentisdiscoveredbychance.e.g.thediscoveryofpenicillinAlexanderFlemingpenicillum新药研发医学知识培训15

16②Molecularroulette（分子的轮盘赌）Agreatmanyofnewchemicalstructuresweresynthesizedrandomlyandscreenedbyanimalorin-vitromodelsofhu

mandiseasetoseeifanyofthenewlyobtainedstructuresprovecertaineffect.Disadvantage:wasteful,dependentonsensitivemodelsforscreening新药研发医学

知识培训161718Disadvantagesofpenicillin:◼unstabletoacid◼unstabletoβ-lactamase(内酰胺酶)◼littleeffectonGramnegativebact

eria（革兰氏阴性菌）新药研发医学知识培训1819④Programmedbasicresearchwithsynthesisofspecificchemicalse.g.1Histamie(H2)receptorantagonist(

suchasCimetidine西米替丁)forpepticulcerHistaminereceptorscanbeclassifiedintothreeclasses,H1,H2andH3,theydistributeindifferenttissues,andcausediffere

nteffectswhenagitated.H2receptorexistsingastricwallcells,whenagitatedbyhistaminethesecretionofgastricacidisen

hanced,causingpepticulcer.H2receptorantagonistcanspecificallybindwithH2receptorbutwithoutagitation.新药研发医学知识培训1920

e.g.2angiotensin-convertingenzymeinhibitor(血管紧张素转化酶抑制剂)forhypertensionangiotensinⅠisconvertedtoangiotensinⅡbyangiotens

in-convertingenzyme.angiotensinⅡcanbindwithangiotensinreceptor(AT,existinginvascularsmoothmuscle),leadingtovasoconstrictionandriseofb

loodpressure.angiotensin-convertingenzymeinhibitorsuchasCaptopril（卡托普利）canbindwiththeconvertingenzymes,thusangiotensinⅠcouldn'tbindtot

heconvertingenzymesandwon’tbeconvertedtoangiotensinⅡ.新药研发医学知识培训2021⑤ClinicalobservationofdrugactioninpracticeNewphar

macologicalactionwhichisnotdetectedinanimalmodelsmaybediscoveredinclinicalapplication.thiazidediuretics(噻嗪类利尿剂)areusedforthetreat

mentofedema(水肿),theirantihypertensiveeffectswasnotpredictedfromanimalscreeningtest,butidentifiedafterthedr

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

technologyforproduction,chemicalandphysicalproperties,stability,dosageform,standardsforqualitycontrol新药研发医学知识培训2223②pharmac

ologicalandtoxicologicalstudiesinclude:pharmacodynamic（药物效应动力学）studies:drugaction(therapeuticeffectandadverseeffe

ct)dose-effectrelationship(minimaleffectivedose,maximaleffect,medianeffectivedose,medianlethaldose)mechanismofaction（作用机制）:in

teractionwithitstargetpharmacokinetic（药物代谢动力学）studies:absorption,distribution,metabolismandexcretionofthedrugtoxicityinanimals：acutetox

icity,chronictoxicityspecialtoxicity新药研发医学知识培训2324SomeimportantdefinitionsintoxicologicalassessmentAcutetoxic

itytesting:acutetoxicreactionswithin24hoursaftersingledosingChronictoxicitytesting:toxicreactionswhichresultfromrepeate

ddoses,usuallyforthreemonthsLD50(medianlethaldose):thedosethatkills50%ofanimalsED50(medianeffectivedose):th

edosecausingtherapeuticeffectsin50%ofexperimentalanimalstherapeuticindex=LD50/ED50新药研发医学知识培训2425新药研发医学知识培训2526Significanceofprec

linicalstudy◼determinethepossibilityofconductingclinicaltrials◼predictpossibletoxicityandsafetyrangeinman◼providereferenceforselectionofin

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

ellasthetolerability,thewholeprocesslast6to9months.dose-rangingstudy(剂量递增试验)：todetermineappropriatedosesfortherapeuticuseandtolerability(maximumto

lerateddose最大耐受剂量)inman.informedconsent(知情同意书)：informationaboutaparticulartreatmentortestforsubjectstodecidewhetherornottoundergosuchtreatmentortest.

新药研发医学知识培训2728PhaseⅡ:randomized,controlledandblindstudyareusedtodeterminethetherapeuticeffect,indicationandadverser

eactionofthenewtherapeuticagentonpatients,thetestsubjectsshouldbenolessthan100pairs.PhaseⅢ:largescal

estudy(usuallyinmulti-centerstudyworldwide)tofurtherevaluateefficacyandsafetyofthenewdrug.thetestsubjectsshouldbenolessthan300.A

fterphase3studies,anewdrugapplication(新药申请)issubmittedtotheregulatoryauthoritieswitharequestforproductlicense.新药研

发医学知识培训2829PhaseⅣ:post-marketingstudyunderwideapplicationofthenewdrugtoexaminethetherapeuticeffectsand

adversereactionsofthenewdrugaswellastodiscovernewindicationsandadversereactionsthatwerenotuncoveredbefo

re.Thetestsubjectsshouldbenolessthan2000.新药研发医学知识培训2930Withdrawalofcerivastatin(西立伐他汀)formthemarket:Cerivastatinisasyntheticmemberoftheclassofst

atinsusedtolowercholesterolandpreventcardiovasculardisease.Itwasmarketedinthelate1990s.Duringpost-marketingsurveillance,52deathswerer

eportedinpatientsusingcerivastatin,mainlyfromrhabdomyolysis(横纹肌溶解)anditsresultantrenalfailure(肾衰竭).Cerivastatin

waswithdrawnfromthemarketworldwidein2001.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.Syntheticte

chniqueshaveproducedpuresubstances.Thishasledtoincreasedspecificityofactionand,insomecases,greaterefficacyandreducedtox

icity.6.Whendrugswithspecificactionsonenzymesorreceptorsarebeingstudied,relativelysimplecellfreesystemsorisolate

dtissuepreparationscanbeused.7.ThesafetysurveillanceinPhaseIVtrialisdesignedtodetectanyrareorlong-termadverseeffectsoveramuchlargerpatientpopulati

onandlongertimeperiodthanwaspossibleduringthePhaseI-IIIclinicaltrials.8.PhaseItrialsnormallyincludedoseescalation,sothattheappropriatedosefortherape

uticusecanbefound.新药研发医学知识培训32