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1、第二军医大学药物安全性评价中心陆国才新药临床前毒理学评价PreclinicalToxicologicalEvaluationofNewDrugContents目的意义急性毒性试验(acute)长期毒性试验(chronic)特殊毒性试验(遗传、生殖、致癌)其它毒性试验(过敏、刺激etc.)药物非临床研究质量管理规范(GLP)SFDA新药审评会案例学习目的意义新药评价的核心内容确保临床用药安全>限量、改变途径有毒Toxicity—Everywhere1274宋慈指出万物皆毒CA化学品约一千万,USA每年上
2、市新化学品1500种左右1992年联合国环境与发展大会:有毒化学品21st(1/7)环境问题DrugHazards1935-37美国二硝基酚减肥白内障、骨髓抑制,死亡177人1937美国磺胺酏剂消 炎尿毒症、肾衰,死亡107人1954-56法国有机锡抗感染207人视力障碍、其中102人死亡1959-62欧日反应停镇 静畸胎,12000多人1966-72日本氯碘喹啉肠道感染万余人失明或下肢瘫痪1937-59美国黄体酮先兆流产男性化,600多人TheCOX-2Hypothesis(1992)Prostan
3、oidsArachidonicAcidProstanoidsProtectionofGastricMucosaPlateletFunctionPain,Inflammation,FeverRenalEffectsGastropathyandAntithromboticEffectsEffectsonNa+BalanceAnti-inflammatoryandAnalgesicEffectsNSAIDsCOX-2COX-1CO2HSelectiveCOX-2InhibitorsCOX-2PGI2
4、COX-1COX-1BPTXA2COX-1COX-2COX-2CardiacFibrosis“Merckpullspopularpaindrugduetorisksofheartattacks”Sept.30,2004:959798990001020304059694VioxxMilestonesNDAsubmit:AcutePain/DYSM/OAINDforAlzheimer’s3/98COX-IISafetyACFirstIND2/01AACMeetingReviewofadditionalin
5、formationInternalBriefingsCOX-IISafetyArthritis/DSaRMCOX-IISafetyMeetingGIDACMeeting(APPROVe)4/02LabelUpdate10/02PCPSProstateCa.prevention10/02MerckPooledCVanalysis12/02AdvicelettertoMerck3/04UpdatedAlzhCVData3/04Migraineapproval8/04JRAapproval8/04Kaiser
6、StudyAbstract9/04APPROVeresultsOngoingStudiesStoppedProductWithdrawn6/00VIGORresultsINDforAPPROVe4/99AACmeeting5/99NDAapprovedSabrinaBriertonJohnsonRiskofSeriousCVEventsofCelecoxib*SolomonSD,etal:NEnglJMed352,2005*Inthisanalysis,“seriousCVevents”included
7、eathfromCVcauses,MI,stroke,orheartfailure671AE/ADRThursday,February17,200512:00Lunch1:00OpenPublicHearingDearFDA:WhenIwas6yearsold,Ihadfun……AllofthatendedwhenIcamehomefromthefirstgrade,notfeelingverywell.MyparentsgavemeChildren'sMotrin,butinsteadofgettin
8、gbetter,IgotStevens-JohnsonSyndrome.TakingChildren'sMotriniswhyIamblindtoday.……IwouldliketoasktheFDAtorequireawarninglabelaboutSJSonChildren'sMotrinandonanyotherdrugsthatcancausethishorribledisease.…...SabrinaBriertonJohns