谢雯抗肿瘤治疗相关性肝损伤的防治.ppt

微粒体前列腺素E1合成酶抑制剂注册研究 （Microsomal Prostaglandin E Synthase-1 ，mPGES-1) Inhibitors as Treatment of Pain and Inflammation Treatment Dose Treated Subjects Placebo - 6 Comparator NSAID* 400 mg 6 LY 25 mg 8 LY 75 mg 10 LY 225 mg 9 Phase I clinical trial with healthy volunteers Subject/investigator blind, parallel-group, multiple-dose, dose-escalation study, 28 days duration Hepatic biochemical tests done at least once weekly 5 treatment groups: *Celecoxib 400mg once daily 塞来考昔，cox-2抑制剂 / Clinical Presentation of DILI Cases 4 females, 2 males, ages 32-59 Normal hepatic biochemical tests at baseline Presentation 16-34 days (mean 22 days) after starting study drug Symptoms included epigastric pain, fatigue, nausea, low-grade fever, rash # Age (yrs) M/F Dose (mg) Day of Presentation After Drug Initiation Rash Max ALT(xULN) Max ALP(xULN) Max TBL (mg/dL)(NR: 0?1.2?mg/dL) Max Eos (%) (NR: 0-6%) 1 53 M 75 34 Yes 3.3 0.7 1.5 6 2 58 F 225 17 No 27.3 1.5 1.2 20 3 32 M 225 33 Yes* 5.8 0.6 1.2 10 4 57 F 225 16 No 14.9 0.7 1.0 19 5 59 F 225 16 No 19.2 1.1 0.8 14 6 54 F 225 17 Yes* 45.6 1.2 1.6 21 *Urticaria / * Two patients required hospitalization, and were treated by local hepatologists with N-acetylcysteine Both underwent liver biopsy* ALT returned to normal range within 6-10 weeks after drug discontinuation Clinical Course 0 Weeks Weeks 2 4 6 8 10 12 *Marumoto A, et al. Hawai’i Journal of Medicine & Public Health 2013;72(9)Supp4:30-33 0 2 4 6 8 10 12 1 3 4 5 2 6 药物警戒定律 Hy‘Law For drug induced hepatotoxicity 药物诱发的肝细胞性黄疸是一种严重的肝脏损伤 血清生化指标表现为用药后 ALT>3倍， TBIL>2倍 ALP正常 死亡率是5%-50% 药物警戒定律（美国FDA照此定律监测判定药物肝毒性） Hyman Zimmerman 1917-1999 eDISH Graph 1 in SAS Marked zone 3 necrosis with numerous portal and lobulareosinophils Zone 3 cholestasis No fibrosis Liver Histology Marumoto A, et al. Hawai’i Journal of Medicine & Public Health 2013;72(9)Supp4:30-33 Dose Relationship Treatment Dose Tre