长期毒性第二军医大学新药评价中心新药评价.ppt
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1、长期毒性试验,目的意义基本内容和要求有关问题Mechanic?Innovative?,目的意义,毒性剂量 Toxic dosage安全范围 Safety margin 毒性反应 Toxic reaction:性质、程度、量毒关系、产生时间,达峰时间,持续时间及反复产生毒性反应时间、迟发性、蓄积性、耐受性 毒性反应靶器官 Target organ 毒性反应是否可逆 Reversibility,Procedures,Animals Housing Test articleRoute Dosage and groupAdministration duration Observation,Proced
2、ures 1-animals,rodent non-rodent rat beagle dog mouse mongrel dog monkey,基本内容和要求-动物,二种动物,啮齿类首选大鼠,非啮齿类用犬(Beagle犬),必要时用猴动物应写明供应单位及邮编,品系及生产合格证号大鼠6-8周龄,体重差异不超过平均体重的20。3个月以上可选5-6周龄大鼠Beagle犬4-12月龄各半,Procedures 2-housing,Diet,T,humidity,light,ventilationRat:5/cage or separated,acclimation 1wDog:TB test,ant
3、helmintic acclimation:1-2w/1m,Procedures 3-test article,test article/solvent/excipient name,batch No.,source,specification,purity,preserve condition,etc same quality criterion,基本内容和要求-给药途径,与临床给药途径一致混入饲料或饮水中灌服时保证受试药分布均匀在配制饲料或溶于饮水后仍旧稳定计量准确临床iv 时,大鼠给药周期1月,可用ip代替,im或sc应变换注射部位必要时改变给药途径,基本内容和要求-剂量及分组,三个给药
4、组,单位:mg(ml,IU)/kg 或/m2以不等浓度等容量给药低剂量组-高于有效剂量,不出现毒性反应中剂量组-产生轻微或中等度毒性反应高剂量组-产生明显或严重的毒性反应,或个 别动物死亡空白对照-溶媒或其它赋形剂,若溶媒或赋形 剂有毒性时则增加正常对照组,基本内容和要求-剂量及分组,5 g/kg,iv 2g/kg仍无毒性反应和死亡或仅个别有毒性反应,可只做一个50ACD(犬用30ACD)的剂量组,Procedures 6-ad.duration,Tab.Correspond duration of clinical ad.with animal ad.clinical ad.duration
5、animal ad.duration 13d 14d 1w 1m 4w 3m 1m 6mduration 3m ad.6 day weekly(mon.to sat.),Procedures 7-Observations Clinical Examinations,rodent non-rodent signs of ill health+pupil,T behavioral changes breath,sialosis reaction to treatment vomitingDead or moribund animal:necropsy within 1h,Procedures 7-
6、Observations Hematology,Red blood cell count(RBC)Hemoglobin(Hb)Erythrocyte indices(MCV,MCH,MCHC)Hematocrit(Hct)Platlet count White blood cell count and percent differential Coagulation time(CT)Reticulocyte count,Bone marrow smear,Procedures 7-ObservationsClinical chemistry,Alanine aminotransferase(A
7、LT)(丙)Aspartate aminotransferase(AST)(草)Alkaline phosphatase(ALP)Total bilirubin(Tbill)Blood urea nitrogen(BUN)Creatinine(Cr)Total protein(TP)Albumin(Alb)Glucose(Glu)Total cholesterol(Tch),Procedures 7-ObservationsUrinalysis,Color and appearance pH glucose ketones urobilinogen blood specific gravity
8、 nitrite protein bilirubin WBC microscopy of centrifuged deposit,Procedures 7-Observations Pathology,Organ weight assessment:heart liver thyroid lobes and spleen lung parathyroids kidneys brain(lobes weighed pituitary adrenals together)ovaries testescalculate organ weights relative to body weight,pa
9、ired organs weigh together,Procedures 7-Observations Pathology,Histopathological examination:heart liver spleen lung kidney brain adrenals pancreas stomach duodenum jejunum ileum colon cecum(盲)pituitary thymus spinal cord prostate testes uterus ovaries optic nerve injection site bone and marrow(ster
10、num)urinary bladder lymph nodes(mesenteric)thyroid lobes(and parathyroids),Procedures 7-Observations Pathology,tissues(c+h embedding dead+sectioningtarget)staining examination,基本内容和要求-检测指标心电图导联,大动物长期毒性必须做 主要观察指标:心率、P波电压、P-R间期、R波电压、QRS时间、ST段、T波电压和Q-T间期,Procedures 7-ObservationsRecovery,Observation:1/
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