摘要
目的:通过研究抗流感病毒反义寡核苷酸(antisense oligonucleotides,ASON)药物流感泰得(Flutide,FT)对Wistar大鼠的亚急性毒性作用,为FT临床试验研究提供重要的动物实验数据。方法:48只Wistar大鼠,雌雄各半,随机分为4组,分别为溶媒对照组、FT 10.0,30.0,100.0 mg·kg-1·d-1组,尾静脉注射连续给药14 d,停药后恢复14 d,给药结束和恢复期结束腹腔大静脉取血进行血液学、血清生化检测;剖检各组织脏器进行脏器湿重、病理学、骨髓涂片检查。结果:给药结束,与溶媒对照组比较,FT各剂量组雄性大鼠网织红细胞百分比(%RETIC)、100.0 mg·kg-1·d-1组血小板数量(PLT)降低(P<0.01),血清生化检测发现FT 100.0 mg·kg-1·d-1组雌、雄大鼠尿素氮(BUN)、肌酐(CREA)、肌酸激酶(CK)均升高(P<0.05,P<0.01),且FT 100.0 mg·kg-1·d-1组雄性大鼠血清BUN,CREA水平明显高于雌性大鼠(P<0.01)。另外,FT30.0,100.0 mg·kg-1·d-1组雌雄大鼠肾脏脏器湿重和脏器系数均明显增加(P<0.05,P<0.01),体重下降(P<0.01);恢复期结束,与溶媒对照组比较,FT 100.0 mg·kg-1·d-1组雌性大鼠%RETIC,PLT升高(P<0.05),FT 30.0 mg·kg-1·d-1组雄性大鼠骨髓红系和粒系细胞计数下降(P<0.05),FT 30.0 mg·kg-1·d-1组雌性大鼠肾脏脏器湿重和脏器系数仍明显增加,其余指标除FT 100.0 mg·kg-1·d-1组外均恢复正常。组织病理学检查结果显示,FT各剂量组可致雌、雄大鼠肾脏肾小管不同程度的变性坏死,细胞碎片管型、蛋白管型及嗜碱性小管形成,尤以雄性毒性损伤较重,心脏间质、肝脏门管区、脾脏边缘区见不同程度的组织细胞浸润。结论:FT对Wistar大鼠肾脏、心脏、肝脏和脾脏具有毒性作用,且具有性别差异。
Objective： To study the subacute toxicity of antisense oligonucleotides（ ASON） against influenza virus Flutide（ FT） in Wistar rats and provide important animal experimental data for the clinical trials research.Methods： 48 Wistar rats with half males and half females were divided randomly into 4 groups： vehicle control group and FT 10. 0,30. 0,100. 0 mg·kg^-1·d^-1oups. Wistar rats were administered with FT continuously for 14 days and recovered for 14 days after stopping administration. At the end of treatment and recovery periods,hematology and serum biochemical indexed were determined. The organs were examined pathologically and weighed to obtain organ weights. The bone marrow smears were also examined. Results： At the end of treatment periods,compared with the vehicle control group,% RETIC of male rats peripheral blood of FT each dosage groups were decreased（ P〈0. 01）,PLT of male rats peripheral blood of FT 100. 0 mg·kg^-1·d^-1oup were decreased（ P〈0. 01）. BUN,CREA and CK of both male and female rats peripheral serum of FT 100. 0 mg·kg^-1·d^-1oupwere increased（ P〈0. 05,P〈0. 01）,furthermore,BUN of male rats peripheral serum of FT 100. 0 mg·kg^-1·d^-1oup was higher than female rats（ P〈0. 01）. The kidney organ weights and coefficients of both male and female rats FT 30. 0,100. 0 mg·kg^-1·d^-1oups were increased（ P〈0. 05,P〈0. 01）,and the body weights were decreased（ P〈0. 01）. At the end of recovery periods,compared with vehicle control group,% RETIC,PLT of female rats of FT 100. 0 mg·kg^-1·d^-1oup and the kidney organ weights and coefficients of female rats of 30. 0mg·kg^-1·d^-1oup were increased,simultaneously the results of counting and classification of bone marrow smears showed that granulocyte series and erythrocyte series decreased（ P〈0. 05）. The rest of indexes returned to normal.Histopathological examination showed that the different degrees of degeneration and necrosis of renal tubule,cell debris cast,protein cast,basophilic tubul
出处
《中国新药杂志》
CAS
CSCD
北大核心
2017年第5期562-569,共8页
Chinese Journal of New Drugs
