注射用右旋雷贝拉唑钠Beagle犬13周重复给药毒性实验研究

摘要

目的 研究重复静脉给予注射用右旋雷贝拉唑钠13周对Beagle犬产生的毒性,并与注射用雷贝拉唑钠进行比较.方法 正常Beagle犬50只,分为注射用右旋雷贝拉唑钠2.5、10、40 mg·kg-13个剂量组、注射用雷贝拉唑钠40 mg·kg-1对照组和溶剂对照组,每组静脉滴注给予相应剂量的药物溶液,每天1次,连续13周,停药恢复4周.每周称量1次体重,给药前、给药结束及恢复期结束进行体温、心电、眼科、尿液和粪便检查;采血进行血液学、血液生化学指标检测;给药结束及恢复期结束剖检进行脏器相对重量和组织病理学检查.结果 注射用右旋雷贝拉唑钠40 mg·kg-1剂量下可引起部分动物给药后即刻发现自主活动减少、呼吸急促、流涎、俯卧等症状,血液学指标RBC、HGB、HCT降低,血清生化学指标TP、ALB降低、TC、TG、BUN升高,肝脏相对重量增加以及甲状腺病理组织学病变.结论 重复静脉给予注射用右旋雷贝拉唑钠的主要毒性靶器官为肝脏、肾脏和甲状腺,相同剂量下毒性与注射用雷贝拉唑钠基本一致;犬最大无毒反应剂量(NOAEL)为2.5 mg·kg-1.%Objective To reach the repeated dose toxicity of dexrabeprazole sodium for injection in Beagle dogs and compare the toxicity with rabeprazole sodium for injection.Methods Fifty normal Beagle dogs were divided into five groups:solvent control group,rabeprazole sodium for injection group (40 mg· kg-1) and dexrabeprazole sodium injection group (2.5,10 and 40 mg·kg-1).The dogs were administered intravenously with corresponding drag for 13 weeks continuously.The body weights were detected every week and body temperature,ECG,ophthalmology,urine and stool were examined before and after administration period and recovery for 4 weeks.The serum and plasma of dogs were collected to detect hematology and blood biochemistry index,and dogs were autopsied to detect viscera index and histopathology at the end of administration and recovery for 4 weeks.Results The main toxicity symptoms of some dogs administered with dexrabeprazole sodium for injection (40mg·kg-1) are decreased voluntary activity,shortness of breath,salivation and prone.Abnormal reduction of the levels of RBC,HGB,HCT,TP,ALB and escalation of the levels of TC,TG,BUN and kidney index were found after administration for 13 wk.Pathological changes of thyroid was also found by histopathological examination.Conclusion Major toxic target organs of Beagle dogs after administration with dexrabeprazole sodium for injection (40mg·kg-1) for 13 wk are liver,kidney and thyroid.The toxicity level is similar in dexrabeprazole sodium for injection group and rabeprazole sodium for injection group with same dose.No observed adverse effect level (NOAEL) in Beagle dogs is 2.5 mg·kg-1.