[关键词]
[摘要]
目的 观察SD大鼠重复ig给予单硝酸异山梨酯盐酸伊伐布雷定(单硝伊伐)复方产生的毒性反应,比较单硝酸异山梨酯、盐酸伊伐布雷定两药合用后,毒性是否增加或产生新的毒性。方法 SPF级SD大鼠120只,随机分为空白组,单硝酸异山梨酯组,盐酸伊伐布雷定组,复方低、中、高剂量(35、128、465 mg/kg)组,每组20只,雌雄各半。按照10 mL/kg的给药体积连续ig给药1个月,停药观察2周,试验期间进行一般体征观察、体质量、摄食量、血压、心率、血液学、生化学及组织病理学检查。结果 给药组与空白对照组比较外观体征、行为活动、体质量、摄食量、血液学均未见明显异常。复方药物可使大鼠心率呈剂量相关性的降低,停药后恢复正常。给药末期复方高剂量组收缩压(SBP)、舒张压(DBP)比空白组略低,恢复期结束后出现反弹性升高。生化检测中给药末期复方高剂量组丙氨酸氨基转移酶(ALT)、碱性磷酸酶(ALP)和中剂量组ALT与空白组、单硝酸异山梨酯组、盐酸伊伐布雷定组比较虽具有统计学差异(P<0.05),但无生物学意义,恢复期后恢复正常。病理学检查发现:盐酸伊伐布雷定组、复方组雄性大鼠均可见不同程度的心肌病变动物数量增加或病变程度加重,单硝酸异山梨酯组、复方组均可见个别雌性大鼠脾脏内含铁血黄素的沉积,且以上病变动物数量随复方低、中、高剂量的增加有依次递增现象,停药后未见良好的可恢复性。结论 本试验条件下SD大鼠重复ig给予复方药物,毒性靶器官为心脏、脾脏并有一定的性别差异,同各成分单独使用相比,未见毒性增加或产生新的毒性。
[Key word]
[Abstract]
Objective To evaluate the toxicity of isosorbide 5-mononitrate (ISMN) and Ivabradine (ISMN-I) Compound on SD rats by continuous ig administration and to compare whether the toxicity increased or new toxicity generated after the combination of the two drugs. Methods SPF SD rats (120) were randomly divided into control, ISMN, Ivabradine, low-, mid-, and high-dose [35, 128, and 465 mg/kg] compound groups, 20 in each group, half male and half female. The rats were consecutively drenched at 10 mg/kg for 1 months and observed for 2 weeks after stopping drug administration. General condition, body weight, food consumption, blood pressure, heart rate, haematology, biochemical tests, and histopathology were performed during the experiment. Results The treated groups compared with the control group, there were no significant changes on appearance of the signs, behavior, body weight, food consumption, and haematology. Compound drugs could make the heart rate decreased in a dose dependent manner, but returned to normal after drug withdrawal. SBP and DBP in the high-dose group slightly lower than those in the control group during delivery stage, but increased reboundly after recovery period. Compared with the control group, ISMN and Ivabradine groups, ALT and ALP in the high-dose group and ALT in the mid-dose group had statistically difference, but no biological significance (P < 0.05), and returned to normal after recovery period. Obvious pathological changes were observed: different degrees of the increase in the number of animal disease or myocardial lesions were observed in Ivabradine and Compound groups of male rats, deposition of hemosiderin in the spleen was observed in ISMN and Compound groups of individual female rats, with the increasing dose of compound, the number of disease animal had the increasing order of phenomena, no good recovery after stopping drug administration. Conclusion By continuous ig compound to SD rats, there are the toxic target organs of heart and spleen and some sex differences. The toxicity is not increased or generated compared with the ingredients used alone.
[中图分类号]
[基金项目]