单硝酸异山梨酯、缬沙坦、螺内酯复方对大鼠的长期毒性研究

目的 观察SD大鼠连续6个月口服单硝酸异山梨酯、缬沙坦、螺内酯复方所产生的毒性反应,比较3种药物联合应用后,毒性是否增加或产生新的毒性。方法 健康SD大鼠200只,雌雄各半,分为5组：空白对照组、复方73、244、733 mg·kg-1及缬沙坦600mg·kg-1对照组,每组40只。给药体积为10mL·kg-1,每日ig给药1次,每周给药6d,连续给药6个月,停药观察4周。实验期间,每日进行一般状态观察,每周测定1次体质量及摄食量,于给药3、6个月及停药4周后,各组动物分别进行血压、血液学、血液生化学指标检测,动物剖检并进行病理组织学检查。结果 复方73、244、733 mg·kg-1及缬沙坦600 mg·kg-1对照组血压出现明显降低,为复方药物药理作用结果。244、733 mg·kg-1及缬沙坦600 mg·kg-1对照组RBC、HCT、HGB及Ret均出现明显降低,肾功能指标CREA、UREA及电解质K＋明显升高,组织病理学检查肾脏出现明显病理学改变,当停药恢复期结束后,上述各指标恢复正常。结论 本试验条件下,单硝酸异山梨酯、缬沙坦、螺内酯复方口服6个月无不良反应剂量（NOAEL）为73 mg·kg-1,当大鼠6个月给药剂量达到244 mg·kg-1时,血液学、血钾及肾功出现明显毒性反应,停药后可恢复正常。复方中3种药物联合应用,同缬沙坦单独使用相比未见毒性增加或产生新的毒性。

Experimental Study on Long-term Toxicity of ISMN Valsartan Spironolactone Antihypertensive Compound in Rats

Objective To observe the toxicity of antihypertensive compound （ingredients： isosorbide mononitrate, valsartan, spironolactone） in rats for 6 months by oral administration, and whether the toxicity was increased or not, and whether new toxicity was generated after three ingredients combined application compared with valsartan used alone were also observed. Methods 200 healthy Sprague-Dawley （SD） rats, were randomly disvided into control, valsartan, low-, mid-, and high-dose （73, 244, and 733 mg kg-1） valsartan compound groups, 40 in each group. Dose volume was 10 mL kg-1, with ig administration for 6 months, 6 d per week, and observed for 4 weeks after the last administration. During the experiment, the general conditions of animals were observed daily. Body weight and food consumption were weighed weekly. The related indexes including blood pressure , blood routine, and blood biochemistry were detected at different time points such as month 3 and 6 of administration, and week 4 in recovery period. Then the rats were dissected and histopathologic examination was carried out. Results Compared with control group, the blood pressure in all the drug groups declined obviously but returned to normal after drug withdrawal. In 244, 733 mg kg-1 combination groups and valsartan group, the blood routine R_BC, HCT, HGB and Ret decreased obviously, the serum CtCEA, UREA and K＋ were increased after given drug for 3 months, no obvious pathological changes in organs were observed except kidney appeared server inflammation. These abnormal indexes can return to normal after drug withdrawal. Conclusion In this study, the no observed adverse effect level （NOAEL） of antihypertensive compound is 73 mg kg-1 in rat for 6 months by oral administration. The toxicity of blood routine and kidney was found at dosage of 244 mg kg-1. The damage was reversible, it can return to normal after drug withdrawal. The toxicity was not increased and new toxicity was not generated compared with valsartan used alone after three ingred