CAJ | 학술논문

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600 mg·kg-1对照组，每组40只。给药体积为10 mL·kg-1，每日ig给药1次，每周给药6 d，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。
목적：관찰SD대서련속6개월구복단초산이산리지、힐사탄、라내지복방소산생적독성반응，비교3충약물연합응용후，독성시부증가혹산생신적독성。방법건강SD대서200지，자웅각반，분위5조：공백대조조、복방73、244、733 mg·kg-1급힐사탄600 mg·kg-1대조조，매조40지。급약체적위10 mL·kg-1，매일ig급약1차，매주급약6 d，련속급약6개월，정약관찰4주。실험기간，매일진행일반상태관찰，매주측정1차체질량급섭식량，우급약3、6개월급정약4주후，각조동물분별진행혈압、혈액학、혈액생화학지표검측，동물부검병진행병리조직학검사。결과복방73、244、733 mg·kg-1급힐사탄600 mg·kg-1대조조혈압출현명현강저，위복방약물약리작용결과。244、733 mg·kg-1급힐사탄600 mg·kg-1대조조RBC、HCT、HGB급Ret균출현명현강저，신공능지표CREA、UREA급전해질K+명현승고，조직병이학검사신장출현명현병이학개변，당정약회복기결속후，상술각지표회복정상。결론본시험조건하，단초산이산리지、힐사탄、라내지복방구복6개월무불량반응제량（NOAEL）위73 mg·kg-1，당대서6개월급약제량체도244 mg·kg-1시，혈액학、혈갑급신공출현명현독성반응，정약후가회복정상。복방중3충약물연합응용，동힐사탄단독사용상비미견독성증가혹산생신적독성。
ObjectiveToobservethetoxicityofantihypertensivecompound(ingredients:isosorbidemononitrate, 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 RBC, HCT, HGB and Ret decreased obviously, the serum CREA, 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 normalafter drug withdrawal. The toxicity was not increased and new toxicity was not generated compared with valsartan used alone after three ingredients combined application.