大鼠体内给药途径的探索

目的设计一种新的给药途径,以探讨药物发挥作用的关键时刻以及最佳时刻,并通过在体心肌缺血再灌注模型进行验证。方法新的给药途径为:左心室-主动脉-冠状动脉途径给药,从右侧颈总动脉插管,经动脉瓣到左心室,显示特征性心室波待稳定后,经该管直接给予溶有还原型谷胱甘肽(120mg/kg)的生理盐水1ml至心室,于1min内注入,与常规右侧股静脉给药途径作对比,采用经典大鼠在体缺血再灌注模型验证新法给药途径的优点。结果分别经左心室—主动脉—冠状动脉途径和静脉途径给药,主动脉血浆药物浓度均在1min时达峰值;相同剂量GSH(120mg/kg)经左心室—主动脉—冠状动脉途径给药后主动脉血浆药物浓度(810±100)μmol/L]明显高于静脉途径给药(351±50)μmol/L]。在再灌注早期经左心室—主动脉—冠状动脉途径注射GSH(120mg/kg)干预和静脉注射GSH(120mg/kg)干预,与缺血再灌注对照组相比,心梗面积均显著减小分别为(23±4)%、(39±2)%和(52±1)%],差异有统计学意义(P<0.05),但经左心室—主动脉—冠状动脉途径减小得更明显,差异有统计学意义(P<0.05)。肌酸激酶、丙二醛含量在再灌注末与静脉途径相比(53±1)U/ml,(3.6±0.4)μmol/L],经左心室—主动脉—冠状动脉途径减少更明显(47±3)U/ml,(3.2±1)μmol/L]。结论与经静脉给药相比,经左心室—主动脉—冠状动脉途径注药,可显著提高注射期间主动脉和冠状动脉血浆中的药物浓度,是一条可供药物干预的新途径,并且可以更好地保护心肌缺血再灌注损伤。

To explore a new pathway of administration in rat

Objective To explore for an optimal time window to minimize the post-conditioning effects using the ventriculo-aorta-coronary route in animal models of cardiac ischemia-reperfusion. Methods For the new route of drug administration （left ventriculo-aorta-coronary route）, a cannula was inserted into the right common carotid artery and passed through aortic valves into the left ventricle. With typical ventricular waves displayed stable on the monitor, a bolus of lml normal saline added with Glutathione （120 mg/kg） was injected through the cannula within one minute. The effects of this approach were compared with those of the conventional right femoral route in commonly used rat models of cardiac ischermia-reperfusion. Results The ventricular plasma concentration of Glutathione peaked within 1 minute from drug administration regardless of the mutes used. However, higher concentration of Glutathione E（810± 100） μmol/L] was noted with the new arterial route vs that with the venous via the femoral vein （351μ50 ）μmol/L）. Compared with blank controls of cardiac ischemia-reperfusion （52±1）%], significant reduction in sizes of infarction was shown in both groups treated through arterial （23±4）%] or venous （39±2）%] mutes （P〈0.05）, which was even greater with the arterial than with the venous route （P〈0.05）. Immediately after reperfusion, plasma： levels, of creatine kinase （CK） and malondialdehyde （MDA） were lower in rats treated via arterial route （47±3） U/ml and （3.2±1） μmol/L] than in those via venous route （53±1） U/ml and （3.6±0.4） μmol/L]. Conclusion Compared with the commonly used venous route, use of the new left ventriculo-aorta-coronary route remarkably may result in higher drug concentration in the aorta and coronary arteries, and provide better cardioprotective effect against ischemia-reperfusion injury.