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目的:研制单硝酸异山梨醇乙酰阿魏酰胺(AcFA-201),并与阿魏酸钠(SF)、单硝酸异山梨醇酯(ISMN)和单硝酸异山梨醇乙酰阿魏酸酯(AFI)比较其对心肌缺血/再灌注(MI/R)大鼠心肌的保护作用。同时比较AcFA-201与AFI在模拟胃液中的稳定性。方法:先将ISMN的羟基转化为胺基,再与乙酰化阿魏酰氯反应,生成新化合物AcFA-201。常规建立大鼠MI/R(30 min/3 h)模型,随机给予SF、ISMN、AFI或AcFA-201药物治疗。观察各组大鼠灌注末心功能恢复的情况,同时测定血清肌酸激酶(CK)、乳酸脱氢酶(LDH)、超氧化物歧化酶活性(SOD)、过氧化氢(H2O2)与丙二醛(MDA)的水平及NO的含量。结果:合成路线可行,化合物AcFA-201的化学产率为81.8%。模拟胃液中的稳定性研究结果表明,AFI在给药10 min后,原药剩余很少,30 min完全消失;而AcFA-201在180min后,基本保持初始给药浓度。与SF、ISMN治疗组相比,AcFA-201治疗组左室发展压、左室等容收缩压/舒张期压力上升或下降最大速率(±dp/dtmax)显著提高(n=8,P<0.05)。血清CK、LDH的活性和H2O2、MDA的含量降低而NO含量显著升高(n=8,P<0.05或P<0.01);与AFI组相比,AcFA-201组各项指标均无显著性差异。结论:AcFA-201对MI/R损伤大鼠的心肌具有保护作用,其作用比SF、ISMN强,与AFI没有显著性差异。AcFA-201在模拟胃液中的稳定性明显优于AFI,更适合口服药物的研发。
OBJECTIVE: To develop isosorbide monofretinoacetate ferulic acid amide (AcFA-201) and to study the effects of sodium ferulate (SF), isosorbide dinitrate (ISMN) and isosorbide mononitrate ferulic acid ester ) Were compared for their protective effects on myocardial ischemia / reperfusion (MI / R) in rats. At the same time, the stability of AcFA-201 and AFI in simulated gastric juice was compared. Methods: The hydroxyl group of ISMN was first converted into amine group and then reacted with acetylated ferulicyl chloride to generate new compound AcFA-201. The rats were routinely established MI / R (30 min / 3 h) model, randomized to SF, ISMN, AFI or AcFA-201 drug treatment. The recovery of perfused cardiac function in each group was observed. Serum creatine kinase (CK), lactate dehydrogenase (LDH), superoxide dismutase (SOD), hydrogen peroxide (H2O2) Aldehyde (MDA) levels and NO content. Results: The synthetic route was feasible. The chemical yield of AcFA-201 was 81.8%. The results of simulated gastric fluid stability showed that aflatoxin afforded little residual after 30 min of administration and completely disappeared after 30 min. However, AFFA maintained its initial drug concentration after 180 min. Compared with the SF and ISMN groups, the increase of left ventricular pressure, the increase of left ventricular isovolumic / diastolic pressure (± dp / dtmax) was significantly increased in AcFA-201 group (n = 8, P <0.05 ). The activity of CK, LDH and the content of H2O2 and MDA decreased but the content of NO increased significantly (n = 8, P <0.05 or P <0.01). Compared with AFI group, there was no significant difference difference. CONCLUSION: AcFA-201 has a protective effect on myocardium of MI / R injury rats. Its effect is stronger than that of SF and ISMN, but no significant difference with AFI. AcFA-201 in the simulated gastric fluid was significantly better than the stability of AFI, more suitable for oral drug development.