自组装Tween 20-SDS纳米混合胶束提高普罗布考口服吸收的研究

利用Tween-20与十二烷基硫酸钠的两亲性结构,与普罗布考混合,通过自组装技术制备了具有核-壳结构的纳米混合胶束,其中药物浓度可达到20 mg/ml.所得制品平均粒径为(44.6±1.6) nm,多分散系数为0.179±0.058,且用不同pH介质稀释后粒径未发生显著变化.采用共聚焦显微成像技术观察表明,制品能影响Caco-2细胞骨架蛋白,增强细胞膜流动性.建立了UPLC-UV法测定生物样品中普罗布考的浓度.Caco-2细胞单层模型的细胞摄取试验和大鼠体内药动学研究均表明,本品可显著提高普罗布考的口服吸收.     

普罗布考混合胶束的制备及其大鼠体内药动学研究

目的 制备普罗布考混合胶束(Probucol loaded mixed micelles,PMM)用于提高其口服生物利用度。方法 选择磷脂、脱氧胆酸钠为辅料,以共沉淀法制备普罗布考混合胶束(PMM),并对其体外理化特性以及体内药动学行为进行评价。结果 制备了普罗布考混合胶束,其优化处方组成为磷脂︰脱氧胆酸钠︰普罗布考(3︰4︰1)。PMM平均粒径为82.28 nm,多分散系数为0.179,药物主要以非晶型状态存在于PMM中。大鼠体内药动学研究表明,与原料药相比,口服PMM后,普罗布考的峰浓度和口服生物利用度分别提高了2.28 倍和4.43倍。结论 混合胶束能够显著提高普罗布考的口服生物利用度,为解决难溶性药物的口服吸收问题提供了一种有效策略。     

普罗布考对新西兰兔动脉粥样硬化的影响

目的:研究普罗布考对正常饮食及高脂高胆固醇饮食新西兰兔血脂、肥大细胞及动脉粥样硬化的影响.方法:40只雄性新西兰兔分别给予基础饲料、基础饲料+普罗布考、高脂高胆固醇饲料、高脂高胆固醇饲料+普罗布考喂养4周,取材.采用酶比色法检测血清中脂质水平;甲苯胺蓝染色检测肥大细胞;苏丹Ⅳ染色测定主动脉粥样硬化病变面积.结果:与高脂高胆固醇组比较,高脂高胆固醇+普罗布考组新西兰兔血清三酰甘油(TG)、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)水平均明显降低(P＜0.05);主动脉和空肠脱颗粒的肥大细胞百分率明显减少(P＜0.001);主动脉粥样硬化病变面积明显减少(P＜ 0.001).结论:普罗布考能降低高脂高胆固醇饮食新西兰兔血脂水平;减少主动脉、空肠脱颗粒的肥大细胞百分率以及主动脉粥样硬化病变面积.     

普罗布考对急性冠状动脉综合征患者血清髓过氧化酶和高敏C反应蛋白的影响

目的探讨普罗布考对急性冠状动脉综合征患者血清髓过氧化酶及高敏C反应蛋白的影响及其可能机制。方法将急性冠状动脉综合征患者随机分为普罗布考组和对照组,分别检测治疗前后血清髓过氧化酶和高敏C反应蛋白的浓度。结果普罗布考组和对照组血清髓过氧化酶和高敏C反应蛋白浓度均明显下降（P〈0．001）;但普罗布考组较对照组血清髓过氧化酶下降更加明显（P〈0．05）。结论普罗布考能降低急性冠状动脉综合征患者血清髓过氧化酶和高敏C反应蛋白水平,普罗布考更有效地降低急性冠状动脉综合征患者血清髓过氧化酶,其可能部分解释普罗布考的抗炎和抗氧化作用。     

Dietary prevention of post-angioplasty restenosis. From illusion and disillusion to pragmatism

Prevention of restenosis and major cardiac events after percutaneous coronary intervention (PCI) is of enormous public health importance. Despite the considerable decrease in the restenosis rate in relation to the advent of the drug-eluting stents, it is likely that the complication will still occur in some patients and/or after a certain delay. Thus, dietary or systemic drug prevention will probably have a role in the drama in the future, although the way they can be used is not clear at present. This discussion focuses on the dietary approach of post-PCI restenosis because, among the many drugs that have been tested, none has been consistently shown to be helpful—with the exception of the potent antioxidant drug probucol—, whereas the results of several dietary trials have been encouraging. As discussed in the present issue of NMCD, vitamins of the B group were recently shown to decrease the risk of restenosis, supposedly through an effect on homocysteine metabolization. It seems, however, that homocysteine is a minor risk factor of post-PCI restenosis. On the other hand, 5-methyltetrahydrofolate (the active form of folic acid) was shown to improve endothelial function independently from homocysteine. Thus, folic acid could prevent restenosis not only by reducing homocysteine, but also by promoting nitric oxide formation. Because of their potential to prevent post-PCI restenosis and acute cardiac complications, n-3 fatty acids have been the most widely studied post-PCI medical intervention. Taken together, trial data suggest that if n-3 fatty acids can be useful in certain populations to prevent restenosis, their effects are probably weak. However, according to recent studies on endothelial nitric oxide synthase (eNOS) gene polymorphisms, it is likely that only certain patients could benefit from n-3 fatty acid supplementation. The same reasoning can probably apply to the folic acid and eNOS issue. In conclusion, although none has been concluding, the studies about n-3 fatty acids and folic acid after PCI suggest that certain nutrients (or more probably a combination of nutrients) may be useful for the prevention of post-PCI restenosis. Any future trial involving these nutrients should combine them and take into account some major genetic confounders. In the meantime, it is medically and ethically justified to supplement our CHD patients after PCI. They should receive n-3 fatty acids to prevent sudden cardiac death, and B group vitamins (at the dosages tested in the Swiss Heart Study) to decrease the risk of restenosis. This would be, at least, a low cost intervention, and there is no fear of adverse side effects, contrary to those one can expect from drug treatments.     

普罗布考对老年下肢动脉硬化症患者内皮舒张功能的影响

目的　评价普罗布考对老年下肢动脉硬化症患者内皮舒张功能的影响。方法　采用随机、单盲、自身对照和组间对照方法 ,将 5 4例老年下肢动脉硬化症患者分为两组 ,其中普罗布考治疗组 33例 ,服用普罗布考 0 .5g,2次 /d ,同时服用阿司匹林 10 0mg ,1次 d ;常规治疗组 2 1例 ,仅服用阿司匹林 10 0mg,1次 d ,疗程均为 12周。采用高分辨率超声技术 ,对治疗前后血管内皮舒张功能进行检测。结果　 (1)治疗前老年下肢动脉硬化症患者肱动脉血流介导的舒张功能 (FMD)和硝酸甘油介导的舒张功能 (NMD)均明显低于健康人群 ;(2 )治疗后 ,普罗布考治疗组总胆固醇 (TC)、低密度脂蛋白胆固醇 (LDL C)及高密度脂蛋白胆固醇 (HDL C)明显降低 ;(3)治疗后 ,普罗布考治疗组FMD明显增加 ,而NMD无显著性改变。结论　 (1)老年下肢动脉硬化症患者内皮依赖的舒张功能降低 ;(2 )普罗布考能够改善老年下肢动脉硬化症患者内皮功能 ,并具有良好的调脂作用 ;(3)普罗布考引起的HDL降低并不影响其改善内皮功能的作用。     

普罗布考联合依帕司他治疗早期糖尿病性肾病的疗效观察

目的观察普罗布考联合依帕司他治疗早期糖尿病性肾病(DN)的疗效。方法选取2014年1月至2016年1月于中关村医院就诊的55例早期DN患者随机分为治疗组和对照组。两组患者均在给予优质低蛋白糖尿病饮食、控制血糖、血压达标的基础上,治疗组口服依帕司他(50 mg,3次/d)和普罗布考(0.5 g,2次/d);对照组仅口服普罗布考(0.5 g,2次/d)。两组均随访24周。结果两组患者治疗后血肌酐(SCr)、超敏C反应蛋白(hs-CRP)、尿白蛋白排泄率(UAER)均降低(P0.05);且治疗组较对照组下降更为明显(P0.05)。结论普罗布考与依帕司他联合应用能更有效地降低早期糖尿病患者尿蛋白水平。     

普罗布考对糖基化终末产物引发心脏微血管内皮功能紊乱的作用

目的:观察普罗布考（probucol）对糖基化终末产物（AGEs）作用后的心脏微血管内皮细胞iNOS表达的影响。方法: 原代培养心脏微血管内皮细胞,AGEs（100 mg/L）体外模拟高糖环境,在probucol(5 μmol/L,10 μmol/L,20 μmol/L) 作用后,检测ROS、NO和iNOS变化情况。结果: 与AGEs组比较,probucol组中ROS蛋白表达降低,NO生成增加,而 iNOS蛋白表达降低,且显示有浓度依赖性。结论: probucol可能通过对抗氧化应激的途径,缓解AGEs引发的心脏微血管内皮功能障碍。     

Both Atorvastatin and Probucol Can Down-regulate BMP-2 Expression Induced by Oxidized Low Density Lipoprotein in Human Umbilical Vein Cells

Objectives Bone morphogenetic protein-2 (BMP-2) plays an key role both in vascular development and pathophysiological processes. However, the mechanisms of oxidized low density lipoprotein (ox-LDL) and combinated with atorvastatin or probucol on BMP-2 expression are entirely unknown in human umbilical vein cells. Methods The HUVECs were treated by ox-LDL and combinated with atorvastatin, probucol. The expression of BMP-2, NF-κB65, PPARγ mRNA was examined by RT-PCR analysis and ELISA method. The MDA and SOD were detected by routine methods. Results Ox-LDL can induced BMP-2 mNRA expression, associated with NF-κB65 mNRA expression activation. Both atorvastatin and probucol can suppress BMP-2 and NF-κB65 expression induced by oxLDL and upregulate the expression of PPARγ. Furthermore, the increase of supernatant MDA levels and decrease of supernatant SOD levels resulted from oxLDL treatment can be reversed by probucol or atorvastatin. Conclusions OxLDL-induced BMP-2 mNRA expression can be suppressed by atorvastatin and probucol, which may be accomplished by activating NF-κB65 expression and upregulating the expression of PPARγ. Our findings also indicate that that BMP-2 mNRA expression includes the activation of reactive oxygen species.