脂蛋白相关磷脂酶A2抑制剂Darapladib的药效学研究进展

 脂蛋白相关磷脂酶A2 (lipoprotein- associated Phospholipase A2,Lp- PLA2)是磷脂水解酶超家族中的一员,能水解低密度脂蛋白中的氧化修饰磷脂,产生溶血卵磷脂和氧化性游离脂肪酸两种促炎介质。最近研究发现Lp- PLA2能够介导炎症反应以及促进动脉粥样硬化(atherosclerosis , AS)的形成,现已成为一个新炎性反应标志物和心血管事件的独立风险预示因子。针对这一动脉粥样硬化过程中的关键酶设计的抑制剂很多。其中Darapladib是目前最接近上市的一种Lp- PLA2特异性抑制剂,目前其Ⅲ期临床试验已完成。Darapladib作为一种新兴的抗AS分子靶点药物,受到人们广泛的关注。已有多项研究表明它能降低Lp- PLA2的活性,减轻炎症反应,从而控制AS的发展与恶化。本文综述了Lp- PLA2及其抑制剂Darapladib在AS中的作用机制以及近年来 Darapladib的药效学研究进展。     

颈动脉粥样硬化患者臂踝脉搏波传导速度baPWV与颈动脉内中膜厚度IMT相关性研究

目的:通过联合运用多普勒超声与动脉硬化仪探讨颈动脉粥样硬化患者颈动脉内中膜厚度(IMT)与臂踝脉搏波传导速度(ba PWV)的相关性,综合评价补肾中药复方首参颗粒的临床疗效。方法:选取156例颈动脉粥样硬化患者,随机分为西药组73例和中药组83例,西药组口服普法他汀治疗,中药组服用首参颗粒治疗,疗程均为6个月。分析颈动脉粥样硬化患者ba PWV与IMT的相关性,观察两组患者治疗前、治疗后IMT与ba PWV变化。结果:156例颈动脉粥样硬化患者IMT与ba PWV之间呈显著正相关(相关系数为0.1873),两组治疗后IMT与ba PWV均较治疗前明显降低(P0.01或P0.05),两组间同期比较差异无统计学意义(P0.05)。结论:IMT与ba PWV可作为颈动脉粥样硬化患者临床监测的有效指标,首参颗粒可能通过降低颈动脉粥样硬化患者IMT、ba PWV进而有效干预动脉粥样硬化。     

葛根芩连汤对动脉粥样硬化伴随牙周炎大鼠的影响

目的:讨论葛根芩连汤对动脉粥样硬化伴随牙周炎大鼠模型的治疗效果。方法:将40只健康雄性Wistar大鼠,分为健康正常组和模型组,正常组10只,模型组30只,正畸结扎丝结扎于左上颌第二恒磨牙牙颈部龈沟内,高脂饮食辅助药物诱导造模,造模成功后分为模型组、甲硝唑治疗组(0.05g·kg-1·d-1)、阿伐他汀组(0.08g·kg-1·d-1)、甲硝唑联合阿伐他汀组、葛根芩连汤组(0.42g·kg-1·d-1),每组6只,ig给予相应药物,4周后,HE染色光镜下观察治疗前后牙周组织和腹主动脉病理变化,检测治疗前后牙周袋深度及附着丧失检测和血脂总胆固醇(TC),甘油三脂(TG),低密度脂蛋白(LDL),高密度脂蛋白(HDL)水平的改变。结果:与正常组比较,模型组牙周袋深度及附着丧失和血脂TC,TG,LDL水平明显升高(P<0.05),HDL明显降低(P<0.05);与模型组比较,甲硝唑组、阿伐他汀组、甲硝唑联合阿伐他汀组、葛根芩连汤组牙周袋深度及附着丧失和血脂TC,TG,LDL水平均较模型组显著降低,差异有统计学意义(P<0.05),HDL明显升高(P<0.05);甲硝唑联合阿伐他汀组与葛根芩连汤组比较牙周袋深度及附着丧失和血脂TC,TG,LDL,HDL水平无差异。HE染色观察发现牙周炎症破坏明显,结合上皮与牙面分离,上皮向根方增殖,组织深部可见大量炎症细胞浸润,骨小梁稀疏,牙槽骨表面可见骨吸收,牙槽嵴顶高度降低,呈垂直吸收,牙周膜纤维粗细不均或断裂,排列紊乱,各给药组均有不同程度的改善,尤其是甲硝唑联合阿伐他汀组与葛根芩连汤组更为明显。结论:葛根芩连汤能够改善模型大鼠牙周炎症水平并且能够降低大鼠血脂水平,提示该药对牙周炎伴动脉粥样硬化疾病有良好的治疗效果。     

百令胶囊对尿蛋白阴性的糖尿病肾脏疾病患者踝肱指数、趾肱指数及氧化应激的影响

目的:探讨尿蛋白阴性的糖尿病肾脏疾病发生可能的机制及百令胶囊的干预作用。方法:选择尿蛋白阴性的2型糖尿病患者200例,其中尿蛋白阴性的糖尿病肾脏疾病患者100例(NDN组),无白蛋白尿2型糖尿病患者肾功能正常患者100例(对照组)。比较两组的临床资料和实验室检查,Logistic回归分析肾功能下降的影响因素。NDN组分为常规治疗组、百令胶囊治疗组,每组50例,常规治疗组仅予胰岛素严格控制血糖,百令胶囊治疗组在常规治疗组治疗的基础上加用百令胶囊,5粒/次,3次/d,共服用8周,对比两组患者治疗前后检查的变化。结果:在尿蛋白阴性的糖尿病肾脏疾病患者中踝肱指数(ABI),趾肱指数(TBI),肾小球滤过率(e GFR)显著低于对照组[ABI(0.82±0.17)VS(1.07±0.51),TBI(0.64±0.16)VS(0.99±0.23),e GFR(49.5±6.5)VS(95.4±7.1)m L·min-1·(1.73 m2)-1,血清8-异前列腺素F2α(8-iso-PGF2α),颈动脉内中膜厚度(CIMT)显著高于对照组[8-iso-PGF2α(18.72±3.2)VS(8.21±1.9)μg·L-1,CIMT(1.13±0.19)VS(0.71±0.17)mm](P0.05)。尿蛋白阴性的糖尿病肾脏疾病患者GFR与ABI,TBI呈显著正相关(P0.05);8-异前列腺素F2α,ABI,TBI为尿蛋白阴性的糖尿病肾脏疾病患者的独立危险因素(P0.005,P0.001,P0.001);百令胶囊治疗组治疗后ABI,TBI较常规治疗组改善更明显[ABI(0.98±0.35)VS(0.81±0.35),TBI(0.92±0.23)VS(0.62±0.22)],且差异有统计学意义(P0.05),8-iso-PGF2α下降更明显[(9.34±2.8)VS(18.08±4.1)μg·L-1],且差异有统计学意义(P0.05)。结论:尿蛋白阴性的糖尿病肾脏疾病发生可能与动脉硬化、氧化应激有关,使用百令胶囊干预能延缓其发展。     

高同型半胱氨酸血症与不稳定斑块

血浆同型半胱氨酸的代谢异常导致的高同型半胱氨酸血症是动脉粥样硬化和冠心病的一个独立危险因素。针对高同型半胱氨酸与动脉粥样硬化和斑块稳定之间的确切联系,以及药物干预等问题成为研究的热点。现主要通过致炎症因子、氧化应激及内质网应激、免疫反应等多种细胞机制水平对同型半胱氨酸的作用作一综述。     

高脂血症对兔动脉壁一氧化氮系统的影响及药物的干预效果

将雄性纯种新西兰家兔36只随机分为三组,喂饲胆固醇形成实验性高胆固醇血症,部分加用麝香保心丸喂养;同时采用定量RT-PCR等技术,观察高脂血症对动脉壁一氧化氮系统代谢的影响,以及麝香保心丸的保护作用.结果表明:高脂饮食可造成动脉一氧化氮代谢的紊乱,降低动脉壁内皮型一氧化氮合酶(eNOS)基因的表达(P相似文献   

Mortality and morbidity of diabetes in Papua New Guinea

Summary A 95% follow-up of all known diabetic patients in one racial group in Papua New Guinea was performed. Mortality was high with an average life-span of 4–5 years from the time of diagnosis. Microvascular diabetic complications were detected in over half of the surviving diabetic patients whose average duration of known disease was 3.8 years. At present, diabetes mellitus is both a rapidly fatal and morbid disease in Papua New Guinea.     

兔腹主动脉粥样硬化支架植入后血管壁及内膜改变

目的通过建立兔腹主动脉粥样硬化植入支架动物模型,探讨支架植入后血管壁和内膜变化及发生机制.方法采用兔腹主动脉内膜剥脱术加含1.5%高胆固醇的高脂饮食来建立动脉粥样硬化动物模型,并在此基础上建立兔粥样硬化腹主动脉植入支架模型,并通过组织病理学检查,来揭示支架植入后血管壁和内膜组织形态学变化和病变的发生机制.结果在动脉粥样的动物模型基础上所建立兔腹主动脉粥样硬化植入支架动物模型,经组织形态学和免疫组化检查显示:动物模型目标血管段管腔内膜明显增厚、血管出现不同程度的狭窄,新生内膜中有大量增殖细胞核抗原(PCNA)高表达(着色强度IS:5.268±0.475)的血管平滑肌细胞(VSMC)和泡沫细胞及细胞外基质(ECM).经计算机图像分析仪测定其组织形态学指标分别为残余管腔面积[(9.67±0.18)mm2]、最大内膜厚度[(1.33±0.05)mm]、内膜面积[(5.78±0.23)mm2]和狭窄程度[(31.02±1.91)%].结论本实验成功地建立了兔腹主动脉粥样硬化植入支架动物模型,并认为支架术后血管新生内膜中VSMC过度增殖是导致支架植入后管腔内膜明显增厚的可能原因.     

Glucose inhibits replication of cultured human endothelial cells

Summary Diabetes is an important risk factor for atherosclerosis but the mechanism of the risk is unknown. As endothelial injury is considered to be an early event in the development of atherosclerosis, the effect of glucose on endothelial cell replication was studied. Concentrations of glucose of 11.2, 16.8 and 22.4 mmol/l inhibited DNA synthesis in cultured human umbilical venous endothelial cells by 8.1±10.8, 24.3±8.8 and 30.9±7.4%, respectively. Glucose also inhibited the proliferative response of endothelial cells to experimental wounds in the cell layer. Sorbitol (22.4 mmol/l) inhibited endothelial cell DNA synthesis by 50±13.6%, but mannitol (22.4 mmol/l) inhibited DNA synthesis by only 3±24.3%. It is suggested that in diabetic subjects, high blood glucose levels may cause endothelial injury, or inhibit its repair, and hence allow the exposure of the arterial media to plasma and its constituents.     

Platelet activation in normo- and hyperlipoproteinemias

Summary In the last few years it became obvious that platelets are involved in the development of atherosclerotic diseases. This involvement of platelets has been taken into account in the response to injury hypothesis of atherosclerosis. The hypothesis is based on the assumption that atherosclerotic lesions result from endothelial injury, followed by the interaction of, vessel wall constituents with lipoproteins, macrophages, and platelets.In the first part of this review, general aspects of platelet activation are summarized and the pathways of platelet aggregation as well as their involvement in blood coagulation are discussed.The second part of this paper describes the influence of cholesterol, lipoproteins, and apolipoproteins upon the activation and metabolic behavior of, platelets. Physiological and pathophysiological processes particularly occurring in different types of hyperlipoproteinemias and atherosclerotic disorders are discussed in this context.