【作者】 张凯；

【导师】 李拥军；

【作者基本信息】 河北医科大学 ， 内科学， 2010， 硕士

【摘要】 目的:曲美他嗪(trimetazidine,TMZ)为哌嗪类衍生物,是一种新型的抗心肌缺血药,主要通过抑制3 -酮酰基辅酶A硫解酶(3-KAT)而抑制心肌脂肪酸β氧化,增加葡萄糖氧化,改善糖酵解与糖氧化耦联,优化心肌细胞能量代谢。大量基础研究证实,曲美他嗪能减少细胞内H+、Na+、Ca2 +的超载,抑制氧自由基生成,稳定线粒体膜功能状态,具有抗氧化、抗凋亡等多种细胞保护作用,且不影响血流动力学,无负性肌力作用。其良好的药物学效应,受到临床医师的日益青睐。冠心病(CHD)重要的病理生理环节是动脉粥样硬化,动脉粥样硬化形成是动脉壁细胞、细胞外基质、血液成分、局部血流动力学、环境以及遗传等多因素参与的结果,它始发于血管内皮细胞的损伤,而内皮功能紊乱则是内皮损伤的前期表现。糖尿病是冠心病的等危症及独立危险因素。糖尿病时血管内皮细胞功能障碍,加速动脉粥样硬化,而动脉粥样硬化是CHD发生的重要原因。因此,血管内皮功能障碍可能是DM和CHD的共同通路和病理生理基础。冠心病合并糖尿病患者的冠状动脉病变严重而且弥漫,往往是多支病变,且预后较差。近年来的基础及临床医学研究成果显示血管内皮功能失调是诸多心血管疾病发生、发展的始动因子。已报道冠心病患者以及糖尿病患者血管内皮功能明显受损,而冠心病合并糖尿病患者的血管内皮功能的受损程度更严重。目前,国内外关于曲美他嗪影响血管内皮的报道尚少。本研究旨在通过观察应用负荷量曲美他嗪(60mg)两小时后,血浆一氧化氮(NO)水平,肱动脉内皮依赖性血管舒张功能(FMD)的变化来探讨负荷量曲美他嗪对冠心病合并糖尿病患者内皮功能的短时影响,为临床用药提供理论基础。方法:入选60例冠心病合并糖尿病的患者,男39例,女21例,年龄35～72岁,平均年龄(53.4±12.3)岁,所有入选患者需经冠状动脉造影确诊冠心病(依据国际通用的直径法评定冠状动脉狭窄程度,凡狭窄≥50%者定为CHD,<50%者为NCHD),同时符合1999年世界卫生组织推荐的糖尿病诊断标准,并且除外高血压及高脂血症。检测患者入院后第2天清晨空腹血脂(排除高脂血症)。检测第3天患者病情平稳状态下未服用负荷量盐酸曲美他嗪血浆NO水平,并即刻作肱动脉超声:检测基础状态下肱动脉内径的基础值D0,然后予肱动脉加压,检测肱动脉反应性充血内径D1,并计算出肱动脉血流介导的内皮依赖性血管舒张功能(FMD),随后顿服负荷量曲美他嗪60mg,两小时后检测血浆NO水平,并再次作肱动脉超声,检测FMD。结果:1.顿服负荷量曲美他嗪60mg两小时后血浆NO浓度较服药前显著升高(44.98±2.96 vs 45.87±3.28 umol/L, P<0.05)。2.顿服负荷量曲美他嗪60mg两小时后FMD(%)显著升高(12.69±1.61 vs 13.21±1.96 %,P<0.05)。结论:1.曲美他嗪具有改善冠心病合并糖尿病患者血管内皮依赖性舒张功能的作用2.其机制可能是通过影响NO水平而起作用。更多还原

【Abstract】 Objective: Trimetazidine (trimetazidine, TMZ) for piperazine derivatives, is a new type of anti-ischemic drugs.It inhibits myocardial fatty acidβoxidation and increase glucose oxidation, improve the coupling of glycolysis and glucose oxidation, optimize the energy metabolism of myocardial cell primarily by inhibiting the 3 - keto acyl-coenzyme A thiolase (3-KAT)s. A large number of basic research confirmed that trimetazidine reduces intracellular H +, Na +, Ca2 + overload, inhibits oxygen free radicals, stabilize the functional state of mitochondrial membrane, with anti-oxidation, anti-apoptotic and other cell protective effect.And it does not affect hemodynamics, has no negative inotropic effect . Trimetazidine is increasingly popular for Clinicians with excellent pharmacological effects. Atherosclerosis is an important part of the pathophysiology of Coronary Heart Disease (CHD), formation of atherosclerosis is involved in artery wall cells, extracellular matrix, blood composition, regional blood flow dynamics, and many other environmental and genetic factors, it began with vascular endothelial cell injury, while the endothelial dysfunction is endothelial injury in the early stage of the performance. Diabetes is a CHD risk equivalent and independent risk factors. Diabetes make vascular endothelial cell dysfunction, and accelerate atherosclerosis, whill atherosclerosis is an important reason for CHD occurred. Thus, vascular endothelial dysfunction may be a common pathway and pathological physiological basis between DM and CHD .Coronary artery Lesion is severe and diffuse, often multi-vessel Lesion.The incidence is more common with acute coronary syndrome, and the prognosis is poor. In recent years, basic and clinical research results showed that endothelial dysfunction is the initiating agent in many cardiovascular diseases’s occurrence and development .It has been reported in patients with coronary heart disease or diabetes that endothelial function is significantly impaired, and the level of endothelial function’injury for coronary heart disease in patients with diabetes mellitus is worse. There is rare article at home and abroad on trimetazidine effects of vascular endothelial function. This study was designed to observe the the changes of plasma nitric oxide (NO) levels, brachial artery endothelium-dependent vasodilation (FMD) after loading of trimetazidine (60mg) two hours to explore the short-term effects of endothelial function in load of trimetazidine for coronary artery disease in patients with diabetes, in order to provide a theoretical basis for clinical medicine.Methods: Selected 60 patients with coronary heart disease and diabetes mellitus, 39 males and 21 females, aged 35 to 72 years old, mean age (53.4±12.3) years old. All selected patients had been diagnosed with coronary angiography coronary artery disease (According to internationally accepted method for evaluation of coronary artery diameter stenosis, who were≥50% stenosis as CHD, <50% by the NCHD), while in line with the WHO in 1999 recommended diagnostic criteria of diabetes, and except for hypertension and hyperlipidemia history. Detection of the first two days after admission in patients with fasting lipids (hyperlipidemia excluded). Detect the plasma NO levels in patients with stable disease state who is not taking the loading dose of trimetazidine on the third day, and immediately to the brachial artery ultrasound baseline brachial artery diameter, under the basis of the value of D0, and then to the brachial artery pressure, detection of reactive hyperemia brachial artery diameter D1, and calculate endothelium-dependent vasodilatation(FMD) of brachial artery brachial ,and followed by hydrochloride trimetazidine 60mg are served burton, after two hours detected NO levels, and once again made the brachial artery ultrasound to detected FMD.Results: 1.The plasma NO levels were significantly higher after leighton service load trimetazidine 60mg two hour(s44.98±2.96 vs 45.87±3.28 umol/L, P<0.05)2.FMD was significantly higher(12.69±1.61 vs 13.21±1.96 % ,P<0.05), Conclusion: 1.Trimetazidine can improve ascular endothelial cell function of coronary heart disease in patients with diabetes mellitus2. Its possible mechanism is by affecting NO levels.更多还原