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通脉消斑汤对动脉粥样硬化的抗氧化作用研究
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摘要
背景
     动脉粥样硬化(Atherosclerosis, As)严重威胁人类健康。本病在美国、欧洲等西方国家发病率很高。根据世界卫生组织的调查,由动脉粥样硬化引起的心脑血管疾病,其发病率与死亡率已居全球首位。随着社会的进步与经济的发展,动脉粥样硬化引起的心脑血管疾病已成为威胁我国人民身体健康的头号杀手。动脉粥样硬化的成因非常复杂,在我国发病率与死亡率逐年增加。这种情况与国民饮食结构改变、社会心理模式的转变、生活节奏加快等密切相关,当然还涉及基因、环境、代谢等多个环节。
     中医学没有As所对应的病症与证型,但是“胸痹”、“真心痛”、“痰浊”、“眩晕”、“中风”、“脱疽”等疾病中有类似的记载。其中“胸痹”与“真心痛”的记载类似于As范围中的冠状动脉粥样硬化性心脏病的特点,“痰浊”、“眩晕”、“中风”等类似于As范围中的脑血管病以及外周动脉疾病。其他病症也可散见关于As的记载。该病的病因病机相当复杂,中医学的观点认为:此类病症与年老体虚、饮食不当,情志失调、劳倦内伤等密切相关。该病主要累及的脏腑是心、肝、脾、肾。其病机为本虚标实、虚实夹杂。本虚是指心、肝、脾、肾四脏亏虚,标实是指痰浊、水饮、瘀血等病理因素。
     现代医学治疗As以他汀类药物为主。他汀类药物能够降低血脂,改善血管内皮舒张功能,同时也具有抗炎、抗氧化等作用。但是他汀类药物同其他西药一样,存在副作用。正是由于这个原因,目前关于中医药治疗As的研究成为热点。中医药相对于现代医学来说具备有独特的优势,其整体观及辩证论治的特点能够从多个环节、多个靶点干预As的进程,从而达到全面防治As的目的。
     导师罗陆一教授长期从事心脑血管疾病的诊治研究,对于As的防治颇有心得。他潜心钻研历代医家对于此类疾病的病因、病机的认识及治疗手段,结合多年的临床经验,形成了关于此类疾病一系列成熟的学术思想。其核心在于提出该病的病机为肾虚兼杂痰浊、瘀血。治疗上以补肾化痰、活血通络为根本治则。以此为法研制出多个补肾活血化痰方治疗As,在临床应用中效如桴鼓。基于此背景,本课题以导师罗陆一教授治疗冠心病的补肾活血化痰方通脉消斑汤为主方,以As的“氧化应激作用”为研究方向,重点观察患者治疗前后血脂、脂蛋白、超氧化物歧化酶(SOD)、丙二醛(MDA)、氧化型低密度脂蛋白(ox-LDL)含量的变化以及颈动脉彩超检查的结果。以期通过该研究明确中医药对As的抗氧化作用。从抗氧化作用方面探讨中医药防治As的作用机理,同时评价其疗效及安全性。该研究对于发掘中医药在防治As方面的优势有非常重要的意义。
     临床研究:
     目的:本研究通过观察通脉消斑汤对As患者治疗前后血脂、脂蛋白、超氧化物歧化酶(SOD)、丙二醛(MDA)以及氧化型低密度脂蛋白(ox-LDL)含量的变化以及颈动脉彩超检查的结果,对患者治疗前后的临床症状以及疗效进行客观的评估,从而明确补肾活血化痰方通脉消斑汤对As的抗氧化作用。
     方法与内容:选取我科As的患者150例,其中男性患者83例,女性患者67例。将所有患者随机分成了3个组,包括通脉消斑汤组(blood-activating and phlegm-resolving formula Group, BAPR);西药他汀组(western medicine statin Group, WMS);联合治疗组(combination therapy Group,CTG)。三组患者分别给予通脉消斑汤、西药瑞舒伐他汀和中西药结合口服治疗,观察周期为24周。观察周期结束后,测定患者治疗前后血脂、脂蛋白结果(全自动生化分析仪进行分析)、应用邻苯三酚自氧化法检测超氧化物歧化酶(SOD),应用硫代巴比妥酸法(TBA)检测丙二醛(MDA),酶联免疫吸附法(ELISA)测定氧化型低密度脂蛋白(ox-LDL),颈动脉彩超测量颈动脉内-中膜厚度、明确颈动脉内是否存在有斑块以及斑块的性质、类型,并将结果进行统计学比较分析。统计分析采用SPSS21.0统计软件包,计数资料分析采用卡方检验;计量资料分析采用t检验及方差分析。组内治疗前后比较采用配对样本t检验,组间比较采用独立样本t检验,数值用均数±标准差(X±S)表示。
     研究结果:
     ①通过对三组患者血脂、脂蛋白的检测,三个治疗组患者的TC、TG、LDL-C值均显著降低,HDL-C升高,差异存在统计学意义(P<0.05或P<0.01)。组间比较的结果显示联合治疗组的疗效优于通脉消斑汤组和西药他汀组(P<0.01)。
     ②三组患者SOD、MDA、ox-LDL检测的结果显示:三组患者SOD含量均显著升高(P<0.05), ox-LDL、MDA含量均显著降低(P<0.05或P<0.01)。通脉消斑汤组及联合治疗组抗氧化因子SOD含量显著升高(P<0.01)。组间比较提示联合治疗组在降低ox-LDL、MDA含量方面,疗效明显优于通脉消斑汤组和西药他汀组(P<0.01)。在升高SOD含量方面,疗效与通脉消斑汤组相当(P>0.05)。
     ③三组患者颈动脉彩超结果分析提示:经过治疗后,三治疗组的颈动脉内一中膜厚度均有不同程度的降低(P<0.05),斑块的数量减少(P<0.01)。联合治疗组在降低内-中膜厚度方面的疗效优于通脉消斑汤组及西药他汀组(P<0.01),而减少颈动脉内斑块数量方面,疗效与其他二组相当(P>0.05)。
     ④通过对三组患者治疗前后的临床症状以及疗效评估方面进行比较后发现,联合治疗组在改善患者的中医症候疗效、心绞痛疗效,心电图疗效等方面优于其他二组。在改善中医症状评分方面,与中药组相当。
     结论:通脉消斑汤联合瑞舒伐他汀治疗可有效地调节患者TC、TG、LDL-C、 HDL-C水平,降低ox-LDL、MDA含量,升高SOD含量。联合治疗对于患者颈动脉内-中膜厚度及斑块的数量有很好的调节作用。该疗法在稳定斑块,调节血脂水平,防止LDL被氧化修饰成ox-LDL,保护机体细胞免受自由基的攻击等方面,疗效优于单纯的中药或西药他汀组。推断调脂固斑抗氧化是通脉消斑汤抗As的核心机制。这种中西医结合的治疗模式,可以从多角度、多靶点的干预As的发生、发展,从而减少心血管不良事件的发生。
Atherosclerosis (As) poses a serious threat to human's health and incurs a high incidence rate in the West led by the US and European countries. According to a WHO report, As-caused cardiovascular and cerebrovascular diseases generate the world's highest incidence and death rates. Driven by rapid socioeconomic development, these diseases have become a leading contributor to death in China. As can be triggered by a wide variety of factors and its incidence and death rates grow annually in China. This is largely attributable to changes in Chinese diet and social and mental states, and the faster pace of life, coupled with other factors such as genes, environment and metabolism.
     Traditional Chinese medicine (TCM) does not discuss As symptoms or types, but similar symptoms are described in chest impediment, true heart pain, turbid phlegm, dizziness, and stroke in TCM records. Notably, chest impediment and true heart pain register characteristics similar to those of the As-caused heart disease. Turbid phlegm, dizziness, and stroke, etc show signs similar to those of As-induced cerebrovascular and peripheral arterial diseases. Other symptoms are also documented in As-related records. The disease involves complex etiologies and pathogenesis. TCM attributes the disease primarily to aging and weakness, improper diet, emotional disorder, and fatigue and internal damage. According to TCM, this disease is caused by deficiency in origin and excess in superficiality, deficiency-excess mixing, and in most cases harms zangfu organs such as heart, liver, spleen, and kidney. Deficiency in origin reflects the deficiency in any of these four organs. Excess in superficiality describes pathologic factors such as turbid phlegm, water-rheum, and blood stasis.
     Modern medicine relies mostly on statin drugs to treat As. These drugs reduce blood lipid, improve the dilatation of blood vessel endothelium, and also provide resistance against inflammation and oxidization. However, statin drugs produce side effects like other Western medicines. This stimulates research on As treatment using traditional Chinese medicine, which is unrivalled in the world of modern medicine. The concept of holism and treatment based on syndrome differentiation can suppress the As process through a number of procedures and targets to prevent and treat As.
     Underpinned by his long-term study on the treatment of cardiovascular and cerebrovascular diseases, Professor Luo Luyi has built unique insights about As prevention and treatment. By incorporating the perceptions and treatments of medical experts throughout history regarding the etiological factors and pathogenesis of such diseases into his years of clinical experience, he has developed a series of mature academic thoughts on such diseases. As the cornerstone of these thoughts, he describes the pathogenesis of As as kidney deficiency coupled with turbid phlegm and blood stasis and proposes the methods of tonifying kidney, activating blood and resolving phlegm for treating the disease. Based on these guiding principles, he has developed a number of highly effective prescriptions for clinical use. Based on the blood-activating and phlegm-resolving formula, Professor Luo has developed for treating the coronary heart disease, and this research aims to explore the oxidative stress effect of As. Based on changes in patients'blood lipid, superoxide dismutase (SOD), malonic dialdehyde (MDA), and oxidation low lipoprotein (ox-LDL) before and after the treatment, and the results of neck vascular ultrasound examination, the paper attempts to determine that traditional Chinese medicine can subdue the As process through anti-oxidation. By exploring how TCM prevents and treats As through anti-oxidation and assessing the efficacy and safety of the TCM treatment, this research will contribute significantly to the effort to explore the benefits of TCM in As prevention and treatment.
     Clinical study
     Purpose: Verify that the formula has antioxidant effect on As based on the observation of changes in patients'blood lipid, SOD, MDA and ox-LDL and the results of neck vascular ultrasound examination and an objective assessment of clinical symptoms and efficacy before and after the treatment using the blood-activating and phlegm-resolving formula.
     Method:
     Select150As patients from our department, including83men and67women. Divide the patients randomly into three groups, including one treated with blood-activating and phlegm-resolving formula (blood-activating and phlegm-resolving formula Group, BAPR), one with statin drugs (western medicine statin Group, WMS) and one under combination therapy(combination therapy Group, CTG). These groups are respectively administered the blood-activating and phlegm-resolving formula, Rosuvastatin calcium and a combination of Chinese and Western oral drugs over a period of24weeks. At the end of the observation period, use a biochemical analyzer to detect changes in patients' blood lipid and lipoprotein and the methods of pyrogallol auto-oxidation, TBA and ELISA to examine SOD, MDA and ox-LDL respectively before and after the treatment. Through neck vascular ultrasound examination, measure intima-medic thickness in the carotid artery, check the artery for plaques and determine the nature and types of the detected plaques. Compare the results statistically using the SPSS21.0software. Conduct a chi-square test on quantitative data and T-test and analysis of variance on qualitative data. Perform paired-samples T-test for intra-group comparison and independent-samples T-test for inter-group comparison before and after treatment. All the numeric values are expressed as M±SD (X±S).
     Result:
     1) The results of blood lipid and lipoprotein tests revealed that TC, TG and LDL-C levels are lowered while HDL-C levels are elevated considerably for all the three patient groups, and these results are statistically significant (P<0.05or P<0.01). Inter-group comparison showed that better As curative effects are observed for the combination therapy group than for the other two groups-the group treated with the blood-activating and phlegm-resolving formula and the group administered statin drugs (P<0.01).
     2) The SOD, MDA and ox-LDL tests revealed that SOD are significantly increased, ox-LDL and MDA levels are significantly reduced for all the three patient groups (P<0.05or P<0.01). The TCM treatment group and the group under treatment with a combination of Chinese and Western medicine showed a significantly higher level of antioxidant factor SOD (P<0.01). The inter-group comparison indicated that the combination therapy group showed significantly better curative effects than the other two groups in terms of reducing ox-LDL and MDA levels (P<0.01). In terms of increasing SOD, treatment for the combination therapy group is as equally effective as that for the TCM treatment group (P>0.05).
     3) The results of neck vascular ultrasound examinations on the three groups of patients revealed that intima-medic thickness in the carotid artery is variably reduced (P<0.05) and the number of plaques also lowered (P<0.01) for all the three treatment groups. The combination therapy group showed better curative effects than the other two groups in terms of reducing intima-medic thickness and equal efficacy in terms of reducing the number of plaques inside the carotid artery.
     4) The combination therapy group outperformed the other two groups in terms of TCM symptoms curative effects、angina pectoris curative effect, electrocardiogram curative effect before and after treatment (P<0.05). The same curative as group of BAPR in terms of ameliorate TCM symptom scores.
     Conclusion
     The blood-activating and phlegm-resolving formula combined with rosuvastatin calcium can effectively adjust TC, TG, LDL-C and HDL-C levels, reduce ox-LDL and MDA, and increase SOD for patients. The combination therapy is highly effective in adjusting intima-medic thickness and the number of plaques in the carotid artery. This therapy is more effective than treatment with Chinese or Western medicine only for As patients in terms of easing symptoms and improving efficacy. Specifically, the therapy helps stabilize the number of plaques, control the blood lipid level, prevent LDL from being oxidized into ox-LDL, and protect body cells against free radicals. In other words, the blood-activating and phlegm-resolving formula inhibits As through lipid adjustment, plaque stabilization and anti-oxidation. The combination of Chinese and Western medicine can subdue the occurrence and development of As through a number of procedures and targets to reduce the risk of cardiovascular diseases.
引文
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