血脂康治疗不同中医证型高脂血症的疗效观察

【作者】 王铭；

【导师】 张瑞麟；

【作者基本信息】 中国中医科学院 ， 中西医结合临床， 2008， 硕士

【摘要】 高脂血症(Hyperlipemia,HLP)作为一种人体脂质代谢异常的亢进“模型”,临床上主要表现为血浆血脂含量高于正常水平,是一种对人体危害极大的心血管系统病症。根据目前世界各国对高脂血症的研究进展,我们已经清楚地认识到高脂血症将极大地促进动脉粥样硬化的发生与发展,由此增加与之关系密切的冠心病、脑卒中、肾动脉硬化、周围血管硬化等重大疾病的发病率,所以对于高脂血症的治疗各国都非常重视,各种药物的开发和临床研究方兴未艾。血脂康胶囊是近十年来临床上广泛应用且被证明具有肯定疗效的纯中药降脂制剂,但临床实践中发现血脂康对高脂血症患者的疗效存在差异性。因此,从中西医两种角度地对血脂康临床治疗不同中医证型高脂血症的疗效进行观察研究,充分探明其疗效的差异性,以求更加科学地指导其临床应用将至关重要,也具有深远的意义。本临床研究对300名服用血脂康的患者进行调脂治疗,对其临床疗效进行观察和分析,旨在探明血脂康对不同中医证型高脂血症的疗效差异,分析其产生的原因,为进一步指导临床合理用药奠定基础。1.文献研究本论文详细地介绍了近年来对于高脂血症、调脂治疗和血脂康的中西医文献,主要分为三个大的方面和六个主要部分,分别是:高脂血症病因病机及辨证分型的研究进展、高脂血症的中医药治疗研究进展、高脂血症的发病机制和临床分型研究概况、现代医学对高脂血症的治疗研究进展、血脂康的药理和基础研究概况、血脂康的临床研究进展。纵观这些相关文献,主要有以下一些重要的认识。中医对病因病机的认识是中医药治疗疾病的理论基础。高脂血症是现代医学的术语,中医学中并无高脂血症一词,尽管目前从事这一方向研究的学者专家非常之多,但是整个中医学界尚未对高脂血症的病理机制和临床辩证分型形成统一的认识。从辨病的角度,医家较多地将其归入“眩晕”、“胸痹”、“中风”、“血瘀”、“痰湿”等病证的范畴中;从辨证的角度,又较多归入痰浊和瘀血证;从脏腑辨证的角度,更多归于肝、脾、肾三脏。中医药治疗高脂血症目前主要有三种方式,分别是自拟方、经典方和中成药。自拟方中常见的中药是:泽泻、山楂、何首乌和丹参;经典方较为常见的是:半夏白术天麻汤、血府逐瘀汤、黄连温胆汤和补阳还五汤;中成药常用的是:血脂康、脂必妥等等。从西医的角度看,高脂血症的发生关键在于脂质代谢的紊乱,目前临床上常规使用的调脂药物主要有六类,分别是胆酸螯合树脂类、烟酸类、氯贝丁脂类、他汀类、贝特类和新作用机制药物。血脂康主要就含有他汀类的成分-洛伐他汀。相关研究证实其除了良好的调脂作用外,还有全面的调脂外作用,包括:抑制动脉粥样硬化的形成、对血管内皮细胞功能的保护作用、对血管平滑肌细胞增殖迁移的抑制作用、对脂质在肝脏沉积的抑制作用和改善血液流变学的作用。并且通过文献研究确定了本研究的药物试验剂量和疗程。2.临床研究2.1病例选择门诊及住院高脂血症患者血脂水平满足以下标准者入选:①沉淀法测定血浆低密度脂蛋白(LDL-C)≥3.12(120mg/dl);②酶法测定血清总胆固醇(TC)≥5.20(200mg/dl);③沉淀法测定血浆高密度脂蛋白(HDL-C)＜0.91(35mg/dl)。入选病例共300例,均为中国中医科学院望京医院心内科门诊及住院患者,根据《中药新药临床试验指导原则》中对高脂血症的中医证候分型标准分为五组,每组各60例。痰浊阻遏组:男37例,女23例,平均年龄49±11岁;脾肾阳虚组:男33例,女27例,平均年龄52±9岁;肝肾阴虚组:男36例,女24例,平均年龄48±10岁;阴虚阳亢组:男30例,女30例,平均年龄52±11岁;气滞血瘀组:男31例,女29例,平均年龄53±9岁。5组患者年龄、性别及血脂水平在统计学上无显著差异。2.2方法入选病例口服血脂康胶囊(北大维信生物科技有限公司生产)进行治疗,每次0.6 g,早晚各1次,连续服用8周,治疗期间停用其他降脂药物。2.3观察指标在正常饮食情况下,禁食12～14小时后抽取清晨静脉血检验。①血脂指标:测定治疗前、后的LDL-C、TC和HDL-C含量,计算总胆固醇/高密度脂蛋白(TC/HDL)比值;②中医辩证指标:根据患者的中医症状及其症状的严重程度确定治疗前后的中医证候积分。③用药安全性指标:测定治疗前后的肝功能、肾功能、肌酸磷酸激酶(CK)等生化指标。2.4统计学处理各检测指标数据以均数士标准差((?)±s)表示。所有统计过程均用SPSS13.0软件处理,各组治疗前后比较采用t检验,各组组间比较采用F检验及q检验。P＜0.05为显著性差异。2.5结果(1)治疗前、后五组LDL-C水平的比较:与治疗前比痰浊阻遏组和气滞血瘀组治疗后指标下降最为显著(P均＜0.01),此两组间无明显差异(P＞0.05),并且明显优于其它三组(P均＜0.05);脾肾阳虚组、肝肾阴虚组和阴虚阳亢组治疗前后指标间亦均具有显著差异性(P均＜0.05),但此三组间比较无明显差异(P＞0.05)。(2)治疗前、后五组总胆固醇/高密度脂蛋白(TC/HDL)比值的比较:与治疗前比痰浊阻遏组该比值下降最为明显(P＜0.01),并且明显优于其余四组(P均＜0.05);气滞血瘀组、阴虚阳亢组、肝肾阴虚组该比值的下降均具有显著性(P均＜0.05),但此三组间比较无显著差异(P＞0.05);脾肾阳虚组治疗前后该比值无差异(P＞0.05)。(3)治疗前、后五组中医证候积分的比较:与治疗前比痰浊阻遏组证候积分下降最为显著(P＜0.01),并且明显优于其余四组(P均＜0.05);阴虚阳亢组和气滞血瘀组证候积分也均显著下降(P均＜0.05),这两组间比较差异不显著(P＞0.05);其余肝肾阴虚组、脾肾阳虚组两组的证候积分下降均不明显(P均＞0.05)。(4)安全性指标:所有入选病例,在8周的治疗中和治疗后,未出现肝功能、肾功能和CK等生化指标异常的情况。3.讨论高脂血症(Hyperlipemia,HLP)作为一种人体脂质代谢异常的疾病,它极大地促进动脉粥样硬化的发生与发展,由此增加冠心病、脑卒中、肾动脉硬化、周围血管闭塞等重大疾病的发病率。在血脂指标中,目前研究认为LDL含量和TC/HDL比值是考察高脂血症重大危害性最科学合理的两个项目。因此,将它们作为衡量降脂疗效的考察指标就使本课题更加合理。血脂康是经高产Monacolins的红曲菌通过现代生物技术发酵而得到的特制红曲提取物,其富含羟甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂(洛伐他汀)、多种不饱和脂肪酸和人体必需氨基酸以及甾醇和少量黄酮等多种有效成分。通过对低密度脂蛋白胆固醇(LDL-C)基因多态性的研究已经明确,具有h1等位基因的高脂血症患者对血脂康的反应较差,而具有h2等位基因的患者对其的反应较好,这就从理论上证明了血脂康具有疗效差异性。同时,作为一种纯中药制剂,它就必然存在中药的性味归经特性,由此,从高脂血症不同中医证候分型的角度对其作用差异性进行研究也就更具有其合理性。目前中医界对高脂血症较为一致的认识是:肝脾肾不足是其发生最本质的病理基础,而痰浊、血瘀等病理产物则是其发生、发展、转归和预后的基本病理环节。而血脂康的主要成分是中药红曲,它具有消痰化瘀、健脾和胃之功效,和该药物中的其他辅助成分相配合,就能做到攻中有补、标本兼顾,从而达到加强健脾消食而使痰瘀不生的目的。本次研究可以看出血脂康对痰浊阻遏组的各项治疗效果均是非常显著的,其次对于气滞血瘀组的综合疗效也是显著的;而相对于脾肾阳虚组疗效是最差的。存在这种证型疗效的差异可能是由于从中医理论上未能达到证法方药的高度统一的结果。联系上述的基因多态性研究,还可以进一步探讨属于中医痰浊阻遏证和气滞血瘀证的患者是否更多具有h2等位基因,而属于脾肾阳虚证的患者则更多具有h1等位基因。4.结论血脂康是一种有效成分明确,作用机制清楚,疗效稳定,安全有效,毒副作用小的纯天然中药。运用血脂康进行降脂治疗高脂血症患者,能够显著降低患者血脂水平,但存在证型疗效差异,其中痰浊阻遏组综合疗效最好,而脾肾阳虚组疗效则最不明显。在其临床运用中将它的作用差异性加以考虑,就能够真正做到用药科学合理,临床疗效亦会更加理想。更多还原

【Abstract】 Hyperlipemia(HLP), as a model of abnormal lipid hypermetabolism of human body, is a kind of cardiovascular system disease which is very harm to human body, and its primary clinical symptom is that the blood fat level of blood plasma is abnormal. Now according to the research on HLP of every country, we have realized that HLP could make artherosclerosis occur early and accelerate its development, and the incidence of some important diseases such as incidence, cerebral apoplexy, renal arterial sclerosis, and peripheral vessels sclerosis which are related to HLP is increasing. So the world attaches importance on treating HLP, then exploitation and clinical research of many kinds of medicine to HLP is in the ascendant. XueZhiKang capsule(XZK) is a kind of pure Chinese drugs preparation which is widespread used, and its positive curative effect to lower blood lipid is to be proved, but in the clinical practice we can see that different patients of HLP who are treated with XZK have different curative effect. So we design this topic to observe the clinical effect of different types of syndromes of traditional Chinese medicine(TCM) in 300 patients of HLP treated with XZK, and full find out the variability of curative effect, then instruct clinical application more scientifically. The research is full of essentiality and signality.Documents researchThe rationale of TCM treating disease is the recognition of etiology and pathology. In TCM there is no disease called HLP, which is a modern medicinal terminology. At present many experts are researching on HLP, but there is no common knowledge about HLP on pathomechanism and syndrome differentiation in TCM.From the point of view on disease differentiation, many doctors classify HLP to some diseases such as vertigo, thoracic obstruction, apoplexy, blood stasis, phlegmatic hygrosis, and so on. And from the point of view on syndrome differentiation, HLP belongs to Sputum stasis syndrome or blood stasis syndrome. Then from the point of view on differentiation of syndrome according to Zang-fu organs, HLP belongs to liver, spleen and kidney.At present there are three kinds of methods on treating HLP. They are self working out prescription, classical prescription and Chinese patent medicine. Self working out prescription always contains alisma rhizome, hawthorn, fleeceflower root and salvia miltiorrhiza. And classical prescription may be Banxia Baizhu Tianma decoction, XueFuZhuYu decoction, Huanglian WenDan decoction and BuYangHuanWu decoction. Then Chinese patent medicine are always XZK and ZhiBiTuo.Modern medicine thinks the key of pathogenesis in HLP is lipid metabolic disorder. Now there are 6 kinds of drugs which are common used clinically to regulate blood fat. They are cholic acid chelating resin, nicotinic acid, clofibrate, statins, fibrate and some drugs of new mechanism of action.XZK contains a kind of statins calles lovastatin. And some related researches have proved that XZK could regulate blood fat, then it has all-sided functions except that such as inhibiting atherosclerotic to shape, protecting vascular endothelial cell function, inhibiting vascular smooth muscle cell to proliferate, inhibiting lipid deposite in liver, and improving hemorheological effect so on. So according to these documents we make a decision on this research on the test doses and course of treatment about XZK.Clinical researchCases selection:The HLP patients who accepted clinic service or be in hospital whose blood fat levels were satisfied those standards could be selected. The standards contained:①blood plasma low density lipoprotein (LDL-C)≥3.12(120mg/dl) by precipitation;②blood serumtotal cholesterol(TC)≥5.20(200mg/dl) by enzymic method;③high density lipoprotein (HDL-C)< 0.91(35mg/dl) by precipitation。According to the TCM syndrome differentiation of the book clinical research guide to new Chinese patent medicine, 2002 edition 300 patients of HLP were divided 5 groups, every groups have 60 patients. The five groups were the Sputum stasis syndrome group(37men, 23women, mean age 49±11), the Qi-stagnation induced Blood-stasis syndrome group(31men, 29women, mean age53±9), the Yin-deficiency and Yang-excessive group(30men, 30women, mean age52±11), the Hepatic and Renal Yin deficiency syndrome group(36men, 24women, mean age48±10) and Spleen-Yang deficiency and Kidney-Yang deficiency syndrome group(33men, 27women, mean age52±9). The five groups showed no significant difference in ages, sex and the level of blood fat.Methods: All patients were treated with XZK. The dose was 0.6g at a time, Bid, n&m. The course of treatment was 8 weeks. During the course all drugs to lower blood fat should be prohibited. Changes of index of blood fat and TCM syndrome integral were observed after treatment.Observed index:At the normal diet condition, abstract early morning venous blood venous blood after empty stomach for 12～14 hours.①Test the level of LDL-C, TC and HDL-C and the ratio of TC/HDL before and after treatment.②According to the levels of symptoms in TCM before and after treatment, account the TCM syndrome integral.③Observe biochemical indicators before and after treatment, such as liver function, renal function and CK.Study methods:All data of the observed indexs was showed by x±s. During the statistical course, use t-check before and after treatment in the group, use F-check or q-check groupcomparison. And all of these was treated statistically by SPSS13.0 software. At P < 0.05, itshowed significant difference.Results:(1) After 8 weeks, the LDL-C of all groups were lower than before treatment(P<0.01, P<0.05).And the groups of Sputum stasis syndrome and Qi-stagnation induced Blood-stasis syndromewere superior to the three others(P <0.01), and the two groups showed on significant difference.(2)The TC/HDL-C of Sputum stasis syndrome group was lowest in all groups (P<0.01)andsuperior to other groups (P<0.05); the Qi-stagnation induced Blood-stasis, Yin-deficiency andYang-excessive and Hepatic and Renal Yin deficiency syndrome group showed significantdifference in TC/HDL-C (P<0.05); and the Spleen-Yang Deficiency and Kidney-YangDeficiency syndrome group had no significant difference (P>0.05).(3)The TCM syndrome integral of sputum stasis, yin-deficiency and yang-excessive, andqi-stagnation induced blood-stasis syndrome group were lower than before treatment (P<0.01,P<0.05), but the two other groups showed no significant difference (P>0.05), and the sputumstasis syndrome group was superior to the four other groups (P<0.05).(4)During the treating course, all patients were no abnormal in liver function, renal function andCK.DiscussionHLP, as a kind of abnormal lipid hypermetabolism disease, could make artherosclerosis occur early and accelerate its development, and the incidence of some important diseases such as incidence, cerebral apoplexy, renal arterial sclerosis and peripheral vessels sclerosis which are related to HLP is increasing. Now many experts think that two scientific and rational indexes for observing the great hazardness of HLP are the level of LDL and ratio of TC/HDL. So in this research the two indexes were used to weigh the fact about regulating blood fat.XZK is an extract from productive monascus fermentation used by modern biotechnology, its active ingredients are full of HMG-CoA reducing enzyme inhibitor(lovastatin), many kinds of unsaturated fatty acid and unsaturated fatty acid for human body, some unsaturated fatty acid and a little of anthoxanthin. From the research on gene polymorphism of LDL-C, it was showed that the patients of HLP who had the h1 polymorphism were responded badly to XZK, but who had h1 polymorphism were well responded to it. In the research it showed that the curative effect variability was exacted.As a pure Chinese drugs preparation, XZK has characteristics of nature and flavour and meridian distribution about Chinese drugs. It is rational to do this research on effective variability about XZK from the point of view on TCM syndrome differentiation. At present the common knowledge about HLP is that the most essential patho-base is liver, spleen and kidney deficiency, and patho-products like sputum, and blood stasis are patho-links about occurring, development, turnover and prognosis.The essential component of XZK is red rice, which has the function of eliminating blood stasis and phlegm and fortifying spleen and harmonizing stomach. When combined with the helper constituents, XZK could play the role of attacking and invigorating or dealing with both symptoms and body resistance, so it could fortify spleen and harmonize stomach, then eliminate blood stasis and phlegm.In the research, XZK could regulate the level of blood fat, but the differentiation of syndrome types had existed. After treatment, the Sputum stasis syndrome group had the best effect, the Qi-stagnation induced Blood-stasis group had good effect, but the Spleen-Yang Deficiency and Kidney-Yang Deficiency syndrome type had no significant difference. Maybe the reason was that the syndrome didn’t unified the methods from TCM theory. From the gene polymorphism research, maybe the reason was that the Sputum stasis syndrome group and the Qi-stagnation induced Blood-stasis group had h2 polymorphism, but the Spleen-YangDeficiency and Kidney-Yang Deficiency syndrome group had h1 polymorphism.Conclusions :To sum up, XZK is a pure natural traditional Chinese drug, it has clear active ingredient, certain mechanism of action, stable curative effect, safe and effective, little toxic action and fewer side effects. After treatment there are best effect on the Sputum stasis syndrome group, then the he Spleen-Yang Deficiency and Kidney-Yang Deficiency syndrome type has no significant difference. If take its effect variability into account in clinic, you can really use medicine scientifically and rationally, then clinical curative effect can be more perfect.更多还原