他汀类药物多效性研究进展

他汀类药物为3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂,临床用于降低胆固醇.随着人们对他汀类药物的深入研究,他汀类药物呈现出令人鼓舞的多效性,包括提高一氧化氮生物利用度、修复受损内皮、抗炎、抗氧化、促新生血管生成、稳定动脉粥样硬化(AS)斑块、动员内皮祖细胞、抑制心肌肥厚,抗心律失常~([1])等.他汀类药物的多效性作用机制可能与其降脂作用互不关联.因为人们观察到,在降脂作用尚未显现时,他汀类的多效性作用已经发生~([2]).目前他汀类药物的多效性已成为心血管领域争论和探索的热点,引起了临床医师及科研工作者的广泛关注.     

他汀类药物多效性及在心力衰竭中的应用

他汀类药物除降脂作用外,还有多效的非调脂作用。近年来很多基础和临床研究都表明他汀类药物多效性对心力衰竭的防治有益。本文就他汀类药物多效性在心力衰竭中的临床应用作一综述。     

他汀类药物独立于降脂作用以外的多效性评价

近10多年来,应用他汀类药物预防冠心病的一级、二级试验取得了举世瞩目的成就,肯定了其调脂治疗的益处;同时,他汀类药物调脂以外的作用也备受关注.从临床研究到基础研究,越来越多的证据显示他汀类药物治疗的多效性.这种多效性包括：抑制平滑肌细胞增殖,促进新生血管形成,改善内皮功能,抑制血小板聚集,抑制炎症反应,稳定斑快,降低胰岛素抵抗和骨质吸收.     

他汀类药物作用和作用机制的新认识

他汀类药物自上世纪八十年代晚期开始应用于临床以来,已成为调脂治疗的“里程碑”药物。近年来随着临床应用与研究的逐步深入,人们发现他汀类药物除具有调脂作用外,还有重要的独立于调脂的多重作用,即他汀类药物的“多效性”。他汀类多效性的药理学基础他汀类药物的调脂作用主要表现为其对胆固醇生物合成过程中的的限速酶—3羟3甲基辅酶A(HMG CoA)还原酶的抑制作用,减少细胞内的游离胆固醇,加速循环中极低密度脂蛋白(VLDL)残粒(IDL)和低密度脂蛋白(LDL)的清除,最终直接降低血清中总胆固醇和LDL的水平。除了对细胞内胆固醇合成的直接…     

动脉粥样硬化炎症机制及阿托伐他汀药物多样性的研究进展

近年研究显示,动脉粥样硬化是一种慢性炎症。炎症在动脉粥样硬化的发生、发展和演变过程中起着重要作用。他汀类药物是治疗高脂血症及预防动脉粥样硬化性疾病的基石。已有大量研究证实,他汀类药物通过降脂作用改善心血管疾病的预后,而且还通过抗炎、改善内皮功能、抗血小板活性、稳定斑块等作用使患者获益,即他汀类药物有多效性。现就具有代表性的阿托伐他汀,对他汀类药物多效性的研究进展进行综述。     

他汀类药物多效性的研究进展

他汀类药物在临床上广泛应用,在治疗心血管疾病和肾脏疾病方面取得了很好的效果,为患者解决了很多实际问题,成为患者的福音。这源于这类药物具有较好的药理作用和较少的不良反应。该类药物除了强调脂的药理作用外,还包括调脂以外的药理作用,称之为多效性,其多效性包括改善炎症反应;改善血管的内皮细胞功能;抗血小板聚集和抑制血栓形成;抑制血管平滑肌细胞增殖;保护肾脏等。目前已投入临床使用的该类药物较多,包括阿托伐他汀、辛伐他汀、普伐他汀、氟伐他汀等。现就该类药物的多效性研究进展综述如下。     

Rho激酶：他汀类药物抗动脉粥样硬化的重要靶点

他汀类药物作为抗动脉粥样硬化的经典药物,其降脂外作用即多效性正受到越来越多的关注.近年研究发现,Rho激酶与他汀类药物多效性密切相关.国外大量研究揭示Rho激酶很有可能成为今后心血管疾病治疗的重要靶点.本文结合最新研究进展,概述Rho激酶的结构及激活机制,探讨其与动脉粥样硬化的关系及他汀类药物抑制Rho激酶活性的循证证据及机制,同时展望Rho激酶抑制剂未来在动脉粥样硬化性疾病预防和治疗中的应用前景.     

他汀类药物的多效性作用及其临床意义

他汀类药物(statins)即3-羟基3-甲基戊二酰辅酶A(HMG-CoA)还原酶抑制剂可明显降低心血管事件的发生率和死亡率,是目前临床上应用最广的降胆固醇药物.近年大量实验及临床研究资料显示,他汀类药物除具有显著的降血脂作用外,还有独立于降脂外的作用即多效性,在心血管领域,其多效性主要包括改善血管内皮功能、抑制炎症、抑制平滑肌细胞的增生和促进凋亡、抑制血栓形成和稳定斑块等.然而这些多效性作用在临床治疗中是否具有实际临床获益尚不十分清楚.     

他汀类药物的多效性及其在心血管疾病中的应用

他汀类药物（statins）通过抑制内源性胆固醇合成限速酶还原酶,使细胞内胆固醇合成减少,是治疗动脉粥样硬化（AS）的基本药物。研究表明,他汀类药物还存在着非胆固醇依赖的多效性,包括改善血管内皮功能,抑制血管平滑肌增殖,促进血管新生,抗炎、抗氧化以及减轻血管和心肌重构等。这种“多效性”在急性心肌梗死、心肌肥大以及心力衰竭等心血管疾病的防治中发挥着重要作用。     

他汀类药物的临床应用

他汀类药物可有效抑制胆固醇的合成，其调脂治疗的益处毋庸置疑。但应用他汀类药物的效应，远非常单独由于血脂水平变化引起。从临床研究到基础研究，越来越多的证据显示他汀类药物的治疗具有多效性，其调脂之外的作用成为当前备受关注的热点之一。     

Effect of cholesterol reducing therapy with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor on secondary prevention after myocardial infarction in Japanese patients

Lowering the blood cholesterol level is a safe method to improve survival for primary and secondary prevention of coronary heart disease. However, there is no evidence for any effectiveness in Japanese. This study was designed to evaluate the effect of cholesterol lowering therapy with 3-hydroxy-3-methylglutaryl coenzyme A(HMG-CoA) reductase inhibitor on cardiac events(death and reinfarction) in Japanese patients after myocardial infarction. A total of 290 patients after myocardial infarction were studied retrospectively. The patients were divided into 2 groups with or without HMG-CoA reductase inhibitor therapy for lowering blood cholesterol levels. The cumulative cardiac events and percentage change of cholesterol levels[total cholesterol and low-density lipoprotein (LDL) cholesterol level] were compared between the 2 groups. HMG-CoA reductase inhibitor therapy lowered plasma cholesterol levels significantly (total cholesterol level--11 +/- 20%, LDL cholesterol level--23 +/- 26%) in patients with hypercholesterolemia, whereas there was no change(total cholesterol level 4.3 +/- 22%, LDL cholesterol level--7.2 +/- 24%) in patients without hypercholesterolemia. HMG-CoA reductase inhibitor therapy reduced cardiac events significantly compared in patients with hypercholesterolemia(p = 0.0008), but there was no benefit in patients without hypercholesterolemia. We suggest that treatment with HMG-CoA reductase inhibitor therapy for lowering cholesterol levels was effective for secondary prevention after myocardial infarction in Japanese patients with hypercholesterolemia.     

Effects of rosuvastatin on 3-nitrotyrosine and aortic stiffness in hypercholesterolemia

Background and aimsEarly atherosclerosis is characterized by reduced large artery distensibility, paralleled by an increased peroxynitrite formation and nitration of tyrosine in proteins. The aim of the present study was to investigate the short-term effect of cholesterol lowering with rosuvastatin on 3-nitrotyrosine (3-NT), a marker of peroxynitrite-mediated oxidative stress, and on arterial stiffness.Methods and results71 outpatients with primary hypercholesterolemia were recruited for this randomized open-label intervention study; 35 patients were assigned to 4-week rosuvastatin therapy (10 mg daily) with a low-fat diet, and 36 patients to a low-fat diet only. Within the cohort of 71 hypercholesterolemic patients, there was a significant correlation between cholesterol levels, 3-NT and aortic pulse wave velocity (aPWV), that is a reliable measure of aortic stiffness. Among those patients who received rosuvastatin, significant reductions in plasma cholesterol, 3-NT and aPWV were observed. Reductions in both aPWV and 3-NT levels correlated significantly with the decrease in plasma cholesterol. Reduction of plasma cholesterol was the only independent predictor for reduced arterial stiffness following rosuvastatin therapy.ConclusionCholesterol reduction achieved following short-term rosuvastatin therapy is associated with a decrease in peroxynitrite-mediated oxidative stress and an improvement in large artery distensibility; reduction in arterial stiffness is directly attributable to rosuvastatin-induced cholesterol lowering and not to reduction of plasma 3-NT levels.     

Health policy for treating hyperlipidemia: Analogy with hypertension and prospects for the next decade

Over the past 15 years, efforts by the health profession to detect and treat high blood pressure have grown remarkably successful. A similar growth now seems likely for high blood cholesterol. Three factors are responsible: (1) the continuing emergence of scientific evidence corroborating the benefit of lowering high blood cholesterol levels by diet or drugs, (2) the formulation in 1984 of more specific health policy guidelines by the Consensus Development Conference on Lowering Blood Cholesterol and (3) the creation in 1985 of the National Cholesterol Education Program. This program has been designed to enhance preventive activities by the public and by health care professionals. Its success will depend in part on resolving problems with the efficacy and acceptability of life-style and drug interventions for lowering blood cholesterol levels.     

Statins: immunomodulators for autoimmune rheumatic disease?

Inhibitors of 3-hydroxy-3-methylgluttaryl coenzyme A (HMG-CoA) reductase, or statins, are used extensively to reduced elevated lipid levels and reduce cardiovascular risk. However, accumulated evidence suggests that stains not only act by lowering cholesterol levels, but also exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival and participate in the regulation of cell shape and motility. Thus cardiovascular benefit is provided by lowering raised cholesterol levels and by modulation of the inflammatory component of this disease. Such an anti-inflammatory effect may also benefit patients with autoimmune rheumatic disease. This overview assesses the evidence for using statins in patients with rheumatoid arthritis and systemic lupus erythematosus (SLE).     

Effects of maximal doses of atorvastatin versus rosuvastatin on small dense low-density lipoprotein cholesterol levels

Maximal doses of atorvastatin and rosuvastatin are highly effective in lowering low-density lipoprotein (LDL) cholesterol and triglyceride levels; however, rosuvastatin has been shown to be significantly more effective than atorvastatin in lowering LDL cholesterol and in increasing high-density lipoprotein (HDL) and its subclasses. Our purpose in this post hoc subanalysis of an open-label study was to compare the effects of daily oral doses of rosuvastatin 40 mg with atorvastatin 80 mg over a 6-week period on direct LDL cholesterol and small dense LDL (sdLDL) cholesterol in 271 hyperlipidemic men and women versus baseline values. Rosuvastatin was significantly (p<0.01) more effective than atorvastatin in decreasing sdLDL cholesterol (-53% vs -46%), direct LDL cholesterol (-52% vs -50%), total cholesterol/HDL cholesterol ratio (-46% vs -39%), and non-HDL cholesterol (-51% vs -48%), The magnitude of these differences was modest, and the 2 statins caused similar decreases in triglyceride levels (-24% and -26%). In conclusion, our data indicate that the 2 statins, given at their maximal doses, significantly and beneficially alter the entire spectrum of lipoprotein particles, but that rosuvastatin is significantly more effective than atorvastatin in lowering direct LDL cholesterol and sdLDL cholesterol.     

他汀类药物多效性的临床研究进展

近年来数个大规模临床研究相继证实,应用他汀类药物可明显降低血清总胆固醇和低密度脂蛋白胆固醇水平,显著降低冠心病发病率、心血管病死亡率乃至全因死亡率,从而奠定了他汀在冠心病一级、二级预防中的基石地位。然而,随着基础与临床研究的深入,越来越多的证据表明,他汀类药物具有独立于调脂作用外的多种疗效,即他汀的多效性。现将着重从循证医学的角度对他汀类药物的多效性进行综述。     

The utility of high density lipoprotein cholesterol subclasses measurement

The aim of our study was to estimate the cholesterol concentrations in high density lipoprotein subfractions (HDL2 i HDL3) in plasma of patients with normocholesterolemia and atherosclerosis of coronary arteries and in patients with myeloproliferative diseases. Blood samples from patients with normal plasma cholesterol levels were analyzed in spite of the fact that atherosclerosis of coronary arteries usually exist with hypercholesterolemia and myeloproliferative diseases usually coexist with hypocholesterolemia. In this way we wanted to determine changes in HDL2 i HDL3 metabolism which occur independently from changes of cholesterol levels in other lipoproteins. Our results showed that in patients suffering from atherosclerosis of coronary arteries with normolipemia the lowering of plasma cholesterol level in subfractions HDL2 and HDL3 was observed. In patients with myeloproliferative disease with normocholesterolemia the slight lowering of cholesterol level in subfraction HDL3 may be connected with moderate hypertriglyceridemia. In both groups of patients the lowering of HDL cholesterol in plasma was accompanied with the increased lipid peroxidation.     

他汀类药物的作用多向性效应及其临床应用

他汀类药物能显著降低总胆固醇、低密度脂蛋白胆固醇和升高高密度脂蛋白胆固醇,在急性冠状动脉综合征的治疗中发挥着稳定粥样硬化斑块、降低急性冠状动脉综合征患者急性期病死率的作用。近年来的临床和实验研究证实,他汀类具有作用多向性效应,可以防治20余种疾病,其中多数与调脂作用无关。     

Effects of colesevelam hydrochloride (WelChol) on biomarkers of inflammation in patients with mild hypercholesterolemia

Inflammation is pivotal in atherogenesis. High-sensitivity C-reactive protein (hs-CRP), the prototypic marker of inflammation, has been shown to predict cardiovascular events. Colesevelam hydrochloride (HCl) (WelChol, Sankyo Pharma Incorporated, Parsippany, New Jersey), a specifically engineered bile acid sequestrant, has been shown to be effective in lowering low-density lipoprotein (LDL) cholesterol levels in monotherapy and in combination with statins or fenofibrate. Previously, we have shown that statins lower hs-CRP levels; however, a paucity of data is available examining the effect of colesevelam HCl on hs-CRP levels. The aim of this study was to examine the effect of colesevelam HCl therapy (3.75 g/day for 6 weeks) on hs-CRP in patients with mild hypercholesterolemia in a randomized, double-blind, placebo-controlled study. Twenty-five subjects on colesevelam HCl and 23 subjects on placebo completed the study. The median baseline hs-CRP levels for the treatment and placebo groups are 3.4 and 3.1 mg/L, respectively. Colesevelam HCl therapy resulted in a significant reduction in LDL cholesterol levels (p < 0.001). No significant changes were found in total triglyceride or high-density lipoprotein cholesterol levels between the 2 groups. Furthermore, colesevelam HCl therapy resulted in a significant reduction in hs-CRP levels compared with baseline and placebo (15.9% and 18.7% median reduction, respectively, p < 0.025). No correlation was found between LDL cholesterol lowering and hs-CRP lowering (r = 0.3). In conclusion, our results show that colesevelam HCl monotherapy significantly lowered hs-CRP levels in a double-blind, placebo-controlled study.     

Optimal low-density lipoprotein levels: Evidence from epidemiology and clinical trials

Aggressive lipid lowering was initially controversial due to evidence from epidemiologic studies that implied an increase in total mortality with low cholesterol levels combined with equivocal results from early trials utilizing bile acid resins or fibric acid derivatives. The advent of statin therapy allowed significant reductions of circulating lipid levels and clearly reduced cardiovascular morbidity and mortality. Additionally, in adequately powered trials, total mortality was also reduced. The optimal level of circulating low-density lipoprotein (LDL) has not been definitely established. However, recent clinical trials with aggressive lipid goals have established that LDL cholesterol can be significantly lowered below 100 mg/dL with improvement in both surrogate measurements and hard clinical endpoints. Ongoing clinical trials have been initiated that will determine the optimal level of LDL cholesterol that will insure cardiovascular benefits and establish the risk-benefit relationship of aggressive pharmacologic lowering of circulating lipid levels.