他汀类药物在缺血性脑卒中的应用进展

调脂药他汀类药物对脑卒中患者预后改善及降低缺血性脑卒中发生风险有益.本文针对他汀类药物改善血管内皮细胞功能、抑制血管炎症反应、稳定粥样硬化斑块、抗血小板聚集、抑制血栓形成及增加循环内皮祖细胞数量等多效性作用,综述他汀类药物对缺血性脑血管损伤的神经保护作用.     

谈他汀类药物对心血管疾病的作用

他汀类药物已广泛应用于临床高脂血症的治疗,新的临床应用实验表明,他汀类药物不仅可降低血脂水平,相对急性冠脉综合征的患者,尽早服用他汀类药物可有效降低心脑血管危险。而且还有抑制炎症反应、稳定动脉粥样硬化斑块、抑制血栓形成及对血管平滑肌作用等非降脂功能。本文就他汀类药物对心血管疾病的作用进行综述。     

他汀类药物抗肿瘤作用机制的研究进展

他汀类药物属于3-羟基-3-甲基戊二酸单酰辅酶A还原酶抑制剂,近年来大量的临床研究显示,他汀类药物也具备抗肿瘤作用。他汀类药物可以通过抑制肿瘤细胞增殖、促进肿瘤细胞凋亡、抑制肿瘤细胞侵袭和迁移、抗肿瘤血管生成、增强抗肿瘤免疫等发挥抗肿瘤作用。因此总结了他汀类药物的抗肿瘤作用机制,期望为他汀类药物进一步应用于肿瘤的治疗提供科学依据和理论支撑。     

5种他汀类药物对鸡胚绒毛尿囊膜血管新生的影响

目的:观察5种他汀类药物对鸡胚绒毛尿囊膜(CAM)血管新生的影响,探讨他汀类药物是否具有独立于血脂调节作用以外的促进血管新生作用。方法:制备CAM模型,将不同浓度他汀类药物、重组牛碱性成纤维细胞生长因子和生理盐水分别通过载体加到CAM上,观察CAM特异性血管生长情况及血管数目变化。结果:不同浓度辛伐他汀(0.02,0.1,0.5,2.5,12.5μmol.L-1)中,当辛伐他汀浓度为0.1μmol.L-1时,CAM血管生成数量明显高于生理盐水对照组(P<0.05),与阳性对照组比较无统计学意义(P>0.05);而不同他汀类药物,即瑞舒伐他汀组(0.025μmol.L-1)、阿托伐他汀组(0.05μmol.L-1)、普伐他汀组(0.2μmol.L-1)、氟伐他汀组(0.4μmol.L-1),CAM血管生成数均明显高于生理盐水组(P<0.05),与阳性对照组比较无统计学意义(P>0.05)。结论:常用5种他汀类药物均有促进CAM血管新生作用;不同浓度辛伐他汀对CAM的作用不同。提示他汀类药物促进血管新生的作用可能与药物剂量有关。     

他汀类药物多效性对心肌的保护作用进展

目的 探讨他汀类药物的多效性对心肌的保护作用,为合理应用该类药物提供参考.方法 查阅近期相关文献资料,对他汀类药物的多效性作用进行综合分析.结果 他汀类药物除调脂作用外,还具有抗氧化、抗炎、抗血栓、改善血管内皮功能等多效性作用.结论 他汀类药物的多效性作用对心肌具有保护作用,临床可用于心肌疾病的预防和治疗.     

他汀类药物的临床应用及不良反应

他汀类药物是治疗动脉粥样硬化的传统常规药物,不仅能够降低血脂,还具有抗炎、改善血管内皮功能、减少缺血再灌注损伤、抗氧化应激、调节神经内分泌等作用。然而长期使用他汀类药物也会出现一些不良反应。笔者对他汀类药物的临床应用及不良反应进行综述。     

科技博览

他汀类药稀在心衰治疗中的作用美国耶鲁医学中心正在进行一项开拓性研究,评价他汀类药物在心力衰竭病人治疗中的作用。研究表明,他汀类药物可很有效地降低胆固醇的水平,而目前血管功能减退的心力衰竭患者并未使用他汀类药物治疗。耶鲁的研究观察了他汀类药物用于心力衰竭患者对血管功能的短期疗效,目的是评价他汀类药物短期治疗前后对血管功能的影响。这一随机研究入选了30名胆固醇水平正常的轻-中度慢性心力衰竭患者。在研究开始前和结束时检测胆固醇/低密度脂蛋白的水平。仿制也需要有创新精神鉴于专利药品研制的周期长、投入大、淘汰率高…     

他汀类与心血管药物配伍的安全性分析

目的分析与研究他汀类与心血管药物配伍的安全性。方法分析他汀类和肾素及血管紧张素的转化酶抑制剂、钙拮抗剂、洋地黄类药物、抗心律失常类药物及其他降血脂类药物的配伍情况,并对其安全性进行总结。结果他汀类与肾素及血管紧张素的转化酶抑制剂、钙拮抗剂、洋地黄类药物及其他降血脂类药物配伍的安全性较好,但和抗心律失常类药物配伍需慎重。结论要重视他汀类和心血管类药物的配伍使用,如有需要可在剂量上加以调整,还需注意使用药物疗效的相互影响。     

他汀类药物致药物性肝损伤的研究进展

他汀类药物调脂作用显著,是一类较全面的调脂药,能强效降低血清总胆固醇(TC)和低密度脂蛋白(LDL),在心血管疾病预防和治疗中应用广泛。近年来,随着他汀类药物的广泛应用,对其不良反应的研究也日趋深入。肝毒性是此类药物产生的重要不良反应之一,他汀类药物在使用过程中偶有药物性肝损伤(DILI)发生,对他汀类药物致DILI影响因素、相关机制及防治策略的研究进展进行总结,旨在为他汀类药物临床合理使用及DILI的预防提供依据。     

他汀类药物的血压调节作用

他汀类药物是治疗高胆固醇血症的首选药物 ,临床已广泛应用于血脂异常的治疗。近年来 ,临床研究发现他汀类药物可改善高血压合并血脂异常患者的血压 ,这种作用不仅见于未经治疗的高血压患者 ,对于已经使用抗高血压药物治疗的高血压患者也有一定的疗效。但有一些研究并不完全肯定这一作用。他汀类药物降低血压的作用在很大程度上不依赖于其调脂作用 ,可能与其改善血管内皮功能及调节血管紧张素受体有关。     

Antioxidant effects of statins

Statins, a group of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are widely used in clinical practice for their efficacy in producing significant reductions in plasma cholesterol and LDL cholesterol and in reducing morbidity and mortality from cardiovascular disease. However, several large clinical trials have suggested that the cholesterol-lowering effects of statins may not completely account for the reduced incidence of cardiovascular disease seen in patients receiving statin therapy. A number of recent reports have shown that statins may also have important antiinflammatory effects, in addition to their effects on plasma lipids. Since inflammation is closely linked to the production of reactive oxygen species (ROS), the molecular basis of the observed antiinflammatory effects of statins may relate to their ability block the production and/or activity of ROS. In this review, we will discuss both the inhibition of ROS generation by statins, through interference with NAD(P)H oxidase expression and activity, and the actions of statins that serve to blunt the damaging effects of these radicals, including effects on antioxidant enzymes, lipid peroxidation, LDL cholesterol oxidation and nitric oxide synthase. These antioxidant effects of statins likely contribute to their clinical efficacy in treating cardiovascular disease as well as other chronic conditions associated with increased oxidative stress in humans.     

冠心病住院患者调脂药物应用情况调查

目的 调查冠心病住院患者中调脂药物的应用情况。方法 对347例确诊的冠心病患者在住院期间应用他汀类及贝特类调脂药物的使用情况进行调查，并对不同水平的LDL—C中他汀类药物的应用进行调查。结果 在347例患者中有221例的LDL—C＞2.6mmol/L，占63．69％，但仅有160例使用他汀类药物，使用率为46．1％；而使用贝特类药物的患者只有22例，使用率为6．3％。结论 在冠心病住院患者中存在着他汀类药物量使用不足的现象。     

Effects of HMG-CoA reductase inhibitors on coagulation and fibrinolysis processes

Recent large clinical trials have demonstrated that HMG-CoA reductase inhibitors, or statins, markedly reduce morbidity and mortality when used in the primary and secondary prevention of cardiovascular disease. It has been established that the benefits of statin therapy in cardiovascular disease can be explained not only by the lipid-lowering potential of statins but also by nonlipid-related mechanisms (so-called "pleiotropic effects") that contribute to the positive effect of statins on the incidence of cardiovascular events.The coagulation and fibrinolytic systems are two separate but reciprocally linked enzyme cascades that regulate the formation and breakdown of fibrin. Numerous studies have demonstrated that disturbances of coagulation and fibrinolysis contribute to the development and progression of atherosclerosis, and that they affect the incidence of atherosclerosis-related clinical events. High plasma levels or activities of fibrinogen, factor VII, factor VIII, von Willebrand factor (vWF), soluble thrombomodulin, tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) are thought to be associated with increased morbidity and mortality related to cardiovascular disease.Experimental studies and many clinical studies have recently shown that statins produce favourable effects on haemostatic parameters, including those that are risk factors for cardiovascular disease. Statins diminish procoagulant activity, which is observed at different stages of the coagulation cascade, including tissue factor (TF) activity, conversion of prothrombin to thrombin and thrombin activity. In some studies, statins also reduced fibrinogen levels. By altering the levels and activities of tPA and PAI-1, statins seem to stimulate fibrinolysis. The data on the effects of combined treatment with statins and other drugs on haemostasis are rather limited. They suggest that statins combined with fibric acid derivatives, omega-3 fatty acids and 17beta-estradiol are superior to statins alone. The only two clinical studies performed in patients with acute coronary syndromes showed a relatively weak effect of statins on haemostasis in those patients. Although various statins may produce different effects on individual variables, there are no convincing data showing that differences in their physicochemical and pharmacokinetic properties significantly alter their net effect on excessive procoagulant activity. Apart from the lipid-lowering effect, statins suppress the synthesis of several important nonsterol isoprenoids derived from the mevalonate pathway, especially farnesyl and geranylgeranyl pyrophosphates, which via enhanced protein prenylation, are involved in the regulation of many cellular processes. It is presumed that the inhibitory effect of statins on the mevalonate pathway is involved in the regulation of some key steps of coagulation and fibrinolysis processes. In this way they probably regulate the synthesis of TF, tPA and PAI-1, and perhaps they also control the generation and activity of thrombin.The beneficial effects of statins on coagulation and fibrinolysis may be responsible for their ability to decrease the number of cardiovascular events. The lipid-independent effects of statins on haemostasis may contribute to the marked decrease in the incidence rates of mortality, hospitalisation and revascularisation in patients treated with these drugs.     

Statins decrease TNF-alpha-induced osteoprotegerin production by endothelial cells and smooth muscle cells in vitro

Recent reports have implicated osteoprotegerin (OPG) in cardiovascular disease processes. Endothelial and smooth muscle cells produce OPG and its expression in these cells is upregulated by inflammatory mediators. Statins, which besides their lipid lowering properties have various vasculoprotective effects, have been shown to regulate OPG expression in osteoblasts. We investigated whether statins affect the expression of OPG in human endothelial and smooth muscle cells. Using an ELISA we could demonstrate that statins reduce tumor necrosis factor-alpha (TNF-alpha)-induced OPG production in cultured human endothelial cells and smooth muscle cells. Atorvastatin also downregulated interleukin-1alpha (IL-1alpha)-induced OPG production in endothelial cells. A significant reduction of TNF-alpha-induced OPG was seen when statins were used in the nanomolar range. These results were confirmed at the level of specific mRNA expression by real-time-PCR. Using LDH leakage as a marker of cell damage we show that cell viability was not affected by statins at concentrations used in our study. The effect of statins on TNF-alpha-induced OPG production was reversed by mevalonate and geranyl-geranyl pyrophosphate at the level of protein production and at the level of mRNA expression, suggesting that it was brought about by inhibition of the mevalonic acid pathway and protein prenylation. Through our results we have added OPG to the list of molecules whose TNF-alpha-induced upregulation is counteracted by statins. If such an effect is also operative in the in vivo setting, one could postulate a role for statins in the modulation of cardiovascular disease processes possibly regulated by OPG.     

Molecular mechanisms of toxicity of simvastatin,widely used cholesterol-lowering drug. A review

Statins are widely used and well tolerated cholesterol-lowering drugs, and when used for therapy purposes reduce morbidity and mortality from coronary heart disease. Simvastatin is one of nine known statins, specific inhibitors of hepatic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the rate-limiting step of cholesterol biosynthesis, and is believed to reduce plasma cholesterol levels by decreasing the activity of this enzyme. Statin drugs represent the major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Although statins are generally safe, minor and severe adverse reactions are well known complications of statin use. Adverse events associated with simvastatin therapy are uncommon, but potentially serious. In this review some details about statins including their adverse effects in humans and animals, the effects of simvastatin on various intracellular and mitochondrial processes, and molecular mechanisms underlying simvastatin cytotoxicity are discussed.     

Statins as anti-inflammatory agents in atherogenesis: molecular mechanisms and lessons from the recent clinical trials

Ample evidence exists in support of the potent anti-inflammatory properties of statins. In cell studies and animal models statins exert beneficial cardiovascular effects. By inhibiting intracellular isoprenoids formation, statins suppress vascular and myocardial inflammation, favorably modulate vascular and myocardial redox state and improve nitric oxide bioavailability. Randomized clinical trials have demonstrated that further to their lipid lowering effects, statins are useful in the primary and secondary prevention of coronary heart disease (CHD) due to their anti-inflammatory potential. The landmark JUPITER trial suggested that in subjects without CHD, suppression of low-grade inflammation by statins improves clinical outcome. However, recent trials have failed to document any clinical benefit with statins in high risk groups, such in heart failure or chronic kidney disease patients. In this review, we aim to summarize the existing evidence on statins as an anti-inflammatory agent in atherogenesis. We describe the molecular mechanisms responsible for the antiinflammatory effects of statins, as well as clinical data on the non lipid-lowering, anti-inflammatory effects of statins on cardiovascular outcomes. Lastly, the controversy of the recent large randomized clinical trials and the issue of statin withdrawal are also discussed.     

Statin therapy and myocardial no-reflow

HMG-CoA reductase inhibitors (statins) have now become one of the most powerful pharmacological strategies in the treatment of cardiovascular diseases. Originally, the cardioprotective effects of statins were thought to be mediated through lipid lowering actions. However, it has now become increasingly clear that the beneficial effects of statins are not related to the lipid lowering effects, but rather to a number of pleiotropic actions. Of particular interest, statins have been shown to increase bioavailability of nitric oxide and protect against vascular inflammation and cardiac cell death in a number of cardiovascular disease states. In this present issue of the British Journal of Pharmacology, Zhao and colleagues provide a novel mechanism of action for statins with the observation that simvastatin reduces myocardial 'no-reflow' after ischemia and reperfusion by activating the mitochondrial K(ATP) channel. The findings of the present study have very profound implications for the treatment of cardiovascular disease. This commentary discusses the implications of these findings and how they relate to the established cardioprotective actions of statins.     

Statin mediated protection of the ischemic myocardium

Hypercholesterolemia is a major risk factor in the development of cardiovascular disease and HMG-CoA reductase inhibitors (i.e. statins) were originally designed to reduce serum cholesterol levels and thus reduce this risk factor. However, it has become increasingly apparent that the effects of statins extend well beyond their lipid lowering actions, and these pleiotropic effects have a major role in protecting the myocardium against ischemic injury. There have been a large number of clinical studies demonstrating the safety and efficacy of statins in reducing total mortality as well as many other secondary endpoint markers in patients with cardiovascular disease. In addition, statins appear to benefit patients with a variety of clinical conditions such as acute coronary syndromes and severe heart failure. Recent experimental studies demonstrated that stains can rapidly (i.e. within hours) upregulate endothelial nitric oxide synthase (eNOS) activity and nitric oxide (NO) production. These landmark studies of statins and eNOS function set the foundation for the investigation of the protective effects of statins. Many experimental studies investigating the effects of statins on eNOS and cardiac injury in the setting of ischemia and reperfusion have been performed in an attempt to determine the extent of the protection as well as the mechanism of the protection. This review article will focus on our current understanding of statin-mediated protection of the myocardium against ischemia-reperfusion injury and infarction.     

Efficacy of statins on sirtuin 1 and endothelial nitric oxide synthase expression: the role of sirtuin 1 gene variants in human coronary atherosclerosis

Statins are 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase inhibitors and are used to reduce the risk of coronary artery disease (CAD) due to their pleiotropic effects. Recently, greater focus has been placed on the role of sirtuin 1 (SIRT1) in cardiovascular disease research. However, insufficient data exist on the relationships between statins, SIRT1 protein levels, and SIRT1 gene variants. In the present study, we investigated the effects of statins, atorvastatin and rosuvastatin, in CAD patients by analysing the associations between SIRT1 gene variants, rs7069102C>G and rs2273773C>T, and SIRT1/endothelial nitric oxide (eNOS) expression, as well as total antioxidant and oxidant status, and the oxidative stress index. SIRT1 expression was significantly higher, and eNOS expression was significantly lower in CAD patients when compared with controls. Statin treatment reduced SIRT1 expression and increased eNOS expression, similar to the levels found in the control population, independent from the studied SIRT1 gene variants. Oxidative stress parameters were significantly increased in CAD patients, and were decreased by statin treatment, demonstrating the antioxidative effects of statins on atherosclerosis. These results indicate that statin treatment could produce its protective effect on cardiovascular disease through the inhibition of SIRT1 expression. This is the first study reporting on the effect of statins, specifically atorvastatin and rosuvastatin, on SIRT1 expression in CAD patients.     

The therapeutic potential of statins in neurological disorders

Statins are currently among the most commonly prescribed agents for the prevention of cardiovascular disease. Statins reduce serum cholesterol levels by reversibly inhibiting 3-hydroxy-3-methylglutaryl coenzyme A reductase, the rate-limiting enzyme in cholesterol biosynthesis, in the nanomolar range. Mounting evidence suggests that in addition to their vascular effects such as stabilization of atherosclerotic plaques and decreased carotid intimal-medial thickness, statins have additional properties such as endothelial protection via actions on the nitric oxide synthase system as well as antioxidant, anti-inflammatory and anti-platelet effects. These effects of statins might have potential therapeutic implications in various neurological disorders such as stroke, Alzheimer's disease, Parkinson's disease, multiple sclerosis and primary brain tumors. In this review, the major protective mechanisms of statins and their applicability to the treatment of neurological disease are summarized. Although further experiments are required, currently available data would seem to indicate that clinical trials to determine the safety and efficacy of statins in a number of disorders are warranted.