新型调脂药ezetimibe--胆固醇吸收的选择性抑制剂

传统的树脂类、贝特类等药物因为不良反应大，降低胆固醇效果差而不易被病人接受。他汀类药物降低胆固醇效果好，但某些病人单用他汀类药物不能有效降低体内胆固醇水平。因此本文介绍了新近在美国上市的ezetimibe，一种新型胆固醇吸收的选择性抑制剂，在单用或与他汀类药物联用时，都能稳定降低血浆低密度脂蛋白胆固醇(LDL-C)水平，为临床治疗高脂血症提供了新的选择。     

高胆固醇血症的双相调节与ezetimibe

目前仍有较多高危患者经他汀类单药治疗后低密度脂蛋白胆固醇(LDL-C)不能达到预期的标准，而且以他汀类与其它降脂药物联用常因不良反应增加而受到限制。新型胆固醇吸收抑制剂ezetimibe，与小肠粘膜刷状缘的结构蛋白具极高的亲和力，通过抑制小肠壁对食物及胆汁中的胆固醇吸收而发挥作用。本品口服给药吸收迅速，半衰期长达24小时，且不良反应与安慰剂组相仿。本品与他汀类联合给药具协同效应，且不增加横纹肌溶解等不良反应。据此对高胆固醇血症患者联用上述两类不同作用机制药物的疗效及安全性可予确认。     

新型选择性胆固醇吸收抑制剂依泽麦布

依泽麦布为一种新型口服调血脂药物，它能选择性抑制肠道对胆固醇和相关植物甾醇的吸收。单独应用或与他汀类药物合用，均能降低具有冠心病风险患者的血清胆固醇水平。本文主要对其作用机制、药代动力学、临床疗效和安全性进行综述。     

The implications of the ezetimibe and simvastatin in hypercholesterolemia enhances atherosclerosis regression trial: a return to first principles

To outward appearances, the publication of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial has led to a monolithic backlash against the use of ezetimibe by cardiologists for the treatment of hyperlipidemia. Rather than be swayed by popular opinion, we should each put the results of ENHANCE into context and ask the questions: should I put my trust in an imaging surrogate or in low‐density lipoprotein (LDL) cholesterol (LDL‐C), and how do the safety and efficacy of ezetimibe compare with other nonstatin lipid‐lowering agents? Copyright © 2008 Wiley Periodicals, Inc.     

An Evidence-Based Guideline for Treating Dyslipidemia in Statin-Intolerant Patients

The purpose of this report is to inform nurse practitioners and other health care providers about how to treat dyslipidemia in the statin-intolerant patient while simultaneously achieving optimal cardiovascular outcomes for this patient population. This report will briefly explain how to rechallenge the statin-intolerant patient and the secondary therapies that are available to decrease cardiovascular morbidity and mortality. Algorithms for rechallenging the statin-intolerant patient and secondary therapies are also provided.     

依折麦布辛伐他汀片对兔腹主动脉粥样硬化斑块逆转作用的实验研究

目的：观察腹主动脉粥样斑块内炎性巨噬细胞和平滑肌细胞的表达情况,以探索依折麦布联合他汀类药物在逆转动脉斑块中的作用及机制。方法选取24只健康雄性新西兰大耳白兔,随机分为对照组（n＝8）和高胆固醇血症组（n＝16）。对照组给予普通饲料,喂养12周。高胆固醇血症组喂饲致动脉粥样硬化饲料（由普通颗粒饲料＋15g/L胆固醇＋100g/L猪油＋150g/L蛋黄粉组成）2周后行腹主动脉内膜球囊拉伤术,术后再随机分为模型亚组和依折麦布辛伐他汀（ES）亚组（给予5/10mg/（kg·d）每组8只,两亚组均继续喂饲致动脉粥样硬化饲料10周。喂养第12周时活杀动物,取腹主动脉进行石蜡切片。检测不同时间点脂质和脂蛋白,应用光学显微镜观察动脉粥样硬化进程,采用免疫组化方法分析巨噬细胞和平滑肌细胞在斑块处的表达。结果 ES亚组的血清总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）浓度明显低于模型亚组（P＜0.01）。病理检测显示两亚组及ES亚组斑块直径、斑块厚度和动脉内/中膜厚度经单因素方差分析,差异有统计学意义（P＜0.05）。免疫组化检测结果示ES亚组血管壁中巨噬细胞的表达量较模型亚组显著减少（P＜0.05）,而平滑肌细胞的表达量较模型亚组显著增多（P＜0.01）。结论 ES可能通过减少细胞外脂质的沉积,减少内膜和中膜巨噬细胞的数量和胆固醇的含量,增加胶原和平滑肌细胞面积,从而起到逆转斑块的作用。     

The effect of ezetimibe, administered alone or in combination with simvastatin, on lymphocyte cytokine release in patients with elevated cholesterol levels

Abstract. Krysiak R, Zmuda W, Okopien B (Medical University of Silesia, Katowice; and and Electrotherapy and Angiology Centre, Oswiecim, Poland). The effect of ezetimibe, administered alone or in combination with simvastatin, on lymphocyte cytokine release in patients with elevated cholesterol levels. J Intern Med 2012; 271 : 32–42. Objective. Studies assessing the extra‐lipid effects of ezetimibe have provided contrasting results. In the present study, we compared the effects of ezetimibe and simvastatin, administered alone or in combination, on the secretory function of human lymphocytes, systemic inflammation and endothelial function in subjects with elevated cholesterol levels. Methods. A prospective study involving a group of 178 ambulatory patients with isolated hypercholesterolaemia who were randomly assigned in a double‐blind fashion to 90 days of treatment with ezetimibe (10 mg), simvastatin (40 mg), ezetimibe (10 mg) plus simvastatin (40 mg) or placebo. A total of 170 patients completed the study. Main outcome measures. Lymphocyte cytokine release and plasma levels of high‐sensitivity C‐reactive protein (hsCRP) and intercellular adhesion molecule 1 (ICAM‐1). Results. Although both drugs reduced lymphocyte release of tumour necrosis factor‐α, interferon‐γ and interleukin‐2 in a lipid‐independent manner, only the effect of simvastatin was statistically significant (P < 0.001). This lymphocyte‐suppressing effect, which was accompanied by a decrease in plasma levels of hsCRP and ICAM‐1 (P < 0.001), was strongest in patients receiving both simvastatin and ezetimibe. There were no differences in lymphocyte‐suppressing, systemic anti‐inflammatory and endothelial protective effects of simvastatin between insulin‐resistant and insulin‐sensitive subjects, whereas the effects of ezetimibe and the combined treatment were greater in the former group of patients (P < 0.01 and P < 0.001, respectively). Conclusions. The results of this study indicate that simvastatin is superior to ezetimibe in producing lymphocyte‐suppressing, systemic anti‐inflammatory and endothelial protective effects in patients with elevated cholesterol levels. Hypercholesterolaemic patients with high cardiovascular risk may receive the greatest benefits from concomitant treatment with a statin and ezetimibe.     

依折麦布联合辛伐他汀对冠心病患者的调脂作用

目的:探讨依折麦布联合辛伐他汀对冠心病患者血脂及炎性因子的调节作用。方法: 选取2011年5月~9月我院收治的冠心病患者60例,随机分为试药组和对照组,每组各30例,试药组采用依折麦布(10 mg/d)联合辛伐他汀(20 mg/d),对照组单独使用辛伐他汀（40 mg/d）。在服药前、用药4周、用药8周时分别测定总胆固醇(TC)、三酰甘油(TG)、低密度脂蛋白胆固醇(LDL-C)、高密度脂蛋白胆固醇(HDL-C)、肝功能、肾功能、肌酸激酶(CK)。结果: 与用药前基线水平相比,两组用药4周TC、LDL-C水平均显著下降（P<0.05）,治疗8周均进一步下降（P<0.01）,并且与对照组相比,试药组8周TC、LDL-C下降水平更显著（P<0.05）。两组患者的肝功能、肾功能、CK在用药后均无明显异常。结论: 依折麦布联合辛伐他汀能更有效地降低冠心病患者血脂水平。     

The Effects of High Dose Pravastatin and Low Dose Pravastatin and Ezetimibe Combination Therapy on Lipid,Glucose Metabolism and Inflammation

Objective Coronary artery disease (CAD) is presently the major cause of mortality and morbidity. Anti-hyperlipidemic treatment is one of the main treatment steps in the management of CAD. Statins are the cornerstones in this treatment. Ezetimibe can be reliably used, when statins prove ineffective in treatment, or to reduce their side effects. In the present study we examined the effects of high-dose pravastatin (40 mg) and low-dose pravastatin (10 mg) + ezetimibe (10 mg) combination therapy on lipid and glucose mechanism, as well as inflammation. Methods This study registered 100 cases. Of the cases, 50 [57.1 ± 11.1 years (24 (48%) females and 26 (52%) males)] were administered 40 mg/day pravastatin (group 1) and 50 [53.2 ± 12.2 years (27 (54%) females and 23 (46%) males)] were administered 10 mg pravastatin + 10 mg ezetimibe (group 2). Results In group 1, total cholesterol fell from 231.1 ± 83.5 mg/dl to 211.3 ± 37.2 mg/dl (p = 0.03), triglyceride from 243.5 ± 96.8 mg/dl to 190.9 ± 55.2 mg/dl (p = 0.003), and LDL cholesterol from 165.7 ± 29.7 mg/dl to 133.4 ± 26.6 mg/dl (p = 0.02). In group 2, total cholesterol dropped from 250.9 ± 51.8 mg/dl to 187.9 ± 34.9 mg/dl (p = 0.001), triglyceride from 270.3 ± 158.9 mg/dl to 154.6 ± 60.7 mg/dl (p = 0.001), and LDL cholesterol from 158.1 ± 47.5 mg/dl to 116.9 ± 26.4 mg/dl (p = 0.001). Insulin resistance decreased from 4.05 ± 2.31 to 3.16 ± 1.90 (p = 0.07) in group 1 and from 2.96 ± 1.50 to 2.05 ± 0.55 (p = 0.009) in group 2. High sensitive C-reactive protein fell from 6.69 ± 6.11 mg/l to 3.02 ± 1.70 mg/l (p = 0.01) in group 1 and from 6.36 ± 2.06 mg/l to 2.68 ± 1.69 mg/l (p = 0.001) in group 2. Conclusion Both therapy regimes are effective. However, we found that low-dose pravastatin and ezetimibe combination therapy is more effective than high-dose pravastatin therapy on lipid metabolism, glucose metabolism and inflammation.