Ezetimibe added to atorvastatin compared with doubling the atorvastatin dose in patients at high risk for coronary heart disease with diabetes mellitus,metabolic syndrome or neither

Aim: Type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) are both associated with increased risk for atherosclerotic coronary heart disease (CHD). Thus, it is useful to know the relative efficacy of lipid‐altering drugs in these patient populations. Methods: A double‐blind, parallel group trial of adult patients with hypercholesterolaemia at high‐CHD risk receiving atorvastatin 40 mg/day compared atorvastatin 40 mg plus ezetimibe 10 mg (ezetimibe) vs. doubling atorvastatin to 80 mg. This post hoc analysis reports lipid efficacy results in patients grouped by diagnosis of T2DM, MetS without T2DM or neither. Per cent change from baseline at week 6 was assessed for LDL‐C, total cholesterol, HDL‐C , non‐HDL‐C , Apo A‐I, Apo B and triglycerides. Safety was monitored through clinical and laboratory adverse events (AEs). Results: Compared with doubling atorvastatin, atorvastatin plus ezetimibe resulted in greater reductions in LDL‐C, triglycerides, Apo B, non‐HDL‐C, total cholesterol and lipid ratios in the T2DM, MetS and neither groups. Treatment effects were of similar magnitude across patient groups with both treatments, except triglycerides, which were slightly greater in the T2DM and MetS groups vs. neither group. Changes in HDL‐C , Apo A‐I and high sensitivity C‐reactive protein (hs‐CRP) were comparable for both treatments in all three groups. Safety and tolerability profiles were generally similar between treatments and across patient groups, as were the incidence of liver and muscle AEs. Conclusions: Compared with doubling atorvastatin to 80 mg, addition of ezetimibe to atorvastatin 40 mg produced greater improvements in multiple lipid parameters in high‐CHD risk patients with T2DM, MetS or neither, consistent with the significantly greater changes observed in the full study cohort (clinical trial # NCT00276484).     

Model-based development of gemcabene, a new lipid-altering agent

The purpose of this study was to evaluate the value of model-based, quantitative decision making during the development of gemcabene, a novel lipid-altering agent. The decisions were driven by a model of the likely clinical profile of gemcabene in comparison with its competitors, such as 3-hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), the cholesterol absorption inhibitor ezetimibe, and their combination. Dose-response models were developed for the lipid effects (low-density lipoprotein cholesterol [LDL-C] and high-density lipoprotein cholesterol); adverse effects, such as persistent alanine aminotransferase elevation and myalgia; tolerability issues, such as headache; and risk reduction for coronary artery disease-related events for 5 statins, ezetimibe, gemcabene, and their combinations. The integrated model was based on the joint analysis of publicly available summary-level data and proprietary patient-level data and included information from almost 10,000 patients. The model was made available and accessible to the development team by using the Pharsight Drug Model Explorer model visualization technology. The modeling greatly enhanced the understanding of the clinical profile of gemcabene when given alone or in combination with a statin. The interaction between statins and gemcabene for the LDL-C lowering effect was found to be significantly different from the interaction between statins and ezetimibe. Ezetimibe was found to have a pharmacological-independent interaction resulting in additional LDL-C lowering over the entire statin dose range. The gemcabene interaction was found to be less than independent, resulting in almost no additional LDL-C lowering at high-statin doses, although the drug has a significant LDL-C effect when administered alone or in combination with a low dose of a statin. The quick availability of the model after completion of the first phase II trial in the target patient population and the ability of the team to explore the potential clinical efficacy and safety of gemcabene in comparison with alternative treatment options facilitated a quick decision to stop development.     

新型胆固醇吸收抑制剂依泽替米贝

依泽替米贝是新型选择性胆固醇吸收抑制剂,现对其作用机制、药动学及临床单独使用或与他汀类药物联用治疗高胆固醇血症的研究进展进行综述.     

依折麦布治疗冠心病的作用机制及临床疗效的研究进展

冠心病是威胁人类健康的主要疾病之一,其患病率及死亡率逐年上升。依折麦布作为一种胆固醇肠吸收抑制剂,通过改善血脂水平、抑制炎症反应、缩小或逆转斑块,发挥抗动脉粥样硬化作用,延缓冠心病的发生和进展,并抑制炎性反应,改善血管内皮功能,从而减少临床终点事件的发生,提升患者疗效及预后水平。对依折麦布治疗冠心病的作用机制及临床疗效的研究进展进行综述。     

LC-MS/MS测定人血浆中依折麦布和总依折麦布的含量及其应用

目的 建立人血浆中依折麦布(EZE)和总依折麦布(EZE-T)的LC-MS/MS测定方法,并用于依折麦布片人体生物等效性(bioequivalence,BE)研究。方法 分别采用直接沉淀法和酶解后沉淀法处理血浆样品。内标为依折麦布-d4(EZE-d4)。色谱柱为Waters ACQUITY UPLC?BEH C18(2.1*50mm,1.7μm),流动相为0.1%乙酸-乙腈(A),0.1%乙酸-水(B),梯度洗脱,流速0.2 mL.min-1。在ESI源负离子模式下使用离子对m/z 408.2→271.0(EZE)和m/z 412.2→271.1(EZE-d4)进行MRM定量分析。对健康受试者口服相同剂量的受试制剂或参比制剂依折麦布片后的血药浓度进行定量分析。结果 血浆中内源性物质不干扰待测物定量,EZE、EZE-T及EZE-d4不存在相互干扰和/或相互转化。人血浆中EZE和EZE-T的定量范围分别为0.1～20,1～200 ng.mL-1,线性关系良好。待测物与内标提取回收率均在102.4%~109.8％之间;内标归一化基质效应因子均在98.5%~99.4%,CV均<5%;批内、批间准确度偏差均<15%,CV均<10%。用本法测定得到的EZE和EZE-T的浓度水平及获取的药代参数与文献报道一致,ISR复测值与原测值的偏差均<10%。结论 本法特异性强、灵敏、准确,重复性好,所需样本体积少,满足依折麦布片人体BE研究的定量分析需求。     

胆固醇吸收抑制剂在治疗高胆固醇血症中的作用

高胆固醇血症是冠心病的首要病因,而现有最强力的降脂药他汀类并不能使所有患者达到治疗目标.为此目前急需研制抑制肠吸收胆固醇的药物.本文对在动物模型和人体具有这种作用的植物甾醇类、酰基辅酶A胆固醇酰基转移酶(ACAT)抑制剂类、微粒体甘油三酯转移蛋白(MTP)抑制剂类和2-氮杂环丁酮类药的研究进展做了较全面的综述.其中2-氮杂环丁酮类的ezetimibe单药使用时有较显著的降脂作用,而与他汀类药或非诺贝特伍用时均能额外地降脂,且无药物间相互作用、耐受性好、不良反应也不严重,故伍用疗法有临床应用前途.     

新型降脂药ezetimibe

流行病学调查已经证实,心血管疾病发病率和死亡率与总胆固醇及低密度脂蛋白水平的升高相一致,而与高密度脂蛋白水平的变化相反.大规模的临床研究亦证实,他汀类降脂药不仅能明显改善血脂紊乱,且能降低心血管疾病的发病率和死亡率.但对于血脂紊乱严重的病人单纯使用他汀类药物效果并不理想.ezetimibe属新一类的降脂药物,通过抑制胆固醇的吸收而达到其有效作用,可单用或与他汀类药物联合应用,以减少其药物副作用.本文对此新药的作用机制和临床研究予以综述.