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。     

依折麦布的合成

对氟苯甲醛经Wittig反应和水解反应得到(Z)-5-(4-氟苯基)-4-戊烯酸(3),与(S)-4-苯基-2-噁唑烷酮(4)缩合、N-[4-(苄氧基)苯亚甲基]-4-氟苯胺(6)加成后,在N,O-双(三甲基硅烷基)乙酰胺和氟化四正丁铵三水合物的作用下环合,经Shi氧化得到(3R,4S)-4-[4-(苄氧基)苯基]-1-(4-氟苯基)-3-[[(2S,3R)-3-(4-氟苯基)-2-环氧基]甲基]-2-氮杂环丁酮(10),再经二苯联硒开环、钯炭催化氢化得到胆固醇吸收抑制剂依折麦布,总收率约7％,(S)-羟基de值大于99％.     

立普妥联合依折麦布治疗老年高胆固醇血症临床观察

目的:观察立普妥联合依折麦布治疗老年高胆固醇血症的临床疗效.方法:87例老年高胆固醇血症患者随机分为A、B和C组.A组30例给予立普妥;B组29例予以依折麦布;C组28例予以立普妥联合依折麦布;均每晚顿服,3个月为一疗程.观察3组用药前后血清总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)和高密度脂蛋白胆固醇(HDL-C)水平;比较3组的临床疗效;记录用药期间的不良反应;于治疗1、2、3个月检测丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)和磷酸肌酸激酶(CPK)水平.结果:3组治疗后TC、LDL-C及TG水平较同组治疗前明显降低,HDL-C水平与同组治疗前相比明显升高.C组治疗后TC和LDL-C水平下降最为显著.C组的临床疗效明显高于单独给药的A、B组.A、B和C组用药期间不良反应的发生率分别为16.7%、13.8%和17.8%,差异无统计学意义,不良反应临床症状轻微,患者均可耐受,AST及CPK升高者(均在安全范围内)门诊密切随访,均未进一步升高,不影响治疗.结论:立普妥联合依折麦布治疗老年高胆固醇血症的调脂效果明显且安全性好.     

普伐他汀联合依折麦布治疗冠心病合并高胆固醇血症的临床研究

目的 探讨普伐他汀联合依折麦布治疗冠心病合并高胆固醇血症的临床疗效.方法 选择冠心病合并高胆固醇血症患者共76 例,随机分为观察组38 例,予普伐他汀10mg 每晚一次,依折麦布10mg 每日一次,对照组38 例,予普伐他汀10mg 每晚一次,共8 周,观察胆固醇变化情况及达标率,心血管事件发生情况以及不良反应.结果 两组药物均可使总胆固醇,低密度脂蛋白胆固醇减低(P ＜ 0.05),普伐他汀联合依折麦布组总胆固醇、低密度脂蛋白胆固醇达标率显著高于普伐他汀组,心血管事件发生率有所降低,而不良反应发生率无统计学差异.结论 普伐他汀联合依折麦布可有效安全的治疗冠心病合并高胆固醇血症患者,疗效优于单用普伐他汀组.     

依折麦布联合小剂量普伐他汀治疗高胆固醇血症疗效观察

冠心病严重危害人们健康,高血脂是引起冠心病的高危因素之一。高血脂症是血浆胆固醇(TC)、三酰甘油(TG)、总脂等血脂成分的浓度超过正常标准。高血脂症的主要危害是导致动脉粥样硬化,进而导致众多的相关疾病。调节血脂是防治冠心病的最基本疗法。研究显示他汀类药物剂量增加至常规剂量的数倍才能较大幅度的降低胆固醇,因为其副作增加及患者的耐受性差均不能达到理想要求。他汀类联合另一种降脂药     

新型降胆固醇药物依折麦布的波谱学解析与结构确证

目的对胆固醇吸收抑制剂依折麦布进行系统的波谱学解析与结构确证。方法运用UV、IR、差热与热重分析、圆二色谱、核磁共振、质谱以及粉末X射线衍射等现代分析手段测定样品的波谱学参数,并进行系统结构解析与归属。结果证实依折麦布的结构为1-(4-氟苯基)-(3R)-[3-(4-氟苯基)-(3S)-羟基丙基]-(4S)-(4-羟基苯基)-2-丙内酰胺。结论本法测定结果准确,为依折麦布的生产提供了较为全面的参考标准。     

胆固醇吸收抑制剂依折麦布中2种杂质的合成

目的合成依折麦布原料药中的2种主要杂质。方法依折麦布(1)经氯代铬酸吡啶盐(PCC)氧化制得杂质Ⅰ;以依折麦布中间体1-(4-氟苯基)-3(R)-[3-(4-氟苯基)-羟丙基]-4(S)-[4-(4-苄氧基)-苯基]-氮杂环丁烷-2-酮(2)为原料经催化氢化反应制得杂质Ⅱ。结果所得2种杂质结构经1H-NMR、13C-NMR和ESI-MS确证,纯度经HPLC检测可达98%以上。结论解决了依折麦布杂质的来源问题,为依折麦布的质量控制提供了依据。     

新型调脂药物依折麦布的临床应用

本刊从2003年起开辟继续教育园地栏目,以专家论坛及问答的形式对一些医药知识进行介绍,旨在提高医师、药师、护师们的合理用药水平,更好地服务于病人。每期有问答题,请读者裁下本期问答题（复印无效）,连同本人的答案于2014年12月25日前寄回本杂志社,地址：上海市杨浦区长海路168号,邮编200433。回答正确者由上海市药学会颁发继续医学教育Ⅱ类学分。2013年第6期的学分将与2014年第1～5期的学分一起统计。请将学分证工本费5元（无发票）寄到本杂志社,若要求以挂号信邮寄学分证,需寄8元。另外,经申请并获同意,参加本刊全年（共6期）继续教育园地答题的读者,可获得上海市继续医学教育委员会办公室盖章的继续医学教育学分（Ⅱ类）5分,工本费15元（无发票）。如需此类学分的读者请在答题时注明。     

依折麦布联合辛伐他汀治疗高脂血症的临床疗效分析

目的探讨依折麦布联合辛伐他汀治疗高脂血症的临床疗效。方法选取我院2009年10月至2011年10月收治148例高脂血症的患者,随机分为观察组和对照组各74例,观察组使用依折麦布联合辛伐他汀治疗,对照组单纯使用辛伐他汀治疗,比较两组在治疗后1个月内血浆中的低密度脂蛋白胆固醇(LDL-C)与总胆固醇(TC)的变化情况。结果观察组在治疗后1个月内血浆中的LDL-C与TC均低于对照组,P<0.05,具有统计学意义。结论依折麦布联合辛伐他汀治疗高脂血症的临床疗效显著,值得临床推广应用。     

新型血脂调节药——依折麦布

依折麦布是一种具有新型作用机制的调血脂药,能选择性抑制肠道对食物中固醇(胆固醇和植物固醇)以及胆汁中胆固醇的吸收。该药通过肝肠循环可较长时间维持其药理作用,特殊的代谢途径使得它与许多药物间有临床意义的相互作用较少。可空腹或与食物同服,一般无需调整剂量。本品单用或与其他调血脂药联用为常见及难治的血脂异常疾病提供了新的补充疗法,且普遍耐受良好。     

Pharmacodynamic interaction between ezetimibe and rosuvastatin

SUMMARY

Background: Ezetimibe is a lipid-lowering drug indicated for the treatment of hypercholesterolemia as co-administration with HMG-CoA reductase inhibitors (statins) or as monotherapy. The primary objectives of this study were to evaluate the pharmacodynamic effects and safety of the co-administration of ezetimibe and the new statin rosuvastatin. A secondary objective was to examine the potential for a pharmacokinetic interaction between ezetimibe and rosuvastatin.

Methods: This was a randomized, evaluator (single)-blind, placebo-controlled, parallel-group study in healthy hypercholesterolemic subjects (untreated low-density lipoprotein cholesterol [LDL-C] ≥ 130?mg/dL [3.37?mmol/L]). After the outpatient screening and NCEP Step I diet stabilization periods, 40 subjects were randomized to one of the 4 following treatments: rosuvastatin 10?mg plus ezetimibe 10?mg (n = 12); rosuvastatin 10?mg plus placebo (matching ezetimibe 10?mg) (n = 12); ezetimibe 10?mg plus placebo (matching ezetimibe 10?mg) (n = 8); or placebo (2 tablets, matching ezetimibe 10?mg) (n = 8). All study treatments were administered once daily in the morning for 14 days as part of a 16-day inpatient confinement period. Fasting serum lipids were assessed pre-dose on days 1 (baseline), 7, and 14 by direct quantitative assay methods. Safety was evaluated by monitoring laboratory tests and recording adverse events. Blood samples were collected for ezetimibe and rosuvastatin pharmacokinetic evaluation prior to the first and last dose and at frequent intervals after the last dose (day 14) of study treatment. Plasma ezetimibe, total ezetimibe (ezetimibe plus ezetimibe-glucuronide) and rosuvastatin concentrations were determined by validated liquid chromatography with tandem mass spectrometric detection (LC–MS/MS) assay methods.

Results: All active treatments caused statistically significant (?p ≤ 0.02) decreases in LDL-C concentration versus placebo from baseline to day 14. The co-administration of ezetimibe and rosuvastatin caused a significantly (?p < 0.01) greater reduction in LDL-C and total cholesterol than either drug alone. In this 2-week inpatient study with restricted physical activity there was no apparent effect of any treatment on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The co-administration of ezetimibe and rosuvastatin caused a significantly (?p < 0.01) greater percentage reduction in mean LDL-C (–61.4%) than rosuvastatin alone (–44.9%), with a mean incremental reduction of –16.4% (95%CI –26.3 to –6.53). Reported side effects were generally mild, nonspecific, and similar among treatment groups. There were no significant increases or changes in clinical laboratory tests, particularly those assessing muscle and liver function. There was no significant pharmacokinetic drug interaction between ezetimibe and rosuvastatin.

Conclusions: Co-administration of ezetimibe 10?mg with rosuvastatin 10?mg daily caused a significant incremental reduction in LDL-C compared with rosuvastatin alone. Moreover, co-administering ezetimibe and rosuvastatin was well tolerated in patients with hypercholesterolemia.     

Pharmacodynamic interaction between the new selective cholesterol absorption inhibitor ezetimibe and simvastatin

AIMS: The primary aims of these two single-centre, randomized, evaluator-blind, placebo/positive-controlled, parallel-group studies were to evaluate the potential for pharmacodynamic and pharmacokinetic interaction between ezetimibe 0.25, 1, or 10 mg and simvastatin 10 mg (Study 1), and a pharmacodynamic interaction between ezetimibe 10 mg and simvastatin 20 mg (Study 2). Evaluation of the tolerance of the coadministration of ezetimibe and simvastatin was a secondary objective. METHODS: Eighty-two healthy men with low-density lipoprotein cholesterol (LDL-C) >or=130 mg dl-1 received study drug once daily in the morning for 14 days. In Study 1 (n=58), five groups of 11-12 subjects received simvastatin 10 mg alone, or with ezetimibe 0.25, 1, or 10 mg or placebo. In Study 2 (n=24), three groups of eight subjects received simvastatin 20 mg alone, ezetimibe 10 mg alone, or the combination. Blood samples were collected to measure serum lipids in both studies. Steady-state pharmacokinetics of simvastatin and its beta-hydroxy metabolite were evaluated in Study 1 only. RESULTS: In both studies, reported side-effects were generally mild, nonspecific, and similar among treatment groups. In Study 1, there were no indications of pharmacokinetic interactions between simvastatin and ezetimibe. All active treatments caused statistically significant (P<0.01) decreases in LDL-C concentration vs placebo from baseline to day 14. The coadministration of ezetimibe and simvastatin caused a dose-dependent reduction in LDL-C and total cholesterol, with no apparent effect on high-density lipoprotein cholesterol (HDL-C) or triglycerides. The coadministration of ezetimibe 10 mg and simvastatin 10 mg or 20 mg caused a statistically (P<0.01) greater percentage reduction (mean -17%, 95% CI -27.7, -6.2, and -18%, -28.4, -7.4, respectively) in LDL-C than simvastatin alone. CONCLUSIONS: The coadministration of ezetimibe at doses up to 10 mg with simvastatin 10 or 20 mg daily was well tolerated and caused a significant additive reduction in LDL-C compared with simvastatin alone. Additional clinical studies to assess the efficacy and safety of coadministration of ezetimibe and simvastatin are warranted.     

Clinical experience with ezetimibe/simvastatin in a Mediterranean population

ABSTRACT

Objectives: This study aimed to describe the clinical experience of the ezetimibe (EZE)/simvastatin (SIMVA) combination in a hypercholesterolaemic Greek population who did not attain the cholesterol goals on statin treatment alone.

Methods: Patients already treated with a statin, at any dose, for at least 8 weeks, with LDL-C levels above the goal, (>100, >130 or >160?mg/dl according to their risk category), where the physician chose EZE/SIMVA as appropriate treatment, entered the study. Medical history, demographics and laboratory values were recorded at baseline and 2 months later.

Results: The study included 1514 patients (male 53.4%) of mean age 60.1?±?10.5 years. Diabetes mellitus was reported in 29.9% of the patients, 61.2% had hypertension, 39% were obese, 10.5% had a history of myocardial infarction and 6.8% had a history of stroke or peripheral arterial disease. Current and ex-smoking was reported in 46.8%. Atorvastatin (33%) and SIMVA (27.2%) were the most frequently used statins prior to using the EZE/SIMVA regimen. After 2 months of EZE/SIMVA therapy mean LDL-C was reduced by 33%, mean total cholesterol by 26%, mean triglycerides by 15%, while HDL-C was increased by 10%. The percentage of patients who achieved the LDL-C goal with EZE/SIMVA was 73.8%. One serious adverse event, not related to study treatment and 23 adverse events in total were recorded. There was a significant decrease in serum creatinine levels in patients with baseline values greater than 1.0?mg/dl (88?μmol/L).

Conclusions: Treatment with the EZE/SIMVA combination appears an effective and safe therapeutic option for patients who do not achieve the LDL-C goals on statin therapy alone.     

Dual cholesterol inhibition with ezetimibe/simvastatin in pre-treated hypercholesterolaemic patients with coronary heart disease or diabetes mellitus: prospective observational cohort studies in clinical practice

ABSTRACT

Objective: Patients with primary hypercholesterolaemia and concomitant coronary heart disease (CHD) and/or diabetes mellitus (DM), who are at particularly high risk of cardiovascular events such as stroke or myocardial infarction, benefit from aggressive lipid lowering strategies. The present studies investigated the incremental efficacy and safety of dual cholesterol inhibition with ezetimibe/simvastatin in such high-risk patients pre-treated with statins but not reaching the 100?mg/dL (2.6?mmol/L) low density cholesterol (LDL?C) cholesterol threshold in the primary care setting.

Methods: Two open-label, prospective, non-random­ised, observational studies (study 1 with n = 19?194 patients, predominantly with CHD; study 2 with n = 19?484 patients, predominantly with DM). Patients received – almost all after statin pre-treatment – ezetimibe 10?mg plus simvastatin 10?mg (study 1: 15%, study 2: 16%), 20?mg (in 68% each), 40?mg (12%/10%) or 80?mg (1%/1%) as fixed dose combinations over 3 months (dosage at investigator's discretion).

Results: Mean LDL-C was reduced by 28%/27% (study 1/ study 2) compared with baseline values (on statin monotherapy). Mean total cholesterol was decreased by 22% in each study, mean triglycerides by 16/17%, and mean high density cholesterol (HDL?C) was increased by 9/10%. Adverse events were reported in 0.3% and 0.2% of patients, respectively.

Conclusion: Dual cholesterol inhibition with ezetimibe/simvastatin was effective and well tolerated under real practice conditions in high-risk patients with CHD and/or DM.     

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.     

Reaching goal in hypercholesterolaemia: dual inhibition of cholesterol synthesis and absorption with simvastatin plus ezetimibe

ABSTRACT

Lowering serum cholesterol levels reduces the risk of coronary heart disease (CHD)-related events. Statins are commonly prescribed as first-line treatment but many patients at high-risk for CHD still fail to reach their cholesterol or low-density lipoprotein cholesterol (LDL-C) goals with statin monotherapy.

National and international guidelines for the prevention of CHD recommend the modification of lipid profiles and particularly LDL‐C [e.g. the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III; 2001) and Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (2003) Guidelines]. Several recent clinical trials indicated an added benefit from aggressive lowering of LDL‐C levels. Based on these findings, the NCEP ATP III revised the LDL‐C target from < 100?mg/dL (2.6?mmol/L) to < 70?mg/dL (1.8?mmol/L) (optional target) for very high-risk patients and < 130?mg/dL (3.4?mmol/L) to < 100?mg/dL (2.6?mmol/L) for moderately high-risk patients.

For patients who fail to achieve their LDL‐C target, inhibiting the two main sources of cholesterol – synthesis and uptake – can produce more effective lipid lowering, allowing more patients to reach their LDL‐C goal. Ezetimibe is a highly-selective inhibitor of cholesterol absorption and simvastatin is an evidence-based inhibitor of cholesterol synthesis. The LDL‐C-lowering efficacy of targeting both major sources of cholesterol with ezetimibe plus simvastatin was demonstrated in several multicentre, double-blind, placebo-controlled trials in patients with hypercholesterolaemia. For patients who do not reach their cholesterol goal with a statin, adding ezetimibe 10?mg significantly reduces LDL‐C compared with statin monotherapy. Thus, this treatment option may help patients reach the new ‘stricter’ cholesterol goals.

This review, based on a Medline database search from January 2000 to August 2005, considers the LDL‐C-lowering efficacy of ezetimibe and discusses the role of this agent for patients who fail to achieve guideline cholesterol goals with statin monotherapy.     

新型胆固醇吸收抑制剂Ezetimibe的研究进展

Ezetimibe是一种新型选择性肠胆固醇吸收抑制剂，通过抑制肠上皮细胞的胆固醇吸收蛋白NPC1L1减少胆固醇、植物固醇的吸收以及胆汁胆固醇的再吸收，从而降低血浆固醇水平。Ezetimibe的作用与他汀类药物抑制胆固醇合成的机制互补，在降低血浆低密度脂蛋白胆固醇和总胆固醇水平的同时，升高高密度脂蛋白胆固醇水平，为高胆固醇血症的治疗、动脉粥样硬化和冠心病的防治提供了一种新的有效选择。     

Long-term safety and tolerability of ezetimibe coadministered with simvastatin in hypercholesterolemic patients: a randomized, 12-month double-blind extension study

ABSTRACT

Objectives: To assess the long-term safety and tolerability and to further evaluate the effect of ezetimibe plus simvastatin on LDL-C, HDL-C, and triglyceride levels in subjects with primary hypercholesterolemia.

Methods: This was a 12-month, double-blind, placebo-controlled extension study that enrolled patients with primary hypercholesterolemia who had successfully completed the 12-week, double-blind, placebo-controlled trial of ezetimibe coadministered with simvastatin. The initial dose administered to patients in the extension was ezetimibe 10 mg coadministered with simvastatin 10 mg with the option to up-titrate statin dosage if LDL-C goals were not met. Safety and tolerability were assessed through clinical and laboratory adverse experiences (AEs). Changes from baseline in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglyceride levels were measured.

Results: Overall, 87 patients were randomized to receive ezetimibe + simvastatin and 22 were randomized to receive simvastatin and placebo. Treatment-emergent AEs were reported for 72/87 (83%) ezetimibe + simvastatin-treated patients and for 17/22 (77%) simvastatin-treated patients. The most commonly reported AEs in the simvastatin treatment group were hypertension, gastro-esophageal reflux, and musculoskeletal pain (each reported by 3/22 [14%] patients); and in the ezetimibe + simvastatin group were upper respiratory tract infection (16/87 [18%]), arthralgia and musculoskeletal pain (both reported by 10/87 [11%] patients). Drug-related AEs were reported for 3/22 (14%) simvastatin-treated patients and 21/87 (24%) patients in the coadministration group. AEs considered serious by the investigator were reported by 2/22 (9%) patients taking simvastatin monotherapy and by 20/87 (23%) patients taking ezetimibe + simvastatin. Discontinuations due to AEs occurred in no patients taking simvastatin monotherapy and in 7/87 (8%) patients taking ezetimibe + simvastatin. Percent change ± standard deviation from baseline in LDL-C was ?29% ± 15.4 and ?44% ± 14.2 in subjects taking simvastatin monotherapy and ezetimibe + simvastatin, respectively.

Conclusions: Ezetimibe coadministered with simvastatin was generally well-tolerated and no new safety concerns were raised. Both treatments effectively maintained improvements in lipid parameters throughout the course of the studies. Interpretation of these results was limited by the small convenience sample included in the trial.