辛伐他汀联合依折麦布对2型糖尿病合并动脉粥样硬化大鼠糖脂及VEGF、IL-1β、CRP水平的影响

目的 探讨辛伐他汀联合依折麦布对2型糖尿病合并动脉粥样硬化大鼠糖脂及血管内皮生长因子（vascular endothelial growth factor,VEGF）、白介素-1β（interleukin-1β,IL-1β）、C反应蛋白（C reactive protein,CRP）水平的影响。方法 选取42只SD大鼠,♂,选取8只给予普通饲料作对照组,另34只复制2型糖尿病合并动脉粥样硬化模型,确定造模成功（处死2只）后,随机分为4组：模型组8只给予高脂饲料,辛伐他汀组8只给予高脂饮食+辛伐他汀,依折麦布组8只给予高脂饮食+依折麦布,联合组8只给予高脂饮食+辛伐他汀+依折麦布。于分组完毕后继续喂养12周测定体质量、空腹血糖（fasting blood glucose,FPG）、空腹胰岛素（fasting insulin,FINS）、胰岛素抵抗（insulin resistance,HOMA-IR）,血脂及VEGF、IL-1β、CRP水平。结果 5组大鼠在治疗12周时体质量、FPG、FINS、HOMA-IR,血脂及VEGF、IL-1β、CRP水平均存在变化。在体质量和FPG上,模型组、辛伐他汀组、依折麦布组、联合组、对照组依次降低;在FINS上,对照组、联合组、依折麦布组和辛伐他汀组、模型组依次降低;在HOMA-IR上,联合组、依折麦布组、辛伐他汀组、模型组高于对照组;在甘油三酯（triglyceride,TG）、总胆固醇（total cholesterol,TC）、低密度脂蛋白胆固醇（low density lipoprotein cholesterol,LDL-C）上,模型组、辛伐他汀组和依折麦布组、联合组、对照组依次降低;在HDL-C上,对照组、联合组、依哲麦布组和辛伐他汀组、模型组依次降低;在VEGF、IL-1β及CRP水平上,模型组、辛伐他汀组和依折麦布组、联合组、对照组依次降低。结论 辛伐他汀联合依折麦布可以调节血脂紊乱,下调VEGF和致炎因子IL-1β、CRP水平。     

Update on patented cholesterol absorption inhibitors

Background: Atherosclerosis is one of the most life-threatening diseases primarily associated with hypercholesterolemia and is characterized by increased serum cholesterol level. Cholesterol originates from both its de novo synthesis within the hepatic cells and its absorption into the intestine in the form of dietary or bile cholesterol. Interventions influencing both of these processes are promising therapeutic options to lower the cholesterol level. Hydroxymethyl glutaryl-CoA reductase inhibitors, commonly known as statins, effectively block the rate determining step in the biosynthesis of cholesterol. Ezetimibe is the first new class of drugs used to treat hypercholesterolemia by inhibition of cholesterol absorption through Niemann Pick C1 Like 1 membrane of enterocytes. Therefore, combination therapy of ezetimibe and statins offers an efficacious new approach for the prevention and treatment of hypercholesterolemia. Objectives: The present review focuses on updates on ezetimibe and patented profile of novel cholesterol absorption inhibitors followed by critical analysis of different targets such as cholesterol esterase inhibitors, bile acid transport inhibitors or phospholipase-A₂ inhibitors, etc.which play an important role in the lipid absorption. Conclusion: The discovery of ezetimibe has opened a new door for the management of hyper-cholesterolemia in combination with statins. There are newer analogues that are under clinical trials, among which darapladib, FM-VP4 and A-002 are promising compounds.     

Evaluating the efficacy and safety of atorvastatin + ezetimibe in a fixed-dose combination for the treatment of hypercholesterolemia

Introduction: Cardiovascular disease is a major cause of morbidity and mortality throughout the world and hypercholesterolemia is one of the key risk factors. Statins are the first line treatment to reduce atherogenic lipids and there is substantial and robust evidence with atorvastatin for reduction of cardiovascular events and mortality. Ezetimibe can be combined with any dose of atorvastatin for incremental lipid-lowering effects.

Areas covered: In this review, the authors summarize the pharmacokinetics, pharmacodynamics and clinical efficacy of the components and the combination of ezetimibe and atorvastatin. Clinical benefits have been seen with ezetimibe combined with simvastatin but studies of its combination with atorvastatin are generally limited to the effects on lipid parameters where the addition of ezetimibe to atorvastatin is generally more effective than titrating the atorvastatin dose.

Expert opinion: Although there are no cardiovascular outcomes studies with the combination of ezetimibe and atorvastatin, the greater reduction in atherogenic lipids can be assumed to have greater benefits in reducing cardiovascular events. The ezetimibe–atorvastatin combination is very effective in this respect and well tolerated. Fixed-dose combinations improve medication adherence and this combination should be useful for patients who cannot reach their lipid targets with maximally tolerated statin doses.     

Ezetimibe treatment in hypercholesterolemic kidney transplant patients is safe and effective and reduces the decline of renal allograft function: a pilot study.

BACKGROUND: Ezetimibe has shown efficacy in the therapy of hypercholesterolemia in renal transplant patients. This is the first study investigating the effect of ezetimibe on renal function in kidney transplant recipients. METHODS: Fifty-six patients with statin-resistant hypercholesterolemia (total cholesterol >200 mg/dl) after renal transplantation received additional ezetimibe therapy (10 mg/day) for 12 months. A group receiving statin therapy (n=28) served as controls in this prospective study. RESULTS: Total cholesterol and LDL cholesterol concentrations decreased significantly in the ezetimibe-treated patients but remained stable in the control group (delta total cholesterol: -24+/-49 mg/dl vs 19+/-49 mg/dl, P<0.01; delta LDL: -30+/-39 mg/dl vs -3+/-31 mg/dl, P<0.01). Mean creatinine clearance remained stable in ezetimibe-treated patients but decreased significantly in control group (delta Cockcroft-Gault: 0.9+/-7.3 ml/min vs - 4.8+/-12.8 ml/min, P=0.025; delta Modification of Diet in Renal Disease: -0.4+/-6.2 ml/min/1.73 m(2) vs 4.7+/-8.8 ml/min/1.73 m(2), P=0.033). CONCLUSIONS: The data of our prospective case-control study suggest that ezetimibe appears to ameliorate the decline of renal function after renal transplantation.     

Sitosterol xanthomatosis

BACKGROUND: Sitosterolaemia is a lipid disorder in which plasma plant sterol levels are extremely elevated. Sitosterolaemia is clinically characterized by tuberous and tendon xanthomas, premature vascular disease and arthritis. OBJECTIVE: To report a case of sitosterolaemia diagnosed by cutaneous manifestations and to review this rare disease. METHODS: We report the case of a 60-year-old woman who presented with cutaneous xanthomas, arterial hypertension and polyarthralgias. The patient had had hypercholesterolaemia for many years without reduction of serum cholesterol, despite treatment with fenofibrate. RESULTS: Ezetimibe therapy was started, decreasing sitosterol plasmatic levels and tuberous xanthomas after 3 months of treatment. CONCLUSION: It is important to detect levels of sitosterol in plasma in patients with premature vascular disease, presence of xanthomas, and uncontrolled hypercholesterolaemia. Ezetimibe therapy is effective.     

On the population pharmacokinetics and the enterohepatic recirculation of total ezetimibe

1. Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC).

2. The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modeling, where different EHC models were developed and evaluated for their performance.

3. Total ezetimibe pharmacokinetics was best described by a four-compartment model featuring EHC through the inclusion of an additional gallbladder compartment, which was assumed to release drug at specific time-intervals consistent with food intake.

4. The final PK model was able to adequately estimate the population pharmacokinetic parameters and to allow for a formal characterization of the pharmacokinetic profile and the secondary peaks due to enterohepatic recirculation.

     

Ezetimibe,cardiovascular risk and atherogenic dyslipidaemia

Ezetimibe is a selective cholesterol absorption inhibitor with an excellent side-effect profile, able to reduce low-density lipoprotein (LDL) cholesterol by 15-25% from baseline in monotherapy and on top of statins and fibrates. Yet, it seems that ezetimibe produces quantitative rather than qualitative changes in LDL, with small net effects on atherogenic dyslipidaemia. This is supported by findings from the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) study on atherosclerosis progression, where the addition of ezetimibe to simvastatin in patients with heterozygous familial hypercholesterolaemia did not affect the mean change in carotid intima-media thickness, although a significant reduction in LDL cholesterol levels was observed. The Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study has further shown that combination treatment with simvastatin significantly reduced LDL cholesterol levels in patients with aortic stenosis, but did not affect the primary end point of aortic valve and cardiovascular events, although a significant reduction in the risk of ischaemic events was reported. Formal cardiovascular outcome trials are underway and these will provide additional insights into the long-term effects of ezetimibe on clinical events as well as on atherogenic dyslipidaemia, beyond LDL cholesterol levels.