EZETROL - פרסומים עיקריים

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	LDL-C
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מאמרים המפורסמים באתר זה, או שמקושרים אל ומאתר זה, שייכים לצד שלישי ומוגנים בזכויות יוצרים. משתמשים מורשים רשאים להוריד מהאתר, להציג, לצפות ולהדפיס עותק בודד מהם לשימושם האישי למטרות מחקר ולימוד עצמי. כל שימוש אחר הוא אסור, אלא אם כן הושג אישור מבעל הזכויות. משתמשים מורשים אינם רשאים להסיר, לשנות, או להתאים כל חלק מהמאמרים, ובכלל זה את שמות המחברים ואת הודעות זכויות היוצרים

מוזכרים למטה פרסומי מפתח בנוגע ל ezetimibe המספקים אינפורמציה תומכת על טווח רחב של נושאים, הכוללים בין היתר פרופיל יעילות ובטיחות, מתן משולב עם סטטינים ומנגנון פעולה. רשימה זו אינה הביבליוגרפיה המלאה של ezetimibe. פרסומים נוספים בנוגע ל ezetimibe ניתן למצוא בספריה הלאומית של (National Library of Medicine's Pub Med) Pub Med

באתר http://www.ncbi.nlm.nih.gov/entrez/query.fcgi

Quick Links to Topic Areas
Primary Study Results, Cholesterol Absorption, Preclinical, Cholesterol Management

תוצאות מחקרים ראשוניים

Dose-comparison study of the combination ofezetimibe and simvastatin (Vytorin) versusatorvastatin in patients with hypercholesterolemia:The Vytorin Versus Atorvastatin (VYVA) Study Christie M. Ballantyne, MD,a Nicola Abate, MD,b Zhong Yuan, MD, PhD,c Thomas R. King, MPH,c and Background Low-density lipoprotein cholesterol (LDL-C) is the primary therapeutic target in the National Cholesterol Education Program Adult Treatment Panel III (ATP III) guidelines. This study tested the hypothesis that ezetimibe/simvastatin, a lipid-lowering agent that inhibits both intestinal cholesterol absorption and cholesterol synthesis, provides greater LDL-C reductions than atorvastatin across dose ranges. Methods This multicenter, double-blind, 6-week parallel-group study randomized 1902 patients with LDL-C above ATP III goal to atorvastatin (10, 20, 40, or 80 mg) or to ezetimibe/simvastatin (10/10, 10/20, 10/40, or 10/80 mg). Patients were stratified by prerandomization LDL-C level. Results At each milligram-equivalent statin dose comparison, and averaged across doses, ezetimibe/simvastatin provided greater LDL-C reductions (47%-59%) than atorvastatin (36%-53%). Ezetimibe/simvastatin 10/40 and 10/80 mg also provided significantly greater high-density lipoprotein cholesterol (HDL-C) increases than atorvastatin 40 and 80 mg. Triglyceride reductions were similar for all comparisons. More ezetimibe/simvastatin than atorvastatin patients with coronary heart disease (CHD) or CHD risk equivalents attained the ATP III LDL-C goal of b100 mg/dL and the optional LDL-C target of b70 mg/dL. C-reactive protein reductions were similar between treatment groups. Consecutive elevations in alanine aminotransferase and/or aspartate aminotransferase occurred in significantly more atorvastatin patients than ezetimibe/ simvastatin patients. No myopathy or liver-related adverse events led to study discontinuation with either drug. Conclusions Ezetimibe/simvastatin was more effective than atorvastatin in lowering LDL-C at each dose comparison and provided greater increases in HDL-C at the 40- and 80-mg statin dose. Ezetimibe/simvastatin is a highly efficacious, well-tolerated treatment option for hypercholesterolemic patients. (Am Heart J 2005;149:464-73.)

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Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: A prospective, randomized, double-blind study Ballantyne et al Circulation 2003;107:2409–2415. This randomized double-blind trial included 628 patients with primary hypercholesterolemia (low-density lipoprotein cholesterol [LDL C]=145–250 mg/dL and triglycerides [TG] ≤350 mg/dL) who received 12 weeks of treatment with ezetimibe (10 mg/day), atorvastatin (10, 20, 40, or 80 mg/day), ezetimibe coadministered with each atorvastatin dose, or placebo. Coadministration of ezetimibe with atorvastatin was significantly superior to atorvastatin alone in lowering calculated LDL C at each dose of atorvastatin (53% vs. 37%, 54% vs. 42%, 56% vs. 45%, and 61% vs. 54% for atorvastatin 10 mg, 20 mg, 40 mg, and 80 mg, respectively; all p<0.01). Ezetimibe coadministered with atorvastatin (pooled across doses) was also significantly superior to atorvastatin monotherapy in lowering total cholesterol (TC) and TG and in raising HDL C (all p<0.01). Ezetimibe coadministered with atorvastatin was well tolerated, with a safety profile similar to atorvastatin alone.

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Long-term safety and tolerability profile of ezetimibe and atorvastatin coadministration therapy in patients with primary hypercholesterolemia Ballantyne et al Int J Clin Pract 2004;58:653–658. In this study, 576 patients were randomized to receive EZETROL 10 mg, atorvastatin 10, 20, 40, or 80 mg, EZETROL 10 mg plus atorvastatin 10, 20, 40, or 80 mg, or placebo for 12 weeks. Of these patients, 246 were randomized to receive EZETROL 10 mg plus atorvastatin 10, 20, 40, or 80 mg (n = 201) or atorvastatin 10, 20, 40, or 80 mg (n = 45) for a one-year extension. Patients not at LDL-C goal at six-week intervals were titrated up to the next dose of atorvastatin. At six weeks, EZETROL 10 mg plus atorvastatin 10 mg demonstrated greater reductions in LDL-C, total cholesterol, and triglycerides and greater increases in HDL-C than atorvastatin 10 mg. These differences were maintained at one year. More patients on EZETROL together with atorvastatin achieved LDL-C target goals than did those on atorvastatin monotherapy. Adverse event profiles were similar in both groups. This paper demonstrates that, in patients with hypercholesterolemia, EZETROL together with atorvastatin provides greater LDL-C reduction and greater increase in HDL-C than atorvastatin monotherapy.

Ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia Davidson et al J Am Coll Cardiol 2002;40:2125–2134. This randomized double-blind trial included 668 patients with primary hypercholesterolemia (LDL C=145–250 mg/dL and TG ≤350 mg/dL) who received 12 weeks of treatment with ezetimibe (10 mg/day), simvastatin (10, 20, 40, or 80 mg/day), ezetimibe coadministered with each simvastatin dose, or placebo. Coadministration of ezetimibe plus simvastatin was significantly superior to simvastatin alone in lowering direct LDL C at each dose of simvastatin (44% vs. 27%, 45% vs. 36%, 53% vs. 36%, and 57% vs. 44% for simvastatin 10 mg, 20 mg, 40 mg, and 80 mg, respectively; all p<0.01). Ezetimibe plus simvastatin (pooled across doses) was also significantly superior to simvastatin monotherapy in lowering TC and TG (both p<0.01) and in raising HDL C (p=0.03). Coadministration of ezetimibe with simvastatin was well tolerated, with a safety profile similar to simvastatin alone.

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Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia Gagne et al Am J Cardiol 2002;90:1084–1091. This randomized, double-blind, placebo-controlled study assessed the efficacy and safety profile of coadministering ezetimibe 10 mg or placebo with ongoing statin therapy for 8 weeks in patients with primary hypercholesterolemia. Randomized patients (n=769) had been on a stable dose of statin monotherapy for >6 weeks and had not achieved NCEP ATP II goals for LDL C with dietary alteration. Coadministration of ezetimibe with the statin incrementally decreased LDL C by 25%, TG by 14%, and TC by 17% (all p<0.001 vs. placebo). Ezetimibe also increased HDL C by 2.7% (p<0.05 vs. placebo). A significantly higher percentage of patients receiving ezetimibe achieved LDL-C goal than those receiving placebo (71.5% vs. 18.9%, p<0.001). The coadministration of ezetimibe with statin was well tolerated.

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Efficacy and safety of ezetimibe coadministered with pravastatin in patients with primary hypercholesterolemia: A prospective, randomized, double-blind trial. Melani et al Eur Heart J 2003;24:717–728. This randomized double-blind trial included 538 patients with primary hypercholesterolemia (LDL C ≥3.8 and ≤6.5 mmol/L and TG ≤4.0 mmol/L) who received 12 weeks of treatment with ezetimibe (10 mg/day), pravastatin (10, 20, or 40 mg/day), ezetimibe coadministered with each pravastatin dose, or placebo. Coadministration of ezetimibe with pravastatin was significantly superior to pravastatin monotherapy in lowering direct LDL C at each dose of pravastatin (34% vs. 20%, 38% vs. 24%, and 41% vs. 29% for pravastatin 10 mg, 20 mg, and 40 mg, respectively; all p<0.01). Ezetimibe coadministered with pravastatin (pooled across doses) was also significantly superior to pravastatin monotherapy in lowering TC and TG (both p<0.01). Ezetimibe coadministered with pravastatin was well tolerated, with a safety profile similar to pravastatin alone.

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Effect of Coadministration of Ezetimibe and Simvastatin on High-Sensitivity C-Reactive Protein Sager et al Am J Cardiol 2003;92:1414–1418. In this multicenter, randomized, double-blind trial, 668 patients with LDL-C between 145 and 250 mg/dl and triglycerides <350 mg/dl were randomized to one of the following four treatment groups for 12 weeks: monotherapy with ezetimibe 10 mg; monotherapy with simvastatin 10, 20, 40, or 80 mg; ezetimibe 10 mg plus simvastatin 10, 20, 40, or 80 mg; or placebo. The investigators found that ezetimibe plus simvastatin was almost twice as effective at lowering high-sensitivity C-reactive protein (hs-CRP) than simvastatin alone (34.8% versus 18.2%, respectively [pooled analysis]). The study also demonstrated that ezetimibe plus simvastatin was more effective at lowering LDL-C than simvastatin alone at the corresponding doses (51% versus 37%, respectively [pooled analysis]). Interestingly, the reduction in hs-CRP could not be fully explained by the observed incremental LDL-C decreases with the coadministration of ezetimibe and simvastatin. Thus, the incremental decreases in hs-CRP may be the result of an additional anti-inflammatory effect from dual inhibition of both cholesterol absorption and synthesis with ezetimibe together with simvastatin compared with simvastatin alone.

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ספיגת כולסטרול

Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption Altmann et al Science 2004;303:1201–1204. In this paper, the investigators from Schering-Plough Research Institute describe the important scientific discovery of the mechanism of action of cholesterol absorption. They demonstrated that the expression of the gene NPC1L1 is a critical component of the cholesterol absorption pathway. The NPC1L1 protein is specifically located on the brush border membranes of jejunal enterocytes, the site of cholesterol absorption and ezetimibe activity. NPC1L1-deficient mice absorb 70% less cholesterol than normal mice. Administration of ezetimibe to normal mice reduces cholesterol absorption to a similar degree as in NPC1L1-deficient mice. These findings suggest that ezetimibe interacts with NPC1L1 to reduce cholesterol absorption.

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Inhibition of intestinal cholesterol absorption by ezetimibe in humans Sudhop et al Circulation 2002 Oct 8;106(15):1943–8. This randomized, double-blind, placebo-controlled, crossover trial included 18 patients with mild to moderate hypercholesterolemia who received either ezetimibe (10 mg/day) or placebo for 2 weeks and, following a 2-week washout period, were crossed over to the alternative treatment for 2 weeks. Ezetimibe decreased the fractional cholesterol absorption rate by 54% vs. placebo (p<0.001). Ezetimibe reduced LDL C and TC from baseline values by 20.4% and 15.1%, respectively (both p<0.001). This study confirmed, for the first time in humans, that ezetimibe significantly inhibits cholesterol absorption.

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Ezetimibe: A selective inhibitor of cholesterol absorption Catapano Eur Heart 2001 3(Suppl E):E6–E10. Ezetimibe is the first in a new class of lipid-lowering compounds that selectively inhibits the intestinal absorption of cholesterol. Ezetimibe, with its unique mechanism of action, localizes at the brush border of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in the delivery of intestinal cholesterol to the liver. Ezetimibe has no effect on the absorption of TG, fatty acids, bile acids, or fat soluble vitamins (A, D, E, and K) and has been shown to reduce LDL C levels in animals fed a high-cholesterol diet. Coadministration of ezetimibe with a statin may have a synergistic cholesterol-lowering effect.

Selective cholesterol absorption inhibition: A novel strategy in lipid-lowering management Leitersdorf Int J of Clin Pract 2002 56(2):116–119. There are set goals for lipid levels, but many patients do not achieve them because of ineffective treatment strategies. The efficacy of monotherapy with statins is limited because of failure to titrate the drugs to effective doses and the risk for clinically significant adverse events (e.g., hepatotoxicity and myalgia) with the highest statin doses. Coadministration of ezetimibe with a statin provides greater LDL-C reduction without affecting liver function tests. Coadministration of a selective cholesterol absorption inhibitor with a statin may prove to be an effective strategy for helping more patients achieve their LDL C goals.

מחקרים פרה-קליניים

Pharmacology of ezetimibe Van Heek et al Eur Heart J 2002 ;+4(Suppl J):J5–J8. Ezetimibe blocks intestinal absorption of dietary and biliary cholesterol and does not interfere with absorption of TG, steroid hormones, or fat soluble vitamins. Ezetimibe monotherapy substantially reduces TC and LDL C in hamsters and monkeys fed high-cholesterol diets and also decreases cholesterol in chylomicrons and chylomicron remnants. Coadministration of ezetimibe with a statin to chow-fed dogs resulted in an additive or synergistic effect in lowering plasma cholesterol, and results from apoE knockout mice showed that administration of ezetimibe significantly reduced TC and LDL C as well as the size of aortic atherosclerotic lesions. These preclinical results, along with findings from clinical trials, support the use of ezetimibe in humans with hypercholesterolemia.

Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice Davis et al Arterioscler Thromb Vasc Biol 2001;21:2032–2038. This study determined whether ezetimibe reduces plasma cholesterol and inhibits atherogenesis in highly susceptible apoE knockout mice fed a high-fat western diet, a low-fat diet, or a semisynthetic cholesterol-free diet with or without ezetimibe for 6 months. Ezetimibe decreased plasma cholesterol levels from 964 to 374 mg/dl, from 726 to 231 mg/dl, and from 516 to 178 mg/dl in the western, low-fat, and cholesterol-free diet groups, respectively. Ezetimibe also reduced aortic atherosclerotic lesion surface areas from 20.2% to 4.1% in the mice fed the western diet and from 24.1% to 7.0% in those administered the low-fat diet. It also decreased carotid lesion cross-sectional areas by 97% in the western and low-fat diet groups and by 91% in the cholesterol-free group. These results suggest that ezetimibe may inhibit atherogenesis in humans consuming either restricted-fat or typical western diets.

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טיפול בכולסטרול

Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines Grundy et al Circulation 2004;110:227–239 The Coordinating Committee of the NCEP modified the recommendations from the Adult Treatment Panel III (ATP III) of the NCEP guidelines on cholesterol management, suggesting lower LDL-C goals in patients at high risk for coronary heart disease (CHD). These recommendations were based on their review of the results from the following five major clinical trials: Heart Protection Study (HPS), Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), Antihypertensive and Lipid-Lowering Trial (ALLHAT-LLT), Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA), and Pravastatin or Atorvastatin Evaluation and Infection - Thrombolysis in Myocardial Infarction 22 (PROVE IT - TIMI 22) trial. The analysis concluded that lower is better and therefore more aggressive therapy is needed, which supports the need for Dual Inhibition of two sources of cholesterol.

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Evolving concepts and a new approach for management of hyperlipidemia Ballantyne Eur Heart J 2002;4(Suppl J):J1–J3. Approaches to treatment of hypertension and hypercholesterolemia have evolved over the years, which is reflected by changes in national guidelines for the management of each disease. These guidelines have become more aggressive; those for hypertension now emphasize the importance of combining drugs with complementary mechanisms of action to achieve greater reductions in blood pressure while minimizing the risk for adverse events. This approach is also appropriate for management of hyperlipidemia. Coadministration of ezetimibe with a statin may improve achievement of LDL C goals while avoiding side effects that have limited the usefulness of other combination therapies.

Cholesterol absorption inhibition: Filling an unmet need in lipid-lowering management Leitersdorf Eur Heart J 2001;3(Suppl E):E17–23. Many patients do not reach LDL C goals, even on the highest statin doses, partly because each doubling of the statin dose provides only an additional 6% decrease in LDL C. Patients treated with statins for a prolonged period may also experience “escape,” a slow increase in LDL C. Combination therapy may help patients reach LDL C goals, but most agents that can be combined with statins have side effects that may limit their utility. Coadministration of ezetimibe with a statin can achieve greater reductions in LDL C than statin monotherapy and may fill an unmet need in patients with hypercholesterolemia, offering broader control in lipid-lowering therapy.

A new role for combination therapy in lipid management Kastelein et al Br J Cardiol 2001;8:639–653 Only a small percentage of individuals appropriate for cholesterol-lowering therapy receive pharmacotherapy, and existing treatments are ineffective in many patients. Statins typically lower LDL C levels by 25%–40%, but this is not sufficient to achieve goals for many patients. The development of the selective cholesterol absorption inhibitor ezetimibe provides a new option for lipid management to help more patients meet their LDL C goals. Initial coadministration of ezetimibe 10 mg/day with a statin yields an incremental 16%–18% reduction in LDL C, which is approximately equivalent to a three-step (eight-fold) dose increase with statin alone

Combination therapy: Its rationale and the role of ezetimibe Stone Eur Heart J 2002;4(Suppl J):J19–J22. Many patients with hypercholesterolemia do not achieve their treatment goals; this failure is most common for individuals at the greatest risk for cardiac events. Combination therapy with a statin and one or more additional lipid-lowering agents has the potential to improve LDL C lowering and goal achievement, but may be limited by inconvenient dosing schedules or intolerable side effects. An ideal drug for coadministration with a statin should have a mechanism of action complementary to that of statins and should not increase the risk for adverse events. Ezetimibe fills these requirements: it blocks cholesterol absorption rather than synthesis, lowers LDL C by about 18%, decreases TG, increases HDL C, and is well tolerated when coadministered with a statin.

סקירה כללית

Ezetimibe Bays Expert Opin Investig Drugs 2002;11(11):1587–1604. Ezetimibe is the first member of a new class of cholesterol absorption inhibitors. The mechanism of action for ezetimibe is different from those of phytosterols/phytostanols, resins, and polymers; it is also easier to take and better tolerated. Ezetimibe is safe and effective as monotherapy and when coadministered with a statin in patients with hypercholesterolemia. When coadministered with ongoing therapy of atorvastatin, simvastatin, pravastatin, lovastatin, or fluvastatin, ezetimibe lowered LDL C by 21% vs. the addition of placebo. Coadministration of ezetimibe with a statin does not increase the risk for myopathy or symptomatic elevations in liver enzymes. Ezetimibe is administered at a dose of 10 mg once daily and may be taken without regard to meals.

Ezetimibe (ADIS Drug Profile) Darkes et al Am J Cardiovasc Drugs 2003;3(1):67–76. Ezetimibe is the first of a new class of drugs that inhibits the intestinal absorption of cholesterol. Ezetimibe is readily taken up by the liver from the portal blood and excreted into the bile, resulting in low peripheral blood concentrations. Enterohepatic recycling of ezetimibe results in an elimination half-life of about 30 hours. The coadministration of ezetimibe (10 mg/day) with all currently approved doses of atorvastatin, simvastatin, pravastatin, or lovastatin results in greater reductions in LDL C vs. statin monotherapy. Ezetimibe also effectively lowers LDL C when coadministered with ongoing statin therapy in patients with primary hypercholesterolemia or homozygous familial hypercholesterolemia. Ezetimibe is well tolerated when coadministered with a statin or as monotherapy

Evolving concepts: The role of ezetimibe in the management of hypercholesterolemia Eur Heart J 2002;4(Suppl J):J1–J24. The four papers comprising this supplement summarize the evolution in the approaches to the treatment of hypercholesterolemia, the pharmacology of the new cholesterol absorption inhibitor ezetimibe, the clinical profile of ezetimibe, and the rationale for coadministration of ezetimibe with a statin.

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