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Enrico P. Veltri - One of the best experts on this subject based on the ideXlab platform.
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pooled analyses of effects on c reactive protein and low density lipoprotein cholesterol in placebo controlled trials of Ezetimibe monotherapy or Ezetimibe added to baseline statin therapy
American Journal of Cardiology, 2009Co-Authors: Thomas A Pearson, Enrico P. Veltri, Arvind Shah, Jianxin Lin, Christie M Ballantyne, Steven R Bird, Elizabeth Rosenberg, Andrew M. TershakovecAbstract:Inflammation is associated with coronary artery disease (CAD), and statins reduce the inflammatory marker C-reactive protein (CRP). The effects of Ezetimibe, alone or in combination with statins, on CRP and low-density lipoprotein (LDL) cholesterol were examined in 2 pooled analyses of randomized, placebo-controlled trials of Ezetimibe 10 mg/day in patients with hypercholesterolemia: 6 12-week trials as monotherapy (n = 1,372) and 7 6- to 8-week trials as add-on to baseline statin therapy (n = 3,899). Mean percentage changes from baseline in CRP and LDL cholesterol were examined using analysis of variance in patients with CRP < or =10 mg/L. Effects within subgroups (age, gender, race, body mass index, diabetes mellitus, metabolic syndrome, CAD, baseline CRP or lipids, and statin potency) and correlations between CRP and LDL cholesterol were also examined. Reduction in CRP by Ezetimibe monotherapy was numerically greater than with placebo (treatment difference 6%, p = 0.09). Added to statin therapy, Ezetimibe was associated with a significant additional reduction in CRP (treatment difference 10%, p <0.001). Treatment effects were generally consistent across subgroups for the 2 analyses. With monotherapy and add-on to statin therapy, LDL cholesterol reduction with Ezetimibe was significantly greater than with placebo (treatment differences -19% and -23%, respectively, p <0.001). Spearman's correlation coefficients among baseline values and percentage changes from baseline in CRP and LDL cholesterol ranged from -0.007% to 0.13%. In conclusion, the addition of Ezetimibe to statin treatment provides significantly enhanced CRP reductions over and above those achieved with statin monotherapy. Correlations between changes in CRP and changes in LDL cholesterol were weakly positive and significant only when Ezetimibe was added to statin treatment. The effects of Ezetimibe monotherapy are not well defined. The effects of Ezetimibe on CRP were consistent across patient subgroups.
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zetia inhibition of niemann pick c1 like 1 npc1l1 to reduce intestinal cholesterol absorption and treat hyperlipidemia
Journal of Atherosclerosis and Thrombosis, 2007Co-Authors: Harry R Davis, Enrico P. VeltriAbstract:Zetia (Ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than Ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of Ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When Ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals.
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Efficacy and safety of Ezetimibe and Ezetimibe plus statin therapy in patients aged under 65, 65–74 and 75 years and older
Aging Health, 2007Co-Authors: Jennifer G. Robinson, Enrico P. Veltri, Michael H. Davidson, Arvind Shah, Jianxin Lin, David Neff, Paul Delucca, Joanne E. Tomassini, Andrew M. TershakovecAbstract:Although the greatest burden of cardiovascular disease occurs after age 65 years, limited efficacy and safety data are available for cholesterol-lowering drugs in elderly patients. We undertook a pooled analysis of individual data from 13,282 patients aged 18–93 years in 16 published trials of Ezetimibe and Ezetimibe added on to or coadministered with a statin (Ezetimibe/statin). Overall, Ezetimibe reduced low-density lipoprotein cholesterol by 20% compared with placebo and Ezetimibe/statin reduced low-density lipoprotein cholesterol by 17% compared with a statin alone, with consistent treatment effects across age groups (
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efficacy and safety of Ezetimibe coadministered with statins randomised placebo controlled blinded experience in 2382 patients with primary hypercholesterolemia
International Journal of Clinical Practice, 2004Co-Authors: M H Davidson, Ramachandran Suresh, Christie M Ballantyne, B Kerzner, L Melani, P T Sager, L J Lipka, J Strony, Enrico P. VeltriAbstract:We assessed pooled safety and lipid-regulating efficacy data from four similarly designed trials of Ezetimibe coadministered with statins in 2382 patients with primary hypercholesterolemia. Patients were randomised to one of the following double-blind treatments for 12 weeks: placebo; Ezetimibe 10 mg; statin; or statin + Ezetimibe. Statin doses tested were 10, 20, 40 mg/day (atorvastatin, simvastatin, pravastatin or lovastatin) or 80 mg/day (atorvastatin, simvastatin). Treatment with Ezetimibe + statin led to significantly greater reductions in low-density lipoprotein cholesterol (LDL-C), total cholesterol, triglycerides, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B and increases in HDL-C, compared to statin alone. At each statin dose, treatment with Ezetimibe + statin led to a greater LDL-C reduction compared to the next highest statin monotherapy dose. Ezetimibe + statin had a safety profile similar to statin monotherapy. Coadministration of Ezetimibe + statin offers a well-tolerated, highly efficacious new treatment strategy for patients with hypercholesterolemia.
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effects of Ezetimibe a new cholesterol absorption inhibitor on plasma lipids in patients with primary hypercholesterolemia
European Heart Journal, 2003Co-Authors: R H Knopp, Leslie Lipka, Alexandre Lebeaut, Ramachandran Suresh, Bo Yang, H Gitter, T Truitt, Harold E Bays, C V Manion, Enrico P. VeltriAbstract:Aims This randomized, double-blind, placebo-controlled, parallel-group study evaluated the safety and efficacy of Ezetimibe 10mg/day in patients with primary hypercholesterolemia. Methods and results Following dietary stabilization, a 2–12-week washout period, and a 4-week, single-blind, placebo lead-in period, 827 patients with baseline low-density lipoprotein cholesterol (LDL-C) ≥3.36mmol/l (130mg/dl) to ≤6.47mmol/l (250mg/dl) and triglycerides ≤3.95mmol/l (350mg/dl) were randomized 3:1 to receive Ezetimibe 10mg or placebo orally once daily in the morning for 12 weeks. The primary efficacy endpoint was percentage reduction in direct plasma LDL-C. Ezetimibe reduced direct LDL-C by a mean of 17.7% from baseline to endpoint, compared with an increase of 0.8% with placebo \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \((P{<}0.01)\) \end{document}. Response to Ezetimibe was generally consistent across all subgroups analyzed. Ezetimibe also significantly improved levels of plasma total cholesterol, apolipoprotein B, high-density lipoprotein2-cholesterol and lipoprotein(a), and elicited a trend toward lower triglyceride levels. Ezetimibe did not alter the serum concentrations of lipid-soluble vitamins or significantly affect baseline or stimulated cortisol production. Ezetimibe was well tolerated, with a safety profile similar to that of placebo. Conclusions Ezetimibe, which significantly reduces LDL-C and favorably affects other lipid variables, may provide a well tolerated and effective new option for lipid management in the future.
Li Hai - One of the best experts on this subject based on the ideXlab platform.
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first synthesis and characterization of srr rss Ezetimibe
Tetrahedron Letters, 2013Co-Authors: Yun Ren, Yong Deng, Mei Guan, Li HaiAbstract:Abstract The two stereoisomers, SRR -Ezetimibe 2 and RSS -Ezetimibe 3 are related substances of the cholesterol absorption inhibitor drug Ezetimibe 1 . Herein, we present an efficient and practical synthesis approach to deliver these two stereoisomers for the first time, and a proof of SRR -Ezetimibe 2 by single-crystal X-ray analysis. Our research will be of immense help for organic chemists to study the impurity profile of Ezetimibe 1 .
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First synthesis and characterization of SRR/RSS-Ezetimibe
Tetrahedron Letters, 2013Co-Authors: Yun Ren, Yong Deng, Mei Guan, Li HaiAbstract:Abstract The two stereoisomers, SRR -Ezetimibe 2 and RSS -Ezetimibe 3 are related substances of the cholesterol absorption inhibitor drug Ezetimibe 1 . Herein, we present an efficient and practical synthesis approach to deliver these two stereoisomers for the first time, and a proof of SRR -Ezetimibe 2 by single-crystal X-ray analysis. Our research will be of immense help for organic chemists to study the impurity profile of Ezetimibe 1 .
Joseph Azuri - One of the best experts on this subject based on the ideXlab platform.
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Usefulness of Ezetimibe Versus Evolocumab as Add-On Therapy for Secondary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus.
American Journal of Cardiology, 2019Co-Authors: Ronen Arbel, Ariel Hammerman, Joseph AzuriAbstract:Evolocumab and Ezetimibe, were both proven to significantly reduce the incidence of major adverse cardiovascular events (MACE), in type 2 diabetes patients with atherosclerotic cardiovascular disease and low-density lipoprotein (LDL) cholesterol >70 mg/dl despite statin therapy. Providing evolocumab for all such patients may be a significant burden on healthcare systems. Therefore, we analyzed the treatment cost of Ezetimibe versus evolocumab to prevent 1 MACE. We extracted the number needed to treat (NNT) with evolocumab or with Ezetimibe for avoiding MACE from the published FOURIER and IMPROVE-IT trials respectively. Drug costs were based on 2018 US prices. Sensitivity and scenario analyses were performed to overcome variances in terms of population risk, efficacy of therapies, and costs. In FOURIER, the 1-year NNT for avoiding MACE with evolocumab was 104 (95% confidence intervals [CI] 66 to 235). In IMPROVE-IT, the 1-year NNT with Ezetimibe was 124 (95% CI 73 to 288). The annual cost of evolocumab and Ezetimibe is $6,540 and $88, respectively. Therefore, the cost to prevent 1 MACE in the FOURIER and IMPROVE-IT trials would have been $678,981 (95% CI $429,810 to $1,537,910,149) and $10,870 (95% CI $6,384 to $25,322), respectively. Ezetimibe was consistently a cost-saving strategy compared with evolocumab, in all analyses performed, except for the case where evolocumab price is significantly reduced and the branded Ezetimibe is used. In conclusion, treatment with Ezetimibe seems to be a major cost-saving strategy for preventing MACE in this patient population.
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Usefulness of Ezetimibe Versus Evolocumab as Add-On Therapy for Secondary Prevention of Cardiovascular Events in Patients With Type 2 Diabetes Mellitus.
American Journal of Cardiology, 2019Co-Authors: Ronen Arbel, Ariel Hammerman, Joseph AzuriAbstract:Evolocumab and Ezetimibe, were both proven to significantly reduce the incidence of major adverse cardiovascular events (MACE), in type 2 diabetes patients with atherosclerotic cardiovascular disease and low-density lipoprotein (LDL) cholesterol >70 mg/dl despite statin therapy. Providing evolocumab for all such patients may be a significant burden on healthcare systems. Therefore, we analyzed the treatment cost of Ezetimibe versus evolocumab to prevent 1 MACE. We extracted the number needed to treat (NNT) with evolocumab or with Ezetimibe for avoiding MACE from the published FOURIER and IMPROVE-IT trials respectively. Drug costs were based on 2018 US prices. Sensitivity and scenario analyses were performed to overcome variances in terms of population risk, efficacy of therapies, and costs. In FOURIER, the 1-year NNT for avoiding MACE with evolocumab was 104 (95% confidence intervals [CI] 66 to 235). In IMPROVE-IT, the 1-year NNT with Ezetimibe was 124 (95% CI 73 to 288). The annual cost of evolocumab and Ezetimibe is $6,540 and $88, respectively. Therefore, the cost to prevent 1 MACE in the FOURIER and IMPROVE-IT trials would have been $678,981 (95% CI $429,810 to $1,537,910,149) and $10,870 (95% CI $6,384 to $25,322), respectively. Ezetimibe was consistently a cost-saving strategy compared with evolocumab, in all analyses performed, except for the case where evolocumab price is significantly reduced and the branded Ezetimibe is used. In conclusion, treatment with Ezetimibe seems to be a major cost-saving strategy for preventing MACE in this patient population.
Teddy Kosoglou - One of the best experts on this subject based on the ideXlab platform.
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The effect of fluvastatin on the pharmacokinetics and pharmacodynamics of Ezetimibe.
Current Medical Research and Opinion, 2005Co-Authors: Larisa Reyderman, Teddy Kosoglou, Stephen E. Maxwell, David L. Cutler, Paul StatkevichAbstract:ABSTRACTObjective: The objective of this study was to evaluate the pharmacodynamic effects and safety of the co-administration of Ezetimibe and fluvastatin in healthy hypercholesterolemic subjects at clinically-relevant doses and to evaluate the potential for a pharmacokinetic drug interaction between Ezetimibe and fluvastatin.Methods: In a single-center, evaluator-blind, placebo-controlled, multiple-dose, parallel-group study 32 healthy subjects with hypercholesterolemia were randomized to 4 treatments administered once daily for 14 days: Ezetimibe 10 mg plus Ezetimibe placebo, fluvastatin 20 mg plus Ezetimibe placebo, fluvastatin 20 mg plus Ezetimibe 10 mg, and Ezetimibe placebo. Blood samples were collected to measure serum lipids and to determine steady-state pharmacokinetics.Results: Ezetimibe 10 mg significantly ( p ≤ 0.01) decreased total-cholesterol and low-density lipoprotein cholesterol (LDL‐C) concentrations compared to placebo at Day 14. Fluvastatin 20 mg also caused a significant ( p = 0.01) ...
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Ezetimibe
Clinical Pharmacokinetics, 2005Co-Authors: Teddy Kosoglou, Paul Statkevich, Amy Johnson-levonas, John F. Paolini, Arthur J. Bergman, Kevin B. AltonAbstract:Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, Ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active Ezetimibe-glucuronide. Total Ezetimibe (sum of ‘parent’ Ezetimibe plus Ezetimibe-glucuronide) concentrations reach a maximum 1–2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of Ezetimibe and Ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of Ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of Ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on Ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for Ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5′-diphosphate-glucuronosyltransferase isoenzymes to form Ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as Ezetimibe, with the balance found in the urine mainly as Ezetimibe-glucuronide. Overall, Ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between Ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on Ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of Ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of Ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased Ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total Ezetimibe). Hence, Ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of Ezetimibe. Finally, higher Ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and Ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating Ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.
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Ezetimibe : A review of its metabolism, pharmacokinetics and drug interactions
Clinical Pharmacokinetics, 2005Co-Authors: Teddy Kosoglou, Paul Statkevich, Amy Johnson-levonas, John F. Paolini, Arthur J. Bergman, Kevin B. AltonAbstract:Ezetimibe is the first lipid-lowering drug that inhibits intestinal uptake of dietary and biliary cholesterol without affecting the absorption of fat-soluble nutrients. Following oral administration, Ezetimibe is rapidly absorbed and extensively metabolised (>80%) to the pharmacologically active Ezetimibe-glucuronide. Total Ezetimibe (sum of 'parent' Ezetimibe plus Ezetimibe-glucuronide) concentrations reach a maximum 1-2 hours post-administration, followed by enterohepatic recycling and slow elimination. The estimated terminal half-life of Ezetimibe and Ezetimibe-glucuronide is approximately 22 hours. Consistent with the elimination half-life of Ezetimibe, an approximate 2-fold accumulation is observed upon repeated once-daily administration. The recommended dose of Ezetimibe 10 mg/day can be administered in the morning or evening without regard to food. There are no clinically significant effects of age, sex or race on Ezetimibe pharmacokinetics and no dosage adjustment is necessary in patients with mild hepatic impairment or mild-to-severe renal insufficiency. The major metabolic pathway for Ezetimibe consists of glucuronidation of the 4-hydroxyphenyl group by uridine 5'-diphosphate-glucuronosyltransferase isoenzymes to form Ezetimibe-glucuronide in the intestine and liver. Approximately 78% of the dose is excreted in the faeces predominantly as Ezetimibe, with the balance found in the urine mainly as Ezetimibe-glucuronide. Overall, Ezetimibe has a favourable drug-drug interaction profile, as evidenced by the lack of clinically relevant interactions between Ezetimibe and a variety of drugs commonly used in patients with hypercholesterolaemia. Ezetimibe does not have significant effects on plasma levels of HMG-CoA reductase inhibitors commonly known as statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibric acid derivatives (gemfibrozil, fenofibrate), digoxin, glipizide, warfarin and triphasic oral contraceptives (ethinylestradiol and levonorgestrel). Concomitant administration of food, antacids, cimetidine or statins had no significant effect on Ezetimibe bioavailability. Although coadministration with gemfibrozil and fenofibrate increased the bioavailability of Ezetimibe, the clinical significance is thought to be minor considering the relatively flat dose-response curve of Ezetimibe and the lack of dose-related increase in adverse events. In contrast, coadministration with the bile acid binding agent colestyramine significantly decreased Ezetimibe oral bioavailability (based on area under the plasma concentration-time curve of total Ezetimibe). Hence, Ezetimibe and colestyramine should be administered several hours apart to avoid attenuating the efficacy of Ezetimibe. Finally, higher Ezetimibe exposures were observed in patients receiving concomitant ciclosporin, and Ezetimibe caused a small but statistically significant effect on plasma levels of ciclosporin. Because treatment experience in patients receiving ciclosporin is limited, physicians are advised to exercise caution when initiating Ezetimibe in the setting of ciclosporin coadministration, and to carefully monitor ciclosporin levels.
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assessment of a multiple dose drug interaction between Ezetimibe a novel selective cholesterol absorption inhibitor and gemfibrozil
Principles and Practice of Constraint Programming, 2004Co-Authors: Larisa Reyderman, Teddy Kosoglou, Paul Statkevich, Melton B. Affrime, L Pember, T Boutros, S E Maxwell, Vijay BatraAbstract:Objective: Ezetimibe is a novel lipid-lowering drug that prevents intestinal absorption of dietary and biliary cholesterol leading to significant reduction in total-C, LDL-C, Apo B, and TG and increases in HDL-C in patients with hypercholesterolemia. Gemfibrozil, a fibric acid derivative, is an effective lipid-modulating agent that increases serum high-density lipoprotein cholesterol and decreases serum TG. The objective of this study was to evaluate the potential for a pharmacokinetic (PK) interaction between Ezetimibe and gemfibrozil. Methods: This was a randomized, open-label, 3-way crossover, multiple-dose study in 12 healthy adult male volunteers. All subjects received the following 3 treatments orally for 7 days: Ezetimibe 10 mg once daily, gemfibrozil 600 mg every 12 hours, and Ezetimibe 10 mg once daily plus gemfibrozil 600 mg every 12 hours. A washout period of ≥ 7 days separated the 3 treatments. In each treatment, blood samples were collected on day 7 to assess the steady-state PK of Ezetimibe and gemfibrozil. The oral bioavailability of Ezetimibe coadministered with gemfibrozil relative to each drug administered alone was evaluated with an analysis-of-variance model. Results: Ezetimibe was rapidly absorbed and extensively conjugated to its glucuronide metabolite. Ezetimibe did not alter the bioavailability (based on AUC) of gemfibrozil. The mean AUC 0 - 1 2 of gemfibrozil was 74.7 and 74.1 μg h/ml with and without Ezetimibe coadministration, respectively (log-transformed geometric mean ratio (GMR) = 99.2; 90% confidence interval (Cl) = 92 - 107%). Conversely, gemfibrozil significantly (p < 0.05) increased the plasma concentrations of Ezetimibe and total Ezetimibe (i.e. Ezetimibe plus Ezetimibe-glucuronide). Exposure to Ezetimibe and total Ezetimibe was increased approximately 1.4-fold and 1.7-fold, respectively (CI = 109 - 173% for Ezetimibe and 142 - 190% for total Ezetimibe), however, this increase was not considered to be clinically relevant. Ezetimibe and gemfibrozil administered alone or concomitantly for 7 days was well tolerated. Conclusions: The coadministration of Ezetimibe and gemfibrozil in patients is unlikely to cause a clinically significant drug interaction. The coadministration of these agents is a promising approach for patients with mixed dyslipidemia. Additional clinical studies are warranted.
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Pharmacokinetic interaction between Ezetimibe and lovastatin in healthy volunteers.
Current medical research and opinion, 2004Co-Authors: Larisa Reyderman, Teddy Kosoglou, Tanya Boutros, Michael Seiberling, Paul StatkevichAbstract:SUMMARYBackground: Ezetimibe (Zetia†) is a novel inhibitor of intestinal absorption of cholesterol that is approved for the treatment of primary hypercholesterolemia. In a separate pilot study, co-administration of Ezetimibe and lovastatin resulted in a significant pharmacodynamic interaction, leading to an additive reduction in LDL-C. The current study was designed to further investigate the potential for pharmacokinetic interaction between Ezetimibe and lovastatin.Methods: This was a randomized, open-label, 3-way crossover study in 18 healthy adult volunteers. All subjects received the following treatments orally once daily for 7 days: Ezetimibe 10 mg, lovastatin 20 mg, or Ezetimibe 10 mg plus lovastatin 20 mg. Plasma samples obtained on day 7 were evaluated for steady-state pharmacokinetics of Ezetimibe (unconjugated), total Ezetimibe (Ezetimibe and Ezetimibe-glucuronide conjugate), lovastatin, and β-hydroxylovastatin.Results: Co-administration of Ezetimibe with lovastatin did not affect the pharmacoki...
Harry R Davis - One of the best experts on this subject based on the ideXlab platform.
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Effects of Ezetimibe on atherosclerosis in preclinical models.
Atherosclerosis, 2011Co-Authors: Harry R Davis, Robert S. Lowe, David NeffAbstract:Abstract Ezetimibe (Zetia ® , Ezetrol ® , Merck, Whitehouse Station, NJ) is a potent inhibitor of sterol absorption, which selectively blocks the uptake of biliary and dietary cholesterol in the small intestine. Clinical trials have demonstrated the beneficial effects of Ezetimibe on the reduction of atherogenic lipoproteins and the attainment of guideline-recommended lipid levels. Direct evidence that these improvements translate to a reduction in atherosclerosis or cardiovascular events is limited, although reductions in major atherosclerotic events that are consistent with the LDL-C lowering achieved have recently been presented for patients with chronic kidney disease treated with Ezetimibe/simvastatin 10/20mg in the SHARP trial. Animal models of atherosclerosis have played a central role in defining the mechanisms involved in initiation and development of disease and have been used in drug development to evaluate potential therapeutic efficacy. The effect of Ezetimibe on atherosclerosis has been examined in several of these animal model systems. ApoE knockout mice develop severe hypercholesterolemia and premature atherosclerosis with features similar to that seen in humans and techniques ranging from gross visualization of plaque to high-resolution MRI have demonstrated the consistent ability of Ezetimibe to significantly inhibit atherosclerosis. sr-b1 −/− / apoE −/− double knockout mice exhibit additional characteristics common to human coronary heart disease (CHD), and the one study of Ezetimibe in sr-b1 −/− / apoE −/− mice showed a significant reduction in aortic sinus plaque (57%), coronary arterial occlusion (68%), myocardial fibrosis (57%), and cardiomegaly (12%) compared with untreated controls. The effects of Ezetimibe have also been evaluated in ldlr −/− / apoE −/− double knockout mice, demonstrating that functional LDL receptors were not required for Ezetimibe-mediated reduction of plasma cholesterol or atherosclerosis. For the few studies that have been conducted in rabbits, Ezetimibe has been shown to significantly inhibit diet and vascular-injury-induced atherosclerosis as measured by intima/media thickness, atherosclerotic lesion composition, and thrombosis. The current body of preclinical evidence consistently demonstrates that Ezetimibe reduces atherosclerosis in animals, presumably due primarily to the decrease in circulating levels of atherogenic lipoproteins that the drug produces. Demonstration that Ezetimibe-mediated lowering of atherogenic lipoproteins in humans has a similar effect on atherosclerosis and cardiovascular risk awaits additional results from recently completed and ongoing outcomes trials.
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zetia inhibition of niemann pick c1 like 1 npc1l1 to reduce intestinal cholesterol absorption and treat hyperlipidemia
Journal of Atherosclerosis and Thrombosis, 2007Co-Authors: Harry R Davis, Enrico P. VeltriAbstract:Zetia (Ezetimibe) is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1), which keeps cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it binds with higher affinity for NPC1L1 than Ezetimibe to prevent cholesterol absorption. Enterohepatic recirculation of Ezetimibe and/or its glucuronide ensures repeated delivery to the intestinal site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug-drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals and by 58% in vegetarians. Ezetimibe alone reduced plasma total and LDL-Cholesterol (18%) levels in patients with primary hypercholesterolemia. When Ezetimibe was added to on-going statin treatment, an additional 25% reduction in LDL-C was found in patients with primary hypercholesterolemia and an additional 21% reduction in LDL-C in homozygous familial hypercholesterolemia. Ezetimibe in combination with statins produces additional reductions in plasma cholesterol levels and allows for more patients to achieve their LDL-C goals.
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in vivo responsiveness to Ezetimibe correlates with niemann pick c1 like 1 npc1l1 binding affinity comparison of multiple species npc1l1 orthologs
Molecular Pharmacology, 2007Co-Authors: Brian E. Hawes, Kim Oneill, James H Crona, Michael P Graziano, Harry R Davis, Scott W AltmannAbstract:Ezetimibe is the first in class 2-azetidinone that decreases plasma cholesterol by blocking intestinal cholesterol absorption. Ezetimibe effectively reduces plasma cholesterol in several species including human, monkey, dog, hamster, rat, and mouse, but the potency ranges widely. One potential factor responsible for this variation in responsiveness is diversity in Ezetimibe metabolism. After oral administration, Ezetimibe is glucuronidated. Both Ezetimibe and the glucuronide lower plasma cholesterol; however, the glucuronide exhibits greater potency. Recent identification of Niemann-Pick C1 Like-1 (NPC1L1) as the molecular target of Ezetimibe enables direct binding studies to be performed. Here, we report the cloning of NPC1L1 derived from multiple species and assess amino acid sequence homology among human, monkey, dog, hamster, rat, and mouse. The rank order of affinity of glucuronidated Ezetimibe for NPC1L1 in each species correlates with the rank order of in vivo activity with monkey > dog > hamster and rat ≫ mouse. Ezetimibe analogs that bind to NPC1L1 exhibit in vivo cholesterol-lowering activity, whereas compounds that do not bind NPC1L1 are inactive. Specific structural components of Ezetimibe are identified as critical for binding to NPC1L1. The results demonstrate that small variations in Ezetimibe structure or in NPC1L1 amino acid sequence can profoundly influence Ezetimibe/NPC1L1 interaction and consequently in vivo activity. The results demonstrate that the ability of compounds to bind to NPC1L1 is the major determinant of in vivo responsiveness.
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The target of Ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1).
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Margarita Garcia-calvo, Jeanmarie Lisnock, Duane A. Burnett, Matthew P. Braun, Herbert G. Bull, Brian E. Hawes, Dennis C. Dean, James H Crona, Harry R Davis, Patricia A DetmersAbstract:Ezetimibe is a potent inhibitor of cholesterol absorption that has been approved for the treatment of hypercholesterolemia, but its molecular target has been elusive. Using a genetic approach, we recently identified Niemann-Pick C1-Like 1 (NPC1L1) as a critical mediator of cholesterol absorption and an essential component of the Ezetimibe-sensitive pathway. To determine whether NPC1L1 is the direct molecular target of Ezetimibe, we have developed a binding assay and shown that labeled Ezetimibe glucuronide binds specifically to a single site in brush border membranes and to human embryonic kidney 293 cells expressing NPC1L1. Moreover, the binding affinities of Ezetimibe and several key analogs to recombinant NPC1L1 are virtually identical to those observed for native enterocyte membranes. KD values of Ezetimibe glucuronide for mouse, rat, rhesus monkey, and human NPC1L1 are 12,000, 540, 40, and 220 nM, respectively. Last, Ezetimibe no longer binds to membranes from NPC1L1 knockout mice. These results unequivocally establish NPC1L1 as the direct target of Ezetimibe and should facilitate efforts to identify the molecular mechanism of cholesterol transport.
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Ezetimibe: first in a new class of cholesterol absorption inhibitors
International Congress Series, 2004Co-Authors: Harry R DavisAbstract:Ezetimibe is a selective cholesterol absorption inhibitor, which potently inhibits the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol, which keeps the cholesterol in the intestinal lumen for excretion. Ezetimibe undergoes glucuronidation to a single metabolite and localizes at the intestinal wall, where it prevents cholesterol absorption. Enterohepatic recirculation of Ezetimibe and/or its glucuronide ensures repeated delivery to the site of action and limited peripheral exposure. Ezetimibe has no effect on the activity of major drug metabolizing enzymes (CYP450), which reduces any potential drug–drug interactions with other medications. Ezetimibe (10 mg/day) was found to inhibit cholesterol absorption by an average of 54% in hypercholesterolemic individuals (p
