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Stephen J Nicholls, Kausik K Ray, Christie M Ballantyne, Lauren A Beacham, Debra L Miller, Giacomo Ruotolo, Steven E Nissen, Jeffrey S Riesmeyer
BACKGROUND AND AIMS: The optimal approaches to management of patients treated with moderate statin doses on lipid parameters are unknown. The ACCENTUATE study aimed to compare the effects of adding the cholesteryl ester transfer protein inhibitor (CETP) evacetrapib, ezetimibe or increasing statin dose in atorvastatin-treated high-vascular risk patients on lipid parameters. METHODS: 366 patients with atherosclerotic cardiovascular disease (ASCVD) and/or diabetes were treated with atorvastatin 40 mg/day for 28 days prior to randomization to atorvastatin 40 mg plus evacetrapib 130 mg, atorvastatin 80 mg, atorvastatin 40 mg plus ezetimibe 10 mg or atorvastatin 40 mg plus placebo, daily for 90 days at 64 centers in the United States...
April 8, 2017: Atherosclerosis
William J Breslin, Kim G Hilbish, Ellen A Cannady, Tammy L Edwards
BACKGROUND: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was under development for the treatment of cardiovascular (CV) disease. The purpose of this pre-postnatal study in rabbits was to evaluate the effects of evacetrapib on pregnancy, parturition, and lactation of the maternal animals and on the growth, viability, development, and reproductive performance of the first filial (F1) offspring. The rabbit is considered a relevant species for toxicity testing with evacetrapib as it demonstrates significant CETP expression, whereas mice and rats do not express significant levels of CETP...
April 17, 2017: Birth Defects Res
William J Breslin, Kim G Hilbish, Ellen A Cannady, Tammy L Edwards
BACKGROUND: The purpose of these studies was to evaluate the effects of evacetrapib on male and female fertility and on embryo-fetal development (EFD). METHODS: Evacetrapib, a potent and selective inhibitor of cholesteryl ester transfer protein (CETP), was administered daily by oral gavage starting 2 weeks (for female) or 4 weeks (for male) before mating, during cohabitation, and until necropsy in the male rat fertility study or through gestation day (GD) 17 in the female rat combined fertility/EFD study...
April 17, 2017: Birth Defects Res
Na Li, Christopher J Gilpin, Lynne S Taylor
Miscibility is critical for amorphous solid dispersions (ASDs). Phase-separated ASDs are more prone to crystallization, and thus can lose their solubility advantage leading to product failure. Additionally, dissolution performance can be diminished as a result of phase separation in the ASD matrix. Water is known to induce phase separation during storage for some ASDs. However, the impact of water introduced during preparation has not been as thoroughly investigated to date. The purpose of this study was to develop a mechanistic understanding of the effect of water on the phase behavior and microstructure of ASDs...
April 19, 2017: Molecular Pharmaceutics
Branko Simic, Pavani Mocharla, Margot Crucet, Elena Osto, Adelheid Kratzer, Simona Stivala, Susan Kühnast, Thimoteus Speer, Petia Doycheva, Hans M Princen, Jose W van der Hoorn, J Wouter Jukema, Hector Giral, Anne Tailleux, Ulf Landmesser, Bart Staels, Thomas F Lüscher
BACKGROUND AND AIMS: High-density lipoprotein cholesterol (HDL-C) is inversely related to cardiovascular risk. HDL-C raising ester transfer protein (CETP) inhibitors, are novel therapeutics. We studied the effects of CETP inhibitors anacetrapib and evacetrapib on triglycerides, cholesterol and lipoproteins, cholesterol efflux, paraoxonase activity (PON-1), reactive oxygen species (ROS), and endothelial function in E3L and E3L.CETP mice. METHODS: Triglycerides and cholesterol were measured at weeks 5, 14 and 21 in E3L...
February 2017: Atherosclerosis
Vaughn A Eyvazian, William H Frishman
Evacetrapib is a cholesteryl ester transfer protein (CETP) inhibitor that has been recently studied as a cholesterol modifying agent to reduce cardiovascular risk and mortality in high risk cardiovascular disease patients. Evacetrapib acts to decrease lipid exchange through CETP inhibition. CETP acts to transfer cholesteryl esters from high-density lipoprotein-cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) and very-low-density lipoprotein (VLDL-C). HDL-C is involved in reverse cholesterol transport and its blood levels have been shown to be inversely correlated with cardiovascular risk...
March 2017: Cardiology in Review
Robert DuBroff
The global campaign to lower cholesterol by diet and drugs has failed to thwart the developing pandemic of coronary heart disease around the world. Some experts believe this failure is due to the explosive rise in obesity and diabetes, but it is equally plausible that the cholesterol hypothesis, which posits that lowering cholesterol prevents cardiovascular disease, is incorrect. The recently presented ACCELERATE trial dumbfounded many experts by failing to demonstrate any cardiovascular benefit of evacetrapib despite dramatically lowering low-density lipoprotein cholesterol and raising high-density lipoprotein cholesterol in high-risk patients with coronary disease...
March 2017: Evidence-based Medicine
Ján Murín, Miroslav Pernický, Soňa Kiňová
In the treatment of dyslipidemias about 5-6 years back a new class of drugs emerged, CETP (cholesteryl ester transfer protein)-inhibitors. Their benefit was due to an increase of HDL-cholesterol (HDL-C) serum levels. This treatment mode was supported by epidemiological and clinical studies, as people with high serum HDL-C levels suffered less from cardiovascular (CV) events. Three studies with CETP inhibitors (ILLUMINATE with torcetrapib, dal-OUTCOMES with dalcetrapib and ACCELERATE with evacetrapib) were unfortunately negative, and torcetrapib was even harmful to patients due to an increase of aldosterone serum levels...
2016: Vnitr̆ní Lékar̆ství
Julian Hardy McLain, Andrew Jacob Alsterda, Rohit R Arora
The cholesteryl ester transfer protein (CETP) is a plasma protein that plays an important role in the transfer of lipids between plasma lipoproteins. The CETP inhibitors have been widely studied as a pharmacologic therapy to target plasma cholesterol in order to reduce the risk of atherosclerotic cardiovascular disease . Using CETP inhibitors as cholesterol modifiers was based on the genetic research that found correlations between CETP activity and cholesterol levels. Although CETP inhibitors are successful at altering targeted cholesterol markers, recent phase 3 outcome trials have shown limited benefit on cardiovascular outcomes when combined with the current standard of care...
August 10, 2016: Journal of Cardiovascular Pharmacology and Therapeutics
Shizuya Yamashita, Yuji Matsuzawa
PURPOSE OF REVIEW: To re-evaluate the functions of plasma cholesteryl ester transfer protein (CETP) in atherosclerosis based upon recent findings from human genetics and pharmacological CETP manipulation. RECENT FINDINGS: CETP is involved in the transfer of cholesteryl ester from HDL to apolipoprotein B-containing lipoproteins, a key step of reverse cholesterol transport (RCT). CETP inhibitors have been developed to raise serum HDL-cholesterol (HDL-C) levels and reduce cardiovascular events...
October 2016: Current Opinion in Lipidology
David S Small, Jane Royalty, Ellen A Cannady, Christine Hale, Ming-Dauh Wang, Delyn Downs, Jeffrey G Suico
STUDY OBJECTIVE: To examine the effect of increased gastric pH on exposure to evacetrapib, a cholesteryl ester transfer protein inhibitor evaluated for the treatment of atherosclerotic heart disease. DESIGN: Open-label, two-treatment, two-period, fixed-sequence crossover study. SETTING: Clinical research unit. SUBJECTS: Thirty-four healthy subjects. INTERVENTION: In period 1, subjects received a single oral dose of evacetrapib 130 mg on day 1, followed by 7 days of analysis for evacetrapib plasma concentrations...
July 2016: Pharmacotherapy
Stephen J Nicholls, Giacomo Ruotolo, H Bryan Brewer, Ming-Dauh Wang, Liping Liu, Mark B Willey, Mark A Deeg, Kathryn A Krueger, Steven E Nissen
BACKGROUND: Potent CETP inhibitors reduce plasma concentrations of atherogenic lipoprotein biomarkers of cardiovascular risk. OBJECTIVES: To evaluate the effects of the cholesteryl ester transfer protein (CETP) inhibitor evacetrapib, as monotherapy or with statins, on atherogenic apolipoprotein B (apoB)-containing lipoproteins in mildly hypercholesterolemic patients. METHODS: VLDL and LDL particle concentrations and sizes (using nuclear magnetic resonance spectroscopy) and lipoprotein(a) concentration (using nephelometry) were measured at baseline and week 12 in a placebo-controlled trial of 393 patients treated with evacetrapib as monotherapy (30 mg/d, 100 mg/d, or 500 mg/d) or in combination with statins (100 mg plus simvastatin 40 mg/d, atorvastatin 20 mg/d, or rosuvastatin 10 mg/d; Clinicaltrials...
May 2016: Journal of Clinical Lipidology
T D Filippatos, E Klouras, F Barkas, M Elisaf
INTRODUCTION: Cholesteryl ester transfer protein (CETP) inhibitors substantially increase the concentration of high-density lipoprotein cholesterol (HDL-C), which may have a possible beneficial effect for cardiovascular disease risk reduction. AREAS COVERED: Current data regarding the effects of CETP inhibitors on cardiovascular disease risk and possible mechanisms for their effects and safety are presented in this review. Expert commentary: The first CETP inhibitor, torcetrapib, was discontinued because of increased off-target adverse effects (increased serum aldosterone and blood pressure levels)...
August 2016: Expert Review of Cardiovascular Therapy
David S Small, Wei Zhang, Jane Royalty, Ellen A Cannady, Delyn Downs, Demetrio Ortega, Jeffrey G Suico
PURPOSE: The aim of this study is to investigate the effect of hepatic or renal impairment on the pharmacokinetics of a single 130-mg evacetrapib dose. METHODS: Two open-label, parallel-design studies in males and females with normal hepatic function or Child-Pugh mild, moderate, or severe hepatic impairment, or with normal renal function or severe renal impairment. Non-compartmental pharmacokinetic parameters were estimated from plasma concentration-time data. Evacetrapib safety and tolerability were assessed...
May 2016: European Journal of Clinical Pharmacology
Stephen J Nicholls, A Michael Lincoff, Philip J Barter, H Bryan Brewer, Keith A A Fox, C Michael Gibson, Christopher Grainger, Venugopal Menon, Gilles Montalescot, Daniel Rader, Alan R Tall, Ellen McErlean, Jeffrey Riesmeyer, Burkhard Vangerow, Giacomo Ruotolo, Govinda J Weerakkody, Steven E Nissen
BACKGROUND: Potent pharmacologic inhibition of cholesteryl ester transferase protein by the investigational agent evacetrapib increases high-density lipoprotein cholesterol by 54% to 129%, reduces low-density lipoprotein cholesterol by 14% to 36%, and enhances cellular cholesterol efflux capacity. The ACCELERATE trial examines whether the addition of evacetrapib to standard medical therapy reduces the risk of cardiovascular (CV) morbidity and mortality in patients with high-risk vascular disease...
December 2015: American Heart Journal
Ellen A Cannady, Aktham Aburub, Chris Ward, Chris Hinds, Boris Czeskis, Kenneth Ruterbories, Jeffrey G Suico, Jane Royalty, Demetrio Ortega, Brian W Pack, Syeda L Begum, William F Annes, Qun Lin, David S Small
This open-label, single-period study in healthy subjects estimated evacetrapib absolute bioavailability following simultaneous administration of a 130-mg evacetrapib oral dose and 4-h intravenous (IV) infusion of 175 µg [(13) C8 ]-evacetrapib as a tracer. Plasma samples collected through 168 h were analyzed for evacetrapib and [(13) C8 ]-evacetrapib using high-performance liquid chromatography/tandem mass spectrometry. Pharmacokinetic parameter estimates following oral and IV doses, including area under the concentration-time curve (AUC) from zero to infinity (AUC[0-∞]) and to the last measureable concentration (AUC[0-tlast ]), were calculated...
May 30, 2016: Journal of Labelled Compounds & Radiopharmaceuticals
Amirhossein Sahebkar, Luis E Simental-Mendía, Fernando Guerrero-Romero, Jonathan Golledge, Gerald F Watts
BACKGROUND: Evacetrapib, a new cholesteryl ester transfer protein inhibitor, is being investigated as a potential therapeutic option for reducing cardiovascular events through increasing high-density lipoprotein cholesterol (HDL-C) concentrations. How evacetrapib affects other lipid parameters is less certain. The present study aimed to estimate the effect of evacetrapib on plasma lipid concentrations and to assess its safety through a systematic review and meta-analysis of randomized controlled trials...
2016: Current Pharmaceutical Design
Stephen J Nicholls, Giacomo Ruotolo, H Bryan Brewer, John P Kane, Ming-Dauh Wang, Kathryn A Krueger, Steven J Adelman, Steven E Nissen, Daniel J Rader
BACKGROUND: Potent cholesteryl ester transfer protein (CETP) inhibitors have been shown to substantially increase high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels as monotherapy and combined with statins. However, data on the effects of this class of drugs on macrophage cholesterol efflux capacity (CEC), a functional assay that characterizes a key step in the process of reverse cholesterol transport, are limited. OBJECTIVES: This study assessed the impact of evacetrapib, statins, or combination therapy on CEC...
November 17, 2015: Journal of the American College of Cardiology
Ellen A Cannady, Ming-Dauh Wang, Stuart Friedrich, Jessica L F Rehmel, Ping Yi, David S Small, Wei Zhang, Jeffrey G Suico
Evacetrapib is an investigational cholesteryl ester transfer protein inhibitor (CETPi) for reduction of risk of major adverse cardiovascular events in patients with high-risk vascular disease. Understanding evacetrapib disposition, metabolism, and the potential for drug-drug interactions (DDI) may help guide prescribing recommendations. In vitro, evacetrapib metabolism was investigated with a panel of human recombinant cytochromes P450 (CYP). The disposition, metabolism, and excretion of evacetrapib following a single 100-mg oral dose of (14)C-evacetrapib were determined in healthy subjects, and the pharmacokinetics of evacetrapib were evaluated in the presence of strong CYP3A or CYP2C8 inhibitors...
October 2015: Pharmacology Research & Perspectives
V Scott Sharp, Megan A Gokey, Chad N Wolfe, Gregory A Rener, Mary R Cooper
Using multiple HPLC chromatographic modes and various chiral columns in the context of an automated screening system, a potential separation was initially identified for the methyl ester of evacetrapib and its stereoisomers using an immobilized polysaccharide-based HPLC column. The bonded nature of this column, the Chiralpak(®) IC, allows for enhanced separation development with a diverse solvent range not amenable to standard coated chiral stationary phases. The ternary eluent system ultimately identified provided isomer resolutions not obtainable via the more established hexane/alcohol or polar organic chromatographic modes...
October 16, 2015: Journal of Chromatography. A
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