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Evacetrapib

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https://www.readbyqxmd.com/read/28932532/evacetrapib-and-cardiovascular-outcomes-reasons-for-lack-of-efficacy
#1
EDITORIAL
Theodosios D Filippatos, Moses S Elisaf
No abstract text is available yet for this article.
August 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28839974/effect-of-evacetrapib-on-cardiovascular-outcomes-in-patients-with-high-risk-cardiovascular-disease
#2
EDITORIAL
Wilbert S Aronow
No abstract text is available yet for this article.
July 2017: Journal of Thoracic Disease
https://www.readbyqxmd.com/read/28799819/no-cardiovascular-benefit-with-evacetrapib-is-this-the-end-of-the-road-for-the-cetrapibs
#3
Sheila A Doggrell
Increasing high-density lipoprotein(HDL) cholesterol levels predict improved cardiovascular outcomes. However, inhibiting cholesteryl ester transfer protein (CETP) to increase HDL cholesterol, with the 'cetrapibs' (torcetrapib and dalcetrapib), did not improve cardiovascular clinical outcomes. Despite these findings, the clinical outcomes trial with evacetrapib continued. Areas covered: Treatment with evacetrapib increased the levels of HDL by ~130%, and decreased low-density lipoprotein (LDL) cholesterol by ~37%...
October 2017: Expert Opinion on Pharmacotherapy
https://www.readbyqxmd.com/read/28777919/binding-profiles-of-cholesterol-ester-transfer-protein-with-current-inhibitors-a-look-at-mechanism-and-drawback
#4
Zhiwei Yang, Yang Cao, Dongxiao Hao, Xiaohui Yuan, Lei Zhang, Shengli Zhang
Although the pharmacological inhibition of cholesterol ester transport protein (CETP) has been proposed as a method of preventing and treating cardiovascular disease (CVD), the adverse effects of currentinhibitors have cast doubton theinteraction mechanisms of inhibitors and CETP.In response,a molecular dynamicssimulation was used to investigate their interaction and shed light onthe lipid exchange mechanism of CETP.Results showed that torcetrapib, anacetrapib, and evacetrapib can induce the incremental rigidityof CETP, yet decrease the stability of Helix X and the hydrophobic tunnel of CETP, withpassable binding abilities (ΔGbind, -61...
August 4, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28768921/efficacy-and-safety-of-the-cholesteryl-ester-transfer-protein-inhibitor-evacetrapib-in-combination-with-atorvastatin-in-japanese-patients-with-primary-hypercholesterolemia
#5
Tamio Teramoto, Arihiro Kiyosue, Takeshi Iimura, Yasushi Takita, Jeffrey S Riesmeyer, Masahiro Murakami
BACKGROUND: Inhibition of cholesteryl ester transfer protein by evacetrapib when added to atorvastatin may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal.Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel-group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib with atorvastatin in reducing LDL-C in 149 Japanese patients (evacetrapib/atorvastatin, n=53; ezetimibe/atorvastatin, n=50; placebo/atorvastatin, n=46) with primary hypercholesterolemia...
August 3, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/28652529/efficacy-and-safety-of-cholesteryl-ester-transfer-protein-inhibitor-evacetrapib-administered-as-monotherapy-in-japanese-patients-with-primary-hypercholesterolemia
#6
Tamio Teramoto, Arihiro Kiyosue, Takeshi Iimura, Yasushi Takita, Jeffrey S Riesmeyer, Masahiro Murakami
BACKGROUND: Inhibition of cholesteryl ester transfer protein with evacetrapib may provide an additional treatment option for patients who do not reach their low-density lipoprotein cholesterol (LDL-C) goal with statins or patients who cannot tolerate statins.Methods and Results:This multicenter, randomized, 12-week, double-blind, parallel group, placebo-controlled, outpatient, phase 3 study evaluated the efficacy of evacetrapib in reducing LDL-C in 54 Japanese patients (27 evacetrapib, 27 placebo) with primary hypercholesterolemia...
June 23, 2017: Circulation Journal: Official Journal of the Japanese Circulation Society
https://www.readbyqxmd.com/read/28611186/success-failure-and-transparency-in-biomarker-based-drug-development-a-case-study-of-cholesteryl-ester-transfer-protein-inhibitors
#7
Spencer Phillips Hey, Jessica M Franklin, Jerry Avorn, Aaron S Kesselheim
BACKGROUND: Although biomarkers are used as surrogate measures for drug targeting and approval and are generally based on plausible biological hypotheses, some are found to not correlate well with clinical outcomes. Over-reliance on inadequately validated biomarkers in drug development can lead to harm to trial subjects and patients and to research waste. To shed greater light on the process and ethics of biomarker-based drug development, we conducted a systematic portfolio analysis of cholesterol ester transfer protein inhibitors, a drug class designed to improve lipid profiles and prevent cardiovascular events...
June 2017: Circulation. Cardiovascular Quality and Outcomes
https://www.readbyqxmd.com/read/28531833/development-of-an-in-vivo-relevant-drug-product-performance-method-for-an-amorphous-solid-dispersion
#8
Brian W Pack, Yelizaveta Babayan, Mark A Schrad, Paul A Stroud, David C Sperry, Kevin C White, Aktham Aburub
The purpose of this work was to develop a meaningful in vitro dissolution method for evacetrapib spray-dried dispersion (SDD) tablets that is discriminating for crystalline drug substance (DS) content. Justification of the method conditions included evaluation of dissolution media, rotation speed, surfactant selection and level of surfactant to achieve sink conditions. Discrimination was illustrated by testing SDD tablets spiked with 10%, 20%, and 30% crystalline DS. The results demonstrated a 13%, 22% and 32% drop in the dissolution end point, respectively, as compared to unspiked SDD tablets...
May 17, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28514624/evacetrapib-and-cardiovascular-outcomes-in-high-risk-vascular-disease
#9
RANDOMIZED CONTROLLED TRIAL
A Michael Lincoff, Stephen J Nicholls, Jeffrey S Riesmeyer, Philip J Barter, H Bryan Brewer, Keith A A Fox, C Michael Gibson, Christopher Granger, Venu Menon, Gilles Montalescot, Daniel Rader, Alan R Tall, Ellen McErlean, Kathy Wolski, Giacomo Ruotolo, Burkhard Vangerow, Govinda Weerakkody, Shaun G Goodman, Diego Conde, Darren K McGuire, Jose C Nicolau, Jose L Leiva-Pons, Yves Pesant, Weimin Li, David Kandath, Simon Kouz, Naeem Tahirkheli, Denise Mason, Steven E Nissen
BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease...
May 18, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28412650/comparative-effects-of-cholesteryl-ester-transfer-protein-inhibition-statin-or-ezetimibe-on-lipid-factors-the-accentuate-trial
#10
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
https://www.readbyqxmd.com/read/28398632/prenatal-and-postnatal-assessment-in-rabbits-with-evacetrapib-a-cholesteryl-ester-transfer-protein-inhibitor
#11
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 research
https://www.readbyqxmd.com/read/28398618/fertility-and-embryo-fetal-development-assessment-in-rats-and-rabbits-with-evacetrapib-a-cholesteryl-ester-transfer-protein-inhibitor
#12
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 research
https://www.readbyqxmd.com/read/28394617/understanding-the-impact-of-water-on-the-miscibility-and-microstructure-of-amorphous-solid-dispersions-an-afm-lcr-and-tem-edx-study
#13
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
https://www.readbyqxmd.com/read/28152406/anacetrapib-but-not-evacetrapib-impairs-endothelial-function-in-cetp-transgenic-mice-in-spite-of-marked-hdl-c-increase
#14
COMPARATIVE STUDY
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
https://www.readbyqxmd.com/read/28099220/evacetrapib-another-cetp-inhibitor-for-dyslipidemia-with-no-clinical-benefit
#15
REVIEW
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
https://www.readbyqxmd.com/read/27998881/cholesterol-paradox-a-correlate-does-not-a-surrogate-make
#16
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
https://www.readbyqxmd.com/read/27900865/-treatment-of-dyslipidemia-is-here-still-place-for-cetp-inhibitors
#17
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...
December 0: Vnitr̆ní Lékar̆ství
https://www.readbyqxmd.com/read/27512081/cholesteryl-ester-transfer-protein-inhibitors-trials-and-tribulations
#18
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
https://www.readbyqxmd.com/read/27454452/re-evaluation-of-cholesteryl-ester-transfer-protein-function-in-atherosclerosis-based-upon-genetics-and-pharmacological-manipulation
#19
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
https://www.readbyqxmd.com/read/27284735/impact-of-increased-gastric-ph-on-the-pharmacokinetics-of-evacetrapib-in-healthy-subjects
#20
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
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