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https://www.readbyqxmd.com/read/28343601/effects-of-rg7652-a-monoclonal-antibody-against-pcsk9-on-ldl-c-ldl-c-subfractions-and-inflammatory-biomarkers-in-patients-at-high-risk-of-or-with-established-coronary-heart-disease-from-the-phase-2-equator-study
#1
Amos Baruch, Sofia Mosesova, John D Davis, Nageshwar Budha, Alexandr Vilimovskij, Robert Kahn, Kun Peng, Kyra J Cowan, Laura Pascasio Harris, Thomas Gelzleichter, Josh Lehrer, John C Davis, Whittemore G Tingley
RG7652 (MPSK3169A), a fully human immunoglobulin G1 (IgG1) monoclonal antibody directed against proprotein convertase subtilisin/kexin type 9 (PCSK9), blocks the interaction between PCSK9 and low-density lipoprotein (LDL) receptor. EQUATOR (ClinicalTrials.govNCT01609140), a randomized, double-blind, and dose-ranging phase 2 study, evaluated RG7652 in patients (1) at high risk for or (2) with coronary heart disease (CHD). The primary end point was change in LDL cholesterol (LDL-C) from baseline to day 169. Patients (n = 248; median age, 64 years; 57% men; 52% with established CHD; 82% on statins) with baseline LDL-C levels of 90 to 250 mg/dl (mean, 126 mg/dl) continuing on standard-of-care therapy were randomized to receive 1 of 5 RG7652 doses or placebo, subcutaneously every 4, 8, or 12 weeks for 24 weeks...
March 1, 2017: American Journal of Cardiology
https://www.readbyqxmd.com/read/28341307/the-efficacy-advantage-of-evolocumab-amg-145-dosed-at-140mg-every-2weeks-versus-420mg-every-4weeks-in-patients-with-hypercholesterolemia-evidence-from-a-meta-analysis
#2
Xiao-Xiao He, Rong Zhang, Pei-Yuan Zuo, Yu-Wei Liu, Xiang-Nan Zha, Sheng-Shuai Shan, Cheng-Yun Liu
BACKGROUND: Evolocumab (AMG 145), a PCSK9 inhibitor, has been shown to decrease low-density lipoprotein cholesterol (LDL-C) levels. Doses of 140mg administered every 2weeks (Q2W) and 420mg administered every 4weeks (Q4W) are widely used, and both dosing schedules were effective in clinical trials. However, some researchers have speculated that 140mg Q2W administration has equal or even greater efficacy. This meta-analysis was performed to assess the differences in efficacy and safety between the two doses...
March 2017: European Journal of Internal Medicine
https://www.readbyqxmd.com/read/28337713/the-potential-role-of-fibroblast-growth-factor-21-in-lipid-metabolism-and-hypertension
#3
REVIEW
Zhe Huang, Aimin Xu, Bernard M Y Cheung
Fibroblast growth factor (FGF) 21 belongs to the FGF superfamily that is involved in cell proliferation and differentiation, neural development, angiogenesis, and metabolism. FGF21 requires β-Klotho as a co-receptor. Tissues involved in metabolism such as the liver, adipose tissues, skeletal muscle, and pancreas express FGF21. Starvation increases hepatic expression of FGF21, which then acts centrally to increase hepatic gluconeogenesis. FGF21 also increases fatty acid oxidation. This may be relevant in cold exposure, when expression of FGF21 is induced...
April 2017: Current Hypertension Reports
https://www.readbyqxmd.com/read/28336922/novel-and-traditional-lipid-related-biomarkers-and-their-combinations-in-predicting-coronary-severity
#4
Sha Li, Yuan-Lin Guo, Xi Zhao, Yan Zhang, Cheng-Gang Zhu, Na-Qiong Wu, Rui-Xia Xu, Ping Qing, Ying Gao, Xiao-Lin Li, Jing Sun, Geng Liu, Qian Dong, Jian-Jun Li
We investigated simultaneously traditional and novel lipid indices, alone or in combination, in predicting coronary severity assessed by Gensini score (GS) in 1605 non-lipid-lowering-drug-treated patients undergoing coronary angiography. Firstly, levels of triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), non high density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, lipoprotein (a) [Lp(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC3, small dense LDL (sdLDL) and large HDL were increased, while HDL-C and apoA1 levels were decreased as GS status (all p for trend <0...
March 23, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28334053/new-insights-of-altered-lipid-profile-in-fragile-x-syndrome
#5
Artuela Çaku, Nabil G Seidah, Audrey Lortie, Nancy Gagné, Patrice Perron, Jean Dubé, Francois Corbin
BACKGROUND: Fragile X Syndrome (FXS) is the main genetic cause of autism and intellectual deficiency resulting the absence of the Fragile X Mental Retardation Protein (FMRP). Clinical picture is characterized by cognitive impairment associated with a broad spectrum of psychiatric comorbidities including autism spectrum disorders and attention-deficit/hyperactivity disorders. Some of these disorders have been associated with lipid abnormalities and lower cholesterol levels. Since lipids are important for neuronal development, we aim to investigate the lipid profile of French Canadian-FXS individuals and to identify the altered components of cholesterol metabolism as well as their association with clinical profile...
2017: PloS One
https://www.readbyqxmd.com/read/28331223/therapeutic-efficacy-and-safety-of-pcsk9-monoclonal-antibodies-on-familial-hypercholesterolemia-and-statin-intolerant-patients-a-meta-analysis-of-15-randomized-controlled-trials
#6
Li Jun Qian, Yao Gao, Yan Mei Zhang, Ming Chu, Jing Yao, Di Xu
Proprotein convertase subtilisin/kexin9 monoclonal antibodies (PCSK9-mAb) have been studied intensively to identify their effect in lowering levels of low density lipoprotein cholesterol (LDL-C). However, the applicable target of PCSK9-mAbs remains inconclusive so far. Therefore, this first meta-analysis was carried out to clarify the therapeutic efficacy and safety of PCSK9-mAbs on the potential patients: familial hypercholesterolemia and statin-intolerant patients. All randomized controlled trials that met the search terms were retrieved in multiple databases...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28330911/pcsk9-variant-long-chain-n-3-pufas-and-risk-of-nonfatal-myocardial-infarction-in-costa-rican-hispanics
#7
Zhi Yu, Tao Huang, Yan Zheng, Tiange Wang, Yoriko Heianza, Dianjianyi Sun, Hannia Campos, Lu Qi
Background: Previous studies have indicated that the cardioprotective effects of long-chain (LC) n-3 (ω-3) polyunsaturated fatty acids (PUFAs) may vary across various ethnic populations. Emerging evidence has suggested that the gene-environment interaction may partly explain such variations. Proprotein convertase subtilisin/kexin type 9 (PCSK9) was shown to have a mutually regulating relation with LC n-3 PUFAs and also to reduce the risk of cardiovascular diseases (CVDs). Therefore, we hypothesized that certain PCSK9 genetic variants may modify the association between LC n-3 PUFA intake and CVD risk...
March 22, 2017: American Journal of Clinical Nutrition
https://www.readbyqxmd.com/read/28329241/lipoprotein-a-the-revenant
#8
Baris Gencer, Florian Kronenberg, Erik S Stroes, François Mach
In the mid-1990s, the days of lipoprotein(a) [Lp(a)] were numbered and many people would not have placed a bet on this lipid particle making it to the next century. However, genetic studies brought Lp(a) back to the front-stage after a Mendelian randomization approach used for the first time provided strong support for a causal role of high Lp(a) concentrations in cardiovascular disease and later also for aortic valve stenosis. This encouraged the use of therapeutic interventions to lower Lp(a) as well numerous drug developments, although these approaches mainly targeted LDL cholesterol, while the Lp(a)-lowering effect was only a 'side-effect'...
February 17, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28329114/pcsk9-monoclonal-antibodies-reverse-the-pro-inflammatory-profile-of-monocytes-in-familial-hypercholesterolaemia
#9
Sophie J Bernelot Moens, Annette E Neele, Jeffrey Kroon, Fleur M van der Valk, Jan Van den Bossche, Marten A Hoeksema, Renate M Hoogeveen, Johan G Schnitzler, Marie T Baccara-Dinet, Garen Manvelian, Menno P J de Winther, Erik S G Stroes
Aims: Migration of monocytes into the arterial wall contributes to arterial inflammation and atherosclerosis progression. Since elevated low-density lipoprotein cholesterol (LDL-C) levels have been associated with activation of plasma monocytes, intensive LDL-C lowering may reverse these pro-inflammatory changes. Using proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies (mAbs) which selectively reduce LDL-C, we studied the impact of LDL-C lowering on monocyte phenotype and function in patients with familial hypercholesterolaemia (FH) not using statins due to statin-associated muscle symptoms...
February 18, 2017: European Heart Journal
https://www.readbyqxmd.com/read/28328015/pcsk9-inhibitor-access-barriers-issues-and-recommendations-improving-the-access-process-for-patients-clinicians-and-payers
#10
REVIEW
Seth J Baum, Peter P Toth, James A Underberg, Paul Jellinger, Joyce Ross, Katherine Wilemon
The proprotein convertase subtilisin/kexin type 9 inhibitors or monoclonal antibodies likely represent the greatest advance in lipid management in 30 years. In 2015 the US Food and Drug Administration approved both alirocumab and evolocumab for high-risk patients with familial hypercholesterolemia (FH) and clinical atherosclerotic cardiovascular disease requiring additional lowering of low-density lipoprotein cholesterol. Though many lipid specialists, cardiovascular disease prevention experts, endocrinologists, and others prescribed the drugs on label, they found their directives denied 80% to 90% of the time...
March 22, 2017: Clinical Cardiology
https://www.readbyqxmd.com/read/28326559/a-phase-1-study-to-evaluate-the-safety-and-ldl-cholesterol-lowering-effects-of-rg7652-a-fully-human-monoclonal-antibody-against-proprotein-convertase-subtilisin-kexin-type-9
#11
Amos Baruch, Diana Luca, Robert S Kahn, Kyra J Cowan, Maya Leabman, Nageshwar R Budha, Cecilia P C Chiu, Yan Wu, Daniel Kirchhofer, Andrew Peterson, John C Davis, Whittemore G Tingley
BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) downregulates low-density lipoprotein (LDL) receptors, thereby leading to a rise in circulating LDL cholesterol (LDL-C). RG7652 is a fully human monoclonal antibody against PCSK9. This placebo-controlled, phase 1 ascending-dose study in healthy subjects evaluated the safety of RG7652 and its efficacy as a potential LDL-C-lowering drug. HYPOTHESIS: Anti-PCSK9 antibody therapy safely and effectively reduces LDL-C...
March 22, 2017: Clinical Cardiology
https://www.readbyqxmd.com/read/28325524/current-status-of-lipid-management-in-acute-coronary-syndrome
#12
REVIEW
Koichiro Fujisue, Kenichi Tsujita
The development of coronary revascularization has dramatically improved early cardiovascular outcomes in patients with acute coronary syndrome (ACS). However, patients who have experienced myocardial infarction (MI) are at high risk of recurrence of cardiovascular events compared with those who are healthy or have stable coronary artery disease. Acute coronary events induce further inflammatory responses and plaque vulnerability in either a coronary culprit or whole vessels. The majority of data have supported the importance of coronary risk management to prevent secondary events...
March 18, 2017: Journal of Cardiology
https://www.readbyqxmd.com/read/28323820/selective-stalling-of-human-translation-through-small-molecule-engagement-of-the-ribosome-nascent-chain
#13
Nathanael G Lintner, Kim F McClure, Donna Petersen, Allyn T Londregan, David W Piotrowski, Liuqing Wei, Jun Xiao, Michael Bolt, Paula M Loria, Bruce Maguire, Kieran F Geoghegan, Austin Huang, Tim Rolph, Spiros Liras, Jennifer A Doudna, Robert G Dullea, Jamie H D Cate
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in regulating the levels of plasma low-density lipoprotein cholesterol (LDL-C). Here, we demonstrate that the compound PF-06446846 inhibits translation of PCSK9 by inducing the ribosome to stall around codon 34, mediated by the sequence of the nascent chain within the exit tunnel. We further show that PF-06446846 reduces plasma PCSK9 and total cholesterol levels in rats following oral dosing. Using ribosome profiling, we demonstrate that PF-06446846 is highly selective for the inhibition of PCSK9 translation...
March 2017: PLoS Biology
https://www.readbyqxmd.com/read/28323660/impact-of-rare-variants-in-autosomal-dominant-hypercholesterolemia-causing-genes
#14
Sebastiano Calandra, Patrizia Tarugi, Stefano Bertolini
PURPOSE OF REVIEW: The systematic analysis of the major candidate genes in autosomal dominant hypercholesterolemia (ADH) and the use of next-generation sequencing (NGS) technology have made possible the discovery of several rare gene variants whose pathogenic effect in most cases remains poorly defined. RECENT FINDINGS: One major advance in the field has been the adoption of a set of international guidelines for the assignment of pathogenicity to low-density lipoprotein receptor (LDLR) gene variants based on the use of softwares, complemented with data available from literature and public databases...
March 18, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28306389/inclisiran-in-patients-at-high-cardiovascular-risk-with-elevated-ldl-cholesterol
#15
Kausik K Ray, Ulf Landmesser, Lawrence A Leiter, David Kallend, Robert Dufour, Mahir Karakas, Tim Hall, Roland P T Troquay, Traci Turner, Frank L J Visseren, Peter Wijngaard, R Scott Wright, John J P Kastelein
Background In a previous study, a single injection of inclisiran, a chemically synthesized small interfering RNA designed to target PCSK9 messenger RNA, was found to produce sustained reductions in low-density lipoprotein (LDL) cholesterol levels over the course of 84 days in healthy volunteers. Methods We conducted a phase 2, multicenter, double-blind, placebo-controlled, multiple-ascending-dose trial of inclisiran administered as a subcutaneous injection in patients at high risk for cardiovascular disease who had elevated LDL cholesterol levels...
March 17, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28304296/pcsk9-promotes-oxldl-induced-pc12-cell-apoptosis-through-the-bcl-2-bax-caspase-9-3-signaling-pathway
#16
Lu-Shan Liu, Xue-Qin Bai, Ya Gao, Qi Wu, Zhong Ren, Qing Li, Li-Hong Pan, Ni-Ya He, Juan Peng, Zhi-Han Tang
BACKGROUND: Hyperlipidemia is a risk factor for neurodegenerative diseases. Proprotein convertase subtilisin / Kexin type 9 (PCSK9) degrades hepatic low-density lipoprotein receptor (LDLR) to regulate lipid metabolism. It is unclear if PCSK9 plays a role in neurodegenerative diseases. OBJECTIVE: This study was designed to determine whether PCSK9 is crucial between hyperlipidemia and Alzheimer's disease. The interrelationship between PCSK9 and neuronal apoptosis was explored in PC12 cells in response to treatment with oxidized low-density lipoprotein (oxLDL)...
March 10, 2017: Journal of Alzheimer's Disease: JAD
https://www.readbyqxmd.com/read/28304242/cardiovascular-efficacy-and-safety-of-bococizumab-in-high-risk-patients
#17
Paul M Ridker, James Revkin, Pierre Amarenco, Robert Brunell, Madelyn Curto, Fernando Civeira, Marcus Flather, Robert J Glynn, Jean Gregoire, J Wouter Jukema, Yuri Karpov, John J P Kastelein, Wolfgang Koenig, Alberto Lorenzatti, Pravin Manga, Urszula Masiukiewicz, Michael Miller, Arend Mosterd, Jan Murin, Jose C Nicolau, Steven Nissen, Piotr Ponikowski, Raul D Santos, Pamela F Schwartz, Handrean Soran, Harvey White, R Scott Wright, Michal Vrablik, Carla Yunis, Charles L Shear, Jean-Claude Tardif
Background Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. Methods In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo...
March 17, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28304233/pcsk9-inhibition-to-reduce-cardiovascular-events
#18
Robin P F Dullaart
No abstract text is available yet for this article.
March 17, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28304227/lipid-reduction-variability-and-antidrug-antibody-formation-with-bococizumab
#19
Paul M Ridker, Jean-Claude Tardif, Pierre Amarenco, William Duggan, Robert J Glynn, J Wouter Jukema, John J P Kastelein, Albert M Kim, Wolfgang Koenig, Steven Nissen, James Revkin, Lynda M Rose, Raul D Santos, Pamela F Schwartz, Charles L Shear, Carla Yunis
Background Bococizumab, a humanized monoclonal antibody targeting proprotein convertase subtilisin-kexin type 9 (PCSK9), reduces levels of low-density lipoprotein (LDL) cholesterol. However, the variability and durability of this effect are uncertain. Methods We conducted six parallel, multinational lipid-lowering trials enrolling 4300 patients with hyperlipidemia who were randomly assigned to receive 150 mg of bococizumab or placebo subcutaneously every 2 weeks and who were followed for up to 12 months; 96% were receiving statin therapy at the time of enrollment...
March 17, 2017: New England Journal of Medicine
https://www.readbyqxmd.com/read/28304224/evolocumab-and-clinical-outcomes-in-patients-with-cardiovascular-disease
#20
Marc S Sabatine, Robert P Giugliano, Anthony C Keech, Narimon Honarpour, Stephen D Wiviott, Sabina A Murphy, Julia F Kuder, Huei Wang, Thomas Liu, Scott M Wasserman, Peter S Sever, Terje R Pedersen
Background Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. Methods We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy...
March 17, 2017: New England Journal of Medicine
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