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Vorapaxar

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https://www.readbyqxmd.com/read/29022423/combination-antiplatelet-treatment-in-coronary-artery-disease-patients-a-necessary-evil-or-an-overzealous-practice
#1
Dimitrios Alexopoulos, Konstantinos Katogiannis, Danai Sfantou, John Lekakis
In seeking to improve care in coronary artery disease patients, further platelet inhibition has been occasionally applied beyond that provided by aspirin and a P2Y12 receptor antagonist. This review aims to offer insights about the rationale, the efficacy and safety of combination antiplatelet therapy, involving three or more agents. Overall, the use of glycoprotein (GP) IIb/IIIa inhibitors did not significantly modify the treatment effect of different antiplatelet strategies, including double vs standard clopidogrel, prasugrel vs clopidogrel, ticagrelor vs clopidogrel, cangrelor vs clopidogrel, and vorapaxar vs placebo...
October 12, 2017: Platelets
https://www.readbyqxmd.com/read/28981200/soluble-fibrin-causes-an-acquired-platelet-glycoprotein-vi-signaling-defect-implications-for-coagulopathy
#2
M Y Lee, C C Verni, B A Herbig, S L Diamond
Essentials Collagen and thrombin when used simultaneously generate highly activated platelets. The effect of thrombin stimulation on subsequent glycoprotein VI (GPVI) function was observed. Soluble fibrin, but not protease activated receptor (PAR) activation, prevented GPVI activation. Circulating soluble fibrin in coagulopathic blood may cause an acquired GPVI signaling defect. SUMMARY: Background In coagulopathic blood, circulating thrombin may drive platelet dysfunction. Methods/Results Using calcium dye-loaded platelets, the effect of thrombin exposure and soluble fibrin generation on subsequent platelet GPVI function was investigated...
October 5, 2017: Journal of Thrombosis and Haemostasis: JTH
https://www.readbyqxmd.com/read/28881236/investigating-detailed-interactions-between-novel-par1-antagonist-f16357-and-the-receptor-using-docking-and-molecular-dynamic-simulations
#3
Carolyn Readmond, Chun Wu
Currently, Vorapaxar is the only recently FDA-approved antiplatelet drug targeting Protease-activated receptor 1 (PAR1). However, a novel antagonist, F16357, has been shown to prevent painful bladder syndrome, also known as interstitial cystitis (IC). Unfortunately, there is no high resolution structure of the F16357-receptor complex, hindering its optimization as a therapeutic agent. In this study, we used docking and molecular dynamic (MD) simulations to investigate the detailed interactions between F16357 and PAR1 at a molecular level...
August 24, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28854078/changes-in-treatment-patterns-and-incremental-health-care-utilization-due-to-p2y12-associated-complications-in-patients-with-acute-coronary-syndrome
#4
Ami Vyas, Lori D Bash, Mehul D Patel, Ross J Simpson
BACKGROUND: P2Y12 antiplatelet therapy (APT) is highly efficacious in reducing the incidence of ischemic events in patients with acute coronary syndrome (ACS); however, it is associated with several adverse complications. Data on P2Y12-associated complications and adherence to APT are sparse. OBJECTIVE: To describe the characteristics, frequency of P2Y12-associated complications, adherence and persistence to P2Y12 APT, and health care utilization among ACS patients on P2Y12 APT...
September 2017: Journal of Managed Care & Specialty Pharmacy
https://www.readbyqxmd.com/read/28818855/paradigm-of-biased-par1-protease-activated-receptor-1-activation-and-inhibition-in-endothelial-cells-dissected-by-phosphoproteomics
#5
Bart L van den Eshof, Arie J Hoogendijk, Pelle J Simpson, Floris P J van Alphen, Sara Zanivan, Koen Mertens, Alexander B Meijer, Maartje van den Biggelaar
OBJECTIVE: Thrombin is the key serine protease of the coagulation cascade and mediates cellular responses by activation of PARs (protease-activated receptors). The predominant thrombin receptor is PAR1, and in endothelial cells (ECs), thrombin dynamically regulates a plethora of phosphorylation events. However, it has remained unclear whether thrombin signaling is exclusively mediated through PAR1. Furthermore, mechanistic insight into activation and inhibition of PAR1-mediated EC signaling is lacking...
October 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28618904/antiplatelet-and-antithrombotic-treatment-for-secondary-prevention-in-ischaemic-heart-disease
#6
Maddalena Lettino, Sergio Leonardi, Elia De Maria, Sigrun Halvorsen
Platelets play a key role in the pathogenesis of acute coronary syndromes and this is why antiplatelet drugs are essential, both in the acute phase and in the long-term follow-up in preventing recurrent myocardial infarction, stroke and cardiovascular death. Aspirin is the most used agent and still remains the first choice drug for lifelong administration in secondary prevention after myocardial infarction. Dual antiplatelet therapy, targeting more than one pathway of platelet activation, has significantly improved the outcome of patients with acute coronary syndromes despite an increased risk of bleeding complications...
June 2017: European Journal of Preventive Cardiology
https://www.readbyqxmd.com/read/28604119/vorapaxar-in-secondary-prevention-where-we-stand
#7
Anastazia Kei, Moses Elisaf
No abstract text is available yet for this article.
July 6, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28565918/role-for-thrombin-receptor-antagonism-with-vorapaxar-in-secondary-prevention-of-atherothrombotic-events-from-bench-to-bedside
#8
Jae Youn Moon, Francesco Franchi, Fabiana Rollini, Dominick J Angiolillo
In spite of treatment with the current standard of care antiplatelet regimens including dual antiplatelet therapy, recurrence rates of ischemic events remain elevated for high-risk patients with atherosclerotic disease. This may be in part attributed to the fact that other key platelet activation pathways remain uninhibited and can thus continue to trigger platelet activation and lead to thrombotic complications. Thrombin is a powerful inducer of platelet activation and mediates its effects directly on platelets through protease activator receptors (PARs), particularly the PAR-1 subtype, making PAR-1 inhibition an attractive approach for reducing atherothrombotic events...
January 1, 2017: Journal of Cardiovascular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28560760/oral-antiplatelet-therapy-impact-for-transfusion-medicine
#9
REVIEW
T Gremmel, S Panzer
Patients on antiplatelet therapy, be it aspirin only, or aspirin in combination with oral adenosine diphosphate (ADP) receptor inhibitors like clopidogrel, prasugrel and ticagrelor, or the protease-activated receptor-1 inhibitor vorapaxar, may develop bleeding or need transient reversal of platelet blockade for acute interventions. In this review, we summarize reports on patients with antiplatelet therapy receiving platelet concentrates due to bleeding, and in vitro experiments estimating the feasibility to restore platelet function by spiking blood from healthy individuals or patients on antiplatelet treatment with noninhibited platelets...
May 30, 2017: Vox Sanguinis
https://www.readbyqxmd.com/read/28558960/targeting-par1-now-what
#10
REVIEW
Robert Flaumenhaft, Karen De Ceunynck
Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs since the 1990s. Vorapaxar and drotrecogin-alfa are approved PAR1-targeted therapeutics, but safety concerns have limited the clinical use of vorapaxar and questions regarding the efficacy of drotrecogin-alfa led to its withdrawal from the market...
August 2017: Trends in Pharmacological Sciences
https://www.readbyqxmd.com/read/28445455/structural-insight-into-allosteric-modulation-of-protease-activated-receptor-2
#11
Robert K Y Cheng, Cédric Fiez-Vandal, Oliver Schlenker, Karl Edman, Birte Aggeler, Dean G Brown, Giles A Brown, Robert M Cooke, Christoph E Dumelin, Andrew S Doré, Stefan Geschwindner, Christoph Grebner, Nils-Olov Hermansson, Ali Jazayeri, Patrik Johansson, Louis Leong, Rudi Prihandoko, Mathieu Rappas, Holly Soutter, Arjan Snijder, Linda Sundström, Benjamin Tehan, Peter Thornton, Dawn Troast, Giselle Wiggin, Andrei Zhukov, Fiona H Marshall, Niek Dekker
Protease-activated receptors (PARs) are a family of G-protein-coupled receptors (GPCRs) that are irreversibly activated by proteolytic cleavage of the N terminus, which unmasks a tethered peptide ligand that binds and activates the transmembrane receptor domain, eliciting a cellular cascade in response to inflammatory signals and other stimuli. PARs are implicated in a wide range of diseases, such as cancer and inflammation. PARs have been the subject of major pharmaceutical research efforts but the discovery of small-molecule antagonists that effectively bind them has proved challenging...
May 4, 2017: Nature
https://www.readbyqxmd.com/read/28403576/no-pharmacokinetic-drug-drug-interaction-between-prasugrel-and-vorapaxar-following-multiple-dose-administration-in-healthy-volunteers
#12
Matt S Anderson, Teddy Kosoglou, Paul Statkevich, Jing Li, Jennifer Rotonda, Alan G Meehan, David L Cutler
Vorapaxar is a first-in-class antagonist of the protease-activated receptor-1, the primary thrombin receptor on human platelets, which mediates the downstream effects of thrombin in hemostasis and thrombosis. Prasugrel is a platelet inhibitor that acts as a P2Y12 receptor antagonist through an active metabolite, R-138727. This study investigated the interaction of these 2 platelet antagonists when coadministered. This was a randomized, open-label, multiple-dose study in 54 healthy volunteers consisting of a fixed-sequence crossover and a parallel group design...
April 12, 2017: Clinical Pharmacology in Drug Development
https://www.readbyqxmd.com/read/28277861/state-transition-model-vorapaxar-added-to-standard-antiplatelet-therapy-to-prevent-thrombosis-post-myocardial-infarction-or-peripheral-artery-disease
#13
Mark Du, Monica Chase, Mustafa Oguz, Glenn Davies
OBJECTIVE: To evaluate long-term health benefits and risks of adding vorapaxar (VOR) to the standard care antiplatelet therapy (SC) of aspirin and/or clopidogrel, among a population with a recent myocardial infarction (MI) and/or peripheral artery disease (PAD). RESEARCH DESIGN AND METHODS: In a state-transition model, patients transition between health states (event-free, recurrent MI, stroke, death), while at risk of experiencing non-transition-related revascularization and non-fatal bleeding events...
March 12, 2017: Current Medical Research and Opinion
https://www.readbyqxmd.com/read/28267691/vorapaxar-and-amyotrophic-lateral-sclerosis-coincidence-or-adverse-association
#14
REVIEW
Victor L Serebruany, Seth D Fortmann, Daniel F Hanley, Moo Hyun Kim
BACKGROUND: Vorapaxar, a novel antiplatelet thrombin PAR-1 inhibitor, is currently approved for post myocardial infarction and peripheral artery disease indications with concomitant use of clopidogrel and/or aspirin. The vorapaxar safety profile was acceptable. However, aside from heightened bleeding risks, excesses of solid cancers and diplopia, there were more amyotrophic lateral sclerosis (ALS) diagnoses after vorapaxar. STUDY QUESTION: To assess the Food and Drug Administration (FDA) reviews on the potential association of vorapaxar with ALS...
March 2017: American Journal of Therapeutics
https://www.readbyqxmd.com/read/28267389/molecular-requirements-involving-the-human-platelet-protease-activated-receptor-4-mechanism-of-activation-by-peptide-analogues-of-its-tethered-ligand
#15
I C Moschonas, T F Kellici, T Mavromoustakos, P Stathopoulos, V Tsikaris, V Magafa, A G Tzakos, A D Tselepis
Thrombin is the most potent agonist of human platelets and its effects are primarily mediated through the protease-activated receptors (PARs)-1 and -4. Although PAR-1 has higher affinity for thrombin than PAR-4, both receptors contribute to thrombin-mediated actions on platelets. Recently, a potent and selective PAR-1 antagonist (vorapaxar) was approved for clinical use in selected patients. In contrast, despite the fact that several PAR-4 antagonists have been developed, few of them have been tested in clinical trials...
December 2017: Platelets
https://www.readbyqxmd.com/read/28230176/antithrombotic-therapy-for-patients-with-stemi-undergoing-primary-pci
#16
REVIEW
Francesco Franchi, Fabiana Rollini, Dominick J Angiolillo
Antithrombotic therapy, including antiplatelet and anticoagulant agents, is the cornerstone of pharmacological treatment to optimize clinical outcomes in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). Intravenous anticoagulant drugs available for PPCI include the indirect thrombin inhibitors unfractionated heparin and low-molecular-weight heparin, and the direct thrombin inhibitor bivalirudin. Intravenous antiplatelet drugs mainly include glycoprotein IIb/IIIa inhibitors and the P2Y12-receptor inhibitor cangrelor...
June 2017: Nature Reviews. Cardiology
https://www.readbyqxmd.com/read/28148395/tissue-factor-factor-viia-complex-triggers-protease-activated-receptor-2-dependent-growth-factor-release-and-migration-in-ovarian-cancer
#17
Alice Chanakira, Pamela R Westmark, Irene M Ong, John P Sheehan
OBJECTIVE: Enhanced tissue factor (TF) expression in epithelial ovarian cancer (EOC) is associated with aggressive disease. Our objective was to evaluate the role of the TF-factor VIIa-protease-activated receptor-2 (PAR-2) pathway in human EOC. METHODS: TCGA RNAseq data from EOC databases were analyzed for PAR expression. Cell and microparticle (MP) associated TF protein expression (Western blot) and MP-associated coagulant activity were determined in human EOC (SKOV-3, OVCAR-3 and CaOV-3) and control cell lines...
April 2017: Gynecologic Oncology
https://www.readbyqxmd.com/read/28135897/pharmacokinetic-drug-evaluation-of-vorapaxar-for-secondary-prevention-after-acute-coronary-syndrome
#18
REVIEW
Jose-Angel Perez-Rivera, Jairo Monedero-Campo, Clara Cieza-Borrella, Pablo Ruiz-Perez
Vorapaxar is the first protease-activated receptor-1 inhibitor approved for clinical use. Its main indication is the reduction in thrombotic cardiovascular events in patients with previous myocardial infarction or symptomatic peripheral artery disease. Areas covered: This article reviews the pharmacokinetics of vorapaxar and its potential use in secondary prevention after an acute coronary syndrome. Expert opinion: Vorapaxar inhibits platelet aggregation mediated by thrombin. This effect is carried out without affecting to coagulation parameters and bleeding times...
March 2017: Expert Opinion on Drug Metabolism & Toxicology
https://www.readbyqxmd.com/read/28063023/vorapaxar-the-current-role-and-future-directions-of-a-novel-protease-activated-receptor-antagonist-for-risk-reduction-in-atherosclerotic-disease
#19
REVIEW
Rebecca J Gryka, Leo F Buckley, Sarah M Anderson
INTRODUCTION: Despite the current standard of care, patients with cardiovascular disease remain at a high risk for recurrent events. Inhibition of thrombin-mediated platelet activation through protease-activated receptor-1 antagonism may provide reductions in atherosclerotic disease beyond those achievable with the current standard of care. OBJECTIVE: Our primary objective is to evaluate the clinical literature regarding the role of vorapaxar (Zontivity™) in the reduction of cardiovascular events in patients with a history of myocardial infarction and peripheral artery disease...
March 2017: Drugs in R&D
https://www.readbyqxmd.com/read/28062625/high-sensitivity-troponin-i-in-stable-patients-with-atherosclerotic-disease-in-the-tra-2%C3%A2-p-timi-50-trial
#20
RANDOMIZED CONTROLLED TRIAL
Alon Eisen, Marc P Bonaca, Petr Jarolim, Benjamin M Scirica, Harvey D White, Michal Tendera, Mikael Dellborg, Jose C Nicolau, Joao Morais, Keith A A Fox, Erin A Bohula, Sabina A Murphy, Eugene Braunwald, David A Morrow
BACKGROUND: Cardiac troponin I, measured with a high-sensitivity assay (hs-TnI), is well-established for risk prediction in acute coronary syndromes. However, its prognostic role in stable atherosclerotic disease, particularly for future myocardial infarction (MI), is less well defined. METHODS: We measured hs-TnI (Abbott ARCHITECT) in 15833 patients with prior MI, ischemic stroke, or peripheral arterial disease from the placebo-controlled Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events (TRA 2°P)-Thrombolysis in Myocardial Infarction (TIMI) 50 trial of the platelet inhibitor vorapaxar, excluding patients with recent MI (<30 days)...
January 2017: Clinical Chemistry
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