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Vorapaxar

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https://www.readbyqxmd.com/read/29774092/vorapaxar-treatment-reduces-mesangial-expansion-in-streptozotocin-induced-diabetic-nephropathy-in-mice
#1
Maaike Waasdorp, JanWillem Duitman, Sandrine Florquin, C Arnold Spek
Background: Twenty years after the onset of diabetes, up to 40% of patients develop diabetic nephropathy. Protease-activated receptor-1 (PAR-1) has recently been shown to aggravate the development of experimental diabetic nephropathy. PAR-1 deficient mice develop less albuminuria and glomerular lesions and PAR-1 stimulation induces proliferation and fibronectin production in mesangial cells in vitro . Vorapaxar is a clinically available PAR-1 inhibitor which is currently used for secondary prevention of ischemic events...
April 24, 2018: Oncotarget
https://www.readbyqxmd.com/read/29763961/the-novel-protease-activated-receptor-1-antagonist-vorapaxar-as-a-treatment-for-thrombosis-in-afibrinogenemia
#2
Bernard Tawfik, Elizabeth Pollard, Yu-Min Shen
No abstract text is available yet for this article.
May 15, 2018: Seminars in Thrombosis and Hemostasis
https://www.readbyqxmd.com/read/29747915/prognostic-and-practical-validation-of-current-definitions-of-myocardial-infarction-associated-with-percutaneous-coronary-intervention
#3
Pierluigi Tricoci, L Kristin Newby, Robert M Clare, Sergio Leonardi, C Michael Gibson, Robert P Giugliano, Paul W Armstrong, Frans Van de Werf, Gilles Montalescot, David J Moliterno, Claes Held, Philip E Aylward, Lars Wallentin, Robert A Harrington, Eugene Braunwald, Kenneth W Mahaffey, Harvey D White
OBJECTIVES: In 13,038 patients with non-ST-segment elevation acute coronary syndrome undergoing index percutaneous coronary intervention (PCI) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Non-ST-Segment Elevation Acute Coronary Syndrome) and TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trials, the relationship between PCI-related myocardial infarction (MI) and 1-year mortality was assessed. BACKGROUND: The definition of PCI-related MI is controversial...
May 14, 2018: JACC. Cardiovascular Interventions
https://www.readbyqxmd.com/read/29731231/structural-properties-of-the-human-protease-activated-receptor-1-changing-by-a-strong-antagonist
#4
Patrizia M Spoerri, Hideaki E Kato, Moritz Pfreundschuh, Stefania A Mari, Tetiana Serdiuk, Johannes Thoma, K Tanuj Sapra, Cheng Zhang, Brian K Kobilka, Daniel J Müller
The protease-activated receptor 1 (PAR1), a G protein-coupled receptor (GPCR) involved in hemostasis, thrombosis, and inflammation, is activated by thrombin or other coagulation proteases. This activation is inhibited by the irreversible antagonist vorapaxar used for anti-platelet therapy. Despite detailed structural and functional information, how vorapaxar binding alters the structural properties of PAR1 to prevent activation is hardly known. Here we apply dynamic single-molecule force spectroscopy to characterize how vorapaxar binding changes the mechanical, kinetic, and energetic properties of human PAR1 under physiologically relevant conditions...
April 17, 2018: Structure
https://www.readbyqxmd.com/read/29685684/characterization-of-protease-activated-receptor-par-ligands-parmodulins-are-reversible-allosteric-inhibitors-of-par1-driven-calcium-mobilization-in-endothelial-cells
#5
Disha M Gandhi, Mark W Majewski, Ricardo Rosas, Kaitlin Kentala, Trevor J Foster, Eric Greve, Chris Dockendorff
Several classes of ligands for Protease-Activated Receptors (PARs) have shown impressive anti-inflammatory and cytoprotective activities, including PAR2 antagonists and the PAR1-targeting parmodulins. In order to support medicinal chemistry studies with hundreds of compounds and to perform detailed mode-of-action studies, it became important to develop a reliable PAR assay that is operational with endothelial cells, which mediate the cytoprotective effects of interest. We report a detailed protocol for an intracellular calcium mobilization assay with adherent endothelial cells in multiwell plates that was used to study a number of known and new PAR1 and PAR2 ligands, including an alkynylated version of the PAR1 antagonist RWJ-58259 that is suitable for the preparation of tagged or conjugate compounds...
April 6, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29564693/clinical-effects-with-inhibition-of-multiple-coagulative-pathways-in-patients-admitted-for-acute-coronary-syndrome
#6
REVIEW
Ilaria Cavallari, Giuseppe Patti
Platelets and the coagulation cascade play key roles in initiation, amplification, and perpetuation of acute coronary syndromes (ACS). In the past few years, there has been great progress in ACS antithrombotic treatment with the introduction of novel anticoagulants (fondaparinux and bivalirudin), more potent P2Y12 inhibitors (prasugrel and ticagrelor) and protease-activated receptor antagonists (vorapaxar). Nonetheless, patients with ACS frequently have recurrent ischemic events despite the use of currently recommended dual antiplatelet therapy, revascularization procedures as appropriate, and other evidence-based secondary preventive measures...
March 21, 2018: Internal and Emergency Medicine
https://www.readbyqxmd.com/read/29514266/sch79797-improves-outcomes-in-experimental-bacterial-pneumonia-by-boosting-neutrophil-killing-and-direct-antibiotic-activity
#7
Naveen Gupta, Roland Liu, Stephanie Shin, Ranjeet Sinha, Joseph Pogliano, Kit Pogliano, John H Griffin, Victor Nizet, Ross Corriden
Objectives: The role of protease-activated receptor 1 (PAR1) in the pathogenesis of pneumonia and sepsis is ambiguous given the existing literature. As PAR1 is classically activated by the coagulation-based protease thrombin and leads to vascular leakage, our hypothesis was that PAR1 blockade with SCH79797 would be therapeutically beneficial in an experimental model of murine Gram-negative pneumonia. Methods: In this study, we administered SCH79797 via the intrapulmonary route 6 h after the establishment of Escherichia coli pneumonia and observed a significant improvement in survival, lung injury, bacterial clearance and inflammation...
March 5, 2018: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/29485009/oral-submucous-fibrosis-as-an-overhealing-wound-implications-in-malignant-transformation
#8
Mohit Sharma, Smitha Sammith Shetty, Raghu Radhakrishnan
BACKGROUND: Oral submucous fibrosis is an oral potentially malignant disorder with high incidence of malignant transformation and rising global prevalence. However, the genesis of oral submucous fibrosis is still unclear despite superfluity of literature. In the background of ineffective treatment, it is necessary to decode its onset and progression before designing customized treatment regimens. OBJECTIVE: The objective of this article is to decipher the pathogenesis of oral submucous fibrosis in order to identify novel drug targets...
February 26, 2018: Recent Patents on Anti-cancer Drug Discovery
https://www.readbyqxmd.com/read/29471161/peripheral-artery-disease-and-antiplatelet-treatment
#9
REVIEW
Vasiliki Tsigkou, Gerasimos Siasos, Kleanthis Rovos, Niki Tripyla, Dimitris Tousoulis
Peripheral artery disease (PAD) is one of the most important causes of cardiovascular morbidity and mortality and its prevalence is alarmingly increasing in modern societies. PAD shares common characteristics with the other atherosclerotic diseases but involves specifically the arteries of the lower extremities. Apart from the changes in lifestyle, antiplatelet agents are the hallmark of the treatment and improve the symptoms as well as the progression of the disease. Aspirin is the cornerstone of treatment and is administrated in doses ranging from 75 to 325mg daily...
February 19, 2018: Current Opinion in Pharmacology
https://www.readbyqxmd.com/read/29345587/is-there-a-role-for-oral-triple-therapy-in-patients-with-acute-coronary-syndromes-without-atrial-fibrillation
#10
Nikolaos Spinthakis, Mohamed Farag, Zaki Akhtar, Diana Adrienne Gorog
BACKGROUND: Acute coronary syndrome (ACS) patients, despite treatment with dual antiplatelet therapy (DAPT), have up to 10% risk of recurrent major adverse cardiac events (MACE) in the short term. METHODS: Here we review studies using more potent antithrombotic agent combinations to reduce this risk, namely triple therapy (TT) with the addition of an oral anticoagulant, PAR-1 antagonist, or cilostazol to DAPT (mainly aspirin and clopidogrel), and discuss the limitations of trials to date...
January 16, 2018: Current Vascular Pharmacology
https://www.readbyqxmd.com/read/29160765/antithrombotic-treatment-in-peripheral-artery-disease
#11
REVIEW
Dan-Mircea Olinic, Dan Alexandru Tataru, Calin Homorodean, Mihail Spinu, Maria Olinic
This review treats antithrombotic use for peripheral arterial disease (PAD). In asymptomatic patients, there are no scientific data to support single antiplatelet therapy (SAPT) for primary prophylaxis. In symptomatic PAD, SAPT with aspirin or clopidogrel is indicated. The efficacy of aspirin is controversial. Clopidogrel may be preferred over aspirin. Ticagrelor is not superior to clopidogrel in reducing major adverse cardiovascular events and major adverse limb events, but lowers the risk of ischaemic stroke...
February 2018: VASA. Zeitschrift Für Gefässkrankheiten
https://www.readbyqxmd.com/read/29022423/combination-antiplatelet-treatment-in-coronary-artery-disease-patients-a-necessary-evil-or-an-overzealous-practice
#12
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
#13
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...
December 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
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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 2018: Journal of Cardiovascular Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28560760/oral-antiplatelet-therapy-impact-for-transfusion-medicine
#20
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...
August 2017: Vox Sanguinis
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