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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
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
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
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
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...
November 21, 2017: VASA. Zeitschrift Für Gefässkrankheiten
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
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
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
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
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
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
Anastazia Kei, Moses Elisaf
No abstract text is available yet for this article.
July 6, 2017: Current Medical Research and Opinion
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
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
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
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
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
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
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
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
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