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Factor Xa inhibitors

Raffaele De Caterina, Peter Kelly, Pedro Monteiro, Jean Claude Deharo, Carlo de Asmundis, Esteban López-de-Sá, Thomas W Weiss, Johannes Waltenberger, Jan Steffel, Joris R de Groot, Pierre Levy, Ameet Bakhai, Wolfgang Zierhut, Petra Laeis, Paul-Egbert Reimitz, Paulus Kirchhof
AIM: Edoxaban, a nonvitamin K antagonist oral anticoagulant, is an oral factor Xa inhibitor approved for the prevention of stroke and systemic embolism in adult patients with atrial fibrillation and for the treatment and secondary prevention in adult patients with venous thromboembolism (VTE). This study details the design of the Edoxaban Treatment in routiNe clinical prActice for patients with Atrial Fibrillation in Europe (ETNA-AF-Europe) study - a postauthorization observational study, which is part of the postapproval plan for edoxaban agreed with the European Medicines Agency...
December 11, 2018: Journal of Cardiovascular Medicine
Cesar de Oliveira, Haoyu S Yu, Wei Chen, Robert Abel, Lingle Wang
Accurate prediction of ligand binding affinities is of key importance in lead optimization and a central task in computational medicinal chemistry. Over the years, advances in both computer hardware and computational methodologies have established free energy perturbation (FEP) methods as among the most reliable and rigorous approaches to compute protein-ligand binding free energies. However, accurate description of ionization and tautomerism of ligands is still a major challenge in structure-based prediction of binding affinities...
December 11, 2018: Journal of Chemical Theory and Computation
Simran Kaur, Arpita Devi, Bhaskarjyoti Saikia, Robin Doley
Trancriptomic analysis of the venom gland cDNA library of Bungarus flaviceps revealed Kunitz-type serine protease inhibitor as one of the major venom protein families with three groups A, B, C. One of the group B isoforms named Flavikunin, which lacked an extra cysteine residue involved in disulfide bond formation in β-bungarotoxin, was synthesized, cloned, and overexpressed in Escherichia coli. To decipher the structure-function relationship, the P1 residue of Flavikunin, histidine, was mutated to alanine and arginine...
December 10, 2018: Journal of Biochemical and Molecular Toxicology
Carmelo Lafuente-Lafuente, Christel Oasi, Joël Belmin
Vitamin-K antagonists (VKA) have been the standard for oral anticoagulation. However, they carry several problems in older patients: frequent bleeding complications, complex management, risk of interactions with multiple drugs. Two classes of direct oral anticoagulants (DOA) are currently available in France: (a) direct thrombin inhibitors: dabigatran; and (b) direct factor Xa inhibitors: rivaroxaban, apixaban and others. Their management is easier: quickly effective after administration, they are given at fixed doses and do not need regular laboratory monitoring...
December 7, 2018: La Presse Médicale
Pavel Roudnický, Jiří Vorel, Jana Ilgová, Michal Benovics, Adam Norek, Lucie Jedličková, Libor Mikeš, David Potěšil, Zbyněk Zdráhal, Jan Dvořák, Milan Gelnar, Martin Kašný
BACKGROUND: Serpins are a superfamily of serine peptidase inhibitors that participate in the regulation of many physiological and cell peptidase-mediated processes in all organisms (e.g. in blood clotting, complement activation, fibrinolysis, inflammation, and programmed cell death). It was postulated that in the blood-feeding members of the monogenean family Diplozoidae, serpins could play an important role in the prevention of thrombus formation, activation of complement, inflammation in the host, and/or in the endogenous regulation of protein degradation...
2018: Parasite: Journal de la Société Française de Parasitologie
Jürgen Koscielny, Christoph Rosenthal, Christian von Heymann
Despite the widespread use of DOAC and recommendations of regulatory agencies and first consensus meetings on handling of bleeding situation under DOAC uncertainty still exists. In case of mild bleeding, the medical care of these patients and the delay of the next dose is advised. A laboratory analysis is indicated i. e. in case of known higher grade liver and kidney failure. The administration of factor concentrates or antidots is not indicated in this situation. In case of moderate to severe bleeding, the primary focus lies on stabilization of cardiopulmonary and circulatory function and parallel on the treatment depending on the localization of the bleeding source...
December 2018: Deutsche Medizinische Wochenschrift
Syed Mahamad, Hina Chaudhry, Rosane Nisenbaum, Amanda McFarlan, Sandro Rizoli, Alun Ackery, Michelle Sholzberg
Direct oral anticoagulants (DOACs) have become the standard for thromboembolic risk management. In cases of major bleeding, trauma, or urgent surgery, accurate monitoring of DOAC activity is desirable; however, there is often no rapid, readily available test. We therefore explored the degree to which DOAC activity correlated with two coagulation assays: rotational thromboelastometry (ROTEM) and a standard coagulation assay in bleeding patients. We conducted a retrospective review of patients who experienced bleeding while on DOAC therapy from 2015 to 2017 at a Level 1 trauma center...
November 30, 2018: Journal of Thrombosis and Thrombolysis
Francielle Almeida Cordeiro, Bárbara Marques Coutinho, Gisele Adriano Wiezel, Karla de Castro Figueiredo Bordon, Cristiane Bregge-Silva, Nathalia Gonsales Rosa-Garzon, Hamilton Cabral, Beatrix Ueberheide, Eliane Candiani Arantes
Background: Lachesis muta rhombeata (Lmr) is the largest venomous snake in Latin America and its venom contains mainly enzymatic components, such as serine and metalloproteases, L-amino acid oxidase and phospholipases A2 . Metalloproteases comprise a large group of zinc-dependent proteases that cleave basement membrane components such as fibronectin, laminin and collagen type IV. These enzymes are responsible for local and systemic changes, including haemorrhage, myonecrosis and inflammation...
2018: Journal of Venomous Animals and Toxins Including Tropical Diseases
Eduardo Ramacciotti, Valéria Cristina Resende Aguiar, Valter Castelli Júnior, Ivan Benaducce Casella, Antonio Eduardo Zerati, Jawed Fareed
Edoxaban, a direct factor Xa inhibitor (FXa), is the fourth direct oral anticoagulant (DOAC) approved for clinical use in the treatment of venous thromboembolism (VTE) in Latin America, following global approvals for this indication. Edoxaban features some particular characteristics when compared to the previously approved DOACs. This review summarizes the main properties of edoxaban, the outcomes results of its pivotal global clinical trials and the peculiar clinical features of this compound. This practical guide aims to help Latin America clinicians understand edoxaban, its proper indication and its use for the appropriate patients with VTE...
November 28, 2018: Clinical and Applied Thrombosis/hemostasis
Jenna Khan, Wayne L Chandler
Objectives: To determine the relationship between baseline variations in the partial thromboplastin time (PTT) and the discordance between the PTT and anti-Xa heparin activity (anti-Xa) during heparin therapy. Methods: The baseline PTT on heparin was determined using automated heparin neutralization with protamine (prPTT). The prPTT was used to calculate a baseline-corrected PTT on heparin to reduce discordance with anti-Xa measurements. Results: The prPTT removed up to 1 U/mL of heparin, returning baseline values for normal, factor-deficient, and lupus inhibitor plasmas...
November 25, 2018: American Journal of Clinical Pathology
A Franco-Moreno, L Cabezón-Gutiérrez, M Palka-Kotlowsa, M Villamayor-Delgado, M García-Navarro
Cancer is associated with an increased risk of venous thromboembolism of four to sixfold. Cancer-related interventions such as chemotherapy, hormonal therapy and indwelling central venous catheters also increase the risk of venous thromboembolism. Low molecular weight heparin for at least 3-6 months is the current standard of care for the treatment of cancer associated venous thromboembolism. Anticoagulation should be continued as long as the cancer is active. Over the past few years, direct oral anticoagulants have emerged, including one direct thrombin inhibitor (dabigatran etexilate) and three factor Xa inhibitors (apixaban, edoxaban and rivaroxaban)...
November 22, 2018: Journal of Thrombosis and Thrombolysis
Michael Levine, Anthony Pizon, Michael Beuhler, F Lee Cantrell, Frank LoVecchio, Meghan Spyres, Aaron B Skolnik, Daniel E Brooks
BACKGROUND: Historically, anticoagulants and antiplatelet agents included warfarin and aspirin, respectively. In recent years, numerous novel anticoagulants (eg, direct thrombin inhibitors and factor Xa inhibitors) as well as the adenosine diphosphate receptor antagonists have increased significantly. Little information on the bleeding risk after exploratory ingestion of these agents is available. The primary purpose of this study is to evaluate the bleeding risk of these agents after an exploratory ingestion in children 6 years or younger...
November 19, 2018: Pediatric Emergency Care
Young-A Heo
Andexanet alfa (Andexxa® ), a first-in-class recombinant modified factor Xa protein, is currently the only specific agent available to reverse life-threatening or uncontrolled bleeding with the factor Xa inhibitors apixaban and rivaroxaban. Andexanet alfa acts as a decoy and competes with endogenous factor Xa to bind factor Xa inhibitors, thereby reversing the anticoagulant effects of factor Xa inhibitors, and restoring the activity of endogenous factor Xa. In adults with major bleeding associated with the use of apixaban or rivaroxaban, intravenous administration of andexanet alfa effectively and rapidly reduces anti-factor Xa levels, with reduced levels being maintained during continued treatment...
2018: Drugs & Therapy Perspectives: for Rational Drug Selection and Use
Thomas J Girard, Nina M Lasky, Kristin Grunz, George J Broze
BACKGROUND: Hemostasis requires a balance between pro- and anti-coagulant factors. Hemophiliacs bleed due to a procoagulant deficiency. The targeted reduction in the activity of endogenous anticoagulant pathways is currently being investigated as a means of improving hemostasis in hemophilia. Protein Z (PZ) is a co-factor that serves as a catalyst for PZ-dependent protease inhibitor (ZPI) inactivation of factor (F)Xa at phospholipid surfaces. OBJECTIVES: Evaluate the effects of 1) PZ or ZPI gene-deletion in hemophilia mice and 2) blocking PZ in human hemophilic plasma...
November 16, 2018: Journal of Thrombosis and Haemostasis: JTH
Junhao Xing, Lingyun Yang, Jinpei Zhou, Huibin Zhang
Factor Xa (fXa) is a crucial player in various thromboembolic disorders. Inhibition of fXa can provide safe and effective antithrombotic effects. In this study, a series of anthranilamide compounds were designed by utilizing structure-based design strategies. Optimization at P1 and P4 groups led to the discovery of compound 16g: a highly potent, selective fXa inhibitor with pronounced in vitro anticoagulant activity. Moreover, 16g also displayed excellent in vivo antithrombotic activity in the rat venous thrombosis (VT) and arteriovenous shunt (AV-SHUNT) models...
September 11, 2018: Bioorganic & Medicinal Chemistry
Saravanan Subramaniam, Sandip M Kanse, Hema Kothari, Christoph Reinhardt, Craig Fletcher
: Tissue factor (TF) pathway inhibitor (TFPI) is an endogenous natural anticoagulant that readily inhibits the extrinsic coagulation initiation complex (TF-FVIIa-Xa) and prothrombinase (FXa, FVa and calcium ions). Alternatively, spliced TFPI isoforms (α, β and δ) are expressed by vascular and extravascular cells and regulate thrombosis and haemostasis, as well as cell signalling functions of TF complexes via protease-activated receptors (PARs). Proteolysis of TFPI plays an important role in regulating physiological roles of the TF pathway in host defense and possibly haemostasis...
December 2018: Blood Coagulation & Fibrinolysis: An International Journal in Haemostasis and Thrombosis
Kazunari Ishida, Nao Shibanuma, Kazuki Kodato, Akihiko Toda, Hiroshi Sasaki, Koji Takayama, Shinya Hayashi, Shingo Hashimoto, Takehiko Matsushita, Takahiro Niikura, Masahiro Kurosaka, Ryosuke Kuroda, Tomoyuki Matsumoto
BACKGROUND: This study aimed to determine the appropriate administration duration of edoxaban 15 mg (a factor Xa inhibitor) for the prevention of deep vein thrombosis (DVT) after total knee arthroplasty (TKA). METHODS: Our study comprised 202 patients who underwent TKA (excluding bilateral TKA) at our institution between 2014 and 2015. The subjects received edoxaban 15 mg daily for 1 (n = 93) or 2 (n = 109) weeks; group assignment was random. B-mode ultrasonography was performed 7 and 14 days post-TKA for the detection of DVT...
November 2018: Journal of Orthopaedic Science: Official Journal of the Japanese Orthopaedic Association
Sam Schulman, Peter L Gross, Bruce Ritchie, Susan Nahirniak, Yulia Lin, Lani Lieberman, Marc Carrier, Mark A Crowther, Indy Ghosh, Alejandro Lazo-Langner, Michelle Zondag
No abstract text is available yet for this article.
November 12, 2018: Thrombosis and Haemostasis
Aleš Žula, Izabela Będziak, Danijel Kikelj, Janez Ilaš
Spumigins are marine natural products derived from cyanobacteria Nodularia spumigena , which mimics the structure of the d-Phe-Pro-Arg sequence and is crucial for binding to the active site of serine proteases thrombin and factor Xa. Biological evaluation of spumigins showed that spumigins with a (2 S ,4 S )-4-methylproline central core represent potential lead compounds for the development of a new structural type of direct thrombin inhibitors. Herein, we represent synthesis and thrombin inhibitory activity of a focused library of spumigins analogues with indoline ring or l-proline as a central core...
October 27, 2018: Marine Drugs
Xiaopeng Tang, Mengrou Chen, Zilei Duan, James Mwangi, Pengpeng Li, Ren Lai
Antistasin, first identified as a potent inhibitor of the blood coagulation factor Xa, is a novel family of serine protease inhibitors. In this study, we purified a novel antistasin-type inhibitor from leech Poecilobdella manillensis called poecistasin. Amino acid sequencing of this 48-amino-acid protein revealed that poecistasin was an antistasin-type inhibitor known to consist of only one domain. Poecistasin inhibited factor XIIa, kallikrein, trypsin, and elastase, but had no inhibitory effect on factor Xa and thrombin...
October 26, 2018: Toxins
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