Exosite 1 thrombin inhibition with JNJ-64179375 inhibits thrombus formation in a human translational model of thrombosis.

Abstract:

AIMS:JNJ-64179375 (hereafter JNJ-9375) is a first-in-class, highly specific, large molecule, exosite 1 thrombin inhibitor. In preclinical studies, JNJ-9375 demonstrated robust antithrombotic protection with a wider therapeutic index when compared to apixaban. The purpose of the present study was to examine for the first time the antiplatelet, anticoagulant and antithrombotic effects of JNJ-9375 in a translational model of ex vivo human thrombosis. METHODS AND RESULTS:Fifteen healthy volunteers participated in a double-blind randomized crossover study of JNJ-9375 (2.5, 25, and 250 μg/mL), bivalirudin (6 μg/mL; positive control), and matched placebo. Coagulation, platelet activation, and thrombus formation were determined using coagulation assays, flow cytometry, and an ex vivo perfusion chamber, respectively.JNJ-9375 caused concentration-dependent prolongation of all measures of blood coagulation (prothrombin time, activated partial thromboplastin time, and thrombin time; P < 0.001 for all) and agonist selective inhibition of thrombin (0.1 U/mL) stimulated platelet p-selectin expression (P < 0.001) and platelet-monocyte aggregates (P = 0.002). Compared to placebo, JNJ-9375 (250 μg/mL) reduced mean total thrombus area by 41.1% (95% confidence intervals 22.3 to 55.3%; P < 0.001) at low shear and 32.3% (4.9 to 51.8%; P = 0.025) at high shear. Under both shear conditions, there was a dose-dependent decrease in fibrin-rich thrombus (P < 0.001 for both) but not platelet-rich thrombus (P = ns for both). CONCLUSION:Exosite 1 inhibition with JNJ-9375 caused prolongation of blood coagulation, selective inhibition of thrombin-mediated platelet activation, and reductions in ex vivo thrombosis driven by a decrease in fibrin-rich thrombus formation. JNJ-9375 represents a novel class of anticoagulant with potential therapeutic applications.

journal_name

Cardiovasc Res

journal_title

Cardiovascular research

authors

Wilson SJ,Connolly TM,Peters G,Ghosh A,Johnson M,Newby DE

doi

10.1093/cvr/cvy227

subject

Has Abstract

pub_date

2019-03-01 00:00:00

pages

669-677

issue

3

eissn

0008-6363

issn

1755-3245

pii

5089939

journal_volume

115

pub_type

杂志文章,随机对照试验
  • Characterisation of the effect of oxygen tension on response of fetal rabbit ductus arteriosus to vasodilators.

    abstract:OBJECTIVE:The aims of the study were (1) to elucidate the effects of raised oxygen tension on the response of the ductus arteriosus to a range of vasodilators; and (2) to establish the effect, if any, of cyclo-oxygenase inhibition on the interaction between oxygen and prostaglandin (PG)E2. METHODS:Rings of ductus arte...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/27.12.2205

    authors: Smith GC,McGrath JC

    更新日期:1993-12-01 00:00:00

  • Slc26a6 functions as an electrogenic Cl-/HCO3- exchanger in cardiac myocytes.

    abstract:AIMS:Alterations in cardiac acid-base balance can produce profound impact on excitation-contraction coupling and precipitate cardiac dysfunction and arrhythmias. A member of the solute carrier (SLC) family, Slc26a6, has been shown to be a chloride-hydroxyl exchanger and the predominant chloride-bicarbonate exchanger in...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvt195

    authors: Kim HJ,Myers R,Sihn CR,Rafizadeh S,Zhang XD

    更新日期:2013-12-01 00:00:00

  • Expression of human ERG K+ channels in the mouse heart exerts anti-arrhythmic activity.

    abstract:OBJECTIVE:The K(+) channel encoded by the human ether-a-go-go-related gene (HERG) is crucial for repolarization in the human heart. In order to investigate the impact of HERG current (I(Kr)) on the incidence of cardiac arrhythmias, we generated a transgenic mouse expressing HERG specifically in the heart. METHODS AND ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/j.cardiores.2004.09.030

    authors: Royer A,Demolombe S,El Harchi A,Le Quang K,Piron J,Toumaniantz G,Mazurais D,Bellocq C,Lande G,Terrenoire C,Motoike HK,Chevallier JC,Loussouarn G,Clancy CE,Escande D,Charpentier F

    更新日期:2005-01-01 00:00:00

  • Inhibitors of poly (ADP-ribose) synthetase protect rat cardiomyocytes against oxidant stress.

    abstract:OBJECTIVE:Inhibitors of poly (ADP-ribose) synthetase (PARS) activity reduce the infarct size caused by regional myocardial ischaemia and reperfusion in the rabbit and rat in vivo. The mechanism of action of these inhibitors is unclear. Here we investigate the effects of the PARS inhibitor 3-aminobenzamide (3-AB) on inf...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(98)00221-1

    authors: Bowes J,McDonald MC,Piper J,Thiemermann C

    更新日期:1999-01-01 00:00:00

  • Transgenic alpha1A-adrenergic activation limits post-infarct ventricular remodeling and dysfunction and improves survival.

    abstract:OBJECTIVE:Myocardial contractility is enhanced in transgenic (TG) mice with cardiac-restricted overexpression of the alpha1A-adrenergic receptors (alpha1A-AR). We tested the hypothesis that this enhanced inotropy protects against dysfunction and remodeling after myocardial infarction (MI). METHODS:We subjected alpha1A...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/j.cardiores.2006.06.015

    authors: Du XJ,Gao XM,Kiriazis H,Moore XL,Ming Z,Su Y,Finch AM,Hannan RA,Dart AM,Graham RM

    更新日期:2006-09-01 00:00:00

  • Endothelin-1 induced proinflammatory markers in the myocardium and leukocytes of guinea-pigs: role of glycoprotein IIB/IIIA receptors.

    abstract:AIM:To assess whether endothelin-1 (ET-1) induces the in vivo expression of inflammatory-related proteins, namely cyclooxygenase-2 (COX-2) and tissue factor, in the myocardium and circulating leukocytes of guinea-pigs. The involvement of platelets was also analyzed. METHODS:ET-1 (0.013 microg/min) was infused to male ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(02)00657-0

    authors: Molero L,Farré J,García-Mendez A,Jiménez Mateos-Caceres P,Carrasco Martín C,Millás I,Navarro F,Córdoba M,Casado S,López-Farré A

    更新日期:2003-01-01 00:00:00

  • Localisation of neuropeptide Y in nerves of the rat cardiovascular system and the effect of 6-hydroxydopamine.

    abstract::The distribution of neuropeptide Y (NPY) in the rat cardiovascular system has been examined by radioimmunoassay, chromatographic analysis of tissue extracts, and immunocytochemistry. High concentrations of NPY were identified throughout the heart and within the major blood vessels of the rat in particular in the renal...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/19.9.570

    authors: Allen JM,Polak JM,Rodrigo J,Darcy K,Bloom SR

    更新日期:1985-09-01 00:00:00

  • Effects of long term treatment with an alpha 1 adrenoceptor blocker on cardiac hypertrophy, contractility, and myosin isoenzymes in spontaneously hypertensive rats.

    abstract:STUDY OBJECTIVE:The aim was to investigate the effects of long-term treatment with an alpha 1 blocker, bunazosin hydrochloride, on blood pressure, heart weight, myocardial contractility, and ventricular myosin isoenzyme pattern in spontaneously hypertensive rats (SHR). DESIGN:Bunazosin hydrochloride was given orally i...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/25.7.565

    authors: Takeda N,Nakamura I,Ohkubo T,Iwai T,Tanamura A,Nagano M

    更新日期:1991-07-01 00:00:00

  • Statistics on mortality following acute myocardial infarction in 842 897 Europeans.

    abstract:AIMS:To compare ST-segment elevation myocardial infarction (STEMI) and non-STEMI (NSTEMI) mortality between Sweden and the UK, adjusting for background population rates of expected death, case mix, and treatments. METHODS AND RESULTS:National data were collected from hospitals in Sweden [n = 73 hospitals, 180 368 pati...

    journal_title:Cardiovascular research

    pub_type: 杂志文章,多中心研究

    doi:10.1093/cvr/cvz197

    authors: Alabas OA,Jernberg T,Pujades-Rodriguez M,Rutherford MJ,West RM,Hall M,Timmis A,Lindahl B,Fox KAA,Hemingway H,Gale CP

    更新日期:2020-01-01 00:00:00

  • Alterations of cross-bridge kinetics in human atrial and ventricular myocardium.

    abstract:CONDENSED ABSTRACT:We analyzed actomyosin cross-bridge kinetics in human atrial and ventricular muscle strip preparations by using sinusoidal length changes from 0.1 to 60 Hz. The minimum stiffness frequency was higher in atrial than in ventricular human myocardium and lower in failing than in non-failing left ventricu...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(98)00164-3

    authors: Ruf T,Schulte-Baukloh H,Lüdemann J,Posival H,Beyersdorf F,Just H,Holubarsch C

    更新日期:1998-12-01 00:00:00

  • Vascularizing the heart.

    abstract::As the developing heart grows and the chamber walls thicken, passive diffusion of oxygen and nutrients is replaced by a vascular plexus which remodels and expands to form a mature coronary vascular system. The coronary arteries and veins ensure the continued development of the heart and facilitate cardiac output with ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章,评审

    doi:10.1093/cvr/cvr035

    authors: Riley PR,Smart N

    更新日期:2011-07-15 00:00:00

  • Changes in regional coronary blood flow with hypertonic mannitol in conscious dogs.

    abstract::Systemic haemodynamics and regional myocardial blood flow responses to hypertonic mannitol were studied in 10 conscious and 23 anaesthetized dogs. Mannitol infusion significantly increased regional myocardial blood flow in the conscious, intact dogs. Mannitol increased total coronary flow 20% in anasethetized animals ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/9.1.47

    authors: Hutton I,Marynick SP,Fixler DE,Templeton GH,Willerson JT

    更新日期:1975-01-01 00:00:00

  • Physiological and pathophysiological roles of eicosanoids in the microcirculation.

    abstract::Eicosanoids are important mediators of both physiological and pathophysiological responses of the microcirculation. These biologically active lipid mediators can be produced locally by the cellular elements within the microvasculature (endothelium, pericytes, smooth muscle cells) as well as interstitial cells (e.g. fi...

    journal_title:Cardiovascular research

    pub_type: 杂志文章,评审

    doi:

    authors: Gerritsen ME

    更新日期:1996-10-01 00:00:00

  • Early exercise training after myocardial infarction prevents contractile but not electrical remodelling or hypertrophy.

    abstract:AIMS:Exercise started early after myocardial infarction (MI) improves in vivo cardiac function and myofilament responsiveness to Ca(2+). We investigated whether this represents partial or complete reversal of cellular remodelling. METHODS AND RESULTS:Mice with MI following left coronary ligation were given free access...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvp381

    authors: Bito V,de Waard MC,Biesmans L,Lenaerts I,Ozdemir S,van Deel E,Abdel-Mottaleb Y,Driesen R,Holemans P,Duncker DJ,Sipido KR

    更新日期:2010-04-01 00:00:00

  • Reactive and reparative fibrillar collagen remodelling in the hypertrophied rat left ventricle: two experimental models of myocardial fibrosis.

    abstract:STUDY OBJECTIVE:The aim was to compare the temporal sequence and structural relationship between perivascular and interstitial fibrosis and microscopic scarring seen in the left ventricle in response to either a transient or sustained stimulus to fibrosis. DESIGN:In 72 male Wistar rats (250-350 g) the transient stimul...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/24.9.741

    authors: Silver MA,Pick R,Brilla CG,Jalil JE,Janicki JS,Weber KT

    更新日期:1990-09-01 00:00:00

  • Echocardiographic determination of stroke volume during rapid atrial pacing and volume loading in normal rats.

    abstract:OBJECTIVE:The aim was to validate echocardiographic assessment of acute changes of left ventricular stroke volume in normal rats. METHODS:By transthoracic use of a 7.5 MHz ultrasonic transducer, the left ventricular dimensions were determined before and during rapid atrial pacing and saline infusion in seven Wistar ra...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/26.8.765

    authors: Nakamura T,Matsumuro A,Kuribayashi T,Matsubara K,Shima M,Shimoo K,Katsume H,Nakagawa M

    更新日期:1992-08-01 00:00:00

  • Intravenous administration of the natriuretic peptide urodilatin at low doses during coronary reperfusion limits infarct size in anesthetized pigs.

    abstract:OBJECTIVE:It has been shown that cGMP content is reduced in post-ischemic myocardium, and that stimulation of cGMP synthesis prevents cardiomyocyte hypercontracture and cell death in vitro. This study was aimed at determining whether administration of the natriuretic peptide urodilatin (URO) at the time of reperfusion ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(01)00242-5

    authors: Padilla F,Garcia-Dorado D,Agulló L,Barrabés JA,Inserte J,Escalona N,Meyer M,Mirabet M,Pina P,Soler-Soler J

    更新日期:2001-08-15 00:00:00

  • Prevention of VEGF-mediated microvascular permeability by C-peptide in diabetic mice.

    abstract:AIMS:Human C-peptide has a beneficial effect on the prevention of diabetic neuropathy, nephropathy, and vascular complications; however, its role in protection against increased vascular permeability in diabetes remains unclear. Our purpose was to explore the potential protective role of C-peptide against microvascular...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvt238

    authors: Lim YC,Bhatt MP,Kwon MH,Park D,Lee S,Choe J,Hwang J,Kim YM,Ha KS

    更新日期:2014-01-01 00:00:00

  • Peroxisome proliferator-activated receptor delta (PPARdelta) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis.

    abstract:OBJECTIVE:Activation of peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARgamma plays beneficial roles in cardiovascular disorders such as atherosclerosis and heart reperfusion. Although PPARalpha and gamma have been documented to reduce oxidative stress in the vasculature and the heart, the role of ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/j.cardiores.2005.10.019

    authors: Pesant M,Sueur S,Dutartre P,Tallandier M,Grimaldi PA,Rochette L,Connat JL

    更新日期:2006-02-01 00:00:00

  • Generation of reentrant arrhythmias by dominant-negative inhibition of connexin43 in rat cultured myocyte monolayers.

    abstract:AIMS:Alteration of connexin43 (Cx43)-mediated intercellular communication is known to promote susceptibility to ventricular tachyarrhythmias. However, the precise mechanism of the altered Cx43 responsible for arrhythmogenesis remains unclear. We sought to understand changes in impulse propagation of ventricular myocyte...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvn084

    authors: Nakagami T,Tanaka H,Dai P,Lin SF,Tanabe T,Mani H,Fujiwara K,Matsubara H,Takamatsu T

    更新日期:2008-07-01 00:00:00

  • The microRNA-15 family inhibits the TGFβ-pathway in the heart.

    abstract:AIMS:The overloaded heart remodels by cardiomyocyte hypertrophy and interstitial fibrosis, which contributes to the development of heart failure. Signalling via the TGFβ-pathway is crucial for this remodelling. Here we tested the hypothesis that microRNAs in the overloaded heart regulate this remodelling process via in...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/cvu184

    authors: Tijsen AJ,van der Made I,van den Hoogenhof MM,Wijnen WJ,van Deel ED,de Groot NE,Alekseev S,Fluiter K,Schroen B,Goumans MJ,van der Velden J,Duncker DJ,Pinto YM,Creemers EE

    更新日期:2014-10-01 00:00:00

  • Sympathomimetic amines and cardiac arrhythmias.

    abstract:STUDY OBJECTIVE:The aim was to investigate the arrhythmogenic properties of several sympathomimetic amines and their antagonism by adrenergic blocking drugs. DESIGN:Arrhythmia was induced by the investigated drugs, injected intravenously: adrenaline (ADR); noradrenaline (NA); phenylephrine (PE); isoprenaline (IP); ter...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/24.9.754

    authors: Oppenheimer E,Akavia E,Shavit S,Korczyn AD

    更新日期:1990-09-01 00:00:00

  • Effect of physiological mechanical perturbations on intact human myocardial repolarization.

    abstract:OBJECTIVE:The objective of this study was to investigate the relationship between acute decreases in right ventricular volume during Valsalva strain (with resultant changes in autonomic neural tone) and measures of local endocardial repolarization time independent of heart rate and autonomic neural tone. METHODS:Patie...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(99)00261-8

    authors: Nanthakumar K,Dorian P,Paquette M,Hutchison S,Andrews J,Newman D

    更新日期:2000-01-14 00:00:00

  • Hyperlipidemia induced by a cholesterol-rich diet leads to enhanced peroxynitrite formation in rat hearts.

    abstract:OBJECTIVE:We investigated the influence of experimental hyperlipidemia on the formation of cardiac NO, superoxide, and peroxynitrite (ONOO(-)) in rat hearts. METHODS:Wistar rats were fed 2% cholesterol-enriched diet or normal diet for 8 weeks. Separate groups of normal and hyperlipidemic rats were injected twice intra...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1016/s0008-6363(03)00330-4

    authors: Onody A,Csonka C,Giricz Z,Ferdinandy P

    更新日期:2003-06-01 00:00:00

  • Role of glycolytic flux in effect of glucose in decreasing fatty-acid-induced release of lactate dehydrogenase from isolated coronary ligated rat heart.

    abstract::The mechanisms whereby glucose reduces fatty acid-induced release of enzyme from the coronary-ligated isolated perfused working rat heart are investigated. Alterations in the tissue contents of ATP, phosphocreatine, or glycogen could be excluded as possible mechanisms for the beneficial effect of glucose in this syst...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/13.12.693

    authors: Opie LH,Bricknell OL

    更新日期:1979-12-01 00:00:00

  • Deaminovasopressin has direct and modulatory effects on ventricular automaticity in the rat heart.

    abstract:OBJECTIVE:Some neuropeptides have direct cardiac effects and also modulate the cardiac effects of catecholamines. Vasopressin is an abundantly available neuropeptide having well known interactions with catecholamines in vascular smooth muscle. The aim of this study was to determine the direct and modulatory effects of ...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/27.9.1624

    authors: Sun LS,Sawyer WH,Steinberg SF,Rosen MR

    更新日期:1993-09-01 00:00:00

  • Evaluation of reperfusion strategy for the globally ischaemic rat heart. Recovery of function and energy metabolism.

    abstract:OBJECTIVE:The sequelae of myocardial ischaemia can in principle be alleviated by repeated reperfusion, but the accumulation of adenosine monophosphate (AMP) and the loss of interstitial adenosine may lead to adenylate depletion. Repeated oxidative stress could predispose the heart to reperfusion injury. The aim of this...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/26.5.502

    authors: Høst N,Peuhkurinen K,Haunsø S,Hassinen I

    更新日期:1992-05-01 00:00:00

  • The role of taurine in the pathogenesis of the cardiomyopathy of insulin-dependent diabetes mellitus.

    abstract::The cellular and molecular physiology and pathology of insulin-dependent diabetes mellitus (IDDM) and non-insulin-dependent diabetes mellitus (NIDDM) are mostly studied and understood through the use of animal models. Fundamental differences between the IDDM and NIDDM animal models may help to explain the etiology beh...

    journal_title:Cardiovascular research

    pub_type: 杂志文章,评审

    doi:10.1016/s0008-6363(00)00025-0

    authors: Militante JD,Lombardini JB,Schaffer SW

    更新日期:2000-06-01 00:00:00

  • Accumulation of technetium-99m pyrophosphate in experimental infarctions in the rat.

    abstract::Cardiac accumulation patterns of pyrophosphate labelled with techetium-99m (TcPyP) in rats one hour to 7 days after coronary artery ligation were studied by light microscopy, myocardial scintigraphy, imaging the isolated heart and by direct measurement of tissue activity. Results suggest that myocardial cells taking u...

    journal_title:Cardiovascular research

    pub_type: 杂志文章

    doi:10.1093/cvr/14.6.352

    authors: Lessem J,Polimeni PI,Page E,Resnekov L,Harper PV,Stark V

    更新日期:1980-06-01 00:00:00

  • Cardiovascular reflex responses induced by epicardial chemoreceptor stimulation.

    abstract::The cardiac mechano- and chemoreceptors are broadly distributed in the myocardium and coronary vessels. A portion of these receptors extends over the epicardium and pericardium and therefore can be excited by mechanical or chemical stimuli directly applied to the surface of the heart. Excitation of epicardial receptor...

    journal_title:Cardiovascular research

    pub_type: 评论,杂志文章,评审

    doi:10.1016/s0008-6363(99)00319-3

    authors: Cinca J,Rodríguez-Sinovas A

    更新日期:2000-01-01 00:00:00