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 Resjournal_title
Cardiovascular researchauthors
Wilson SJ,Connolly TM,Peters G,Ghosh A,Johnson M,Newby DEdoi
10.1093/cvr/cvy227subject
Has Abstractpub_date
2019-03-01 00:00:00pages
669-677issue
3eissn
0008-6363issn
1755-3245pii
5089939journal_volume
115pub_type
杂志文章,随机对照试验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
更新日期:1993-12-01 00:00:00
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
更新日期:2013-12-01 00:00:00
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
更新日期:2005-01-01 00:00:00
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
更新日期:1999-01-01 00:00:00
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
更新日期:2006-09-01 00:00:00
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
更新日期:2003-01-01 00:00:00
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
更新日期:1985-09-01 00:00:00
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
更新日期:1991-07-01 00:00:00
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
更新日期:2020-01-01 00:00:00
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
更新日期:1998-12-01 00:00:00
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
更新日期:2011-07-15 00:00:00
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
更新日期:1975-01-01 00:00:00
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:
更新日期:1996-10-01 00:00:00
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
更新日期:2010-04-01 00:00:00
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
更新日期:1990-09-01 00:00:00
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
更新日期:1992-08-01 00:00:00
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
更新日期:2001-08-15 00:00:00
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
更新日期:2014-01-01 00:00:00
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
更新日期:2006-02-01 00:00:00
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
更新日期:2008-07-01 00:00:00
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
更新日期:2014-10-01 00:00:00
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
更新日期:1990-09-01 00:00:00
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
更新日期:2000-01-14 00:00:00
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
更新日期:2003-06-01 00:00:00
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
更新日期:1979-12-01 00:00:00
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
更新日期:1993-09-01 00:00:00
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
更新日期:1992-05-01 00:00:00
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
更新日期:2000-06-01 00:00:00
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
更新日期:1980-06-01 00:00:00
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
更新日期:2000-01-01 00:00:00