Abstract:
:Currently used antiplatelet drugs including aspirin, ticlopidine, and others are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need for a more effective therapy. Thus our study was undertaken to define the antiplatelet efficacy, specificity, and the intravenous and oral antiplatelet/antithrombotic effects of a nonpeptide glycoprotein alphaIIb beta3 integrin (GPIIb/IIIa) antagonist XR300, an ethyl ester prodrug of XR299. XR300, on its conversion to the active form XR299, inhibited human platelet aggregation induced by 100 microM adenosine diphosphate (ADP) with a median inhibitory concentration (IC50) of 0.09 microM. Similarly, XR299 inhibited 125I-fibrinogen binding to human gel-purified platelets (IC50, 0.01 microM) regardless of the agonist used. In purified human GPIIb/IIIa, XR299 demonstrated a competitive high-affinity binding with an IC50 of 1.2 nM. XR299 demonstrated a high degree of specificity for platelet GPIIb/IIIa (alphaIIb beta3) as compared with other integrins including alpha(v)beta3, alpha(v)beta5, and alpha4beta1, where IC50 values were >10 microM. XR300 administered to mongrel dogs either intravenously (0.5-1.0 mg/kg, i.v.) or orally at 1.0-2.0 mg/kg, demonstrated maximal antiplatelet effects with rapid onset and extended duration. XR300 demonstrated maximal antithrombotic efficacy in preventing the incidence of occlusive thrombosis or cyclic flow reduction (CFR) in the carotid or femoral artery thrombosis models induced either electrolytically or by mechanical injury along with stenosis. In conclusion, XR300 is a novel intravenous and oral antiplatelet/antithrombotic agent with high affinity and specificity for platelet GPIIb/IIIa receptors.
journal_name
J Cardiovasc Pharmacoljournal_title
Journal of cardiovascular pharmacologyauthors
Mousa SA,Forsythe M,Wityak J,Bozarth J,Mu DXdoi
10.1097/00005344-199803000-00016subject
Has Abstractpub_date
1998-03-01 00:00:00pages
441-8issue
3eissn
0160-2446issn
1533-4023journal_volume
31pub_type
杂志文章abstract::The effect of two dihydropyridine derivatives, nifedipine and felodipine, on myocardial blood flow distribution 1 h after ligation of the left anterior descending coronary artery (LAD) was studied in open-chest dogs by means of radioactive microspheres. The myocardium normally perfused from the LAD was first labeled w...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-198507000-00003
更新日期:1985-07-01 00:00:00
abstract::The acute and chronic arterial effects of the angiotensin-converting enzyme (ACE) inhibitor ramipril were studied in hypertensive patients. Hemodynamic and biological parameters were measured 3 h after the first dose of 5 mg of ramipril, and then again after 4 weeks of treatment, 3 and 24 h after drug administration. ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-01-01 00:00:00
abstract::We examined the influence of the new angiotensin-converting enzyme inhibitor (ACEI) fosinopril on function and perfusion of the diabetic rat heart. Streptozotocin-diabetic rats (60 mg/kg body weight) were treated with fosinopril (10 mg/kg body weight/day) for 4 months. Cardiac performance was analyzed in the isolated ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199601000-00011
更新日期:1996-01-01 00:00:00
abstract::To evaluate the safety and pharmacologic activity of ITF 296 in humans, three groups of healthy male normotensive subjects were studied. The first two groups (six subjects each) received, in ascending order, three dose levels of ITF 296 by 30-min intravenous infusion (group I, 0.1, 0.5, 1.0 microgram/kg/min; group II,...
journal_title:Journal of cardiovascular pharmacology
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1995-01-01 00:00:00
abstract::Acute myocardial infarction (AMI) is known to alter the pharmacokinetics of several antiarrhythmic agents. To study the effects of AMI on the kinetics of mexiletine (MEX), a single intravenous dose of 200 mg MEX HCl was infused over 30 min in 11 patients with AMI. The study was performed within 24 h of the onset of pa...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-01-01 00:00:00
abstract::The effects of various doses of creatine phosphate have been examined in a rat model of acute myocardial ischaemia. When given directly into the lumen of the left ventricle in pentobarbitone-anaesthetised male rats, creatine phosphate (50 and 100 mg/kg) markedly reduced the incidence of ventricular ectopic beats, and ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-198201000-00009
更新日期:1982-01-01 00:00:00
abstract::Both acetylcholine (ACh) and cyclopiazonic acid (CPA) caused vasodilation of the mesenteric arterial bed in a concentration-dependent manner. When the mesenteric arterial bed was perfused with 0.1% Triton X-100 for 30 s, ACh- or CPA-induced vasodilation was almost abolished. ACh-induced vasodilation was significantly ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199604000-00022
更新日期:1996-04-01 00:00:00
abstract::The nitric oxide (NO) synthase activity present in murine J774.2 monocyte/macrophages was characterized in terms of its intracellular localization, substrate specificity, and Ca2+ dependency. Traces of constitutive NO synthase activity were found in the microsomal fraction from noninduced J774.2 cells, whereas no NO s...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199204002-00039
更新日期:1992-01-01 00:00:00
abstract::Regeneration of the heart after a stroke would be the best biologic response to restore its function. However, although this phenomenon occurs in primitive organisms, the regenerative potential is lost in mammals. Thus, the search for an appropriate cardiac progenitor with the potential to differentiate into a functio...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章,评审
doi:10.1097/FJC.0b013e3181d8bc6d
更新日期:2010-07-01 00:00:00
abstract::Adenosine and verapamil have successfully been used in the treatment of clinical no-reflow after direct angioplasty for acute myocardial infarction. However, their effects on anatomic perfusion defects in experimental myocardial ischemia/reperfusion are unknown. Thus the area of no-reflow (ANR), visualized after in-vi...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-200404000-00014
更新日期:2004-04-01 00:00:00
abstract::We studied the kinetics of amiodarone in three healthy volunteers after single oral (400 mg) and intravenous (150 mg) doses and in six patients with supraventricular tachycardia. Three patients were studied after the first oral dose (400 mg) and during subsequent therapy (200 mg/day); the other three after 5 mg/kg of ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-198203000-00015
更新日期:1982-03-01 00:00:00
abstract::To establish a model of hypertension in marmosets, increasing doses of the immune-modulator cyclosporin (from 3 to 30 mg/kg/day) were given orally to marmosets for 31 days. Cyclosporin consistently induced hypertension with doses greater than or equal to 10 mg/kg/day. Time course and level of hypertension reached were...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-07-01 00:00:00
abstract::Oxidative stress is believed to play a role in diabetes-induced vascular complications. In this study, we tested whether chronic treatment with a known hydroxyl radical scavenger, dimethylthiourea (DMTU), could prevent endothelial dysfunction in diabetes. Lewis strain rats were made diabetic by an intravenous injectio...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199612000-00002
更新日期:1996-12-01 00:00:00
abstract::The purpose of this study was to investigate the renal effects of aranidipine, a novel calcium channel blocker of the dihydropyridine type, and its active metabolite in anesthetized dogs and conscious spontaneously hypertensive rats (SHRs). When infused into the renal artery in anesthetized dogs, aranidipine (0.03 mic...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199802000-00014
更新日期:1998-02-01 00:00:00
abstract::Histamine receptors are present in adrenergic terminals, and histamine is reported to inhibit release of the neurotransmitter norepinephrine (NE) at certain neuroeffector junctions. However, a physiological role for histamine in modifying adrenergic neurotransmission has not been established. To examine the interactio...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-198705000-00012
更新日期:1987-05-01 00:00:00
abstract::Ghrelin is a novel growth hormone (GH)-releasing peptide, isolated from the stomach, which is identified as an endogenous ligand for GH secretagogues receptor. Although both ghrelin and its specific receptor are expressed in blood vessels, the cardiovascular effects of ghrelin remain unknown. To clarify whether ghreli...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-200206000-00001
更新日期:2002-06-01 00:00:00
abstract::The cardioprotective effects on myocardial ischemia of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) inhibitor, cyclopiazonic acid (CPA), were studied. We used the isolated arterially perfused interventricular septum of the rabbit heart submitted to 30-min global ischemia/30-min reperfusion. Mechanical [maximal ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199811000-00022
更新日期:1998-11-01 00:00:00
abstract::Chemokines are small secreted proteins with chemoattractant properties that play a key role in inflammation, metastasis, and embryonic development. We previously demonstrated a nonchemotactic role for one such chemokine pair, stromal cell-derived factor-1α and its G-protein coupled receptor, CXCR4. Stromal cell-derive...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/FJC.0b013e3181f713fe
更新日期:2010-11-01 00:00:00
abstract::Roughly 40% of all diabetics, whether insulin dependent or not, develop persistent albuminuria, a decline in their glomerular filtration rate, and elevated blood pressure, i.e., diabetic nephropathy. Diabetic nephropathy is the single most important cause of end-stage renal disease in the Western world, accounting for...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章,评审
doi:10.1097/00005344-199219006-00004
更新日期:1992-01-01 00:00:00
abstract::Relationships between lipoprotein fractions, lipoprotein lipase activities, thyroid hormones, and coronary lesion growth were studied among 35 male patients with severe coronary atherosclerosis, who had participated in the Leiden Intervention Trial, a lipid-lowering dietary intervention program. Coronary arteriography...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-01-01 00:00:00
abstract::Trans-diclofurime has been shown to be a very potent class II calcium antagonist (see preceding report), and we have examined its molecular interactions with the different receptor sites at the Ca2+ channel. Trans-diclofurime did not affect [3H]nitrendipine binding to rat cortical membranes at 37 degrees C and showed ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-198704000-00012
更新日期:1987-04-01 00:00:00
abstract::This study was undertaken to determine and confer the cardioprotective effects of the adenosine A2 receptor (A2AR) and its impact on myocardial autophagy in the setting of reperfusion. We established a rat ischemia model by subjecting rats to 30 minutes of ischemia (I) and 120 minutes of reperfusion (R). The A2AR agon...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/FJC.0000000000000239
更新日期:2015-07-01 00:00:00
abstract::To evaluate a possible mechanism for the chronic regulation of MAPK/ERK kinase-1 (MEK-1) and p42 mitogen-activated protein kinase (MAPK) we studied the long-term effects of the G-protein-coupled receptor agonist endothelin-1 (ET-1) and the protein tyrosine kinase-coupled receptor agonist platelet-derived growth factor...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-01-01 00:00:00
abstract::Calcium sensitizers increase myocardial contractile function without affecting Ca2+ homeostasis, which might be beneficial in the treatment of patients with heart failure. However, it remains uncertain whether Ca sensitizers induce quantitatively similar inotropic responses in control and failing hearts. To compare th...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-200101000-00003
更新日期:2001-01-01 00:00:00
abstract::The autonomic nervous system exerts broad control over the involuntary functions of the human body through complex equilibrium between sympathetic and parasympathetic tone. Imbalance in this equilibrium is associated with a multitude of cardiovascular outcomes, including mortality. The cardiovascular static state of t...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章,评审
doi:10.1097/FJC.0000000000000559
更新日期:2018-03-01 00:00:00
abstract::Warfarin international normalized ratio (INR)-related phenotypes such as the percentage of INR time in the therapeutic range (PTTR) and INR variability are associated with warfarin adverse reactions. However, INR-related phenotypes greatly vary among patients, and the underlying mechanism remains unclear. As a key cof...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/FJC.0000000000000834
更新日期:2020-07-01 00:00:00
abstract::In conscious, spontaneously hypertensive rats (SHR) oral prazosin (0.03-3.0 mg/kg) resulted in dose-related reductions of systolic blood pressure measured with a tail cuff. In SHR whose tail artery blood pressure was continuously monitored the antihypertensive effect of prazosin (1.0 mg/kg, p.o.) was accompanied by a ...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-197901000-00004
更新日期:1979-01-01 00:00:00
abstract::Among other mediators, platelet-derived serotonin (5-HT) may contribute to thromboembolic complications of atherosclerosis. We determined whether long-term oral treatment with the 5-HT2 antagonist naftidrofuryl (NAF, 50 mg/kg daily for 12 weeks) alters platelet function in cholesterol-fed (1%) rabbits. Hypercholestero...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199302000-00021
更新日期:1993-02-01 00:00:00
abstract::The antiischemic and antiarrhythmic effects of alinidine and a number of novel alinidine analogs were examined by using perfused rat-heart models. In the isolated working rat heart, the alinidine analog TH91:21 (10 microM; a butyl derivative) significantly increased the postischemic recovery of the heart in terms of b...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-199704000-00011
更新日期:1997-04-01 00:00:00
abstract::Spirapril (SCH 33844; 7-N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl-1,4-dithia- 7-azaspiro[4,4]-nonane-8(S)-carboxylic acid) is a new angiotensin-converting enzyme (ACE) inhibitor. SCH 33844 diacid inhibited hydrolysis of hip-his-leu by rabbit lung ACE in a potent (Ki = 0.74 nM), selective, and noncompetitive fa...
journal_title:Journal of cardiovascular pharmacology
pub_type: 杂志文章
doi:10.1097/00005344-198706107-00020
更新日期:1987-01-01 00:00:00