Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The antiaggregatory and antithrombotic actions of MK-0383, a low molecular weight, nonpeptide antagonist of the platelet glycoprotein IIb/IIIa, were evaluated in a variety of canine models. Inhibition of ex vivo platelet aggregation responses to ADP and collagen were observed after the acute sequential i.v. administrations of 10 to 500 micrograms/kg or 360-min continuous i.v. infusions of 1 to 10 micrograms/kg/min of MK-0383. Hemostatic function normalized within 30 (platelet response to collagen, template bleeding times) to 90 min (platelet response and sensitivity to ADP) after the termination of 360-min i.v. MK-0383 infusions, suggesting no protracted, direct effects on platelet function. With acute sequential i.v. administrations of MK-0383, platelet response to ADP was abolished without significant extension of bleeding time. In a model of platelet-dependent cyclic flow reductions in injured, stenosed left circumflex coronary artery, the bolus i.v. administrations of 300 and 1000 micrograms/kg of MK-0383 totally abolished cyclic flow reductions for periods of 18 +/- 1 and 37 +/- 5 min, respectively. In a model of electrically induced left circumflex coronary artery occlusive thrombosis, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before electrical injury prevented occlusive thrombosis in three of six preparations despite continued electrical stimulation of the vessel for 300 min, delayed occlusion in three of six preparations (160.3 +/- 5.5 min) and reduced thrombus mass (5.1 +/- 1.3 mg), compared to the development of occlusive thrombosis in six of six saline-treated preparations (50.5 +/- 8.7 min; 19.1 +/- 3.0 mg). When administered as an adjunct to thrombolytic agents in the presence of background heparin for lysis of electrically induced left circumflex coronary artery occlusive thrombus, 10 micrograms/kg/min i.v. of MK-0383 initiated 15 min before tissue-type plasminogen activator or streptokinase increased the incidence of (tissue-type plasminogen activator: eight of nine MK-0383 vs. three of eight saline; streptokinase: eight of eight MK-0383 vs. two of eight saline) and accelerated reperfusion, and reduced the incidence of acute thrombotic reocclusion during continued MK-0383 infusion. These findings indicate significant antithrombotic potential for MK-0383 alone or as an adjunct to thrombolytic therapy in the treatment of coronary artery ischemic syndromes.
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PMID:Nonpeptide glycoprotein IIb/IIIa inhibitors. 5. Antithrombotic effects of MK-0383. 781 34

Current prevention or treatment of coronary thrombosis relies on antiplatelet agents (aspirin), antithrombin agents (heparin), and plasminogen activators (t-PA). The purpose of this review is to describe novel antithrombotic agents in each of these classes and to discuss recent and future clinical trials with the new agents. Whereas aspirin is a cyclo-oxygenase inhibitor, the most promising new antiplatelets are directed at an integrin cell surface receptor--glycoprotein (GP) IIb/IIIa--which represents the final common pathway for platelet aggregation. The monoclonal F(ab) antibody c7E3, a chimeric murine-human immunoglobulin G (IgG) fragment, is the most intensively studied to date. c7E3 was assessed by the Evaluation of Platelet Monoclonal Antibody to Prevent Ischemic Complications (EPIC) trial in which 2,099 high-risk angioplasty patients were randomized to bolus (placebo) plus infusion (placebo), bolus (c7E3, 0.25 mg/kg) plus infusion (placebo), and bolus (c7E3, 0.25 mg/kg) plus infusion (c7E3, 10 micrograms/min; 12 hours). The overall event rate at 30 days was significantly decreased from 12.8% (placebo) to 8.3% (c7E3), a 36% relative reduction (p = 0.009). Integrelin is a cyclic heptapeptide with marked specificity for GP IIb/IIIa integrin. It was studied during the Integrelin to Manage Platelet Aggregation to Prevent Coronary Thrombosis (IMPACT) trial, which enrolled 150 routine coronary intervention patients. At endpoint, overall event rate was reduced from 11.9% (placebo) to 5.6% (integrelin). The much larger (4,010 patients) IMPACT-II trial has just completed enrollment to confirm and extend these encouraging results. Hirudin is the prototype of the direct antithrombins; it binds to the active catalytic site and the substrate recognition site (exosite) of thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Novel antithrombotic approaches to coronary artery disease. 786 68

Patients with unstable angina, refractory to intensive medical therapy, are at high risk for developing thrombotic complications, such as recurrent ischemia, myocardial infarction and coronary occlusion during coronary angioplasty. As both platelet aggregation and/or thrombus formation play an important role in this ongoing ischemic process, a monoclonal platelet GPIIb/IIIa receptor antibody (c7E3) or thrombolytic therapy (alteplase) might be able to modify the clinical course and underlying coronary lesion morphology. To evaluate whether alteplase or c7E3 could influence the incidence of complications, we randomized 36 and 60 patients, respectively to alteplase or placebo, or c7E3 or placebo. All patients exhibited dynamic ECG changes and recurrent pain attacks, despite maximal tolerated medical therapy. Patients were randomized in both studies after initial angiography had demonstrated a culprit lesion amenable for angioplasty. After study drug infusion quantitative angiography was repeated and angioplasty performed. Recurrent ischemia during study drug infusion occurred in 5, 6, 9 and 16 patients from the alteplase, placebo, c7E3 and placebo group, respectively. Major events defined as death, myocardial infarction or urgent intervention occurred in 7, 3, 1 and 7 patients, respectively. Two patients died: one in the alteplase group and one in the placebo group from the c7E3 study. The first patient due to retroperitoneal hemorrhage, the second as a result of recurrent infarction. Qualitative angiography showed resolution of clots in the c7E3 group only, while the same group of patients showed in 20% an improvement in TIMI flow grade, without deterioration in any patient from this group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Correlation between clinical course and quantitative analysis of the ischemia related artery in patients with unstable angina pectoris, refractory to medical treatment. Results of two randomized trials. The European Cooperative Study Group. 787 57

This study was undertaken to determine the role of platelet glycoprotein (GP) IIb/IIIa receptors in the modulation of plasminogen activator type-1 (PAI-1) release from human platelets as compared to other platelet functions. To address this issue, the effect of various agonists on human platelet aggregation, [125I]fibrinogen binding and the release of PAI-1 was examined in normal and Glanzmann's thrombasthenic (GT) platelets. In control subjects, maximum platelet aggregation and PAI-1 secretion were observed within 5 min in response to the different agonists including thrombin, collagen, adenosine diphosphate (ADP), and arachidonic acid. Agonist-induced platelet GpIIb/IIIa receptor activation was confirmed by [125I]fibrinogen binding analysis. In contrast, platelets from GT subjects demonstrated a lack of fibrinogen binding and a lack of an aggregatory response to all agonists tested except to the GPIb- mediated aggregation induced by ristocetin. However, GT platelets demonstrated normal responsiveness in secreting PAI-1 in response to the various agonists. Similarly, when platelet GpIIb/IIIa receptors were blocked in normal platelets by the tripeptide Arg-Gly-Asp (RGD) or the tetrapeptide Arg-Gly-Asp-Ser (RGDS) at 10(-3) M, agonist-induced platelet aggregation and fibrinogen binding were blocked, but platelet PAI-1 release was not blocked. Furthermore, flow cytometric analysis using dual fluorescence markers for the platelet GPIIb/IIIa membrane receptors (FITC-labeled cyclic RGD analog, XL086) and for the alpha granule (PE-monoclonal antibody for P-selectin) demonstrated a dissociation between the platelet GPIIb/IIIa receptors and granular secretion. These results suggest a lack of a role for platelet GpIIb/IIIa receptors in the modulation of platelet PAI-1 release.
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PMID:Role of platelet GpIIb/IIIa receptors in the modulation of platelet plasminogen activator inhibitors type-1 (PAI-1) release. 815 39

Inhibition of the platelet glycoprotein (GP) IIb/IIIa receptor with the murine monoclonal antibody 7E3 abolishes ex vivo platelet aggregation, reduces thrombogenicity, and sustains arterial recanalization with recombinant tissue-type plasminogen activator (rt-PA). A chimeric murine/human Fab fragment of 7E3 (c7E3-Fab) has a markedly reduced immunogenicity, but its potency as an adjunct for thrombolysis with rt-PA has not been evaluated. The effects of a single intravenous bolus injection of aspirin (17 mg/kg) or c7E3-Fab (0.45 mg/kg) on thrombolysis and reocclusion induced with rt-PA were studied in groups of six baboons with femoral arterial thrombosis and superimposed high-grade stenosis. This dose of c7E3-Fab blocked 96 +/- 1% of the platelet GPIIb/IIIa receptors and abolished ADP-induced platelet aggregation. Bolus intravenous injections of rt-PA (0.25 mg/kg) were repeated at 15-minute intervals until reperfusion occurred (maximum of four injections). In the aspirin group, reperfusion was obtained within 51 +/- 16 minutes (mean +/- SD) but was rapidly followed by reocclusion within 6 +/- 9 minutes and by cyclic reflow and reocclusion. In the c7E3-Fab group, reperfusion was obtained within 25 +/- 8 minutes (P < .01 versus aspirin group) and was associated with a delayed reocclusion of 63 +/- 63 minutes (P < .05 versus aspirin group). Template bleeding times remained unchanged in the aspirin/rt-PA group but were markedly prolonged (to > 30 minutes) in the c7E3-Fab/rt-PA group.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A chimeric murine/human antibody Fab fragment directed against the platelet GPIIb/IIIa receptor enhances and sustains arterial thrombolysis with recombinant tissue-type plasminogen activator in baboons. 824 Nov 5

Platelet transfusion therapy became to be largely used in the last 20 years. This development was related to the progress of plastic bags and of blood cell separators. In parallel the platelet immunology has moved from serological techniques to molecular biology. The biochemical characterization of platelet antigen and the genetic basis of the polymorphism was discovered in the last years. The platelet RNA PCR amplification and specific oligonucleotide typing are now accessible to several laboratories. Five major human platelet antigen (HPA) systems are completely characterized. HPA-1 (PLA, Zw) localized on platelet glycoprotein GPIIIa correspond to a single amino acid substitution (leu<==> Pro 33). HPA-2 (Ko, Sib) present on GPIb is due to a Thre<==>Met substitution in 145. HPA-3 formerly Bak, Lek correspond to a polymorphism in 843 (Ile<==>ser) on GPIIb. HPA-4 (Pen, Yuk) as HPA1 is on GPIIIa but in a different location (Arg<==>Gln 143). HPA-5 (Br, He, Zav) and HPA-6 (Ca, Tu) are on GPIa and GPIIIa respectively. The major progress made in the field of platelet immunology has not yet been largely applied to the clinical situation of platelet transfusion. We can hope that it could help in the future to a better platelet-transfusion compatibility and consequently an improved clinical efficacy of platelet transfusion.
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PMID:Platelet alloantigens and transfusion. 833 18

G4120, L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha- aspartyl-cyclic(1-->5)-sulfide, 5-oxide, a synthetic cyclic Arg-Gly-Asp-containing pentapeptide, has a high affinity (dissociation constant of 4 nM) for the platelet glycoprotein (GP) IIb/IIIa receptor. The effects of its intravenous or endobronchial administration on thrombolysis, reocclusion, and bleeding time prolongation induced with 0.45 mg/kg bolus injections of recombinant tissue-type plasminogen activator in combination with intravenous heparin (4,000-unit bolus and 1,000 units each hour) were studied in a canine model consisting of an erythrocyte-rich blood clot in the left anterior descending coronary artery. Coronary patency was monitored for 3 hours both by ultrasonic flow probe and by repeat coronary angiography. Four groups of six to 10 dogs were studied with intravenous infusions of 0, 0.1, 0.2, or 0.3 mg/kg G4120 over 60 minutes. G4120 at a dose of 0.3 mg/kg reduced the time to reflow from a mean control value of 45 to 8 minutes (p = 0.036) and delayed reocclusion (p = 0.001). Four groups of five or six dogs were studied with endobronchial instillation of G4120 in a randomized, blinded study design using 0, 0.13, 0.25, or 0.5 mg/kg G4120. Endobronchial G4120 at a dose of 0.5 mg/kg reduced the time to reflow from a mean control value of 52 to 7 minutes (p = 0.039) and abolished cyclic reocclusion and reflow (p = 0.008). G4120 induced a dose-related transient prolongation of the template bleeding time and inhibition of ADP-induced platelet aggregation. G4120, a synthetic low-molecular-weight GPIIb/IIIa inhibitor that may be produced by chemical synthesis, may be of clinical value as a conjunctive agent for thrombolysis in patients with ischemic coronary syndromes.
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PMID:Intravenous and endobronchial administration of G4120, a cyclic Arg-Gly-Asp-containing platelet GPIIb/IIIa receptor-blocking pentapeptide, enhances and sustains coronary arterial thrombolysis with rt-PA in a canine preparation. 848 25

The inhibitory effect of a novel orally active platelet membrane glycoprotein receptor complex IIb/IIIa (GP IIb/IIIa) inhibitor, SC-54684A is studied on intimal thickening in the guinea pig femoral artery. A segment of the femoral artery was occluded by a platelet-rich thrombus induced by photochemical reaction between systemically administered Rose Bengal and transluminal green light which causes endothelial injury followed by platelet adhesion and aggregation at the site of photochemical reaction. Three weeks after successful thrombolysis by tissue-type plasminogen activator, intimal thickening occurred at the irradiated site. SC-54684A (30 mg/kg), administered 2 h before photochemical reaction, significantly (P < 0.05) prolonged the time to occlusion of the femoral artery; in this respect aspirin (100 mg/kg) was ineffective. A combination of SC-54684A and recombinant tissue-type plasminogen activator (rt-PA) increased the frequency of reopening and significantly (P < 0.05) prolonged the duration of reflow compared with rt-PA alone. Further, SC-54684A administered orally twice a day for 3 weeks significantly (P < 0.05) inhibited intimal thickening but aspirin, administered orally once a day for 3 weeks, was ineffective. Scanning electron microscopy revealed extensive platelet adhesion and aggregation on the denuded vessel walls in the untreated group 24 h after successful thrombolysis. In separate experiments, SC-54684A markedly inhibited platelet aggregation ex-vivo. Inhibition of platelet adhesion and aggregation at the site of endothelial injury by SC-54684A (via GPIIb/IIIa inhibition) may account for its inhibitory effect on intimal thickening.
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PMID:Inhibitory effect of a novel orally active GP IIb/IIIa inhibitor, SC-54684A on intimal thickening in the guinea pig femoral artery. 895 Jul 93

We examined the effect of a specific thrombin inhibitor, Ro 46-6240, alone and combined with an antagonist of the platelet GP IIb/IIIa, Ro44-9883, on the response to tissue-type plasminogen activator in a canine model of thrombolysis. Platelet activity was determined by measuring the excretion of 2,3-dinorthromboxane (TX)B2, an enzymatic metabolite of TXA2. Ro 46-6240 administered before tissue-type plasminogen activator induced a dose-dependent prolongation of the activated partial thromboplastin time and prothrombin time. The time to reperfusion decreased dose-dependently (P < .01) to 10 +/- 6 min vs. 52 +/- 5 min in controls. Ro 46-6240 also prevented reocclusion, which occurred in every case in control experiments. Urinary excretion of 2,3-dinor-TXB2 increased from 3 +/- 1 to 37 +/- 9 ng/mg creatinine in controls after reperfusion. This increase was reduced in a dose-dependent fashion by Ro 46-6240, such that at the highest dose, urinary 2,3-dinor-TXB2 after reperfusion was 5.6 +/- 1 ng/mg creatinine. Similar functional and biochemical effects were seen when a subthreshold dose of Ro 46-6240 was combined with Ro 44-9883. At the dose used, Ro 44-9883 alone abolished platelet aggregation ex vivo but failed to modify the response to tissue-type plasminogen activator or the excretion of 2,3-dinor-TXB2 after reperfusion (51 +/- 6 ng/mg creatinine, n = 3). However, the combination of Ro 44-9883 and Ro 46-6240 reduced the time to reperfusion (40 +/- 8 vs. 68 +/- 15 min; n = 7, P < .05), prevented reocclusion and abolished the rise in urinary 2,3-dinor-TXB2 (5 +/- 1 ng/mg creatinine, n = 4). These findings suggest that thrombin mediates platelet activation during coronary thrombolysis. The increased platelet activity results in platelet aggregation and a subsequent increase in TXA2 formation.
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PMID:Interaction of a thrombin inhibitor and a platelet GP IIb/IIIa antagonist in vivo: evidence that thrombin mediates platelet aggregation and subsequent thromboxane A2 formation during coronary thrombolysis. 919 Aug 51

RGD-containing peptides and other antagonists of the platelet glycoprotein (GP) IIb/IIIa may induce a high-affinity binding site for fibrinogen and the expression of novel epitopes, called ligand-induced binding sites (LIBS). The functional relevance of LIBS expression in a canine model of coronary thrombolysis induced by tissue-type plasminogen activator (t-PA) was examined. Ro43-5054 (N-[N-[N-(p-amidinobenzoyl)-b-alanyl]-l-a-aspartyl]-3-phenyl-l- alanine) and Ro44-9883 ([1-(N-(p-amidinobenzoyl)-l-tyrosyl)-4-piperidinyl)oxy]acetic acid), antagonists of the GP IIb/IIIa receptor, were administered in increasing doses of 2 to 10 microg/kg/min, beginning 30 min before the infusion of t-PA. LIBS expression was determined by the binding of the monoclonal antibody, D3GP3, to platelets on exposure to Ro43-5054, Ro44-9883 and t-PA. Ro43-5054 was shown to induce LIBS, whereas Ro44-9883 and t-PA did not. Both drugs abolished platelet aggregation in response to U46619 and ADP ex vivo. Reocclusion was prevented with both Ro43-5054 and Ro44-9883, but neither drug altered reperfusion times (49 +/- 8 and 55 +/- 39 min). Both drugs increased the rate of bleeding compared with t-PA alone, but there was no difference in hemostasis between the two drugs. To determine whether the drugs differed in their effect on platelet activation in vivo, urinary 2,3-dinor-thromboxane (TX) B2, a major metabolite of TXB2, was determined by gas chromatography-mass spectrometry. After reperfusion, the urinary 2,3-dinor-TXB2 increased in the Ro43-5054-treated group, similar to control groups (32 +/- 8 and 37 +/- 9 ng/mg creatinine). This increase was blunted in the Ro44-9883-treated group (9 +/- 3 ng/mg creatinine). GP IIb/IIIa antagonists that do not induce LIBS result in a greater suppression of platelet activity but not in any discernible functional benefit in vivo.
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PMID:Functional relevance of the expression of ligand-induced binding sites in the response to platelet GP IIb/IIIa antagonists in vivo. 969 54


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