Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: UNIPROT:P00750 (PLA)
16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The publication of the positive results of the National Institute of Neurological Disorders and Stroke (NINDS) trial of alteplase (a recombinant tissue plasminogen activator; rt-PA) for acute stroke patients in 1995 and its approval by the US Food and Drug Administration as well as the American Academy of Neurology and American Heart Association increased the interest and attention of the medical community in acute stroke treatment. However, the implication of this NINDS Stroke Study and other thrombolytic trials in clinical practice remains controversial and debated. Furthermore, the recent publication of the results from the European Cooperative Acute Stroke Study II (ECASS II) and Alteplase Thrombolysis of Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) studies will feed the controversy, since the results of these two studies are disappointing and do not confirm the positive results of the NINDS Stroke Study as expected by clinicians managing patients with acute stroke. The Standard Treatment with Alteplase to Reverse Stroke (STARS) and Cleveland studies, which involved a large number of community hospitals to assess the safety profile and the benefit of rt-PA thrombolysis for acute stroke patients in clinical practice, have shown controversial results. Consequently, the issue arises of which is the more reasonable position concerning thrombolysis by alteplase, which seems to work but has not been proven yet beyond reasonable doubt? The recent publication of the results from the Prolyse in Acute Cerebral Thromboembolism (PROACT II) study has shown that intra-arterial thrombolysis with prourokinase is a benefit treatment in stroke patients with a proven middle cerebral artery occlusion within 6 h of stroke onset. Numerous trials devoted to neuroprotection against acute ischemic stroke have been prematurely stopped because of safety concerns or poor risk-benefit ratios, but some new neuroprotective drugs seem promising and are being tested in ongoing studies. The third issue under study concerns the use of antithrombotic drugs in the acute phase of stroke, particularly the new potent platelet glycoprotein IIb/IIIa antagonists such as abciximab. In this paper, we have reviewed selected recent clinical trials focusing on recent advances in acute stroke therapy.
...
PMID:Recent progress in drug treatment for acute ischemic stroke. 1124 3

The interaction of lipoprotein(a) [Lp(a)] with platelets is not well defined, particularly with regards to the individual contribution of the protein components of Lp(a), the apo B-100 and the apolipoprotein apo(a). This study investigated the binding of different recombinant apo(a) [r-apo(a)] isoforms, to human platelets and its effect on platelet aggregation. Scatchard analysis of saturation binding experiments demonstrated that human platelets display a single class of high affinity r-apo(a) binding sites (71 +/- 46 molec./platelet, Kd = 5.6 +/- 2.0 nmol/L). Platelet activation with strong agonists (thrombin, arachidonic acid) increased 2- to 10-fold the r-apo(a) binding, without affecting the affinity. Competition assays showed that the binding sites are highly specific for r-apo(a) and Lp(a). At high concentration t-PA could also bind to the r-apo(a) binding sites. By contrast, neither fibrinogen nor plasminogen inhibited to the r-apo(a) binding. The lysine analogue EACA inhibits the binding of r-apo(a) to platelets, thus suggesting the involvement of lysine residues in that interaction. Moreover, the r-apo(a) binding to platelets is unlikely mediated by GPIIb/IIIa-attached fibrin since it is not affected by platelet treatment with either LJ-CP8, a monoclonal antibody that specifically blocks fibrinogen binding to GPIIb/IIIa, nor GPRP, an inhibitor of fibrin polymerisation. Finally, we show that the distinct recombinant apo(a) proteins, as well as native Lp(a), promote an aggregation response of platelets to otherwise subaggregant doses of arachidonic acid. This proaggregant effect of r-apo(a) is dependent on its binding to platelets since it requires a minimum incubation time, and it is prevented by EACA at concentration inhibiting the r-apo(a)-platelet interaction. These results suggest that the prothrombotic action of Lp(a) may be in part mediated by modulating the platelet function through the interaction of its apo(a) subunit with a specific receptor at the platelet surface.
...
PMID:Binding of recombinant apolipoprotein(a) to human platelets and effect on platelet aggregation. 1134 6

This is the first Hungarian paper on the platelet glycoprotein IIb/IIIa (LeuPro 33) polymorphism in stroke patients. There are conflicting data about the role of this polymorphism in the pathogenesis of arterial thrombosis. The aim of our study was to describe the prevalence of PLA1/PLA2 in healthy persons and in stroke patients. From the same study population other polymorphism (prothrombin gene 20210 G/A) also has been determined. Blood sample was investigated by polymerase chain reaction in 173 unrelated healthy donors and 234 stroke patients. Stroke was documented by CT and MRI. We used a rutin questionnaire to study previous vascular events and conventional risk factors of patients. Prevalence of PLA1/PLA2 was 23.5% among healthy persons. That is higher than in other European countries (15%). It was 30.4% in stroke patients (OR: 1.42, 95%; CI: 0.87-2.31; p = 0.15). Heterozigous PLA was found in patients older than 50 by 33.6% (OR: 1.65, 95%; CI: 0.94-2.87; p = 0.09). Previous vascular events and conventional risk profil were not significantly different between PLA1/PLA1 and PLA1/PLA2 groups of patients. In patients under 50 having 20-85% stenosis of internal carotid artery there was a higher prevalence (p = 0.09). Comparing stroke patients to control population there was a slight increase (OR: 7.0; p = 0.06) in the frequency of two polymorphisms (PLA and factor II) together in the stroke cases. Polymorphism of GP IIb/IIIa LeuPro 33 seemed to be increased in stroke patients above 50 years. Carotid stenosis with polymorphism is a risk factor for young patients. PLA variant together with prothrombin gene polymorphism results very high risk for stroke.
...
PMID:[Platelet glycoprotein IIb/IIIa (LeuPro 33) polymorphism in stroke patients]. 1136 63

Although the Fab fragment of the mouse-human chimeric anti-alphaIIbbeta3 (GP IIb/IIIa) monoclonal antibody (MoAb) c7E3 facilitates recombinant tissue-type plasminogen activator (rt-PA)-mediated thrombolysis, it is not clear whether this is due to inhibition of new clot formation and/or a direct effect on the lysis rate. We employed an in vitro flow (re)circulation model to investigate how c7E3 Fab affected (a) platelet adhesion to clotted fibrin substrates under laminar flow at wall shear rates of 100 or 500 s(-1) and (b) rt-PA-induced lysis of preformed mural platelet-fibrin substrates at 500 s(-1). c7E3 Fab dose-dependently (0.5-5 microg/ml) inhibited platelet adhesion from flowing whole blood onto fibrin substrates ( approximately 14 microm thick) at each wall shear rate. When at 5 min after the onset of flow, c7E3 Fab (0.1-10 microg/ml) and rt-PA (1 microg/ml) were coinjected in flowing blood, it was found that modest fibrinolysis caused major platelet release from fibrin substrates and there was no difference in the lysis rate in the presence of rt-PA + c7E3 Fab compared to rt-PA alone. Platelet pretreatment with c7E3 Fab (10 microg/ml) had no effect on the lysis rate of thin ( approximately 40 microm), and slightly delayed the lysis rate of thick (< 250 microm), platelet-fibrin substrates containing evenly dispersed platelets (10(9)/ml). When the platelets within thick platelet-fibrin substrates were organized in platelet-rich regions ("residual thrombi"), these substrates followed a nonuniform lysis pattern, where fibrin between the thrombi lysed first and the residual thrombi lysed at a slower rate. Platelet pretreatment with c7E3 Fab (10 microg/ml) abolished the formation of the lytic-resistant residual thrombi and the associated platelet-protected fibrin zones. Hence, treatment with c7E3 Fab has no direct effect on the rate of rt-PA-mediated lysis, but is expected to block platelet-fibrin interactions that lead to clot retraction, thus maintaining a fibrin architecture that is more susceptible to lysis.
...
PMID:Differential effects of c7E3 Fab on thrombus formation and rt-PA-Mediated thrombolysis under flow conditions. 1139 27

Primary angioplasty results in higher reperfusion rates than fibrinolysis in patients with acute myocardial infarction (MI). Two recent trials have shown improved rates of reperfusion when a reduced-dose thrombolytic is combined with the platelet glycoprotein IIb/IIIa receptor inhibitor abciximab. We present a case report of acute MI successfully treated with a combination of tirofiban and half-dose alteplase and eventual percutaneous coronary intervention.
...
PMID:Adjunctive therapies in the cath lab. Combination of tirofiban and alteplase in acute myocardial infarction. 1153 4

Thrombolytic therapy is an established reperfusion strategy in acute myocardial infarction with proven long-term survival benefit. New thrombolytic agents including reteplase, lanoteplase, and tenecteplase have been developed to optimize thrombolytic therapy. With respect to efficacy the new thrombolytic agents show mortality equivalent to front-loaded alteplase, the present gold standard of thrombolytic therapy. With respect to ease of application there are advantages because third generation agents can be given as a single or double bolus instead of a bolus followed by an infusion. The most promising strategy to optimize coronary thrombolysis seems to be the combination of thrombolytic agents in reduced dose and GP IIb/IIIa blockers in full dose. The corresponding clinical trials (TIMI-14, SPEED, and INTRO-AMI) have also shown that there is an evolution in the surrogate end points for an optimal thrombolysis. In the past, optimal thrombolysis was associated with an open infarct-related coronary artery. A few years ago it was realized that TIMI-3 flow in the epicardial coronary artery was associated with the best results. Presently, normal myocardial microcirculation is regarded an additional prerequisite for further reduced mortality in acute myocardial infarction.
...
PMID:[Optimal thrombolysis]. 1156 15

A number of experimental and clinical studies have recently underlined the importance, in acute myocardial infarction, of platelet adhesion and aggregation after plaque rupture. During clot resolution, platelet-rich thrombi are relatively resistant to fibrinolytic agents, mainly due to the release of plasminogen inhibitor-1 by platelets which are activated as a result of the increase in thrombin generation induced by plasminogen activator therapy despite heparin administration. Platelet glycoprotein (GP) IIb/IIIa integrin receptor blockers prevent platelet aggregation by blocking the final pathway of platelet activation. Thus, they also prevent the formation of an intraluminal white thrombus without affecting adhesion. Animal and human studies have shown that the potent inhibition of platelet GP IIb/IIIa receptors can lead to modest reperfusion rates even without exogenous fibrinolytic therapy. This suggests that combining the "dethrombotic" effects of a GP IIb/IIIa antagonist with lower fibrynolytic doses may result in a synergistic effect. Preclinical studies including patients with myocardial infarction have shown that such combined treatment increases the incidence, speed and durability of reperfusion. It has also been proved to be useful in improving the microcirculatory coronary flow and in facilitating subsequent percutaneous coronary interventions. In the phase III GUSTO V trial, abciximab combined with 5 + 5 U of reteplase and low-dose weight-adjusted heparin led to a 30-day mortality rate that was similar to that obtained with full-dose reteplase (10 + 10 U) and standard heparin therapy, without causing a significant increase in the incidence of intracranial hemorrhage. The results of this trial offer a rationale for alternative reperfusion therapy, although further analyses, including a 1-year follow-up, are needed to define the patient groups that are most likely to benefit from such a new regimen.
...
PMID:[New strategies in the treatment of acute myocardial infarction]. 1172 6

This feasibility study evaluated the therapeutic potential of combined GP IIb/IIIa receptor inhibition with abciximab and low-dose fibrinolysis with reteplase for treatment of acute femoropopliteal thrombosis. The simultaneous intra-arterial administration of abciximab in conjunction with low-dose reteplase (< or = 0.5 U/hr) was safe in 13 patients; 2 patients experienced major hemorrhagic complication at a reteplase dose of 1 U/hr. The primary success rate was 100%; all patients experienced an excellent clinical response with no clinical evidence of distal embolization. No patient required repeat endovascular or surgical revascularization during mean follow-up of 9.3 months. This promising new thrombolytic strategy for the treatment of peripheral arterial occlusive disease requires further study.
...
PMID:Combined glycoprotein IIb/IIIa receptor inhibition and low-dose fibrinolysis for peripheral arterial thrombosis. 1194 91

The best conventional fibrinolytic regimens succeed in restoring unimpeded coronary flow (i.e., TIMI grade 3 reperfusion) in only about 50% of lytic-eligible patients. In experienced hands, percutaneous coronary intervention (angioplasty + stent implantation) can restore TIMI 3 flow in more than 80% of patients; however, it is not universally available, and usually cannot be performed as promptly as fibrinolytic therapy. Researchers now recognize that one key reason fibrinolytic therapy fails is that it does not adequately address the role of platelets in both the initial formation and posttreatment recurrence of coronary thrombus activated, aggregating platelets at the site of plaque fissure or rupture form the core ("white" clot) of an intracoronary thrombus. The platelets contribute to the further development of a meshwork of fibrin, thrombin, and entrapped blood cells ("red" clot), which usually makes up the bulk of an occlusive coronary thrombus. Plasminogen activators, such as alteplase and reteplase, lyse fibrin in the red thrombus but leave the platelet-rich core intact. The glycoprotein (GP) IIb/IIIa antagonists abciximab, tirofiban, and eptifibatide bind to GP IIb/IIIa receptors on the surfaces of activated platelets. By preventing the receptors from binding to fibrinogen (and, hence, to each other) GP IIb/IIIa inhibitors block the "final common pathway" to platelet aggregation. Combining fibrinolysis with GP IIb/IIIa blockade to treat acute myocardial infarction could, theoretically, yield a number of benefits. It would attack both red and white components of the occlusive thrombus, help suppress the thrombotic rebound effect of fibrinolytics by preventing platelet activation in response to newly exposed thrombin, improve reperfusion and microvascular flow, reduce the incidence of postfibrinolytic hemorrhagic stroke (currently approximately 1%) if combination therapy permits use of lower dosages of fibrinolytic agents. Two phase II trials of fibrinolytic therapy plus GP IIb/IIIa blockade have recently been reported. In TIMI 14, the reduced-dose combinations of alteplase plus abciximab produced TIMI 3 rates higher than the control group. In the TIMI 14 reteplase substudy, TIMI 3 flow rates with reteplase at 90 min was 70% for standard dose reteplase alone, 70% for reteplase 5 IU + 5 IU plus abciximab, and 77% for reteplase 10 IU + 5 IU plus abciximab. In the SPEED pilot study the highest TIMI 3 rates was seen with the regimen of 5 IU + 5 IU double-bolus reteplase plus abciximab (54 vs 47%). The findings of both the SPEED and TIMI 14 trials were incorporated into the design of the large (approximately 17,000 patients) GUSTO V mortality trial, which compared standard reteplase therapy with abciximab plus low-dose reteplase. Unfortunately, the results did not confirm the favorable angiographic findings of the phase II trials reported above, because the two strategies showed the same mortality rate at 30-day follow-up. The present review will try to shed light on the "dark side of the moon" of the association between IIb/IIIa inhibitors and fibrinolytic drugs in order to understand the unexpected GUSTO V results, now matched by the ASSENT-3 disappointing results with tenecteplase plus abciximab.
...
PMID:[Combination therapy for acute myocardial infarction with glycoprotein IIb/IIIa inhibitors and fibrinolysis]. 1206 94

ST-segment elevation acute myocardial infarction (AMI) in patients who have undergone previous coronary artery bypass grafting (CABG) is associated with low reperfusion rates and poor outcome after fibrinolytic therapy. The efficacy of a combination strategy (reduced fibrinolytic plus platelet glycoprotein IIb/IIIa agent) in this setting is unknown. In the Global Use of Streptokinase and TPA for Occluded coronary arteries V (GUSTO V) trial, 553 patients with a history of CABG were treated with standard-dose reteplase (n = 273), or half-dose reteplase and full-dose abciximab (n = 280) in the first 6 hours of evolving ST-segment elevation MI. Mortality at 30 days was significantly higher in patients who underwent prior CABG compared with patients with no prior CABG (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.21 to 2.24, p = 0.001). In patients who underwent prior CABG, mortality at 7 days was reduced 15% with combination therapy compared with reteplase alone, which was not statistically significant (OR 0.85, 95% CI 0.40 to 1.81, p = 0.66). Patients who underwent prior CABG treated with the combination therapy had fewer episodes of recurrent ischemia (OR 0.60, 95% CI 0.37 to 0.96, p = 0.02), high degree atrioventricular block (OR 0.17, 95% CI 0.02 to 0.82, p = 0.01), and ventricular tachycardia (OR 0.29, 95% CI 0.07 to 0.96, p = 0.04). There was a trend toward reduced urgent revascularization (OR 0.61, 95% CI 0.36 to 1.03, p = 0.06) but no significant difference in reinfarction (OR 0.61, 95% CI 0.31 to 1.52, p = 0.40). In the GUSTO V trial, patients who underwent prior CABG had significantly higher event rates compared with patients without CABG. As in the overall trial, combination therapy in patients who underwent prior CABG led to a consistent reduction in key secondary complications of AMI, including recurrent ischemia and a trend toward reduced urgent revascularization.
...
PMID:Outcome of acute myocardial infarction in patients with prior coronary artery bypass grafting treated with combination reduced fibrinolytic therapy and abciximab. 1245 May 98


<< Previous 1 2 3 4 5 6 7 8 Next >>

---