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)

Limitations in the standard treatment of acute myocardial infarction have focused attention on inhibition of platelet activity by its final common pathway of activation, the glycoprotein IIb/IIIa receptor. Animal studies have suggested that a glycoprotein IIb/IIIa inhibitor could accelerate thrombolysis and prevent reocclusion after successful thrombolysis. Studies evaluating the use of a glycoprotein IIb/IIIa inhibitor alone without thrombolysis or percutaneous transluminal coronary revascularization do not suggest that isolated use of glycoprotein IIb/IIIa inhibitors restores TIMI 3 flow in a sufficient proportion of patients. Clinical studies evaluating the combination of thrombolytic therapy and glycoprotein IIb/IIIa inhibitors appear most promising, with evidence of improved angiographic outcomes. Reducing the dose of thrombolytic agents may result in reduction in bleeding risk. Current and future trials will investigate reduced-dose reteplase with abciximab and eptifibatide with reduced-dose alteplase. Available evidence suggests that glycoprotein IIb/IIIa inhibition may facilitate thrombolysis, thus adding a new element to future reperfusion regimens.
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PMID:Glycoprotein IIb/IIIa inhibitors in acute ST segment elevation myocardial infarction. 1059 35

Current therapy of acute coronary syndromes (i.e., unstable angina and non-Q-wave myocardial infarction, Q-wave myocardial infarction) consists of thrombolytic, anti-platelet, and anti-coagulant therapy. In most cases of acute coronary syndromes, the pathogenesis is a mural thrombus formation on a ruptured or eroded atherosclerotic plaque. Both platelets and thrombin play an essential role in the pathophysiology of acute coronary syndromes. Aspirin and heparin are essential treatments for patients with acute coronary syndromes. Novel thrombin and platelet inhibitors have been developed and demonstrated useful effects for improving both acute and long-term clinical outcomes in acute coronary syndromes. Tissue plasminogen activator is the compound for effective thrombolytic therapy. New developments like reteplase and TNK-tPA can be administered as bolus injection and result in rapid reperfusion. Combination of thrombolytic therapy and glycoprotein IIb/IIIa inhibitors seem to accelerate and improve reperfusion. Clopidogrel as anti-aggregatory compound demonstrated profound effects following stent implantation as well as in patients with aspirin intolerance. Administration of glycoprotein IIb/IIIa inhibitors like abciximab, eptifibatide, tirofiban results in reduction of cardiovascular events in patients with unstable angina and following coronary intervention. Low-molecular-weight heparins like enoxiparin and dalteparin seem to be more effective than heparin, and their use is evolving in patients with unstable angina. Anti-thrombin therapy with hirudin results in slight reduction of cardiovascular events in combination with tolerable safety profile. It has yet to be determined which combination of agents and procedural strategies most significantly reduces mortality and serious events in patients with acute coronary syndromes.
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PMID:Antithrombotic therapy in acute coronary syndromes. 1099 90

Thrombolytic agents activate plasminogen and induce a systemic fibrinolytic and anticoagulant state. Interaction of fibrinolysis with coagulation and platelet aggregation might be important for synergistic interactions with other antiplatelet or anticoagulant drugs. Thrombolytic agents are most often used in patients with coexisting cardiovascular medication, including various antihypertensives, beta-blocking agents, nitrates and aspirin (acetylsalicylic acid). In acute coronary syndromes, anticoagulants and antiplatelet compounds such as clopidogrel or glycoprotein IIb/IIIa receptor antagonists might be given. Inducers or inhibitors of the cytochrome P450 system are not reported to affect the pharmacokinetics of any thrombolytic agent. Since the elimination of the recombinant plasminogen activators saruplase and alteplase is dependent on liver blood flow, drugs affecting hepatic blood flow could theoretically affect the hepatic clearance of these agents. In fact, a reduction in thrombolytic activity has only been demonstrated for alteplase with nitroglycerin (glyceryl trinitrate). Pharmacodynamic interactions occur more often. The additive and beneficial effect of aspirin as concomitant therapy to thrombolysis has been demonstrated without excessive bleeding rates. No data are available on the interaction between ticlopidine or clopidogrel and thrombolytic agents in humans. Anticoagulation by heparin concomitantly with thrombolysis improves the patency rate of the occluded coronary vessel, but bleeding complications are seen more frequently. Although there has been no controlled study on the interaction between oral anticoagulants and thrombolytic agents, patients with myocardial infarction who were taking an oral anticoagulant before admission seem to be at higher risk for intracranial haemorrhage during thrombolytic therapy. Currently, no recommendations can be given for possible dose adjustment of thrombolytic therapy in patients receiving antiplatelet comedication. For comedication with heparin, it has been advised to monitor activated partial thromboplastin time frequently and to avoid values >2.5-fold normal. Patients receiving thrombolytic treatment should be monitored frequently for bleeding and the physician should be aware of any comedication exerting antiplatelet (e.g. aspirin, clopidogrel and ticlopidine) or anticoagulant (e.g. warfarin) effects.
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PMID:Thrombolytics: drug interactions of clinical significance. 1108 46

The optimal method of reperfusion for patients with ST-segment elevation acute myocardial infarction has been a point of controversy over the last two decades. Tenecteplase and reteplase are comparable to accelerated-dose alteplase but more convenient because they can be delivered as a bolus. Combination regimens represent a further advance in reperfusion therapy; planned and ongoing studies will evaluate the clinical efficacy and safety of combination therapy. Promising early results of primary coronary intervention with glycoprotein IIb/IIIa receptor inhibition have been reported, and this strategy may emerge as a mainstay of therapy at hospitals with on-site interventional facilities. A possible future approach that could be universally applied consists of combination therapy and adjunctive/rescue percutaneous intervention in selected patients.
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PMID:New Thrombolytic Agents: Does Direct Angioplasty Still Have a Role? 1109 74

Stroke represents the third common cause of death and hospitalization. However, there are yet no drugs that have reliable effects on acute stroke in Japan. Therefore, the development of new drugs that can support patients is required. There are various candidate drugs for acute stroke such as antithrombotic agents, anticoagulants, thrombolytic agents, neuroprotectants, and so on. Recently clinical trials suggest that aspirin may improve outcome, although these studies demonstrated a modest benefit of aspirin. Abciximab (ReoPro) is a human/mouse monoclonal antibody directed against the platelet receptor glycoprotein IIb/IIIa. It appears to be safe and might improve functional outcome. The large randomized trails were started to test the hypothesis that thrombolysis by an intravenous administration of a recombinant tissue type plasminogen activator (rtPA) could restore cerebral blood flow and improve patient outcome in acute ischemic stroke. These results can support the use of intravenous rtPA for stroke treatment within 3 h after onset, but not beyond 3 h. Development of an effective neuroprotective agent for the treatment of acute stroke remains problematic. Antioxidants, MCI-186 and ebselen, have finished phase III of clinical trials in Japan and were effective. We hope that efficacious drugs for acute stroke can be used for patients.
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PMID:[The development of new drugs for acute stroke]. 1118 6

Despite major innovations in antithrombotic and antiplatelet therapy, unfractionated intravenous heparin is widely used to treat acute coronary syndromes. Recommendations for unfractionated heparin dosing in acute myocardial infarction and unstable angina have been issued in two recent American College of Cardiology/American Heart Association guidelines. An initial heparin bolus of 60 U/kg (maximum, 4000 U) followed by a 12-U/kg/h infusion (maximum 1000 U/h) is recommended with alteplase for ST-elevation myocardial infarction. When intravenous heparin is administered for myocardial infarction with non-ST elevation and unstable angina, an initial bolus of 60 to 70 U/kg (maximum, 5000 U) followed by a 12- to 15-U/kg/h infusion is recommended. The goal is to achieve an activated partial thromboplastin time of 50 to 70 seconds. Here, we review these new dosing regimens and explain the rationale for their use. We also review the risk of bleeding with heparin, especially when administered concurrently with aspirin, thrombolytic agents, and glycoprotein IIb/IIIa antagonists, and the relationship between activated partial thromboplastin time and cardiac events.
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PMID:New heparin dosing recommendations for patients with acute coronary syndromes. 1138 73

The contemporary management of acute myocardial infarction continues to evolve rapidly. The ultimate goal of therapy is timely, complete, and sustained myocardial reperfusion. There is a powerful time-dependent effect on mortality, and thus the balance between the time and likelihood of maximal reperfusion is crucial in deciding whether to use primary percutaneous balloon angioplasty or thrombolysis as the initial reperfusion strategy. Newer thrombolytic agents allow for equivalent coronary reperfusion compared with the standard accelerated alteplase (tPA) regimen with the advantage of easier dosing regimens. Low molecular weight heparin has been shown to be superior to unfractionated heparin and likely will be the standard of care in the near future. The use of glycoprotein IIb/IIIa inhibitors has been shown to decrease the short- and long-term complication rates in patients with acute coronary syndromes treated medically and with percutaneous coronary interventions; however, the choice of the optimal agent and dosing regimen in various clinical settings remains controversial. Combination therapy with low-dose fibrinolytics, glycoprotein IIb/IIIa inhibitors, and low molecular weight heparin, with or without subsequent early planned percutaneous coronary interventions, may provide the optimal strategy for maximal coronary reperfusion, but the results of large, randomized mortality trials currently underway need to be analyzed. Risk stratification will continue to play a major role in determining which patients should receive a specific therapy. The care of the patient with an acute myocardial infarction will continue to be a challenge requiring the proper selection from the vast pharmaceutic and interventional options available.
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PMID:The contemporary management of acute myocardial infarction. 1145 Mar 24

In four patients with acute basilar artery thrombosis, complete arterial recanalization and good neurologic outcome were achieved with a treatment combining alteplase with tirofiban. In no cases were cerebral or extracerebral hemorrhagic complications observed. Combined fibrinolytic agents and glycoprotein IIb/IIIa inhibitors may have high potential in the treatment of acute cerebrovascular thrombosis.
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PMID:Treatment of acute basilar artery thrombosis with a combination of systemic alteplase and tirofiban, a nonpeptide platelet glycoprotein IIb/IIIa inhibitor: report of four cases. 1171 81

Using tracings of (125)I-labeled fibrin(ogen) in rodents, we examined the hypothesis that platelets impede the lysis of pulmonary emboli. (125)I-Microemboli (ME, 3-10 micron diameter) lodged homogeneously throughout the lungs after intravenous injection in both rats and mice (60% of injected dose), caused no lethality, and underwent spontaneous dissolution (50 and 100% within 1 and 5 h, respectively). Although lung homogenates displayed the most intense fibrinolytic activity of all the major organs, dissolution of ME was much slower in isolated perfused lungs (IPL) than was observed in vivo. Addition of rat plasma to the perfusate facilitated ME dissolution in IPL to a greater extent than did addition of tissue-type plasminogen activator alone, suggesting that permeation of the clot by plasminogen is the rate-limited step in lysis. Platelet-containing ME injected in rats lysed much more slowly than did ME formed from fibrin alone. (125)I-Thrombi, formed in the pulmonary vasculature of mice in response to intravascular activation of platelets by injection of collagen and epinephrine, were essentially resistant to spontaneous dissolution. Moreover, injection of the antiplatelet glycoprotein IIb/IIIa antibody 7E3 F(ab')(2) facilitated spontaneous dissolution of pulmonary ME and augmented fibrinolysis by a marginally effective dose of Retavase (10 microg/kg) in rats. These studies show that platelets suppress pulmonary fibrinolysis. The mechanism(s) by which platelets stabilize ME and utility of platelet inhibitors to facilitate their dissolution deserves further study.
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PMID:Platelets inhibit the lysis of pulmonary microemboli. 1183 49

Early achievement of TIMI 3 (normal) flow in the infarct-related artery is the goal of therapy of acute myocardial infarction (AMI) in order to reduce infarct size and improve clinical outcome. By the mid 1990s mechanical treatment (primary angioplasty) has been recognized as the best method to gain this goal but fibrinolysis still remains the standard of care because of logistic limitations of angioplasty. Benefit of aspirin in association with fibrinolytic drugs encouraged the use of antagonists of the glycoprotein IIb/IIIa receptor (abciximab, eptifibatide, tirofiban), which block the final common pathway of platelet aggregation in AMI therapy. In dose-finding and dose-confirmation studies the combination of a fibrinolytic agent with a glycoprotein IIb/IIIa receptor antagonist, such as abciximab, resulted in nearly 80% of patients achieving complete reperfusion at 90 min without a substantial increase in side effects. This combination was tested in the phase III GUSTO V study. Compared to full-dose reteplase alone, the association of half-dose of reteplase and abciximab significantly reduced most non-fatal complications of myocardial infarction such as reinfarction and need of urgent revascularization. Failure to show a reduction in mortality with "combo therapy" must be related to the low 30-day mortality observed in both arms of the study, the lowest ever found in fibrinolytic trials. Warning about an increase in non-intracranial bleeding is counterbalanced by similar rates of intracranial hemorrhages and non-fatal disabling strokes in the two groups. On the basis of the GUSTO V results it appears clear that future advances in the management of AMI will only be possible by combining different reperfusion modalities (lytics, IIb/IIIa antagonists and coronary angioplasty). Whichever is the best combination, mechanical reperfusion will play a central role in the management of AMI. A major challenge for cardiologists will be reinforcement of collaboration and synergy between institutions with different levels of resources.
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PMID:[Combination therapy for acute myocardial infarction with glycoprotein IIb/IIIa inhibitors and fibrinolysis]. 1206 93


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