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)

Inhibition of thromboxane (TX) A2 with aspirin enhances the response to coronary thrombolysis. However, experimental evidence suggests that platelet activation during coronary thrombolysis is mediated by a number of agonists, in addition to TXA2. As a consequence, greater benefit would be expected with antiplatelet agents that have a broader spectrum of activity. However, a recent clinical trial, combining tissue plasminogen activator (t-PA) with the prostacyclin analog, iloprost, did not detect such a benefit. To address the mechanism of this response, we compared the effect of iloprost, a stable analog of prostacyclin, with GR32191, a TXA2/prostaglandin endoperoxide receptor antagonist, on the response to i.v. t-PA in a closed chest, canine model of coronary thrombosis. GR32191 reduced the time to reperfusion by 47% (n = 6, P less than .05), consistent with a role for TXA2-mediated platelet activation in impairing thrombolysis. In contrast, iloprost increased the time to reperfusion by 50% (n = 5, P = NS) and in four of nine animals reperfusion failed to occur despite inhibition of platelet aggregation. In a separate series of experiments, steady-state plasma t-PA clearance increased by 38% (407 +/- 49 vs. 294 +/- 42 ml/min; n = 8, P less than .02) during infusion of iloprost and recovered after its withdrawal. This appeared to be a specific effect, as infusion of nitroglycerin at a dose which induced a similar fall in blood pressure altered neither the time to reperfusion nor plasma t-PA. Iloprost impairs the thrombolytic response to t-PA via an increase in the clearance of this agent.
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PMID:A prostacyclin analog impairs the response to tissue-type plasminogen activator during coronary thrombolysis: evidence for a pharmacokinetic interaction. 170 25

Dynamic coronary vasoconstriction may play a role in coronary artery reocclusion after successful thrombolysis. The effect of nitroglycerin on the thrombolytic effects of recombinant tissue-type plasminogen activator (rt-PA) was examined in dogs with an electrically induced occlusive coronary artery thrombus. Eleven dogs were randomly given rt-PA alone and seven rt-PA with nitroglycerin. The dose of rt-PA was 0.75 mg/kg body weight given over 20 min and the dose of nitroglycerin was 125 micrograms/min for 40 min. The reperfusion rate in the dogs given rt-PA alone was 73% (8 of 11 dogs) and that in the rt-PA plus nitroglycerin group was 57% (four of seven dogs) (p = NS). The time to thrombolysis (or reperfusion) in dogs receiving rt-PA plus nitroglycerin was 70% greater than in those receiving rt-PA alone (means +/- SD/29.8 +/- 9.9 versus 17.6 +/- 5.9 min, p less than 0.02), and the duration of reperfusion much shorter (11 +/- 17 versus 42 +/- 16 min, p less than 0.02). Peak coronary blood flow after reperfusion in dogs receiving rt-PA plus nitroglycerin was also less than in those receiving rt-PA alone (36 +/- 52 versus 63 +/- 20 ml/min, p less than 0.02). Reocclusion occurred in all dogs given rt-PA with nitroglycerin and in six of eight given rt-PA alone (p = NS). Plasma concentrations of rt-PA were lower when nitroglycerin was given with rt-PA alone (427 +/- 279 versus 1,471 +/- 600 ng/ml, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Concurrent nitroglycerin administration decreases thrombolytic potential of tissue-type plasminogen activator. 189 81

Recombinant tissue-type plasminogen activator (rt-PA), streptokinase (SK), and anisoylated plasminogen-streptokinase activator complex (APSAC) have salutary effects on mortality when administered to patients with evolving acute myocardial infarction (MI). Studies suggest that intravenous rt-PA is more effective in reperfusing occluded infarct-related arteries than SK, and the results of ongoing studies directly comparing the influence of SK and rt-PA on mortality are awaited. The clinical role of agents such as APSAC, urokinase, and pro-urokinase, used alone or in combination, remains to be determined. It is evident that a variety of thrombolytic agents will be effective, and variables such as ease of administration, pharmacokinetics, fibrin specificity, effects on blood viscosity, and incidence of adverse effects need to be assessed to determine which agents are the most suitable for clinical use. There is an increased risk of bleeding at vascular puncture sites with all thrombolytic agents. Current indications for thrombolytic therapy include ischemic chest pain of at least 30 min duration that is unrelieved by nitroglycerin and is associated with ST-segment elevations of at least 0.1 mV in two contiguous electrocardiographic leads. Such therapy is usually reserved for patients less than 75 years old who are not at increased risk for bleeding and whose chest pain began less than 4-6 prior to treatment. Trials are under way to determine whether patients with shorter pain duration, transient ST-segment changes (ie, unstable angina patients), chest pain associated with ST-segment depressions or T-wave inversions (ie, non-Q-wave infarction patients), or patients whose pain began more than 4 to 6 h earlier will benefit from early thrombolytic therapy. Other factors such as patient age, the likelihood of the diagnosis of MI, and the estimated risk of bleeding should also be considered. The findings of available major randomized trials indicate that early invasive procedures are generally unnecessary and that meticulous care must be exercised in the selection and management of patients subjected to thrombolytic therapy.
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PMID:Thrombolytic therapy in acute myocardial infarction. 210 51

A drug-use evaluation (DUE) of i.v. alteplase for the treatment of acute myocardial infarction (AMI) in two community hospitals is described. From November 1987 to June 1989, all 118 patients who were treated with i.v. alteplase for suspected AMI at two large community hospitals were monitored daily to determine patterns of use of alteplase, clinical outcomes, the hospital time needed to diagnose AMI and begin therapy, and the pharmacy time needed to prepare and deliver alteplase. Patient inclusion criteria were (1) chest discomfort of less than six hours' duration and unrelieved by nitroglycerin or nifedepine, (2) age less than 75 years, and (3) electrocardiographic evidence of transmural AMI. Each patient received alteplase 100 mg i.v. and i.v. heparin therapy; 58% of the patients were also given aspirin 81-325 mg/day. The data for the two institutions were combined; there was no control group. The mean +/- S.D. age of patients was 58 +/- 10 years; 75% were men. Treatment began at a mean of 181 +/- 111 min after symptom onset, including the time it took for the 96 patients whose symptoms began outside the hospital to reach the hospital. The mean hospital time required to initiate treatment was 89 +/- 65 min. The mean pharmacy time required to prepare and deliver alteplase was 12 +/- 6 min. The in-hospital mortality rate was 6.4%, the rate of patency of the infarct-related artery was 85% at a mean of seven days in the 95 patients who underwent coronary angiography, and the nonfatal reinfarction rate was 1.8%. Severe bleeding complications occurred in only two patients, and no patient suffered a stroke.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Use of alteplase for myocardial infarction in two community hospitals. 211 88

Criteria for selecting patients for thrombolytic therapy are presented, the major benefits of the currently approved thrombolytic agents are reviewed, and management considerations, including contraindications and the role of ancillary therapy, are discussed. Coronary thrombosis is now believed to play a central role in the pathogenesis of acute myocardial infarction (AMI). Re-establishment of coronary perfusion by thrombolysis has been extensively studied in the past decade and is now regarded as established therapy for patients with ischemic pain of brief (less than six hours') duration who have electrocardiographic ST-segment elevation, are less than 75 years of age, and have no contraindications. Studies supporting thrombolytic therapy have focused on the endpoints of (1) coronary artery patency or reperfusion, (2) improvement in left ventricular function, and (3) reduction in mortality. Benefits for each of these three endpoints have been established and are reviewed with respect to streptokinase, alteplase, and anistreplase, the three agents that have been approved for intravenous use in patients with AMI. The risk of bleeding, including intracranial hemorrhage, remains a concern for all patients. Ancillary therapies to be considered include aspirin, heparin, nitroglycerin, and beta blockers. Recent studies testing different strategies for coronary angiography and angioplasty plus surgery have generally supported a conservative approach, with interventions performed for clinical reasons rather than prophylaxis. Although the currently approved agents have differing pharmacologic profiles, none has yet proved to be clearly superior in the management of patients with AMI. Nonetheless, these agents remain the most promising means of treating selected patients.
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PMID:Therapeutic management of acute myocardial infarction. 220 53

To determine the clinical consequences of reocclusion of an infarct-related artery after reperfusion therapy, we evaluated 810 patients with acute myocardial infarction. Patients were admitted into four sequential studies with similar entry criteria in which patency of the infarct-related artery was assessed by coronary arteriography 90 minutes after onset of thrombolytic therapy. Successful reperfusion was established acutely in 733 patients. Thrombolytic therapy included tissue-type plasminogen activator (t-PA) in 517, urokinase in 87, and a combination of t-PA and urokinase in 129 patients. All patients received aspirin, intravenous heparin and nitroglycerin, and diltiazem during the recovery phase. A repeat coronary arteriogram was performed in 88% of patients at a median of 7 days after the onset of symptoms. Reocclusion of the infarct-related artery occurred in 91 patients (12.4%), and 58% of these were symptomatic. Angiographic characteristics at 90 minutes after thrombolytic therapy that were associated with reocclusion compared with sustained coronary artery patency were right coronary infarct-related artery (65% versus 44%, respectively) and Thrombolysis in Myocardial Infarction (TIMI) flow 0 or 1 (21% versus 10%, respectively) before further intervention. Median (interquartile value) degree of stenosis in the infarct-related artery at 90 minutes was similar between groups: 99% for reoccluded (value, 90/100%) compared with 95% for patent (value, 80/99%). Patients with reocclusion had similar left ventricular ejection fractions compared with patients with sustained patency at follow-up. However, patients with reocclusion at follow-up had worse infarct-zone function at -2.7 (value, -3.2/-1.8) versus -2.4 (SD/chord) (value, -3.1/-1.3) (p = 0.016). The recovery of both global and infarct-zone function was impaired by reocclusion of the infarct-related artery compared with maintained patency; median delta ejection fraction was -2 compared with 1 (p = 0.006) and median delta infarct-zone wall motion was -0.10 compared with 0.34 SD/chord (p = 0.011), respectively. In addition, patients with reocclusion had more complicated hospital courses and higher in-hospital mortality rates (11.0% versus 4.5%, respectively; p = 0.01). We conclude that reocclusion of the infarct-related artery after successful reperfusion is associated with substantial morbidity and mortality rates. Reocclusion is also detrimental to the functional recovery of both global and infarct-zone regional left ventricular function. Thus, new strategies in the postinfarction period need to be developed to prevent reocclusion of the infarct-related artery.
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PMID:Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. TAMI Study Group. 188 72

Endothelial cells produce at least three substances that can attenuate the platelet aggregation response: tissue-type plasminogen activator; the platelet inhibitory prostaglandins I2 and E1; and endothelium-derived relaxing factor, one form of which exhibits properties of nitric oxide. Since platelet aggregates formed in vivo are involved in the initiation of many clinically important occlusive vascular syndromes, we tested the hypothesis that these endothelial products act synergistically to disperse platelet aggregates. Our data reveal that tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin (an organic nitrate activator of guanylate cyclase analogous to endothelium-derived relaxing factor) act synergistically to disaggregate platelets and do so in part by modulation of platelet cyclic nucleotides. These data suggest a potential mechanism by which the endothelium protects against the formation of platelet aggregates in vivo and offer a potential strategy for improving the efficacy of thrombolytic therapy.
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PMID:Synergistic disaggregation of platelets by tissue-type plasminogen activator, prostaglandin E1, and nitroglycerin. 250 9

Influences of vasoactive agents on plasminogen activator release (PA release) and perfusion pressure (PP) were studied in isolated perfused pig ears. The pig ear was perfused with oxygenated Tyrode's solution, pH 7.4, at 37 degrees C via the main artery and the perfusate from the veins was collected at 2-min intervals. The drug was injected into a rubber tube connected in the front of arterial cannula, and the fibrinolytic activity in the collected perfusate was measured by the fibrin plate method. Acetylcholine, bradykinin, and histamine enhanced PA release in a dose-dependent fashion (0.1-3.0 micrograms). Purified human thrombin also enhanced PA release in a dose-dependent fashion (1.5-12 U). In coronary vasodilators, dilazep caused a dose-dependent increase of PA release (10-100 micrograms) and dipyridamole caused a slight increase at a dose of 300 micrograms. However, nitroglycerin, papaverine, diltiazem, and trapidil did not exert any effects on PA release and neither did adenosine and ATP. Vasoconstricting agents, namely, epinephrine, norepinephrine, phenylephrine, and serotonin exerted hypertensive effects in a dose-dependent fashion (0.1-3.0 micrograms); however, they did not cause measurable increases of PA release. These results suggest that vasodilating substances may be essential for the enhancement of PA release from vascular bed.
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PMID:Pharmacological observations of plasminogen activator release caused by vasoactive agents in isolated perfused pig ears. 618 38

The aim of this study was to evaluate the impact of concurrent nitroglycerin administration on the thrombolytic efficacy of recombinant tissue-type plasminogen activator (rTPA) in patients with acute anterior myocardial infarction (AMI). Sixty patients (53 men, 7 women; mean age 54 +/- 7 years) with AMI entered the study. Thirty-three patients were randomized to receive rTPA alone (100 mg in 3 hours) (group A) and 27 to receive rTPA plus nitroglycerin (100 micrograms/min) (group B). Time from the onset of chest pain and delivery of rTPA was similar in the two groups of patients. Patients in group A had signs of reperfusion more often than the patients in group B (25 of 33 or 75.7% vs 15 of 27 or 55.5%, p < 0.05). Time to reperfusion was also shorter in group A than in group B (19.6 +/- 9.4 minutes vs 37.8 +/- 5.9 minutes, p < 0.05). Group B had a greater incidence of in-hospital adverse events (9 of 27 vs 5 of 33, p < 0.05) and a higher incidence of coronary artery reocclusion (8 of 15 or 53.3% vs 6 of 25 or 24%, p < 0.05). Peak plasma levels of rTPA antigen were higher in group A compared with group B (1427 +/- 679 vs 512 +/- 312 ng/ml, p < 0.01). In conclusion, concurrent nitroglycerin administration reduces the thrombolytic efficacy of rTPA in patients with AMI probably by lowering the plasma levels of rTPA antigen. The diminished efficacy of rTPA is associated with an adverse outcome.
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PMID:Concurrent nitroglycerin administration reduces the efficacy of recombinant tissue-type plasminogen activator in patients with acute anterior wall myocardial infarction. 920 Apr 1

Adjunctive therapy for acute myocardial infarction should include aspirin, beta-adrenergic blocking agents, and, in most patients, consideration of the use of angiotensin-converting enzyme inhibitors, especially if left ventricular function is reduced. Heparin has an important adjunctive role in enhancing early vessel patency in patients who receive tissue-type plasminogen activator and in decreasing the frequency of reocclusion of an infarct-related artery during any thrombolytic therapy. Heparin must also be administered to all patients who undergo primary angioplasty. Intravenously administered nitroglycerin and orally administered nitrates are probably most effective in patients with symptomatic ischemia. Calcium channel blockers and prophylactic antiarrhythmic agents are not indicated for most patients with acute myocardial infarction. Currently, insufficient evidence is available to recommend the widespread use of intravenously administered magnesium sulfate in the setting of acute myocardial infarction. In patients with ischemic pain, judicious intravenous administration of morphine can provide relief. Use of warfarin sodium should be reserved for patients at risk for left ventricular mural thrombus. Although the use of lipid-lowering agents after myocardial infarction has been controversial, recent studies have demonstrated the importance of such therapy for secondary prevention of death and morbidity.
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PMID:Adjunctive therapy in the management of patients with acute myocardial infarction. 773 Dec 56


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