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

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Query: EC:3.4.21.68 (tissue plasminogen activator)
11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-nine patients with acute myocardial infarction were treated with recombinant human tissue-type plasminogen activator (rt-PA). The incidence of acute coronary reocclusion and its prevention by a maintenance infusion of rt-PA were studied. Intravenous rt-PA was given at a rate of 0.4 to 0.75 mg/kg over 60 to 120 min after angiographic documentation of complete coronary occlusion. Reperfusion was accomplished within 1 hr in 24 of 29 patients (83%) and was associated with a decrease of the plasma fibrinogen level by 20%. In a first group of 13 patients, 11 of whom were successfully reperfused, prevention of reocclusion was attempted with heparin anticoagulation. However, acute reocclusion within 1 hr after cessation of rt-PA was demonstrated angiographically in five of these patients (45%). Quantitative angiographic analysis indicated that acute reocclusion only occurred in patients with 80% or greater residual stenosis. In patients with less than 80% residual stenosis, heparin anticoagulation was sufficient to maintain patency during the hospital stay in four of five patients. In a second group of patients (n = 16), 13 of whom underwent reperfusion with intravenous rt-PA, seven demonstrated a residual stenosis of 80% or greater. These patients were given heparin and, in addition, 10 mg of rt-PA per hour for 4 hr. None developed acute angiographic reocclusion or clinical signs of reocclusion during the hospital stay. Repeat angiography at 10 to 14 days confirmed persistent patency in six of the seven patients. The maintenance infusion resulted in only a moderate additional drop in fibrinogen, while a steady-state plasma rt-PA level of 750 +/- 250 ng/ml was maintained.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion. 308 Feb 62

Recent trials have shown that recombinant tissue plasminogen activator (rt-PA) is an effective thrombolytic agent in patients with acute myocardial infarction. Because rt-PA converts plasminogen to plasmin, which is known to activate complement in vitro, we tested the hypothesis that rt-PA can induce in vivo activation of complement. Studies were performed in 12 patients with acute myocardial infarction. Six control patients had patent coronary arteries and did not receive rt-PA; these patients had normal values of the components of the complement system C4a (409 +/- 111 ng/ml) and C5a (8.8 +/- 1.8 ng/ml) with a slight elevation of C3a (204 +/- 6.6 ng/ml) in samples collected before coronary arteriography (253 +/- 25 minutes after onset of pain). After coronary arteriography, there was a slight decrease in the values of C4a (224 +/- 37 ng/ml), C5a (7.3 +/- 1.3 ng/ml) and C3a (164 +/- 35 ng/ml). The remaining six patients had complete coronary occlusion and received rt-PA (80 to 150 mg intravenously). In this treated group, before coronary arteriography the values of C4a (406 +/- 51.6 ng/ml) and C5a (8.1 +/- 1.9 ng/ml) were normal, and those of C3a were slightly elevated (250 +/- 76 ng/ml). All complement values obtained before rt-PA were similar to those in the untreated group. However, after administration of rt-PA (but before any angiographically detectable reperfusion), there was a striking increase in C4a (2,265 +/- 480 ng/ml; p less than 0.01), C3a (600 +/- 89 ng/ml; p less than 0.05) and C5a (30.0 +/- 4.5 ng/ml; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of the complement system by recombinant tissue plasminogen activator. 311 50

Intracoronary streptokinase can accomplish reperfusion in 70 to 75% of patients with acute myocardial infarction (AMI), and intravenous streptokinase in approximately 50% of those with prior documented coronary occlusion. The time constraints for accomplishing significant myocardial salvage have proved to be quite restrictive, however. Studies in which treatment has begun after an average of 4 hours of symptoms have not shown significant improvement in ventricular function. In contrast, those in which intervention has been applied earlier, particularly in less than 2 to 3 hours, have consistently shown benefit. The price for applying thrombolytic therapy includes the risk of severe bleeding (about 5%) but, fortunately, mortality as a result of bleeding has been rare (less than or equal to 0.5%). Reperfusion may be only transient or incomplete (and insufficient). An early reocclusion rate of about 15 to 20% has been commonly noted, in fact. Recently, major studies have pointed to a reduction in early mortality in patients treated early (within about 3 hours) after the onset of symptoms. Much interest is now being focused on developing safer, more effective thrombolytic agents such as tissue plasminogen activator and anisoylated plasminogen streptokinase activator complex (APSAC). Adjunctive therapy with coronary angioplasty is also being applied. In the judgement of many, reperfusion therapy may represent the greatest advance in the approach to AMI of the current decade.
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PMID:Recent clinical developments in thrombolysis in acute myocardial infarction. 331 95

In the ischemic state, which leads to myocardial infarction, there is a gradation of cardiac muscle injury and a sequence of functional loss. On coronary occlusion an immediate cellular leak of potassium occurs and the rate of relaxation declines. Within 1 to 2 minutes there is complete loss of contraction followed by the onset of contracture in 7 to 10 minutes in isolated preparations. The major problem of this initial period, if the occlusion zone is not too great, is electrical dysfunction. The next 1 to 6 hours is the period of variable reversible injury. Positron emission tomography technique and fatty acid and carbohydrate tracers quantitatively assess regions that are metabolically competent. The problem is to maintain and improve the competence of these regions during reperfusion, whether by thrombolytic therapy (streptokinase) or tissue plasminogen activator, percutaneous transluminal angioplasty, acute coronary artery bypass graft or by total vented bypass and regional reperfusion without thoracotomy (procedure under development).
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PMID:Cardiac ischemia. Part I--Metabolic and physiologic responses. 361 16

Forty-five patients with acute transmural myocardial infarction and angiographically confirmed complete coronary occlusion were prospectively randomized, two for one, to treatment of acute coronary thrombosis with intravenous recombinant human tissue-type plasminogen activator (rt-PA) or placebo. Each of five additional consecutive patients was treated with a high dose of rt-PA for 2 hr. Twenty-five of 33 patients (75%) receiving 0.5 to 0.75 mg/kg of rt-PA over 30 to 120 min had angiographically proven recanalization within 90 min of initiation of therapy. Only one of 14 patients given placebo had spontaneous recanalization within 45 min (p less than .001). Thirteen placebo-treated patients were crossed over to the intracoronary rt-PA group. Nine (69%) exhibited subsequent recanalization within 45 min. Levels of circulating fibrinogen decreased after treatment with rt-PA by an average of only 8% of baseline values. None of the patients manifested a depletion of fibrinogen level to below 100 mg/dl. Six patients who were completely unresponsive to rt-PA were subsequently treated with intracoronary streptokinase and none responded. Thus, either intravenous or intracoronary rt-PA induced coronary thrombolysis without eliciting clinically significant fibrinogenolysis in patients with evolving myocardial infarction due to thrombotic coronary occlusion.
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PMID:Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial. 638 98

In a canine copper coil-induced coronary thrombosis model, the differences in frequency of reperfusion arrhythmias (premature ventricular complexes: PVC) and mortality rate after thrombolysis by intravenous bolus injection of a novel modified tissue-type plasminogen activator (t-PA), E6010, and by continuous intravenous infusion of native t-PA or urokinase were evaluated. Rapid coronary occlusion and reperfusion were produced with a balloon catheter in another group of dogs, and the findings were compared with those in the thrombolysis groups. Reperfusion occurred gradually after the administration of E6010, but was significantly more rapid after administration of native t-PA and urokinase (P < 0.05). PVC were observed more frequently in native t-PA, urokinase and balloon occlusion-reperfusion groups than in the E6010 group. The mortality rate due to ventricular fibrillation was 0.0% in the E6010 group, 50.0% in the native t-PA and balloon occlusion-reperfusion groups, and 33.3% in the urokinase group. These results suggest that the more gradual reperfusion of the coronary artery at an earlier period after drug administration led to the lower frequency of reperfusion arrhythmias and low mortality rate in the E6010 group than in the native t-PA, urokinase and balloon occlusion-reperfusion groups.
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PMID:A novel modified tissue-type plasminogen activator (t-PA), E6010, gradually increases coronary blood flow after thrombolysis compared with native t-PA, urokinase and balloon catheter occlusion-reperfusion. 753 43

Using the centerline method in a canine model, we compared left ventricular function after coronary thrombolysis induced by a novel modified recombinant tissue plasminogen activator (rt-PA) (E6010: 84Cys-->84Ser) to that induced by rt-PA or urokinase. Thirty minutes after occlusion, a bolus injection of E6010 (0.2 mg/kg) or a continuous infusion of either rt-PA (0.6 mg/kg over 1 h) or urokinase (0.38 mg/kg over 1 h) was administered intravenously. Animals with sustained copper coil-occlusion served as non-reperfused controls. Left ventricular ejection fraction and regional wall motion (expressed as the infarction chord number; ie, the number of chords < -2SD among chords 12-66) were 42 +/- 5%** and 5 +/- 3,** respectively, in the E6010 group, 31 +/- 8% and 16 +/- 12 in the rt-PA group, and 31 +/- 2% and 32 +/- 13 in the urokinase group 1 h after reperfusion, indicating earlier recovery of left ventricular function after thrombolysis in the E6010 group than in the rt-PA and urokinase groups (**p < 0.01 vs control). Coronary reperfusion with E6010 induced earlier recovery of left ventricular function than reperfusion with rt-PA or urokinase. These results suggest that E6010 may be of clinical value in the treatment of coronary occlusion.
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PMID:A novel modified t-PA, E-6010, induces faster recovery of ventricular function after coronary thrombolysis than native t-PA in a canine thrombosis model. 765 13

A model for thrombolysis in rats was developed. Repeated, focal external heating was applied to the carotid artery which leads to the development of a cyclic blood flow with slow, steady decreases followed by abrupt increases. When this cyclic blood flow stops spontaneously, the entire arterial segment (approximately 10 mm) can be demarcated with snares to create an arterial thrombus of fixed size, with a platelet-rich head and an erythrocyte-rich tail. The usefulness of the model was tested by evaluating the thrombolysis induced by a low dose of recombinant tissue-type plasminogen activator (rt-PA) alone and rt-PA in combination with standard heparin and recombinant hirudin. Re-canalization of the artery was measured as blood flow and as the residual 125I-radioactivity in the artery at the end of the experiment, resulting from 125I-fibrinogen incorporated during the formation of the thrombus. Both blood flow and 125I-activity measurements show that hirudin, but not heparin in combination with rt-PA, significantly improves thrombolysis, which is in accordance with previous experimental findings. It is concluded that the model, with a thrombus resembling the thrombus found in man after coronary occlusion, enables complicated experiments with thrombolysis frequently performed only in large animals to be performed in rats.
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PMID:A new rat model of arterial thrombosis with a platelet-rich head and an erythrocyte-rich tail: thrombolysis experiments with specific thrombin inhibition. 849 64

The case of a 20-year-old man with acute myocardial infarction is described. He developed acute myocardial infarction on 11 July 1995. An emergency coronary arteriogram revealed total occlusion of the proximal left anterior descending coronary artery. Reperfusion was achieved by intracoronary injection of 6.4 x 10(6) units of native tissue plasminogen activator, which left multiple, angiographically identifiable, thrombi in the left anterior descending coronary artery. As a coronary angiogram 28 days after the onset showed no organic stenosis or wall irregularity, we conducted an ergonovine provocation test. The infusion of 32 micrograms of ergonovine into the left coronary artery provoked diffuse, high-grade vasospasm. The patient's medical history showed that he had been diagnosed as having Kimura's disease when he was 19 year-old. Additionally, he had exhibited persistent eosinophilia of unknown origin for 10 months or more. Thus, his condition was consistent with a diagnosis of hypereosinophilic syndrome (HES). This is the first report to document angiographically the presence of acute coronary obstruction in a patient with HES. The acute coronary occlusion was thought to be related to coronary artery vasospasm.
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PMID:Acute myocardial infarction associated with hypereosinophilic syndrome in a young man. 929 13

YM866 is a novel modified tissue-type plasminogen activator (t-PA). Its effects on left ventricular function and myocardial infarct development in dogs with copper coil-induced coronary artery thrombosis were compared with those of a native t-PA, alteplase. YM866 (bolus injection) and alteplase (bolus plus infusion) were administered 15 min after coronary artery occlusion. YM866 and alteplase produced reperfusion in all animals, with a median time to reperfusion of 10 min. In contrast, no reperfusion occurred in the vehicle control group. Left ventricular ejection fraction (LVEF) significantly decreased 15 min after coronary occlusion. YM866 and alteplase improved LVEF 3 hr and 4 hr after administration, respectively, while LVEF did not improve in the vehicle control group. Only slight myocardial infarct areas were observed in both YM866- and alteplase-administered groups, while the area in the vehicle control group accounted for 18.2% of left ventricular myocardial area. In conclusion, although both YM866 and alteplase reperfused occluded coronary arteries, inhibited myocardial infarct development and improved LVEF in dogs with coronary artery thrombi, only a single bolus injection of YM866 was necessary to achieve these improvements. Therefore, YM866 shows promise as an improved clinical agent in treating acute myocardial infarction.
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PMID:YM866, a novel modified tissue-type plasminogen activator, affects left ventricular function and myocardial infarct development in dogs with coronary artery thrombi. 971 64


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