Intravenous thrombolytic therapy with a combination of single-chain urokinase-type plasminogen activator and recombinant tissue-type plasminogen activator in acute myocardial infarction.

Abstract

The effects of simultaneous intravenous infusions of 12 mg recombinant tissue-type plasminogen activator (rt-PA) over 30 minutes and 48 mg single-chain urokinase-type plasminogen activator (scuPA) over 40 minutes were studied in 38 patients with acute myocardial infarction. Coronary arterial patency was assessed angiographically 60 minutes and 90 minutes after initiation of treatment. Patency was achieved in 19 of 31 patients (61.3%) (95% confidence limits, 42-78%) at 60 minutes and in 27 of 33 patients (81.8%) (95% confidence limits, 65-93%) at 90 minutes. Nonspecific plasminogen activation was monitored by measuring relevant plasma parameters. At 60 minutes and 120 minutes, the fibrinogen concentration decreased slightly to 82.8±24.3% and 91.2±17.4% of the preinfusion level, and the plasminogen concentration to 66.3+± 15.2% and 65.3+13.4%, respectively. A greater consumption of ,2-antiplasmin was observed, which decreased to 30.7+22.8% and 32.2+±21.2% of the preinfusion level at 60 and 120 minutes, respectively. No bleeding necessitating transfusion was observed. Two patients (5.3%) died during hospitalization. The findings suggest that the combined intravenous infusion of rt-PA and scuPA at appropriate doses induces highly effective coronary thrombolysis equal to the best results obtained with either rt-PA or scuPA alone. This efficacy is coupled with high specificity. Thus, the data support the potential use of combinations of rt-PA and scuPA in place of monotherapy. (Circulation 1990;81:907-913 possible with certain combinations of rt-PA and scuPA to induce more effective thrombolysis without compromising specificity. By lowering the overall dose requirements, it might be additionally possible to reduce the cost of therapy.The present study was designed to evaluate this concept. A dosage combination was chosen that was estimated to be just below the threshold at which fibrinogen degradation would be anticipated. Methods MaterialHuman scuPA was highly purified from the conditioned medium of the transformed kidney cellline TCL-598. PatientsInclusion criteria consisted of chest pain typical of myocardial infarction lasting for more than 30 minutes, diagnostic electrocardiographic ST segment elevation of 2 mm in at least three leads or 1 mm in at least three leads accompanied by ST segment depression in three corresponding leads, presentation within 6 hours after the onset of pain, age less than 75 years, and informed consent.Exclusion criteria were recent (<3 months) trauma, stroke or major surgery, previous myocardial damage in the infarct territory, cardiopulmonary resuscitation, cardiogenic shock (systolic blood pressure, <80 mm Hg), hypertension (systolic blood pressure, >200 mmHg; diastolic blood pressure, >110 mmHg; or both) unresponsive to therapy within 10 minutes, or evidence of recent or active bleeding (e.g., peptic ulcer and hemoptysis). The study protocol had been approved by the institutional ethics committee. TreatmentPatients were anticoagulated with 5,000 units heparin at the start of treatme...

Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis

“…The second generation of fibrinolytics comprised rt-PA [111] and singlechain uro-kinase type plasminogen activator [112]. They are both recombinant proteins more or less identical to the endogenous human fibrinolytic activators, and are more fibrin-specific than streptokinase.…”

Comparison of Dose Regimens for the Administration of Recombinant Pro-urokinase in a Canine Thrombosis Model

“…In clinical studies, pro-urokinase has been examined both alone (12)(13)(14)(15)(16) and in combination with t-PA (17) or urokinase (18,19). However, a variety of doses and dosing regimens have been used in these clinical trials.…”

Therapeutic Advantage of Recombinant Human Plasminogen Activator in Endocarditis: Evidence from Experiments in Rabbits

“…Treatment with thrombolytic agents might digest fibrin, reduce the mass and enhance the pharmokinetic aspects of diffusion of antibiotics into the vegetations (2). For these purposes, plasminogen activators might be useful since they induce fibrinolysis and may be efficacious in the treatment of acute coronary thrombosis and venous thrombotic disease (3,4). The rationale for administration of recombinant human tissue plasminogen activator (rt-PA) and antibiotics to treat viridans streptococcal endocarditis has been studied previously in experimental rabbits (5).…”