Recombinant Human Tissue-type Plasminogen Activator Research Articles

Tissue plasminogen activator and acute pulmonary embolism.

We assessed the efficacy and safety of peripheral intravenous recombinant human tissue-type plasminogen activator (rt-PA) in 47 patients with angiographically documented pulmonary embolism (PE). We administered 50 mg/2 h and, if necessary, an additional 40 mg/4 h. By 6 hours, 94% of the patients had angiographic evidence of clot lysis that was slight in 5, moderate in 12, and marked in 27 patients. Among the 34 patients with pulmonary hypertension prior to treatment, average pulmonary artery pressure decreased from 43/17 (27) to 31/13 (19) mm Hg (P less than 0.0001). The average lung scan perfusion defect decreased from 37% before therapy to 16% (P less than 0.01) after therapy among the 19 patients who had pre- and post-treatment lung scans. Of 7 patients with pre- and post-treatment imaging and Doppler echocardiograms, hypokinetic right ventricular wall movement (mild in 1, moderate in 2, and severe in 4) normalized in 5 and improved to mild hypokinesis in 2. Right ventricular diameter decreased from 3.9 +/- 1.0 to 2.0 +/- 0.5 cm (P less than 0.005). Fibrinogen decreased 33% from baseline at 2 h and 42% from baseline at 6 h. However, patients with the greatest degree of angiographic clot lysis at 2 h had a preponderance of fibrinogenolysis over fibrinolysis, demonstrated by a lower ratio of cross-linked fibrin degradation products to fibrin(ogen) degradation products (0.14 +/- 0.09 vs. 0.54 +/- 0.82) (P less than 0.04). Among selected patients, peripheral intravenous rt-PA is associated with rapid lysis of PE, improved pulmonary perfusion, and improved right ventricular function.

Low doses of recombinant human tissue-type plasminogen activator for local thrombolysis in peripheral arteries.

Low doses of recombinant human tissue-type plasminogen activator for local thrombolysis in peripheral arteries.

RANDOMISED CONTROLLED TRIAL OF RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR VERSUS UROKINASE IN THE TREATMENT OF ACUTE PULMONARY EMBOLISM

The effect of intravenous recombinant human tissue-type plasminogen activator (rt-PA) was compared with that of urokinase in 45 patients with angiographically documented pulmonary embolism (PE) in a randomised controlled trial. The two principal end-points were clot lysis at 2 h, as assessed by angiography, and pulmonary reperfusion at 24 h, as assessed by perfusion lung scanning. All patients received the full dose of rt-PA but urokinase infusions were terminated prematurely (on average after 18 h) in 9 patients because of allergy in 1 and uncontrollable bleeding in 8. By 2 h, 82% of rt-PA-treated patients showed clot lysis, compared with 48% of urokinase-treated patients (p=0·008; 95% CI for the difference = 10-58%). Improvement in lung scan reperfusion at 24 h was identical in the two treatment groups. The reduction in fibrinogen did not differ significantly between the rt-PA and urokinase groups (45% vs 39% at 2 h and 34% vs 40% at 24 h). The results indicate that in the dose regimens employed, rt-PA acts more rapidly and is safer than urokinase in the treatment of acute PE.

Laboratory monitoring of hemostasis during thrombolytic therapy with recombinant human tissue-type plasminogen activator

Recombinant tissue-type plasminogen activator (rt-PA) was administered intravenously to 93 patients with acute myocardial infarction and coronary thrombosis in doses of 30 to 150 mg over 1.5 to 6 hours. During this infusion plateau levels of rt-PA in plasma ranged between 0.4 and 2.2 μg/ml. Activation of the plasma fibrinolytic system and fibrinogen breakdown both in vivo and in vitro was observed with this therapy. In vitro fibrinogenolysis in plasma was more effectively prevented by collection of blood samples on aprotinin (200 kallikrein inhibitor units/ml blood), a conventional serine protease inhibitor, than on either of two monoclonal antibodies against t-PA (200 μg/ml plasma), or on D-phenyllanyl-prolyl-arginine-chloromethyl ketone (PPACK), a newly developed synthetic inhibitor of t-PA. Results of fibrinogen measurements during infusion of rt-PA were dependent on the method of assay. In a subgroup of 36 patients after completion of a thrombolytic infusion, fibrinogen decreased in vivo by 27% when measured as total coagulable protein and by 33% with a coagulation rate assay, but increased by 26% with an automated assay system. The extent of fibrinogenolysis was proportional to the plasma level of rt-PA but substantial intersubject variation was observed. Fibrinogenolysis in vivo was also associated with alpha2-antiplasmin depletion and was more pronounced with a two-chain (G11021) than with a single-chain preparation (G11035) of rt-PA. It is concluded that the fibrinolytic state associated with rt-PA infusion in patients may be rapidly and conveniently monitored by measurement of henostatically functional plasma fibrinogen with a coagulation rate assay. This assay should be performed on citrated plasma samples supplemented with aprotinin to prevent in vitro artifactual fibrinogen degradation.

Mediation of reocclusion by thromboxane A2 and serotonin after thrombolysis with tissue-type plasminogen activator in a canine preparation of coronary thrombosis.

Human recombinant tissue-type plasminogen activator (rt-PA) has been shown to be an effective and safe agent for coronary thrombolysis in patients with acute myocardial infarction. However, thrombolysis is associated with a high rate of acute reocclusion after discontinuation of rt-PA. The goals of the present study were to assess whether reocclusion after thrombolysis is caused by intracoronary platelet aggregation and to determine the role of thromboxane A2 (TxA2) and serotonin (5HT) in mediating this phenomenon. Accordingly, coronary thrombosis was induced in anesthetized, open-chest dogs by insertion of a copper coil into the left anterior descending coronary artery (LAD). LAD blood flow was monitored throughout the experiment by means of a Doppler flow probe placed proximally to the coil. Thrombolysis was achieved with rt-PA (0.05 mg/kg bolus + micrograms/kg/min infusion) in 23 +/- 3 min. rt-PA was then discontinued and each animal received a bolus of heparin (150 U/kg) every hour. Reperfusion was followed by repeated cycles of gradual occlusions followed by spontaneous restorations of blood flow (cyclic flow variations, CFVs) before a persistent occlusion recurred. In control dogs (n = 6), heparin alone did not prevent CFVs and reocclusion time was 25 +/- 4 min. Administration of an intravenous bolus of 0.2 +/- 0.06 mg/kg SQ29548, a TxA2/prostaglandin H2-receptor antagonist, and an intravenous bolus of 0.2 +/- 0.04 mg/kg ketanserin, a 5HT2-receptor antagonist, completely abolished CFVs in six of six dogs and reocclusion time was greater than 158 +/- 14 min (p less than .01).(ABSTRACT TRUNCATED AT 250 WORDS)

Pulmonary perfusion after rt-PA therapy for acute embolism: early improvement assessed with segmental perfusion scanning.

To determine if pulmonary perfusion was improved in acute pulmonary embolism after therapy with recombinant human tissue-type plasminogen activator (rt-PA), lung scans were obtained before and a mean of 22 hours after therapy in 19 patients. The posttherapy lung scans were compared with baseline, pretherapy scans with use of two semiquantitative methods--an anteroposterior view method, similar to that used in the Urokinase Pulmonary Embolism Trial, and a segmental method that emphasized pulmonary anatomy. There was an improvement in the defect score from 0.35 to 0.14 (P less than .01) when the anteroposterior view method was used and from 0.37 to 0.16 (P less than .01) when the segmental method was used. These encouraging results in the early posttherapy period suggest that rt-PA is especially effective in improving regional perfusion after pulmonary embolism and that a larger controlled trial of therapy with rt-PA for acute pulmonary embolism should be performed. Scoring lung scans with a segmental method is feasible and appropriate for present-day lung scan technique and should be considered in future studies.

Thrombolysis of peripheral arterial bypass grafts: Surgical thrombectomy compared with thrombolysis: A preliminary report

Twenty-two patients were selected from a group of 33 patients who underwent recombinant human tissue-type plasminogen activator (rt-PA) thrombolysis for thrombosed infrainguinal bypass grafts of the lower extremity and were compared with 38 matched patients who had undergone surgical thrombectomy during the same period. The proportion of persons with diabetes mellitus, smokers, and types of bypass grafts was similar in both groups. More patients in the rt-PA—treated group had hypertension (p = 0.01). To evaluate the different lengths of follow-up, Kaplan-Meier survival analysis was used with a log-rank test to compare the proportion of persons with patent grafts in the two treatment groups. At 30 days, 86% of the rt-PA—treated grafts were still patent compared with 42% of the surgically treated grafts (p = 0.001). When risk factors on the Kaplan-Meier curves were compared, there was no statistical difference with regard to graft patency among the groups. According to simultaneous Cox regression analysis, no risk factor was significantly associated with graft patency. When amputation was evaluated between treatment groups simultaneously with other risk factors in a logistic regression analysis, smoking and age of the graft were marginally significant (p = 0.07), whereas all other factors were clearly not significant. In 91% of the rt-PA—treated patients, a secondary surgical procedure was required to maintain patency of the graft segment. Eighty-nine percent of the surgically treated patients required similar graft revisions. Two patients in the surgical group and one patient in the rt-PA—treated group had major complications. This short clinical experience suggests that better 30-day patency rates and a lower risk of amputation can be achieved when thrombolysis is associated with surgical revision compared with surgical revision alone.

The determination of recombinant human tissue-type plasminogen activator activity by turbidimetry using a microcentrifugal analyzer

A method is described for determining the activity of recombinant human tissue-type plasminogen activator (rt-PA) by turbidimetry using a microcentrifugal analyzer (MCA). A mixture of thrombin and rt-PA is centrifuged into a mixture of fibrinogen and plasminogen to initiate clot formation and subsequent clot dissolution. The resultant profile of absorbance versus time is analyzed to determine the assay endpoint. Different rt-PA assay concentration ranges were studied in conjunction with profile endpoints for assay optimization. Spiked placebo recovery studies were used to evaluate assay accuracy and precision, which were determined to be 99.5 and 5% (relative standard deviation or RSD), respectively. Assay sensitivity was 0.5 ng/ml. Typical analysis time, including calculations, for a standard curve plus 14 samples was less than 30 min. The application of turbidimetry with the MCA for determining rt-PA activity provides rapid sample analysis and high throughput while maintaining accuracy and precision.

Fibrinolytic therapy for deep vein thrombosis and pulmonary embolism.

The troublesome sequelae of pulmonary embolism (PE) and deep vein thrombosis (DVT) justify an aggressive therapeutic approach. Results of anticoagulation in patients with DVT have shown that a significant percentage of patients have no clot resolution and may progress to develop the postphlebitic syndrome. Lytic therapy has been more effective, with patients showing improvement within 24 h of treatment. This approach has also been found to compare favorably with anticoagulation in the treatment of PE. Preliminary research also suggests a potential role for recombinant human tissue-type plasminogen activator to resolve PE.

The Effect of Human Recombinant Tissue-Type Plasminogen Activator on Clinical and Laboratory Parameters of Hemostasis and Systemic Plasminogen Activation in the Dog and the Rat

The effect of human recombinant tissue-type plasminogen activator (rt-PA) on parameters of hemostasis and systemic plasminogen activation was studied in the dog and rat. Effects on screening coagulation times, fibrinogen concentration, fibrin/fibrinogen degradation products, and plasminogen and alpha 2-antiplasmin (alpha 2-AP) activities in plasma were examined following single bolus injections of 0.5-5.0 mg/kg, single and repeated 3 hr infusions of 0.75-7.5 mg/kg and 24 hr infusions of 6.0 and 30.0 mg/kg administered intravenously to dogs. Rats receiving single or 14 daily injections of 5.0-30.0 mg/kg i.v. were similarly monitored. Systemic fibrinogenolysis (greater than 50% decrease in fibrinogen, plasminogen or alpha 2-AP values) was observed in dogs receiving greater than or equal to 1.0 mg/kg as a bolus, greater than or equal to 3.75 mg/kg (20.8 micrograms or 1.19 x 10(4) IU kg-1min-1) as a 3 hr infusion and greater than or equal to 6 mg/kg (4.2 micrograms or 2.42 x 10(3) IU kg-1min-1) as a 24 hr infusion; and in rats treated with bolus injections of 30 mg/kg rt-PA. Clinical and laboratory indications of impaired hemostasis and bleeding (anemia, prolonged coagulation times and post-mortem evidence of hemorrhage) were associated with these effects, which together were dose-dependent and influenced by the rate of infusion. The incidence of major hemorrhage was variable and limited to animals receiving prolonged (24 hr) or repeated infusions.

Efficacy of a two-hour infusion of 150-mg tissue plasminogen activator in acute myocardial infarction

Forty-two patients with acute myocardial infarction received 150-mg recombinant human tissue-type plasminogen activator (rt-PA) at 2.3 ±1.2 hours after the onset of chest pain. After a 40 U/kg bolus of heparin, rt-PA was given as a 10-mg bolus followed by a 2-hour continuous infusion of 90 mg in the first hour and 50 mg in the second hour. Non-angiographic signs of reperfusion occurred during treatment (41 ± 21 minutes) in 35 patients and in 1 other patient about 30 minutes after rt-PA. Three patients had discordant nonangiographic signs of reperfusion, 2 patients had no evidence of reperfusion and 1 patient in cardiogenic shock died before completion of the rt-PA infusion and before reperfusion status could be ascertained. Clinical signs of early reocclusion occurred in 4 of the 36 patients with evidence of reperfusion, 3 of whom were retreated with rt-PA with clinical success in 2. Coronary angiography 10 ± 8 hours later revealed a patent artery of infarction in 35 patients: 32 with nonangiographic signs of sustained reperfusion, both patients with successfully treated reocclusion and 1 of 3 patients with discordant signs of reperfusion. Angiography revealed evidence of partial reperfusion in the remaining 2 patients with discordant signs, and an occluded artery was found in both patients without any evidence of reperfusion and in both patients with clinical signs of persistent reocclusion. Hemorrhagic complications occurred in 9 patients, 7 were related to procedural trauma and 2 patients required a blood transfusion. Four patients died, each of a cardiac cause: 3 in hospital and 1 at home. These data suggest that a 2-hour intravenous infusion of 150-mg rt-PA achieves a high rate of reperfusion in patients with acute myocardial infarction without high incidence of reocclusion or serious bleeding.

Thrombolytic therapy of acute pulmonary embolism: Current status and future potential

Recombinant human tissue-type plasminogen activator (rt-PA), a relatively clot-specific fibrinolytic agent, represents a novel and promising approach to thrombolytic therapy of pulmonary embolism. Therefore, the efficacy and safety of peripheral intravenous rt-PA therapy were assessed in 47 patients with angiographically documented pulmonary embolism. The drug regimen was 50 mg over 2 hours followed by repeat angiography and, if necessary, an additional 40 mg over 4 hours. By 6 hours, 44 of the 47 patients had angiographic evidence of clot lysis that was slight (n = 5), moderate (n = 12) or marked (n = 27). Among the 34 patients with pulmonary hypertension before treatment (mean pulmonary artery pressure exceeding 17 mm Hg), the pressure decreased from 43/17 (mean 27) to 31/13 (mean 19) mm Hg (p less than 0.0001). Fibrinogen decreased 33% from baseline at 2 hours and 42% from baseline at 6 hours. There were two major complications that required surgical control of bleeding: hemorrhage from a pelvic tumor and mediastinal tamponade in a patient 8 days after coronary artery bypass surgery. The initial results demonstrate that, among selected patients, peripheral intravenous rt-PA can rapidly and, for the most part, safely lyse pulmonary embolism within 6 hours.

Thrombolysis with intravenous human recombinant tissue-type plasminogen activator in acute myocardial infarction: The European experience

The initial studies in Europe with tissue-type plasminogen activator (rt-PA) have been coordinated by a European Cooperative Study Group. By February 1987, 258 patients had been entered into comparative coronary patency trials of rt-PA versus streptokinase and rt-PA versus placebo (trials completed and published); 123 patients had entered a coronary patency trial of prolonged rt-PA infusion versus short-term rt-PA infusion (trial completed but results not yet published); and greater than 500 patients had been recruited for left ventricular function and infarct size trials comparing rt-PA with placebo and rt-PA alone with rt-PA plus immediate coronary angioplasty (studies still in progress). The first three studies used two chain rt-PA, 0.75 mg/kg, for the rt-PA versus streptokinase and rt-PA versus placebo studies and 40 or 80 mg for the short-term versus long-term study. The current studies are using single chain rt-PA in a dose of 100 mg (20 mg bolus, 40, 20 and 20 mg in succeeding hours). Coronary patency at angiography 90 minutes after the start of treatment was 70% for rt-PA and 55% for streptokinase, 1.5 million units, in the plasminogen activator versus streptokinase study (p = 0.054), 61% for rt-PA and 21% for placebo in the rt-PA versus placebo study (p less than 0.001). In the first three studies (251 patients allocated to rt-PA) there was one case of retroperitoneal hematoma, one of hematemesis and no cases of cerebral hemorrhage; 38 patients (15%) had a hematoma or bleeding related to arterial catheterization.(ABSTRACT TRUNCATED AT 250 WORDS)

Recombinant human tissue-type plasminogen activator therapy in acute thromboembolic stroke.

Systemic fibrinolytic therapy for acute stroke is no longer recommended because of resulting systemic fibrinolysis and the risk of intracerebral hemorrhage. Human tissue-type plasminogen activator (TPA) is a native enzyme that converts plasminogen to plasmin with subsequent clot lysis. The affinity for plasminogen is increased several-fold when the substrate is bound to fibrin. At appropriate dosage, "clot-specific" thrombolysis may be achieved at the surface of the thrombus without creating systemic fibrinolysis. The authors designed a study to evaluate the effect of intravenous TPA administered 2 hours after acute thromboembolic stroke in rats. This time course was chosen to simulate an analogous clinical situation. Middle cerebral artery embolic stroke was caused by intracarotid injection of 0.025 cc of human blood clot in 16 rats. Regional cerebral blood flow, measured by the hydrogen clearance technique, and electroencephalographic (EEG) recordings were obtained every 30 minutes for 5 hours after thromboembolism. Eight rats received a 1-hour infusion of intravenous TPA (1.5 mg/kg) 2 hours after injection of emboli. Ipsilateral blood flow increased significantly within 30 minutes after intravenous TPA and reached preembolic levels within 60 minutes. Blood flow did not improve in the eight control rats throughout the experiment. Power spectral analysis of the EEG recordings showed improvement in the treated group compared to the control group. Postmortem angiography revealed proximal middle cerebral artery occlusion in control animals and patent middle cerebral arteries in TPA-treated animals. Serum fibrinogen and fibrin split products were unchanged in both groups, indicating the absence of systemic fibrinolysis. There were no intracerebral hemorrhages. It is concluded that, in this rat model, TPA increases blood flow with subsequent improvement in the EEG recording after thromboembolic stroke without evidence of systemic fibrinolysis. Intravenous TPA may be useful in the treatment of acute stroke in man.

Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: Initial patency and influence of maintained infusion on reocclusion rate

An intravenous infusion of 40 mg of recombinant tissue-type plasminogen activator (rt-PA) was given intravenously over 90 minutes to 123 patients with acute myocardial infarction (AMI) of less than 4 hours' duration. A coronary angiogram was recorded at the end of the infusion in 119 patients. Central assessment of the angiograms revealed a patent infarct-related artery in 78 patients (patency rate 66%, 95% confidence limits 57 to 74%). Patients with a patent infarct-related artery at the first angiogram were randomized in a double-blind manner to receive a subsequent 6-hour infusion of either 30 mg of rt-PA or placebo. All patients had received an initial bolus of 5,000 IU of heparin and then 1,000 IU/hour until a second angiogram was recorded 6 to 24 hours after the start of the second perfusion. At central assessment of the second coronary angiogram the reocclusion rate was 2 of 36 patients who received rt-PA at the second infusion and 3 of 37 patients not receiving this drug (or the 2 groups combined 7%, 95% confidence limits 2 to 15%). Three of 60 patients (5%, 95% confidence limits 1 to 14%) with patent arteries on both previous angiograms had a later occlusion as judged on the angiogram recorded at hospital discharge. No difference in late reocclusion rates between the 2 treatment groups was observed.

Recombinant human tissue-type plasminogen activator for thrombolysis in peripheral arteries and bypass grafts: Risius B, Graor RA, Geisinger MA, et al. Radiology 1986;160:183–188

Recombinant human tissue-type plasminogen activator for thrombolysis in peripheral arteries and bypass grafts: Risius B, Graor RA, Geisinger MA, et al. Radiology 1986;160:183–188

Reduction in infarct size and enhanced recovery of systolic function after coronary thrombolysis with tissue-type plasminogen activator combined with beta-adrenergic blockade with metoprolol.

The effect of beta-adrenergic blockade on the salvage and functional recovery of reperfused myocardium was investigated in anesthetized dogs. Immediately after thrombotic occlusion of the left anterior descending coronary artery, the cardioselective beta-blocking agent metoprolol was given intravenously at a dose of 0.5 mg/kg infused over 10 min. One hour after the onset of occlusion, recanalization was initiated by intravenous infusion of recombinant human tissue-type plasminogen activator (rt-PA, 10 micrograms/kg/min for 30 min). Anatomic infarct size expressed as percent of the left ventricular mass (I/LV), global ejection fraction, and mean systolic shortening of the segmental radii (SS) of the infarcted area were measured either after 24 hr or 1 week in six groups of six dogs each: group I (rt-PA + metoprolol, evaluated at 24 hr), group II (rt-PA + metoprolol, evaluated at 1 week, group III (rt-PA alone, evaluated at 24 hr), group IV (rt-PA alone, evaluated at 1 week), group V (persistent occlusion, evaluated at 24 hr), and group VI (persistent occlusion, evaluated at 1 week). The smallest infarcts were found in reperfused dogs given metoprolol, but the differences from dogs receiving rt-PA alone were not statistically significant (I/LV, expressed as mean +/- SEM: 5.5 +/- 0.9% in group I, 6.7 +/- 1.9% in group II, 15.4 +/- 5.0% in group III, 11.4 +/- 3.5% in group IV, 23.6 +/- 2.5% in group V, and 26.9 +/- 2.3% in group VI).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative properties of two clinical preparations of recombinant human tissue-type plasminogen activator in patients with acute myocardial infarction

The biologic properties of two clinical preparations of recombinant human tissue-type plasminogen activator were studied in 52 patients with acute myocardial infarction. The first preparation (G11021) has been used in all clinical trials reported to date, whereas the second preparation (G11035) is now produced for future clinical use. When both preparations were infused intravenously for 90 minutes at rates of 4 to 11 micrograms/kg per min, plateau levels of the drug in plasma ranged from 0.52 +/- 0.15 to 1.8 +/- 0.4 micrograms/ml and were linearly correlated with the infusion rate. However, G11035 yielded plasma levels that were approximately 35% lower than those obtained with G11021 (p less than 0.025). The postinfusion disappearance rate of the drug from plasma could be described by a two compartment disposition model with the following pharmacokinetic variables. For G11021, an alpha half-life of 4.1 to 6.3 minutes, a beta half-life of 41 to 50 minutes, a central compartment volume of 3.5 to 5.4 liters, a total distribution volume of 28 to 44 liters and a plasma clearance of 450 to 640 ml/min. For G11035 these variables were 3.6 to 4.6 minutes, 39 to 53 minutes, 3.8 to 6.6 liters, 27 to 40 liters and 520 to 1,000 ml/min, respectively, indicating that G11035 is cleared more rapidly from the circulation. G11021 at 4 micrograms/kg per min and G11035 at 7 micrograms/kg per min did not effectively produce thrombolysis. A coronary reperfusion rate of 81% (13 of 16 patients) was obtained with 5.3 micrograms/kg per min of G11021 and a rate of 86% (6 of 7 patients) was obtained with 9.4 micrograms/kg per min of G11035.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation by Heparin Fragments of Thrombolysis Induced with Human Tissue-Type Plasminogen Activator or Human Single-Chain Urokinase-Type Plasminogen Activator

The effect of heparin and of two low molecular weight (low Mr) fractions of heparin on thrombolysis with recombinant human tissue-type plasminogen activator (rt-PA, Genentech Inc., So. San Francisco, CA) or human single chain urokinase-type plasminogen activator (scu-PA, Sandoz AG, Basle, Switzerland) was measured in a rabbit jugular vein thrombosis model. Four bolus injections of 200 anti-Factor Xa units/kg body weight of heparin (Liquemine, Hoffmann-La Roche, Basle, Switzerland), of 90 units/kg of CY 216 (Choay, Paris, France) or of 90 units/kg of CY 222 (Choay, Paris, France) were given intravenously, immediately after the start of the infusion of rt-PA or scu-PA and at hourly intervals during their intravenous infusion over 4 hours. The bolus injections resulted in anti-Factor Xa levels in plasma of 5.7 +/- 1.2 units/ml just before the repeat bolus injections of heparin with corresponding values of 3.9 +/- 0.2 units/ml for CY 216 and 1.6 +/- 0.2 units/ml for CY 222. Thrombolysis with 0.25 mg/kg rt-PA was 36 +/- 1 percent (n = 9) in the absence of anticoagulant, 40 +/- 1 percent (n = 7, p less than 0.05) in the presence of heparin, 49 +/- 5 percent (n = 7, p less than 0.02) with CY 216 and 62 +/- 5 percent (n = 7, p less than 0.01) with CY 222.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-dependent thrombolysis, pharmacokinetics and hemostatic effects of recombinant human tissue-type plasminogen activator for coronary thrombosis

The pharmacokinetics, thrombolytic profile and effects on hemostasis of graded intravenous doses of recombinant human tissue-type plasminogen activator (rt-PA) were studied in 45 patients with acute myocardial infarction. Infusion of rt-PA at a rate of 4 to 8.3 μg/kg/min resulted in plateau levels of the drug in plasma of 0.52 to 1.4 μg/ml. A linear relation between infusion rate and plasma rt-PA concentration was observed, although plasma drug levels varied substantially among subjects who received infusions at the same rate. The ratio between plateau levels of rt-PA in plasma and infusion rate was inversely related to initial distribution volume (7.3 ± 2.9 liters, n = 21). The decline in plasma concentration of rt-PA, x(t), as a function of time after cessation of the infusion, was described adequately by the biexponential equation: x(t) = 0.71exp(−0.13t) + 0.29exp(−0.015t). The initial and terminal half-lives of rt-PA in the blood were 5.3 ± 1.7 and 46.2 ± 14 minutes, respectively. The efficacy of rt-PA for coronary thrombolysis was dose-dependent. With 4 μg/kg/min of rt-PA for 90 minutes, no reperfusion was achieved, whereas infusion rates of 5 μg/kg/min or more for 90 minutes accomplished reperfusion in more than 80% of the patients. However, the frequency of occurrence of residual intraluminal thrombus was significantly lower with an infusion rate of 7 μg/kg/min for 90 minutes. A dose-related decrease of the plasma fibrinogen level was also observed to a maximum of 53 ± 12% (± standard error of the mean) of baseline when measured with a coagulation rate assay and to 76 ± 8% when measured as coagulable protein, at the end of an infusion of 7 μg/kg/min for 90 minutes. At this dose, plasminogen and α 2-antiplasmin levels declined to 57 ± 5% and 20 ± 10% of baseline, respectively. In 9 patients the initial rt-PA infusion of 5.5 to 7 μg/kg/min for 90 minutes was followed by an intravenous maintenance infusion of 2 μg/kg/min for 4 hours. This treatment resulted in plateau levels of rt-PA in plasma of 0.43 ± 0.14 μg/ml and was associated with only modest additional fibrinogen breakdown.