Pharmacokinetics and Haemostatic Status During Consecutive Infusions of Recom binant Tissue-Type Plasminogen Activator in Patients with Acute Myocardial Infarction

1989 ◽  
Vol 61 (03) ◽  
pp. 497-501 ◽  
Author(s):  
E Seifried ◽  
P Tanswell ◽  
D Ellbrück ◽  
W Haerer ◽  
A Schmidt
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Plasminogen Activator ◽  
Peak Plasma ◽  
Peak Plasma Concentration ◽  
Tissue Type ◽  
Tissue Type Plasminogen Activator ◽  
Precise Control ◽  
Type Plasminogen Activator

SummaryPharmacokinetics and systemic effects of recombinant tissue type plasminogen activator (rt-PA) were determined during coronary thrombolysis in 12 acute myocardial infarction patients using a consecutive intravenous infusion regimen. Ten mg rt-PA were infused in 2 minutes resulting in a peak plasma concentration (mean ±SD) of 3310±950 ng/ml, followed by 50 mg in 1 h and 30 mg in 1.5 h yielding steady state plasma levels of. 2210±470 nglml and 930±200 ng/ml, respectively. All patients received intravenous heparin. Total clearance of rt-PA was 380±74 ml/min, t,½α was 3.6±0.9 min and t,½β was 16±5.4 min.After 90 min, in plasma samples containing anti-rt-PA-IgG to inhibit in vitro effects, fibrinogen was decreased to 54%, plasminogen to 52%, α2-antiplasmin to 25%, α2-macroglobulin to 90% and antithrombin III to 85% of initial values. Coagulation times were prolonged and fibrin D-dimer concentrations increased from 0.40 to 2.7 μg/ml. It is concluded that pharmacokinetics of rt-PA show low interpatient variability and that its short mean residence time in plasma allows precise control of therapy. Apart from its moderate effect on the haemostatic system, rt-PA appears to lyse a fibrin pool in addition to the coronary thrombus.

Non Neutralizing Antibodies to Tissue Type Plasminogen Activator in the Serum of Acute Myocardial Infarction Patients Treated with the Recombinant Protein

1996 ◽  
Vol 76 (02) ◽  
pp. 234-238 ◽  
Author(s):  
Massimo Cugno ◽  
Marco Cicardi ◽  
Mario Colucci ◽  
Giuliana Bisiani ◽  
Piera Angelica Merlini ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Plasminogen Activator ◽  
Neutralizing Antibodies ◽  
Antibody Formation ◽  
Tissue Type ◽  
Blood Samples ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryRecombinant tissue-type plasminogen activator (rt-PA) is currently used as a thrombolytic agent in the management of acute myocardial infarction (AMI). Since it is known that other recombinant proteins induce antibody formation when administered to humans, we determined the presence of anti-rt-PA antibodies in serial blood samples from 60 AMI patients (43 treated with and 17 without rt-PA). Blood samples were taken upon hospital admission, 15 days and 1, 3,6 months thereafter. A blood sample was also collected from 200 healthy subjects. Using an ELISA, anti-rt-PA antibodies were detected as serum immunoglobulins specifically binding immobilized rt-PA. AMI patients before treatment and normal subjects exhibited negligible levels of anti-rt-PA antibodies; both groups had only one outlier value. Fifteen days after rt-PA treatment, 2 AMI patients showed an increase in antibody titer beyond the highest normal value. This titer progressively decreased during the following 6 months. The antibodies from these two patients bound rt-PA both in a solid and fluid phase. They bound melanoma t-PA to a lower degree and did not bind urokinase type plasminogen activator at all, indicating specificity for t-PA. The marked temporal relationship between rt-PA infusion and antibody appearance indicated that antibody formation had been elicited by the infusion of rt-PA. Nevertheless, the lack of anti-rt-PA antibody interference with rt-PA function in vitro, along with the favourable clinical outcome of those patients having such antibodies would indicate that the appearance of anti-rt-PA antibodies does not interfere with the physiological fibrinolytic activity.

RESULTS OF COAGULATION - FIBRINOLYSIS ANALYSES IN 386 PATIENTS WITH ACUTE MYOCARDIAL INFARCTION TREATED WITH RECOMBINANT TISSUE-TYPE PLASMINOGEN ACTIVATOR (rt-PA) (TAMI TRIAL)

1987 ◽  
Author(s):  
D C Stump ◽  
E J Topol ◽  
R Califf ◽  
A B Chen ◽  
A Hopkins ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Coronary Artery ◽  
Tissue Type ◽  
Single Chain ◽  
Coagulation Rate ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator ◽  
H 20

Three hundred eighty-six patients with acute myocardial infarction received up to 150 mg rt-PA (single chain) IV either over 8 h (60mg over 1 h, 20 mg/h for 2 h,10 mg/h for 5 h)(173 pts) or over"5h(1 mg/kg over 1 h, remainder over 4 h) (213 pts),before randomization to early or late angioplasty. Blood was collected on a lyophilized mixture of citrate and the t-PA inhibitor D-Phe-Pro-Arg-CH2C1 (PPACK), to maximally prevent in vitro fibrinolytic activation and concomitant fibrinogen degradation. The plasma rt-PA level increased to 2.4±2.0 /μg/ml(mean +SD)and 1.7 ±1.3 /μg/ml after 3h and to 1.0 ±1.8 and 1.0 ±0.9 /μg/ml at the end of the infusion.Fibrinogen levels (coagulation rate assay) fell to 5 ± 28 and 52 ± 27% at 3 h and to53 ± 28 and 47 μ 26% at the endof infusion.Fibrinogen degradation productsincreased to 32 /μg/ml (median, with 10 and 90 percentile values of 2 and 512 /μg/ml) after 3h and to3 2 /μg/1 (median, with 10 and 90 percentile values of 2and 512 ug/ml) at the end of infusion. The fibrinogen decreased to below 1 g/1 in 23% of patients and b e low 0-5 g/1 in 11% after 3 h infusion with corresponding values of 33% and 12%at the end of infusion.Thus, at the infusion rates required for rapid coronary artery reperfusion in man, rt-PA remains relatively fibrin-specific. The cause of the extensive fibrinogen depletion occurring in some patients remains to be further investigated.

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