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

Abstract

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.

Tissue Plasminogen Activator Concentration Dependence of 120 kHz Ultrasound-Enhanced Thrombolysis

“…The rt-PA concentrations were chosen to contain the therapeutic concentration range in humans (Seifried et al 1989;Tanswell et al 1991). Individual trials began by slowly injecting 1 mL of hFFP (control trials) or 1 mL of hFFP containing rt-PA (all other trials) into the sample holder.…”

Arrhenius temperature dependence ofin vitrotissue plasminogen activator thrombolysis

“…The aliquots were allowed to thaw at room temperature (~22 °C) when needed for use, and the unused portion discarded after a given trial. The concentration of tPA used in all experiments was 3.15 μg ml −1 which is within the therapeutic concentration range in humans (Tanswell et al 1991,Seifried et al 1989.…”

Effects of Alteplase, a Thrombolytic Agent, in a Rat Photothrombotic Middle Cerebral Artery Occlusion Model

“…Taking into account the rapid clearance of alteplase in rats and species difference in efficacy between rats and humans (alteplase has an amino acid array of human t-PA), we considered that a 3-to 5-fold dosage was required in comparison with the clinical dosage so as to show a similar efficacy and plasma concentration in rats compared with humans. In our study, the plasma concentration of t-PA following a 30-min infusion of 3 mg/kg alteplase was almost the same as that used in the clinical setting for patients with acute myocardial infarction, in whom 100 mg of alteplase was administered for a mean body weight of about 80 kg [18] .…”