caa a22 4500 469077883 CHVBK 20180323132940.0 cr unu---uuuuu 170328e19920701xx s 000 0 eng 10.1007/BF00167579 doi (NATIONALLICENCE)springer-10.1007/BF00167579 Pharmacokinetic and thrombolytic properties of unglycosylated recombinant tissue-type plasminogen activator (BM 06.021) produced in Escherichia coli [Elektronische Daten] [U. Martin, S. Fischer, U. Kohnert, U. Opitz, R. Rudolph, G. Sponer, A. Stern, K. Strein] Summary: Recombinant tissue-type plasmogen activator (rt-PA) was produced in Escherichia coli cells in order to obtain an unglycosylated rt-PA (BM 06.021) with increased thrombolytic potency due to altered pharmacokinetic properties. The pharmacokinetics were studied in rabbits upon intravenous infusion of 200 kU/kg over 30 min. The thrombolytic dose-response effects were evaluated in a rabbit model with 125I-labeled venous thrombi upon intravenous infusion over 4 h. The thrombolytic effects after intravenous bolus injection of 200 kU/kg BM 06.021 were investigated in a canine model of coronary artery thrombosis. All studies were performed comparing BM 06.021 with glycosylated rt-PA (alteplase). BM 06.021 demonstrated a longer (p < 0.05) half-life (5.6±2.6 vs. 2.1±0.3 min) and a lower (p(0.05) clearance rate (7.5±0.8 vs. 22.2±3.1 ml ·min−1·kg−1) than alteplase in rabbits upon intravenous infusion. The doseresponse curve of BM 06.021 for thrombolysis in a rabbit model of jugular vein thrombosis was located to the left of that for alteplase with a 2.1-fold lower effective dose of 50% thrombolysis (ED50) of BM 06.021 (207 vs. 436 kU/kg). Intravenous bolus injection of 200 kU/kg BM 06.021 induced the same reperfusion rate (4/6) as intravenous infusion of 800 kU/kg alteplase over 90 min in a canine model of coronary artery thrombosis. The residual thrombus wet weight did not significantly differ between BM 06.021 and alteplase (5.7 ± 1.8 vs. 6.3 ± 1.1 mg). The results indicate that unglycosylated rt-PA (BM 06.021) has a higher in vivo thrombolytic potency than glycosylated rt-PA (alteplase). The increased potency seems to be due to the altered pharmacokinetic properties of BM 06.021, because the in vitro specific fibrinolytic activities of BM 06.021 and alteplase are virtually identical (783 vs. 800 kU/mg). Springer-Verlag, 1992 Tissue-type plasminogen activator nationallicence Escherichia coli cells nationallicence Pharmacokinetics nationallicence Thrombolysis nationallicence Rabbits nationallicence Dogs nationallicence Martin U. Department of Pharmacology, Mannheim aut Fischer S. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut Kohnert U. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut Opitz U. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut Rudolph R. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut Sponer G. Department of Pharmacology, Mannheim aut Stern A. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut Strein K. Department of Pharmacology, Mannheim aut Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/1(1992-07-01), 108-113 0028-1298 346:1<108 1992 346 210 https://doi.org/10.1007/BF00167579 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/BF00167579 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Martin U. Department of Pharmacology, Mannheim aut NATIONALLICENCE 700 1- Fischer S. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut NATIONALLICENCE 700 1- Kohnert U. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut NATIONALLICENCE 700 1- Opitz U. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut NATIONALLICENCE 700 1- Rudolph R. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut NATIONALLICENCE 700 1- Sponer G. Department of Pharmacology, Mannheim aut NATIONALLICENCE 700 1- Stern A. Biochemical Research Center, Penzberg, Boehringer Mannheim GmbH, Sandhoferstrasse 116, W-6800, Mannheim 31, Federal Republic of Germany aut NATIONALLICENCE 700 1- Strein K. Department of Pharmacology, Mannheim aut NATIONALLICENCE 773 0- Naunyn-Schmiedeberg's Archives of Pharmacology Springer-Verlag 346/1(1992-07-01), 108-113 0028-1298 346:1<108 1992 346 210 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer