title: New derivative of staphylokinase SAK-RGD-K2-Hirul exerts thrombolytic effects in the arterial thrombosis model in rats.
abstract: SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul are recombinant proteins that are derivatives of r-SAK (recombinant staphylokinase). They are characterized by their fibrin-specific plasminogen activation properties and their antithrombin and antiplatelet activities. The difference between these proteins is the presence of the antithrombotic fragment (hirudin or hirulog) in the C-terminal portion of the r-SAK. The aim of the present study was to examine the thrombolytic potentials of SAK-RGD-K2-Hir and SAK-RGD-K2-Hirul in an electrically induced carotid artery thrombosis model in rats and to compare the potentials to that of r-SAK. We determined that a bolus injection of SAK-RGD-K2-Hirul was more effective than one of r-SAK in the improvement and maintenance of carotid patency and in arterial thrombus weight reduction; however, it had the same potency as SAK-RGD-K2-Hir. The bleeding time, prothrombin time and activated partial thromboplastin time were significantly prolonged in the animals that were treated with either dose (1.5 or 3.0 mg/kg) of SAK-RGD-K2-Hir or SAK-RGD-K2-Hirul, whereas no changes were observed in the plasma fibrinogen concentration or the α2 plasmin inhibitor level. r-SAK alone did not change the bleeding time or coagulation parameters. In conclusion, our findings demonstrate the thrombolytic activity of intravenous bolus injection of the novel thrombolytic agent SAK-RGD-K2-Hirul in rats. Although this protein compares favorably with r-SAK, we were unable to show the presence of any beneficial effects of SAK-RGD-K2-Hirul over those of SAK-RGD-K2-Hir. Furthermore, our results suggest that high doses of SAK-RGD-K2-Hirul bear the risk of bleeding.
authors.affiliation: Department of Medical Biochemistry, Medical University of Łódź, Mazowiecka 6/8, PL 92-215 Łódź, Poland. jszemraj@csk.am.lodz.pl
authors.forename: Janusz
authors.initials: J
authors.lastname: Szemraj
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Zakrzeska
authors.forename: George
authors.initials: G
authors.lastname: Brown
authors.forename: Adrian
authors.initials: A
authors.lastname: Stankiewicz
authors.forename: Anna
authors.initials: A
authors.lastname: Gromotowicz
authors.forename: Tomasz
authors.initials: T
authors.lastname: Grędziński
authors.forename: Ewa
authors.initials: E
authors.lastname: Chabielska
mesh_terms: D000818:Animals; D001760:Bleeding Time / Q000379:methods; D001777:Blood Coagulation / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006629:Hirudins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D008666:Metalloendopeptidases / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D005343:Fibrinolytic Agents; D006629:Hirudins; D011993:Recombinant Fusion Proteins; C521927:SAK-RGD-K2-Hir; D008666:Metalloendopeptidases; C571711:SAK-RGD-K2-Hirul; C022653:auR protein, Staphylococcus aureus