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: Janusz Szemraj, Agnieszka Zakrzeska, George Brown, Adrian Stankiewicz, Anna Gromotowicz, Tomasz Grędziński, Ewa Chabielska
• Journal: Pharmacological reports : PR (Pharmacol Rep) Vol. 63 Issue 5 Pg. 1169-79 ( 2011) ISSN: 2299-5684 [Electronic] Switzerland
• PMID: 22180359 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Fibrinolytic Agents
• Hirudins
• Recombinant Fusion Proteins
• SAK-RGD-K2-Hir
• Metalloendopeptidases
• SAK-RGD-K2-Hirul
• auR protein, Staphylococcus aureus

Topics

• Animals
• Bleeding Time (methods)
• Blood Coagulation (drug effects)
• Carotid Artery Thrombosis (drug therapy, pathology)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Fibrinolytic Agents (administration & dosage, pharmacology, toxicity)
• Hirudins (administration & dosage, pharmacology, toxicity)
• Injections, Intravenous
• Male
• Metalloendopeptidases (administration & dosage, pharmacology, toxicity)
• Rats
• Rats, Wistar
• Recombinant Fusion Proteins (administration & dosage, pharmacology, toxicity)