Anticoagulant and antithrombotic actions of a semisynthetic beta-1,3-glucan sulfate.
Sulfation of the natural polysaccharide curdlan results in anticoagulantly active beta-1,3-glucan sulfates whose activity depends on various structural parameters. In this study the anticoagulant and antithrombotic effects of one of these beta-1,3-glucan sulfates (GS) were compared with those of a porcine mucosal heparin. GS produced a concentration dependent anticoagulant effect in all the global coagulation assays with the exception of the anti-Xa assay. The best activity was found in the APTT and the thrombin time assays indicating that protease generation and the direct inhibition of thrombin may be sites of actions of this agent. Whereas the anticoagulant activity of GS was approximately 5 fold lower compared to heparin, a 32 fold higher concentration (ED50 = 550 micrograms/kg) was needed for an antithrombotic effect similar to heparin (ED50 = 17.2 micrograms/kg) in a rabbit model of stasis thrombosis. In contrast to this, when a rat model of clamping induced jugular vein occlusion was used to produce vascular obstruction, GS produced similar antithrombotic actions to heparin. At a 250 micrograms/kg dosage, both agents doubled the number of clampings required for complete vascular obstruction. Since the mechanical injury to the blood vessel is the primary determinant of the thrombogenic response, GS may inhibit some of the pathophysiologic mechanisms responsible for the occlusion of the blood vessel. The current study also points to the fact that the global anticoagulant effects may not reflect the antithrombotic potential of newer sulfated carbohydrate derived drugs.
Alban
S
S
Institute of Pharmacy, University of Regensburg, Germany.
Jeske
W
W
Welzel
D
D
Franz
G
G
Fareed
J
J
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D005936:Glucans / Q000138:chemical synthesis / Q000494:pharmacology* / Q000627:therapeutic use; D006493:Heparin / Q000494:pharmacology; D007601:Jugular Veins; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013552:Swine; D013917:Thrombin / Q000037:antagonists & inhibitors; D013927:Thrombosis / Q000517:prevention & control*; D047071:beta-Glucans
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D005936:Glucans; D047071:beta-Glucans; D006493:Heparin; D013917:Thrombin; C063130:curdlan sulfate