B. Kalaska, K. Kaminski, E. Sokolowska, D. Czaplicki, M. Kujdowicz, K. Stalinska, K. Szczubialka, J. Bereta, D. Pawlak, M. Nowakowska, A. Mogielnicki
Medical University of Bialystok, Poland
pp. 281 - 284
Keywords: heparin, protamine, antidote, dextran, polysaccharides, thrombosis, haemostasis, immune response
Protamine is the only registered antidote preventing bleeding of patients treated with unfractionated heparin (UFH). However protamine may induce anaphylactic shock or serious hypotension. We aimed to develop an alternative fully synthetic UFH antidote as efficient as protamine, but safer and easier to produce. As a starting material, we have chosen generally non-toxic, biocompatible, widely available, inexpensive, and easy to functionalize polymer - dextran. Our approach was to synthesize and purify dextran substituted with glycidyltrimethylammonium chloride groups at a ratio of 0.65 per glucose unit (Dex40-GTMAC3), then to check it for potential heparin-reversal activity in vitro and finally examine efficacy and safety of the modified dextran in Wistar rats and BALB/c mouse models of experimentally induced arterial and venous thrombosis. Efficacy studies included the measurement of thrombus formation and coagulation parameters; safety studies included the measurement of pharmacokinetics, hemodynamic, hematologic, biochemical and immunogenic endpoints. Dex40-GTMAC3 is immediately eliminated from blood. It is efficient as protamine but less immunogenic UFH inhibitor. Basing on our non-clinical evaluation of Dex40-GTMAC3, we believe that the novel polymer has very promising properties and can potentially substitute protamine as the UFH antidote.