Dextran-based materials reducing anticoagulant activity of heparin in animal models in vitro and in vivo

Kamil K. Kamiński 1Krzysztof Szczubiałka 1Maria Nowakowska 1Bartłomiej Kalaska 2Emilia Sokołowska 2Andrzej Mogielnicki 2Włodzimierz Buczko 2

1. Jagiellonian University, Faculty of Chemistry, Ingardena 3, Kraków 30-060, Poland
2. Medical University of Bialystok, Department of Pharmacodynamics (MUB), Miczkiewicza 2C, Białystok 15-089, Poland

Abstract

Heparin is a naturally occurring polysaccharide used in many medical applications, especially for treating cardiovascular diseases [1]. This polymer has a natural ability to prevent blood clot formation in mammals both in vitro and in vivo. Anticoagulative effect of heparin is often difficult to predict and in the case of an emergency (e.g. haemorrhage due to the heparin overdose) it has to be reduced. The only substance currently used in such situations is protamine sulphate (PS)[1].  This protein, however, can be a cause of many adverse effects, e.g. life threatening allergic response [2] or hypotension. Therefore, there is a necessity of developing a safer alternative which could replace it.
      Polysaccharide derivatives with positively charged molecules seem to be promising candidates that could be the answer for this issue [3]. Here we are reporting the studies on the application of the cationic derivatives of dextran (DeX-GTMAC) for heparin deactivation [4]. Studies on the influence of different doses of DeX-GTMAC on the heparin activity in the rat blood using various coagulation tests were performed and compared with those for (PS)First, the in vitro studies were performed to estimate the effective dose of the obtained polymer. The effective dose of  to reverse the effects of heparin in rats in vitro was 5 mg/120 U of heparin (Figure 1).

Figure 1. Dependence of activated thromboplastin time (aPTT) on the applied dose of the polymer

The reversal of heparin action by DeX-GTMAC was clearly seen in the mice developing chemically induced venous thrombosis and was even more potent than the effect of PS. Both DeX-GTMAC and PS reversed the prolongation of bleeding time and aPTT by heparin administered in rats and mice. Moreover, other routinely measured blood parameters are significantly affected. DeX-GTMAC, in contrast to the PS, significantly increase red blood cell counts, hemoglobin level and haematocrit value. The data obtained show that the cationically-modified dextran may be potentially used to reverse anticoagulative heparin activity.

Acknowledgement: The project was operated within the Fundation for Polish Science Team Programme (TEAM/2008-2/6) and Ventures Programme (Ventures/2009-4/4) cofinanced by EU European Regional Development Fund

References:
[1].      Mclaughlin, K. E.; Dunnin, J.Interactive Cardiovascular and Thoracacic Surgery , 2, 424-426, 2003.
[2].      Panos, A. ;Orrit, X. ; Chevalley, C.; Kalangos A., European Journal of Cardio-thoracic Surgary 24, 325-227 2003
[3].      Kaminski, K.; Szczubialka, K.; Zazakowny, K.;Lach, R.; Nowakowska M. J. Med. Chem.. 53, 4141-4147, 2010.
[4]     Kamiński K., Płonka M., Ciejka J., Szczubiałka K., Nowakowska M., Lorkowska B., Korbut R., Lach R. J. Med. Chem., 54 (19),  6586–6596, 2011

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Presentation: Oral at VIII Multidyscyplinarna Konferencja Nauki o Leku, by Kamil K. Kamiński
See On-line Journal of VIII Multidyscyplinarna Konferencja Nauki o Leku

Submitted: 2012-02-26 16:44
Revised:   2012-02-28 10:52
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