Nonclinical Evaluation of Novel Cationically Modified Polysaccharide Antidotes for Unfractionated Heparin

Abstract

Protamine, the only registered antidote of unfractionated heparin (UFH), may produce a number of adverse effects, such as anaphylactic shock or serious hypotension. We aimed to develop an alternative 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 polysaccharides. Our approach was to synthesize, purify and characterize cationic derivatives of dextran, hydroxypropylcellulose, pullulan and γ-cyclodextrin, then to screen them for potential heparin-reversal activity using an in vitro assay and finally examine efficacy and safety of the most active polymers in Wistar rat and BALB/c mouse models of experimentally induced arterial and venous thrombosis. Efficacy studies included the measurement of thrombus formation, activated partial thromboplastin time, bleeding time, and anti-factor Xa activity; safety studies included the measurement of hemodynamic, hematologic and immunologic parameters. Linear, high molecular weight dextran substituted with glycidyltrimethylammonium chloride groups at a ratio of 0.65 per glucose unit (Dex40-GTMAC3) is the most potent and the safest UFH inhibitor showing activity comparable to that of protamine while possessing lower immunogenicity. Cationic polysaccharides of various structures neutralize UFH. Dex40-GTMAC3 is a promising and potentially better UFH antidote than protamine.

An Appraisal of Antidotes’ Effectiveness: Evidence of the Use of Phyto-Antidotes and Biotechnological Advancements

“…Another study synthesized a cationic polysaccharide-based (dextran substituted with glycidyltrimethylammonium chloride groups-Dex40-GTMAC3, which was most potent) molecule/antidote with enhanced unfractionated heparin (UFH) uptake that is as efficient as protamine, but safer with lower immunogenicity and production cost. Until now, protamine had been the only antidote for UFH [62].…”

Cell proliferation induced by modified cationic dextran

“…Polysaccharides modified with GTMAC were synthesized using the general procedure described previously [4], [10], same as in the case of polymers grafted using APTMAC [4], [10]. All the details of polymer synthesis are presented in the Supporting Information.…”

“…Dextran is a polysaccharide widely used in medicine, its cationic derivatives are employed to neutralize heparin, and they exhibit antiviral properties [4], [5]. The 40-kDa dextran is widely described in the literature and has various well-known medical applications, mainly as an antithrombotic substance, reductor of blood viscosity, and a volume expander in hypovolemia [6], [7], [8], [9].…”

“…All polymers used in this article were described previously in the literature [4], [10] and their synthesis and characteristics are included in the Supporting Information.…”

Małopłytkowość indukowana protaminą — nowy problem czy inny typ małopłytkowości poheparynowej?

“…W wyniku syntezy i licznych modyfikacji chemicznych na przełomie kilku ostatnich lat również grupa autorów niniejszego artykułu opracowała szereg polimerów, z któ-rych na podstawie wstępnych badań wyselekcjonowano najbardziej obiecujące zamienniki protaminy. Wśród otrzymanych związków najskuteczniejszym i dobrze tolerowanym okazał się Dex40-GTMAC3 [41][42][43][44]. Jednak jego niska aktywność wobec drobnocząsteczkowych heparyn oraz fondaparinuxu skłoniła autorów niniejszego artykułu do opracowania nowej uniwersalnej odtrutki pozwalającej na neutralizację wszystkich parenteralnych antykoagulantów; HBC (heparin-binding copolymer) jest polimerem Joanna Mikłosz i wsp., Małopłytkowość indukowana protaminą -nowy problem czy inny typ?…”