Nonclinical evaluation of novel cationically modified polysaccharide antidotes for unfractionated heparin

PloS One
Bartlomiej KalaskaAndrzej Mogielnicki

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 inhib...Continue Reading

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Citations

Mar 26, 2016·Frontiers in Pharmacology·Emilia SokolowskaAndrzej Mogielnicki
May 26, 2016·Expert Opinion on Drug Metabolism & Toxicology·Emilia SokolowskaAndrzej Mogielnicki
Apr 1, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Christiana Eleojo AruwaSaheed Sabiu
Feb 19, 2021·Journal of Pharmaceutical and Biomedical Analysis·Bianka VárnaiSzabolcs Béni
Jun 5, 2020·Biomacromolecules·Chanel C LaJayachandran N Kizhakkedathu
May 1, 2021·Clinical and Applied Thrombosis/hemostasis : Official Journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis·Ahmed KoutaJawed Fareed
Sep 8, 2017·Biomacromolecules·Manu Thomas KalathottukarenJayachandran N Kizhakkedathu
Nov 5, 2019·ACS Chemical Biology·Benjamin Ourri, Laurent Vial

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Methods Mentioned

BETA
ELISA
nuclear magnetic resonance

Software Mentioned

ARRIVE

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