title: 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.
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Kalaska
authors.affiliation: Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kaminski
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Emilia
authors.initials: E
authors.lastname: Sokolowska
authors.affiliation: Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Czaplicki
authors.affiliation: Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
authors.forename: Monika
authors.initials: M
authors.lastname: Kujdowicz
authors.affiliation: Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Krystyna
authors.initials: K
authors.lastname: Stalinska
authors.affiliation: Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Bereta
authors.affiliation: Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Szczubialka
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Pawlak
authors.affiliation: Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Nowakowska
authors.affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Mogielnicki
mesh_terms: D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002412:Cations / Q000737:chemistry*; D005260:Female; D006493:Heparin / Q000737:chemistry* / Q000378:metabolism; D006494:Heparin Antagonists / Q000494:pharmacology*; D007114:Immunization; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010314:Partial Thromboplastin Time; D011108:Polymers / Q000737:chemistry / Q000494:pharmacology*; D011134:Polysaccharides / Q000737:chemistry; D011479:Protamines / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013927:Thrombosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism
chemical_list: D000931:Antidotes; D002412:Cations; D006494:Heparin Antagonists; D011108:Polymers; D011134:Polysaccharides; D011479:Protamines; D006493:Heparin