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Nonclinical evaluation of novel cationically modified polysaccharide antidotes for unfractionated heparin.

Kalaska B, Kaminski K, Sokolowska E, Czaplicki D, Kujdowicz M, Stalinska K, Bereta J, Szczubialka K, Pawlak D, Nowakowska M, Mogielnicki A - PLoS ONE (2015)

Bottom Line: We aimed to develop an alternative UFH antidote as efficient as protamine, but safer and easier to produce.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.Dex40-GTMAC3 is a promising and potentially better UFH antidote than protamine.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.

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.

No MeSH data available.


Related in: MedlinePlus

aPTT in plasma of Wistar rats mixed with different concentrations of Dex40-GTMAC.a-P<0.05, b-P<0.01 vs. vehicle, Mann-Whitney test. Results are shown as mean ± SD, n = 5.
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pone.0119486.g005: aPTT in plasma of Wistar rats mixed with different concentrations of Dex40-GTMAC.a-P<0.05, b-P<0.01 vs. vehicle, Mann-Whitney test. Results are shown as mean ± SD, n = 5.

Mentions: In vitro, Dex40-GTMAC3 prolonged aPTT at higher concentration than 50 mg·l-1 (Fig. 5).


Nonclinical evaluation of novel cationically modified polysaccharide antidotes for unfractionated heparin.

Kalaska B, Kaminski K, Sokolowska E, Czaplicki D, Kujdowicz M, Stalinska K, Bereta J, Szczubialka K, Pawlak D, Nowakowska M, Mogielnicki A - PLoS ONE (2015)

aPTT in plasma of Wistar rats mixed with different concentrations of Dex40-GTMAC.a-P<0.05, b-P<0.01 vs. vehicle, Mann-Whitney test. Results are shown as mean ± SD, n = 5.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4362941&req=5

pone.0119486.g005: aPTT in plasma of Wistar rats mixed with different concentrations of Dex40-GTMAC.a-P<0.05, b-P<0.01 vs. vehicle, Mann-Whitney test. Results are shown as mean ± SD, n = 5.
Mentions: In vitro, Dex40-GTMAC3 prolonged aPTT at higher concentration than 50 mg·l-1 (Fig. 5).

Bottom Line: We aimed to develop an alternative UFH antidote as efficient as protamine, but safer and easier to produce.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.Dex40-GTMAC3 is a promising and potentially better UFH antidote than protamine.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, Poland.

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.

No MeSH data available.


Related in: MedlinePlus