Limits...
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

Binding of UFH by the cationic polymers.Dependence of free UFH concentration on the concentration of Dex6-GTMAC expressed as the ratio of the Dex6-GTMAC mass and total UFH mass. Data for protamine are shown for comparison.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4362941&req=5

pone.0119486.g001: Binding of UFH by the cationic polymers.Dependence of free UFH concentration on the concentration of Dex6-GTMAC expressed as the ratio of the Dex6-GTMAC mass and total UFH mass. Data for protamine are shown for comparison.

Mentions: The ability of the studied substances to bind UFH was assessed with a colorimetric method using Azure A, a cationic dye, as described previously [14,15]. Briefly, UFH chains, when present in the solution of Azure A, complex the dye molecules, which then form aggregates absorbing at 513 nm, while the monomeric form of the dye (in the absence of UFH) absorbs at 630 nm. Added polymer disrupts dye aggregates partially (or fully in the case of complete binding of UFH) and increases 630 nm and decreases 513 nm absorption band intensity. A representative example of the plot showing the dependence of free (i.e., uncomplexed and therefore possessing anticoagulant activity) UFH concentration on the cationic polymer concentration, expressed as the ratio of the cationic polymer mass and total UFH mass, is shown in Fig. 1.


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)

Binding of UFH by the cationic polymers.Dependence of free UFH concentration on the concentration of Dex6-GTMAC expressed as the ratio of the Dex6-GTMAC mass and total UFH mass. Data for protamine are shown for comparison.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0119486.g001: Binding of UFH by the cationic polymers.Dependence of free UFH concentration on the concentration of Dex6-GTMAC expressed as the ratio of the Dex6-GTMAC mass and total UFH mass. Data for protamine are shown for comparison.
Mentions: The ability of the studied substances to bind UFH was assessed with a colorimetric method using Azure A, a cationic dye, as described previously [14,15]. Briefly, UFH chains, when present in the solution of Azure A, complex the dye molecules, which then form aggregates absorbing at 513 nm, while the monomeric form of the dye (in the absence of UFH) absorbs at 630 nm. Added polymer disrupts dye aggregates partially (or fully in the case of complete binding of UFH) and increases 630 nm and decreases 513 nm absorption band intensity. A representative example of the plot showing the dependence of free (i.e., uncomplexed and therefore possessing anticoagulant activity) UFH concentration on the cationic polymer concentration, expressed as the ratio of the cationic polymer mass and total UFH mass, is shown in Fig. 1.

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