PMID- 25781030
OWN - NLM
STAT- MEDLINE
DCOM- 20160216
LR  - 20200306
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 3
DP  - 2015
TI  - Nonclinical evaluation of novel cationically modified polysaccharide antidotes 
      for unfractionated heparin.
PG  - e0119486
LID - 10.1371/journal.pone.0119486 [doi]
LID - e0119486
AB  - 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 gamma-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.
FAU - Kalaska, Bartlomiej
AU  - Kalaska B
AD  - Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, 
      Poland.
FAU - Kaminski, Kamil
AU  - Kaminski K
AD  - Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
FAU - Sokolowska, Emilia
AU  - Sokolowska E
AD  - Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, 
      Poland.
FAU - Czaplicki, Dominik
AU  - Czaplicki D
AD  - Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Kujdowicz, Monika
AU  - Kujdowicz M
AD  - Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
FAU - Stalinska, Krystyna
AU  - Stalinska K
AD  - Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Bereta, Joanna
AU  - Bereta J
AD  - Department of Cell Biochemistry, Faculty of Biochemistry, Biophysics and 
      Biotechnology, Jagiellonian University, Krakow, Poland.
FAU - Szczubialka, Krzysztof
AU  - Szczubialka K
AD  - Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
FAU - Pawlak, Dariusz
AU  - Pawlak D
AD  - Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, 
      Poland.
FAU - Nowakowska, Maria
AU  - Nowakowska M
AD  - Faculty of Chemistry, Jagiellonian University, Krakow, Poland.
FAU - Mogielnicki, Andrzej
AU  - Mogielnicki A
AD  - Department of Pharmacodynamics, Medical University of Bialystok, Bialystok, 
      Poland.
LA  - eng
PT  - Evaluation Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150317
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Antidotes)
RN  - 0 (Cations)
RN  - 0 (Heparin Antagonists)
RN  - 0 (Polymers)
RN  - 0 (Polysaccharides)
RN  - 0 (Protamines)
RN  - 9005-49-6 (Heparin)
SB  - IM
MH  - Animals
MH  - Antidotes/*pharmacology
MH  - Blood Pressure/drug effects
MH  - Cations/*chemistry
MH  - Female
MH  - Heparin/*chemistry/metabolism
MH  - Heparin Antagonists/*pharmacology
MH  - Immunization
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Partial Thromboplastin Time
MH  - Polymers/chemistry/*pharmacology
MH  - Polysaccharides/chemistry
MH  - Protamines/metabolism
MH  - Rats
MH  - Rats, Wistar
MH  - Thrombosis/*drug therapy/*immunology/metabolism
PMC - PMC4362941
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/03/18 06:00
MHDA- 2016/02/18 06:00
PMCR- 2015/03/17
CRDT- 2015/03/18 06:00
PHST- 2014/10/16 00:00 [received]
PHST- 2015/01/13 00:00 [accepted]
PHST- 2015/03/18 06:00 [entrez]
PHST- 2015/03/18 06:00 [pubmed]
PHST- 2016/02/18 06:00 [medline]
PHST- 2015/03/17 00:00 [pmc-release]
AID - PONE-D-14-37109 [pii]
AID - 10.1371/journal.pone.0119486 [doi]
PST - epublish
SO  - PLoS One. 2015 Mar 17;10(3):e0119486. doi: 10.1371/journal.pone.0119486. 
      eCollection 2015.