Optimization of the β-Aminoester class of factor Xa inhibitors. part 2: Identification of FXV673 as a potent and selective inhibitor with excellent In vivo anticoagulant activity

2002 ◽  
Vol 12 (12) ◽  
pp. 1671-1674 ◽  
Author(s):  
Kevin R Guertin ◽  
Charles J Gardner ◽  
Scott I Klein ◽  
Allison L Zulli ◽  
Mark Czekaj ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Factor Xa ◽  
Selective Inhibitor ◽  
Factor Xa Inhibitors

The Anticoagulant Properties of a Modified Form of Protein S

1988 ◽  
Vol 60 (02) ◽  
pp. 298-304 ◽  
Author(s):  
C A Mitchell ◽  
S M Kelemen ◽  
H H Salem
Keyword(s):  
Monoclonal Antibody ◽  
Anticoagulant Activity ◽  
Activated Protein C ◽  
Factor Xa ◽  
Protein S ◽  
Human Neutrophil Elastase ◽  
Factor X ◽  
Sds Page

SummaryProtein S (PS) is a vitamin K-dependent anticoagulant that acts as a cofactor to activated protein C (APC). To date PS has not been shown to possess anticoagulant activity in the absence of APC.In this study, we have developed monoclonal antibody to protein S and used to purify the protein to homogeneity from plasma. Affinity purified protein S (PSM), although identical to the conventionally purified protein as judged by SDS-PAGE, had significant anticoagulant activity in the absence of APC when measured in a factor Xa recalcification time. Using SDS-PAGE we have demonstrated that prothrombin cleavage by factor X awas inhibited in the presence of PSM. Kinetic analysis of the reaction revealed that PSM competitively inhibited factor X amediated cleavage of prothrombin. PS preincubated with the monoclonal antibody, acquired similar anticoagulant properties. These results suggest that the interaction of the monoclonal antibody with PS results in an alteration in the protein exposing sites that mediate the observed anticoagulant effect. Support that the protein was altered was derived from the observation that PSM was eight fold more sensitive to cleavage by thrombin and human neutrophil elastase than conventionally purified protein S.These observations suggest that PS can be modified in vitro to a protein with APC-independent anticoagulant activity and raise the possibility that a similar alteration could occur in vivo through the binding protein S to a cellular or plasma protein.

Comparison of the Anticoagulant and Antithrombotic Effects of Synthetic Thrombin and Factor Xa Inhibitors

1990 ◽  
Vol 63 (02) ◽  
pp. 220-223 ◽  
Author(s):  
J Hauptmann ◽  
B Kaiser ◽  
G Nowak ◽  
J Stürzebecher ◽  
F Markwardt
Keyword(s):  
Factor Xa ◽  
Thrombin Inhibitors ◽  
Factor Xa Inhibitors ◽  
Venous Stasis ◽  
Clotting Time ◽  
Thrombosis Model ◽  
Activity Factor ◽  
Antithrombotic Effects

SummaryThe anticoagulant effect of selected synthetic inhibitors of thrombin and factor Xa was studied in vitro in commonly used clotting assays. The concentrations of the compounds doubling the clotting time in the various assays were mainly dependent on their thrombin inhibitory activity. Factor Xa inhibitors were somewhat more effective in prolonging the prothrombin time compared to the activated partial thromboplastin time, whereas the opposite was true of thrombin inhibitors.In vivo, in a venous stasis thrombosis model and a thromboplastin-induced microthrombosis model in rats the thrombin inhibitors were effective antithrombotically whereas factor Xa inhibitors of numerically similar IQ value for the respective enzyme were not effective at equimolar dosageThe results are discussed in the light of the different prelequisiles and conditions for inhibition of thrombin and factor Xa in the course of blood clotting.

A Comparison of Anticoagulation Activity of a Potent Heparin Preparation in Different Test

1979 ◽  
Author(s):  
A.S. Bhargava ◽  
J. Heinick ◽  
Chr. Schöbel ◽  
P. Günzel
Keyword(s):  
Blood Clotting ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Thrombin Time ◽  
Beagle Dogs ◽  
Clotting Time ◽  
Relative Potencies ◽  
Heparin Preparation

The anticoagulant effect of a new potent heparin preparation was compared with a commercially available heparin in vivo after intravenous application in beagle dogs. The anticoagulant activity was determined using thrombin time, activated partial thromboplastin time and whole blood clotting time after 5, 10 and 30 minutes of application. The relative potency of the new heparin preparation (Scherinq) was found to be 1.62 to 2.52 times higher than heparin used for comparison (150 USP units/mg, Dio-synth). The anticoagulant properties of both preparations were also studied in vitro using dog and human plasma. The relative potencies in vitro correlated well with those obtained in vivo. Further characterization with amidolytic method using chromogenic substrate for factor Xa and thrombin (S-2222 and S-2238 from KABI, Stockholm) showed that heparin (Schering) contains 243 to 378 USP units/raq depending upon the test systems used to assay the anticoagulation activity and in addition, proves the validity of the amidolytic method.

Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors

1999 ◽  
Vol 9 (18) ◽  
pp. 2753-2758 ◽  
Author(s):  
Michael R. Becker ◽  
William R. Ewing ◽  
Roderick S. Davis ◽  
Henry W. Pauls ◽  
Cuong Ly ◽  
...  
Keyword(s):  
Factor Xa ◽  
Factor Xa Inhibitors

A Low Molecular Weight Heparin Alters the Fetal Coagulation System in the Pregnant Sheep

1986 ◽  
Vol 55 (03) ◽  
pp. 342-346 ◽  
Author(s):  
M Andrew ◽  
F Ofosu ◽  
F Fernandez ◽  
A Jefferies ◽  
J Hirsh ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Factor Xa ◽  
Coagulation System ◽  
Dermatan Sulphate ◽  
Protamine Sulphate ◽  
Pregnant Sheep ◽  
Pregnant Ewe ◽  
Inhibition Of Thrombin

SummaryStandard heparin and a LMWH, CY222 do not cross the placenta nor alter fetal coagulation when injected into the pregnant ewe. We found that another LMWH, Pharmuka-10169 (PK-10169) alters fetal coagulation without crossing the placenta in the pregnant sheep. To characterize this anticoagulant we measured the in vitro and in vivo effects of 125I-PK-10169 in maternal and fetal plasmas following administration of PK-10169 to the mother or fetus. The fetal anticoagulant activity was not neutralizable by protamine sulphate and was attributable to the inhibition of thrombin but not factor Xa. In vitro, the fetal anticoagulant activity had properties similar to dermatan sulphate : both catalyzed the inhibition of thrombin but not factor Xa by sheep plasma; and neither was neutralizable by protamine sulphate. These effects were due to the enhanced neutralization of thrombin by heparin cofactor II. We conclude that PK-10169 does not cross the placenta, but does induce the release of an endogenous dermatan sulphate-like substance which alters fetal coagulation.

Andexanet alfa for the reversal of anticoagulant activity in patients treated with direct and indirect factor Xa inhibitors

2017 ◽  
Vol 15 (4) ◽  
pp. 237-245 ◽  
Author(s):  
Tarek Nafee ◽  
Aysha Aslam ◽  
Gerald Chi ◽  
Seyedmahdi Pahlavani ◽  
Dima Nimri ◽  
...  
Keyword(s):  
Anticoagulant Activity ◽  
Factor Xa ◽  
Factor Xa Inhibitors ◽  
Andexanet Alfa

scholarly journals Influence of molecular weight of chemically sulfated citrus pectin fractions on their antithrombotic and bleeding effects

2009 ◽  
Vol 101 (05) ◽  
pp. 860-866 ◽  
Author(s):  
Thales Cipriani ◽  
Ana Helena Gracher ◽  
Lauro de Souza ◽  
Roberto Fonseca ◽  
Celso Belmiro ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Venous Thrombosis ◽  
Anticoagulant Activity ◽  
Factor Xa ◽  
Sulfated Polysaccharides ◽  
Antithrombotic Agent ◽  
Total Inhibition ◽  
Almost All

SummaryEvaluated were the anticoagulant and antithrombotic activities, and bleeding effect of two chemically sulfated polysaccharides, obtained from citric pectin, with different average molar masses. Both low-molecular-weight (Pec-LWS, 3,600 g/mol) and high-molecular-weight sulfated pectins (Pec-HWS, 12,000 g/mol) had essentially the same structure, consisting of a (1→4)-linked α-D-GalpA chain with almost all its HO-2 and HO-3 groups substituted by sulfate. Both polysaccharides had anticoagulant activity in vitro, although Pec-HWS was a more potent anti-thrombotic agent in vivo, giving rise to total inhibition of venous thrombosis at a dose of 3.5 mg/kg body weight. Surprisingly, in contrast with heparin, Pec-HWS and Pec-LWS are able to directly inhibit α-thrombin and factor Xa by a mechanism independent of antithrombin (AT) and/or heparin co-factor II (HCII). Moreover, Pec-HWS provided a lower risk of bleeding than heparin at a dose of 100% effectiveness against venous thrombosis, indicating it to be a promising antithrombotic agent.

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