Long-term persistence of low-molecular-weight material with anti-factor Xa activity contributes to anticoagulant and antithrombotic effects after subcutaneous injection of CY 216 in the rabbit

Peyrou, V.; Lormeau, J C; Hérault, Jean-P.; Boneu, B; Jm, Herbert

doi:10.1097/00001721-199704000-00004

Cited by 6 publications

(11 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The TG assay in PPP and PRP was performed according to Hemker et al (22) and Béguin et al (23) with the modification described by Peyrou et al (13,14). Briefly, 60 µl of buffer A (20 mM Hepes, 150 mM NaCl, 0.5 g/l bovine serum albumin, pH 7.35) were added to 240 µl of rat PRP.…”

Section: Thrombin Generation In Ppp Prp and Wbmentioning

confidence: 99%

“…Although erythrocytes are believed to play a minor role in haemostasis, it has been shown that, in pathological conditions, they become procoagulant by exposing anionic phospholipids at their outer surface (8)(9)(10)(11). Moreover, several works have shown important differences between TG performed in platelet rich plasma (PRP) and in whole blood (WB) (12)(13)(14). Recently, we have described a method to measure TG in human whole blood (13,14).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, several works have shown important differences between TG performed in platelet rich plasma (PRP) and in whole blood (WB) (12)(13)(14). Recently, we have described a method to measure TG in human whole blood (13,14). We have suggested that the procoagulant phospholipids exposed at the plasma membrane of a small fraction of normal erythrocytes were efficient triggers of tissue factor-induced blood coagulation (14).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Effect of New Synthetic Heparin Mimetics on Whole Blood Thrombin Generation In Vivo and In Vitro in Rats

Hérault¹,

Bernat²,

Gaich³

et al. 2002

Thromb Haemost

View full text Add to dashboard Cite

SummaryThe effect of new heparin mimetics (synthetic oligosaccharides) was studied in vitro with regard to thrombin generation (TG) in rat platelet rich plasma (PRP) and whole blood (WB) and in vivo on stasis-induced venous thrombosis in the rat.TG in PRP and in WB was highly dependent on platelet count and strongly influenced by the haematocrit. The peak of TG appeared to be significantly higher in WB than in PRP whereas the endogenous thrombin potential (ETP) was not significantly different under either condition.The effect of hirudin, the synthetic pentasaccharide SR90107/ Org31540 (SP) and heparin were measured on TG in PRP and WB. We then compared the effect of two new synthetic heparin mimetics (SR121903A and SanOrg123781) with potent and comparable antithrombin (AT) mediated activity against factor Xa and thrombin. These two compounds were made of a pentasaccharide with a high affinity to AT, prolonged at the non-reducing end by an oligosaccharide chain recognised by thrombin. In SR121903A, the charge density and charge distribution was analogous to that of heparin whereas in SanOrg123781 the charges were only located on the last 5 saccharides of the non-reducing end of the molecule. In PRP and in WB, SR121903A acted on the lag time and on the AUC whereas SanOrg123781 inhibited thrombin formation with no effect on the lag time. SanOrg123781 was more potent in inhibiting TG than SR121903A. This difference was due to the structures of the compounds that differed in their ability to be neutralised by platelet factor 4. The antithrombotic effect of the two compounds was examined in a venous thrombosis model in rats. We observed that SanOrg123781 was more active than SR121903A and heparin.Taken together, these results indicate that the activity of oligosaccharides is greatly influenced by the global charge density of the molecule and show that SanOrg123781 is a potent and promising antithrombotic drug candidate.

show abstract

Section: Thrombin Generation In Ppp Prp and Wbmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of New Synthetic Heparin Mimetics on Whole Blood Thrombin Generation In Vivo and In Vitro in Rats

Hérault¹,

Bernat²,

Gaich³

et al. 2002

Thromb Haemost

View full text Add to dashboard Cite

show abstract

“…In the search for this drug the TGT is the screening procedure of choice. In a later stage, the TGT can also be used to test the effect of drug administration in animals [5], volunteers or patients.…”

Section: Thrombin Generation As a Pharmacological Probementioning

confidence: 99%

“…The test can be applied to platelet-rich plasma (PRP; fig. 1) and, with slight modifications, to whole blood [3][4][5].…”

mentioning

confidence: 99%

On the Coagulation of Platelet-Rich Plasma

Béguin

Keularts²

1999

Pathophysiol Haemos Thromb

View full text Add to dashboard Cite

Thrombin formation and blood platelet reactions are intimately linked in haemostasis and in thrombosis. In vivo, procoagulant phospholipids required for the coagulation mechanism are mainly provided by activated platelets, and thrombin is the most potent platelet activator. To study these interactions, an ancient tool of coagulation physiology, the thrombin generation test, was revived and the results obtained were reviewed. The amount of thrombin activity that develops, expressed as the endogenous thrombin potential (the area under the thrombin generation curve), is influenced by the clotting factors (except XII and XIII), the activated protein C system and natural inhibitors on the one hand and by platelet activity on the other. The platelet reactions that we found to be involved are induced by thrombin via glycoprotein (GP) IIb/IIIa activation and by fibrin via interaction with GPIb. von Willebrand factor is crucial in both reactions and therefore an obligatory factor for normal thrombin generation in the presence of platelets. All antithrombotics, be it anticoagulants (e.g. OAC, all heparins or hirudin) or antiplatelet drugs (aspirin, GPIIb/IIIa blockers) diminish thrombin generation.

show abstract

Pharmacokinetics of New Synthetic Heparin Mimetics

Hérault

Bernat²,

Roye³

et al. 2002

Thromb Haemost

Self Cite

View full text Add to dashboard Cite

SummaryPharmacokinetics of oligosaccharides displaying various affinities for antithrombin (AT) allowed us to show that there was a close relationship between the plasma half-life of these antithrombotic oligosaccharides and their affinity for AT. Recently, we have described new heparin mimetics comprising an AT binding domain and a thrombin binding domain separated by a neutral methylated saccharide sequence. These compounds displayed strong anti-Xa and anti-IIA activities and, in contrast to heparin, escaped neutralisation by platelet factor 4. The aim of this work was to compare the pharmacokinetics of several of these heparin mimetics in rats. These compounds differed by their length, charge and affinity for AT (AT-binding domain). The results obtained indicate that the prolongation of the AT binding domain did not modify significantly their affinities for AT. However, an increase in the number of charges leads to a decrease in the half-life. When a methylated spacer was added in order to minimise the non-specific interactions to other proteins, half-lives of the heparin mimetic were in the same range than that of the pentasaccharide used as an AT binding domain.In conclusion, this study shows the influence of the charge of the oligosaccharides on their pharmacokinetics and underlines the importance of minimising their non-specific binding to plasma proteins in order to obtain compounds with predictive pharmacokinetics.

show abstract

Long-term persistence of low-molecular-weight material with anti-factor Xa activity contributes to anticoagulant and antithrombotic effects after subcutaneous injection of CY 216 in the rabbit

Cited by 6 publications

References 0 publications

Effect of New Synthetic Heparin Mimetics on Whole Blood Thrombin Generation In Vivo and In Vitro in Rats

Effect of New Synthetic Heparin Mimetics on Whole Blood Thrombin Generation In Vivo and In Vitro in Rats

On the Coagulation of Platelet-Rich Plasma

Pharmacokinetics of New Synthetic Heparin Mimetics

Contact Info

Product

Resources

About