Progress in the design of low molecular weight thrombin inhibitors

2005 ◽  
Vol 25 (1) ◽  
pp. 66-92 ◽  
Author(s):  
Stuti Srivastava ◽  
Lalit N. Goswami ◽  
Dinesh K. Dikshit
Keyword(s):  
Molecular Weight ◽  
Thrombin Inhibitors ◽  
Low Molecular Weight

Antithrombotic Effect of Two Low Molecular Weight Thrombin Inhibitors and a Low-Molecular Weight Heparin in a Caval Vein Thrombosis Model in the Rat

1997 ◽  
Vol 78 (05) ◽  
pp. 1404-1407 ◽  
Author(s):  
B I Eriksson ◽  
S Carlsson ◽  
M Halvarsson ◽  
B Risberg ◽  
C Mattsson
Keyword(s):  
Molecular Weight ◽  
Low Molecular Weight Heparin ◽  
Clinical Situation ◽  
Thrombin Inhibitors ◽  
Thrombin Inhibitor ◽  
Low Molecular Weight ◽  
Surgical Trauma ◽  
Antithrombotic Effect ◽  
Caval Vein ◽  
Thrombosis Model

SummaryA sensitive thrombosis model with a high reproducibility was developed in the rat, utilizing stasis of the caval vein and a standardized surgical trauma as the only thrombogenic stimuli. Since no procoagulant substances were used, the results of the present study might be relevant in a clinical situation. The antithrombotic effect of two recently synthesized low-molecular-weight thrombin inhibitors have been compared to dalteparin, (Fragmin) a low-molecular-weight heparin fragment. Each compound was studied at 8 different doses with 10 rats in each group. On a gravimetric basis, the thrombin inhibitor melagatran was twice as potent as dalteparin (ED50 16 and 33 µ/kg per h, respectively). The second thrombin inhibitor, inogatran, had an intermediate effect, with an ED50 of 24 µLg/kg per h. No differences in antithrombotic effect were, however, found when the compounds were compared at anticoagulant equivalent doses (same APTT prolongation). A 50% reduction in the mean thrombus weight was obtained when APTT was prolonged to 1.2 to 1.3 times the pretreatment value.

Recombinant Human FVIIa Reduces Heparin and Low Molecular Weight Heparin (LMWH)-Induced Bleeding in Rats.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2149-2149
Author(s):  
Brian Lauritzen ◽  
Mikael Tranholm ◽  
Peter B. Johansen ◽  
Mirella Ezban
Keyword(s):  
Molecular Weight ◽  
Blood Loss ◽  
Low Molecular Weight Heparin ◽  
Bleeding Time ◽  
Statistical Significance ◽  
Thrombin Inhibitors ◽  
Low Molecular Weight ◽  
Similar Response ◽  
Post Test ◽  
Observation Period

Abstract Recombinant human FVIIa (rFVIIa, NovoSeven, Novo Nordisk A/S) is approved for treatment of bleeding in hemophilia patients with inhibitors. Recent data indicate that rFVIIa is useful in other bleeding conditions. Heparin and low molecular weight heparin (LMWH) are widely used for anticoagulant management of venous thromboembolic events. Both agents can however cause uncontrollable bleeding. While protamine can reverse the anticoagulant effect of heparin no effective antidote for LMWH is currently available. We have tested if rFVIIa was capable of reducing the bleeding caused by either heparin or LMWH in a rat tail bleeding model. We pre-treated rats with a single dose of either heparin (Heparin, Leo; 200 IU/kg; i.v.) or LMWH (tinzaparin; Innohep, Leo; 500 IU/kg; i.v.), which significantly prolonged total bleeding time following tail transection (table 1). Similarly, blood loss increased significantly by pre-treatment with heparin and tinzaparin (table 2). rFVIIa, intravenously injected 5 minutes after induction of tail bleeding in doses of 5, 10 and 20 mg/kg (n=8), dose-dependently reduced bleeding time of the heparin-induced bleeding, reaching statistical significance at 20 mg/kg (table 1). In accordance, blood loss decreased significantly by treatment with 10 and 20 mg/kg rFVIIa (table 2). A similar response was seen in the tinzaparin pre-treated animals with a dose-dependent decrease in bleeding time (table 1), and a significant decrease in blood loss at 10 and 20 mg/kg rFVIIa (table 2). Table 1. Total bleeding time (s) Group Heparin 200 IU/kg (n=8)# Tinzaparin 500 IU/kg (n=9)# Data are analyzed using Mann-Whitneys U-test (A-B) or Kruskall-Wallis test with Dunn’s post-test (B-E). Asterisks indicate statistical significance at: *: p<0.05; **: p<0.01 and ***: p<0.001. #observation period 1800 s. A: No anticoagulant 293 ± 68 542 ± 180 B: Anticoag.+Vehicle 1668 ± 83 ***vs. A 1800 ± 0 ***vs. A C: Anticoag.+5 mg/kg rFVIIa 1194 ± 182 1732 ± 45 D: Anticoag.+10 mg/kg rFVIIa 1023 ± 230 1483 ± 152 E: Anticoag.+20 mg/kg rFVIIa 448 ± 66 **vs. B 1038 ± 206 *vs. B Table 2. Blood loss (nmol hemoglobin/ml) Group Heparin 200 IU/kg (n=8)# Tinzaparin 500 IU/kg (n=9)# Data are mean ± SEM. Data are analyzed after log transformation using Student’s t-test (A-B) or one-way ANOVA with Bonferroni’s post-test (B-E). Asterisks indicate statistical significance at: *: p<0.05; **: p<0.01 and ***: p<0.001. #observation period 1800 s. A: No anticoagulant 4.2 ± 4.0 4.9 ± 4.9 B: Anticoag.+Vehicle 53 ± 19 **vs. A 151 ± 37 ***vs. A C: Anticoag.+5 mg/kg rFVIIa 10.6 ± 5.6 32.3 ± 10.3 D: Anticoag.+10 mg/kg rFVIIa 0.73 ± 0.34 **vs. B 7.7 ± 2.8 ***vs. B E: Anticoag.+20 mg/kg rFVIIa 4.0 ± 1.9 *vs. B 22.6 ± 9.4 *vs. B This study illustrates the pharmacological effect of rFVIIa in the presence of heparin and LMWH and the results indicate that rFVIIa may be an effective way to treat heparin and LMWH induced bleeding, however the dose requirements are specific for the rat and cannot be extrapolated to other species. Future studies will investigate the hemostatic effect of rFVIIa in bleedings induced by coumarin analogues, thrombin inhibitors, factor Xa inhibitors, and platelet inhibitors.

Synthesis of a homologous series of ketomethylene arginyl pseudodipeptides and application to low molecular weight hirudin-like thrombin inhibitors

1992 ◽  
Vol 35 (18) ◽  
pp. 3331-3341 ◽  
Author(s):  
John DiMaio ◽  
Bernard Gibbs ◽  
Jean Lefebvre ◽  
Yasuo Konishi ◽  
Debra Munn ◽  
...  
Keyword(s):  
Molecular Weight ◽  
Homologous Series ◽  
Thrombin Inhibitors ◽  
Low Molecular Weight

Progress in the Design of Low Molecular Weight Thrombin Inhibitors

ChemInform ◽  
2005 ◽  
Vol 36 (13) ◽  
Author(s):  
Stuti Srivastava ◽  
Lalit N. Goswami ◽  
Dinesh K. Dikshit
Keyword(s):  
Molecular Weight ◽  
Thrombin Inhibitors ◽  
Low Molecular Weight
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