Activated factor X(FXa) stimulants as new antihemorrhagic agents for topical use

A blood coagulation factor, local treatment technology, applied in anti-inflammatory agents, medical preparations containing active ingredients, blood diseases, etc., can solve the problems of lack of acute effect, risk of side effects, unstable fibrin clot, etc.

Inactive Publication Date: 2013-03-13
THROMBOTARGETS EURO SL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] (2) Administration requires special equipment
[0026] (4) Unable to provide appropriate or convenient treatment for specific bleeding events
[0027] (5) Lack of acute effect
[0028] (6) Fibrin clot instability
[0029] (7) The side effects are very dangerous
[0054] In this patent application, the inventors demonstrated that phospholipids (phosphatidylserine and phosphatidylcholine in different percentages and molar concentrations) do not enhance the procoagulant effect mediated by lipidated TF (Table 21), which indicates that U.S. Patent No. 4,721,618 No. and WO 02 / 086118 the claimed synergy is limited to serine protease-activated coagulation factors and does not apply to membrane receptors such as TF

Method used

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  • Activated factor X(FXa) stimulants as new antihemorrhagic agents for topical use
  • Activated factor X(FXa) stimulants as new antihemorrhagic agents for topical use
  • Activated factor X(FXa) stimulants as new antihemorrhagic agents for topical use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0461] The results of Example 1 clearly show that:

[0462] 1) In the absence of ligand FVII, lipidated TF can directly interact with FXa, thereby significantly increasing its proteolytic activity (amidolysis and thrombin formation activity), and this result shows for the first time a new role of lipidated TF, That is, it is used as a new cofactor of FXa (unrelated to the known FVa).

[0463] 2) Lipidated TF is able to coagulate FVII-deficient plasma. Lipidated TF is therefore a good alternative therapy for such patients (the only existing therapy is expensive human recombinant FVIIa).

[0464] 3) Lipidated TF acts synergistically with NCIS and FXa (at low concentrations that cannot produce coagulation).

Embodiment 2

[0465] The results of Example 2 clearly show:

[0466] 1) Lipidated TF enables the hydrolysis of prothrombin by physiological concentration of FXa that cannot produce any procoagulant effect, so that thrombin formation occurs.

[0467] 2) Lipidated TF has a novel role as a cofactor for all proteolytic activities of all forms of FXa (soluble FXa and FXa bound to the prothrombinase complex).

[0468] 3) Even FX-deficient plasma (with traces of FX) can be coagulated by lipidated TF. Therefore, lipidated TF is a good alternative therapy for such patients.

[0469] 4) Lipidated TF synergizes with NCIS in the stimulation of FXa activity.

Embodiment 3

[0470] The results of Example 3 clearly show that:

[0471] 1) Lipidated TF can coagulate blood in patients with hemophilia (FVIII, FIX and FXI). Therefore, lipidated TF is a good alternative therapy for such patients.

[0472] 2) Lipidated TF can induce coagulation even in the absence of FV. These results clearly show that lipidated TF has a strong stimulatory effect on FXa, since lipidated TF serves as a cofactor to elicit the same stimulatory effect when its cofactor is absent (FV-deficient plasma).

[0473] 3) Even in FX-deficient plasma (with traces of FX), lipidated TF can induce coagulation. Lipidated TF is therefore an alternative therapy for such patients.

[0474] 4) Lipidated TF can cause coagulation in heparin- and warfarin-treated plasma, which means that lipidated TF interferes with the action of antithrombin III, and possibly through its stimulation of basal concentrations of FXa, which even Can cause coagulation in warfarin-treated plasma.

[0475] 5) Fina...

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PUM

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Abstract

The activated coagulation Factor X (FXa) stimulating agents may be used in the treatment of hemorrhaging in a subject. Compounds and combinations are described which are particularly useful for the topical treatment of hemorrhaging in a healthy subject or in a subject with hemorrhagic diathesis.

Description

field of invention [0001] The present invention relates to the topical treatment of bleeding in an individual through the use of FXa stimulators. The present invention is based on the discovery that lipidated tissue factor (TF) exhibits a novel regulatory action that stimulates all proteolytic activity of both forms of FXa, soluble FXa and FXa bound to the prothrombinase complex (amidolytic activity and prothrombin hydrolytic activity). Background of the invention [0002] 1. Physiology of coagulation [0003] Hemostasis is the mechanism by which an organism responds to bleeding that involves the participation of two processes that act immediately after injury and remain active for long periods of time. The first process, known as primary hemostasis, is characterized by vasoconstriction and formation of platelet aggregates at the site of vascular injury. The second process is called secondary hemostasis, during which a fibrin clot is formed due to the action of proteolyti...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K38/36
CPCA61K38/36A61P1/00A61P7/02A61P7/04A61P9/10A61P25/28A61P29/00A61P35/00
Inventor 哈维尔·佩德雷尼奥埃赫亚路易斯·卡韦达卡塔苏斯
Owner THROMBOTARGETS EURO SL
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