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Methods of treating thromboembolic disorders

A technique for thromboembolism and thrombus, applied in the field of platelet contractility inhibitor to dissolve thrombus

Inactive Publication Date: 2011-02-09
MONASH UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] However, it has not been understood how important contractility, independent of blood coagulation and fibrin clot retraction, is for the regulation of the primary hemostatic plug.

Method used

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  • Methods of treating thromboembolic disorders
  • Methods of treating thromboembolic disorders
  • Methods of treating thromboembolic disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0119] Embodiment 1 Materials and methods

[0120] Material

[0121] The Rho kinase inhibitor H1152 was obtained from Toronto Research Chemicals (Canada). IP 3 The receptor antagonist 2-aminoethoxybiphenylborate (2-APB) was from Cayman Chemicals (Michigan, USA), HA1077, the myosin II inhibitor Blebbistatin[-] and its inactive enantiomer Blebbistatin [+] was obtained from Chemicon (USA). DiIC 12 From BD Biosciences (NSW, Australia). Recombinant hirudin (lepirudin) was purchased from Pharmion (Australia).

[0122] mouse strain

[0123] All involved the use of C57Bl6 and PAR4 - / - Procedures for mice were approved by the Alfred Medical Research and Education Precinct (AMREP) Animal Ethics Committee (AEC) (Melbourne, Australia) under project numbers E / 0569 / 2007 / M, E / 0621 / 2007 / M and E / 0464 / 2006 / M.

[0124] Collection of blood, preparation of PRP and washed platelets

[0125] All processes involving the collection of human and mouse blood were supervised by the Monash Un...

Embodiment 2

[0136] Example 2 Identification of the systolic phase during thrombus development

[0137] The importance of platelets in transmitting cytoskeletal contractile forces to fibrin polymers for clot retraction is well established. But the importance of these contractile mechanisms in regulating the various stages of thrombus growth, especially under physiological blood flow conditions, has not been clearly established. To investigate this, the inventors used an in vitro perfusion system that allowed real-time analysis of platelet adhesion and thrombus growth on immobilized type I fibrin collagen substrates. At arteriole shear rate (1800s -1 ) perfusion of native (non-anticoagulated) whole blood causes rapid platelet adhesion and aggregate formation, forming large stable aggregates within 2 minutes of flow. Analysis of deposited fibrin(ogen) by co-infusion of fluorescently-labeled fibrinogen revealed extensive incorporation of fibrin(ogen) within the developing thrombus, with i...

Embodiment 3

[0139] Example 3 The Importance of Rho Kinase to Thrombus Contraction

[0140] Actinomyosin-based contractility is linked to activation of myosin light chain kinase by calcium / calmodulin-dependent activation of myosin light chain kinase and Rho kinase-dependent inactivation of myosin phosphatase Phosphorylation is closely linked. In platelets, calcium activation of myosin light chain kinase appears to be the major contractile mechanism regulating platelet shape change and fibrin clot retraction 4 . To investigate the role of cytosolic calcium influx in modulating thrombus contraction, whole blood perfusion studies were performed to prevent calcium influx (EGTA / MgCl 2 ) or mobilize calcium from internal stores (IP 3 receptor antagonist-2-APB) experimental conditions. Sequestration of extracellular calcium with EGTA significantly reduced thrombus shrinkage (up to 52% at 5 min perfusion, p image 3 A). Under similar experimental conditions, inhibition of calcium mobilizatio...

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Abstract

The field of the invention relates to methods for dissolving a thrombus using inhibitors of platelet contractility. More particularly, the present invention relates to the use of an inhibitor of platelet contractility in combination with one or more thrombolytic agents and optionally one or more anticoagulants for inhibiting platelet contraction and consolidation in the developing thrombus.

Description

technical field [0001] The present invention relates to methods of dissolving thrombus using inhibitors of platelet contractility. More particularly, the present invention relates to the use of a platelet contractility inhibitor in combination with one or more thrombolytic agents and optionally one or more anticoagulants to inhibit platelet contraction and coagulation in a developing thrombus. Background technique [0002] Thrombosis can be divided into two temporally distinct phases. The first phase is the formation of the primary hemostatic plug, which consists of aggregated platelets and forms independently of fibrin production. The primary platelet plug (or thrombus) then coagulates during a secondary hemostasis phase when fibrin polymers are encapsulated in the developing thrombus to physically stabilize the platelet plug. During the development of a hemostatic plug, platelets undergo a complex series of morphological and functional responses that require extensive re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/551A61K31/4725A61K31/4745A61K38/49A61K31/727A61P7/02A61P9/10A61K31/4409
CPCA61K31/727A61K31/551A61K31/4409A61K38/49A61K31/4745A61K45/06A61K31/4725A61P7/02A61P9/10A61P43/00A61K2300/00
Inventor S·杰克逊S·舍恩韦尔德A·奥诺
Owner MONASH UNIV