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Uses of a glycoprotein VI (GPVI) inhibitor

An inhibitor, glycoprotein technology, applied in immunoglobulins, cells modified by introducing foreign genetic material, biochemical equipment and methods, etc., can solve the problems of protection, reperfusion injury can not provide and so on

Inactive Publication Date: 2010-10-27
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, they do not provide direct protection against reperfusion injury

Method used

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  • Uses of a glycoprotein VI (GPVI) inhibitor
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  • Uses of a glycoprotein VI (GPVI) inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] GPVI deletion protects the mouse heart

[0030] Wild-type and GPVI knockout mice of the same age were anesthetized with 1-1.5% isoflurane, intubated through an endotracheal tube, and attached to a pressure-controlled ventilator. Animals were ventilated with room air and 100% oxygen (4:1 by volume). Before surgery, the mice were given gentamicin (0.7 mg / kg IM). Throughout the experiment, body temperature was carefully monitored by a rectal bougie connected to a digital thermometer and maintained at 37-37.5°C with a heating plate or heat lamp. In the prior study, the carotid artery was catheterized to monitor blood pressure and blood gas analysis in mice. This is to ensure that the mice maintain physiological hemodynamics using these experimental procedures.

[0031] With the aid of a dissecting microscope, open the chest cavity through a left thoracotomy. Use a tapered needle to pass an 8-0 nylon suture (Ethicon, Inc. Johnson & Johnson Co. Somerville, NJ) under the l...

Embodiment 2

[0035] Decreased expression of platelet-selectin in myocardium of GPVI knockout mice

[0036] Platelet activation is measured by the expression of platelet-selectin, which is stored within the platelet α-granule and, once activated, is rapidly translocated to the surface of the platelet. The expression of platelet-selectin was determined by immunohistology.

[0037] Cardiac ischemia / reperfusion in mice: Cardiac ischemia / reperfusion in mice was performed as described in Example 1. GPVI knockout and wild-type mice received left anterior descending coronary artery (LAD) occlusion for 30 minutes followed by 15 minutes of reperfusion. After 15 minutes of reperfusion of the LAD, the heart was removed and washed with DPBS, then short-axis cut into two sections and immediately placed in 4% paraformaldehyde and 0.1M phosphate buffer to fix the tissue. After 2 hours, the tissue was transferred to 25% sucrose overnight.

[0038] Immunofluorescence assay for platelet-selectin: On the f...

Embodiment 3

[0041] endothelial reperfusion injury

[0042]In a normal heart with healthy vasculature, a tight endothelium prevents collagen in the extracellular matrix of the vessel walls from coming into contact with circulating blood components. Collagen may be exposed if the endothelium is damaged, such as during ischemia and reperfusion. Because GPVI binds selectively to collagen, GPVI was used to detect endothelial reperfusion injury in vivo. For this purpose, recombinant sGPVI (sGPVI-FITC) was labeled with the fluorescent marker FITC, and sGPVI-FITC was injected intravenously into mice. Injected sGPVI-FITC binds to collagen exposed due to endothelial injury. The level of sGPVI-FITC binding to exposed collagen can be determined histologically under fluorescence microscopy and provides a measure of endothelial damage.

[0043] sGPVI-FITC (2 mg / kg) was injected into wild-type mice 10 minutes before heart ischemia (30 minutes). In some of these animals, ischemia was followed by repe...

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Abstract

The present invention describes a method for reducing reperfusion injury and / or infarction by using an inhibitor of platelet GPVI. This method may be used to treat patients during or after a heart attack or elective cardiac surgery.

Description

[0001] related application [0002] This application claims priority to U.S. Application No. 60 / 984,334, "Uses of a Glycoprotein VI (GPVI) Inhibitor," filed October 31, 2007, the entire contents of which This application is incorporated by reference. technical field [0003] The present invention relates to methods of inhibiting reperfusion injury and / or infarction using inhibitors of platelet membrane glycoprotein VI (GPVI), including antibodies, protein fragments and small molecule compounds. Background technique [0004] A heart attack occurs when the coronary arteries that supply blood to the heart become blocked. The blockage usually occurs due to the narrowing and closing of arterial vessels by the formation of atherosclerosis and thrombus. A lack of blood supply is called ischemia. Myocardium can only tolerate short periods of oxygen deprivation and infarction occurs within 20-120 minutes. Because cardiomyocytes are largely terminally differentiated, the regenerat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N5/06C12N5/16C12N15/09
CPCC07K16/2803A61K2039/505C07K2317/55A61P7/00A61P7/02A61P9/00A61P9/10
Inventor 刘勇格娜伦德拉·N·坦登潼泽寿男上林纯一
Owner OTSUKA PHARM CO LTD
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