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Use of tumor vascular disrupting agent DMXAA in preparation of antiplatelet and antithrombotic drugs

An anti-thrombotic drug and anti-platelet technology, which can be used in drug combinations, cardiovascular system diseases, blood diseases, etc., and can solve problems such as DMXAA, a tumor vascular destroying agent, which has not yet been seen.

Inactive Publication Date: 2014-05-21
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, there has been no report on the use of the tumor blood vessel destroyer DMXAA in the preparation of antiplatelet and antithrombotic drugs

Method used

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  • Use of tumor vascular disrupting agent DMXAA in preparation of antiplatelet and antithrombotic drugs
  • Use of tumor vascular disrupting agent DMXAA in preparation of antiplatelet and antithrombotic drugs
  • Use of tumor vascular disrupting agent DMXAA in preparation of antiplatelet and antithrombotic drugs

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] Example 1. The Inhibitory Effect of DMXAA on U46619-Induced Human Platelet Aggregation

[0031] The purpose of this example is to prove that DMXAA can inhibit human platelet aggregation induced by U46619

[0032] In this example, platelets were prepared: the platelets came from healthy volunteers who had signed the informed consent form, and the volunteers had not taken any antiplatelet drugs such as aspirin and clopidogrel within 20 days before blood collection; the anticoagulant was ACD (85mmol L -1 sodium citrate, 71.38 mmol L -1 citric acid, and 27.78mmol L -1 Glucose); centrifuged at 300g for 20 minutes to obtain platelet-rich plasma, after taking the supernatant, centrifuged at 900g for 10 minutes to obtain platelets, and finally resuspended with Tyrode's buffer (138mmol L -1 NaCl, 2.7mmolL -1 KCl, 2 mmol L -1 MgCl 2 ,0.42 mmol L -1 NaH 2 PO 4 ,5mmolL -1 Glucose, 10mmol L -1 HEPES, 0.2% bovine serum albumin, and 0.02unit mL -1 apyrase, pH 7.4),...

Embodiment 2

[0039] Example 2. The inhibitory effect of DMXAA 300 μM on human platelet aggregation induced by other various agonists

[0040] The purpose of this example is to demonstrate that DMXAA can inhibit the aggregation of human platelets induced by arachidonic acid, ADP, collagen or rystokinesis.

[0041] In this example, the preparation of platelets and the assay method of platelet aggregation are the same as in Example 1.

[0042] The results are shown in Table 2. DMXAA at 300 μM significantly inhibited the aggregation of aspirin-untreated human platelets induced by arachidonic acid, ADP, collagen or ristomycin (these four agonists were purchased from Chrono-Log Company) .

[0043] Table 2 shows that DMXAA inhibits the aggregation of aspirin-untreated human platelets induced by arachidonic acid, ADP, collagen or rystofamicin (mean ± standard error) (n=3).

[0044] Table 2

[0045]

Embodiment 3

[0046] Example 3.DMXAA inhibits TXA 2 generate test

[0047] The purpose of this example is to prove that DMXAA can inhibit TXA 2 generate.

[0048] In this example, human washed platelets without aspirin treatment were prepared, and the final concentration was adjusted to 2.5×10 8 cells / ml, with 500 μl / tube as the reaction system, on the platelet aggregometer, add drugs and incubate for 3 minutes, then add agonists to stimulate the reaction until the 8th minute, add 1 / 6 volume of indomethacin (0.55mM) and EDTA (22mM) terminated the reaction, quickly placed on ice, centrifuged at 12000g 4°C for 3 minutes to remove platelets, and the resulting supernatant was stored at -80°C; due to TXA 2 Extremely unstable, quickly transitions to TXB 2 , thus detecting TXB 2 TXA 2 Generate; this embodiment adopts the TXB prepared by the thrombus room of Soochow University School of Medicine 2 Enzyme-linked immunoassay kit for detection of TXB 2 Content, specific steps refer to its inst...

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Abstract

The invention belongs to the technical field of drug application, relates to a new use of a tumor vascular disrupting agent DMXAA, and in particular relates to the use of the tumor vascular disrupting agent DMXAA in preparation of antiplatelet and antithrombotic drugs, wherein the tumor vascular disrupting agent DMXAA has the structure represented by the formula (I). Through in-vitro, ex-vivo and in-vivo tests of the DMXAA, results show that a DMXAA antiplatelet mechanism is different from that of known antiplatelet drugs such as aspirin, clopidogrel, prasugrel, ticagrelor, cilostazol and fibrinogen receptor antagonists, and the DMXAA simultaneously has dual activities of TXA2 generation inhibition and TXA2 receptor antagonism; and the experimental results indicate that the DMXAA can be used for the preparation of the effective and safe antiplatelet and antithrombotic drugs, and is used for prevention and treatment of arterial thrombotic diseases, such as coronary heart disease, apoplexy, peripheral vascular disease and the like.

Description

technical field [0001] The invention belongs to the technical field of drug application, and relates to a new drug application of a tumor blood vessel destroyer DMXAA, in particular to the application of DMXAA in the preparation of antiplatelet and antithrombotic drugs, and in the preparation of drugs for the prevention and treatment of arterial thrombosis diseases. Background technique [0002] With the improvement of people's living standards, stroke, coronary heart disease and other arterial thrombosis diseases have become the number one killer threatening the health and life safety of our people. Studies have shown that intravascular thrombus formation caused by abnormal activation of platelets is the pathological basis of arterial thrombosis coronary heart disease and stroke. Therefore, antiplatelet drugs that inhibit platelet activation have become the main means of prevention and treatment of such diseases. Relevant studies have shown that antiplatelet drugs have posi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/352A61P7/02A61P9/10
Inventor 丁忠仁章圣辉张思张艳
Owner FUDAN UNIV
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