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Pharmaceutical composition for inhibiting myocardial fibrosis

A technology of myocardial fibrosis and composition, which is applied in the field of pharmaceutical compositions for inhibiting myocardial fibrosis, can solve the problems of no relevant reports on the inhibitory effect of myocardial fibrosis, and achieve the goal of protecting heart function, improving kinase selectivity, and preventing adverse effects Effects of Cardiac Remodeling

Pending Publication Date: 2021-11-26
SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Nevertheless, the research of BTK inhibitor Acalabrutinib is mainly concentrated in the field of oncology, and the effect of BTK inhibitor Acalabrutinib on myocardial fibrosis in pathological conditions other than oncology (such as hypertension, myocardial infarction or chronic myocardial ischemia and other pathological conditions) Inhibition has not been reported

Method used

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  • Pharmaceutical composition for inhibiting myocardial fibrosis
  • Pharmaceutical composition for inhibiting myocardial fibrosis
  • Pharmaceutical composition for inhibiting myocardial fibrosis

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] This embodiment provides a pharmaceutical composition for inhibiting myocardial fibrosis, the pharmaceutical composition comprising BTK and acalabrutinib. The chemical structural formula of acatinib is as follows:

[0026]

[0027] The molecular formula of acalatinib is C 26 h 23 N 7 o 2 , the molecular weight is 465.51.

[0028] The pharmaceutical composition provided in this embodiment is used for inhibiting myocardial fibrosis under pathological myocardial conditions, such as hypertension, myocardial infarction or chronic myocardial ischemia. The pharmaceutical composition inhibits the function of BTK phosphorylation TβRI in the myocardial fibroblasts by regulating the function of the myocardial fibroblasts, thereby exerting the effect of resisting pathological myocardial fibrosis. Among them, the fibrosis signaling pathway is the downstream canonical SMAD pathway or non-canonical MAPK signaling pathway.

Embodiment 2

[0030] This example is a pharmacodynamic study on the expression of myocardial fibrosis molecules using Acalabrutinib in a cardiac pressure overload model.

[0031] 2.1 Experimental materials

[0032] Mice (C57 strain, 30 males, 8-10 weeks old, purchased by Shanghai Xipuer-Bikay Experimental Animal Co., Ltd.), Trizol reagent (purchased by Invitrogen), SYBR Green RT-PCR kit (purchased by TOYOBO), ABIQuantStudio6 fluorescent quantitative PCR instrument (purchased by Applied Biosystems), Acalabrutinib (purchased by MCE), and isoproterenol.

[0033] 2.2 Experimental method

[0034] 2.1.1 Acalabrutinib Cardiac Pressure Overload Model Construction

[0035]Isoproterenol was used to construct a mouse model of hypertension to mediate cardiac pressure overload, and 30 mice were randomly divided into three groups, 10 in each group. The three groups were normal saline group (NS), isoproterenol group (ISO) and Acalabrutinib+isoproterenol group (Acala+ISO). Among them, mice in the ISO g...

Embodiment 3

[0042] This example is a pharmacodynamic study on the expression of myocardial tissue fibrosis molecules using Acalabrutinib in a cardiac pressure overload model.

[0043] 3.1 Experimental materials

[0044] Mice (C57 strain, 30 males, 8-10 weeks old, purchased from Shanghai Xipro-Bikay Experimental Animal Co., Ltd.), Acalabrutinib (purchased from MCE Company), isoproterenol, and paraformaldehyde.

[0045] 3.2 Experimental method

[0046] The modeling method of this embodiment is similar to that of Embodiment 2, and will not be repeated here. After the modeling was completed according to the method in Example 2, the mice were anesthetized with pentobarbital, the heart was taken, and the left ventricle tissue was cut for Masson staining. Ventricular tissues were fixed in 4% paraformaldehyde for 48 hours, dehydrated in graded alcohol, embedded in paraffin, cut into 4 μm sections, heated overnight in a 60°C incubator, stained after dewaxing, and observed the staining of the sec...

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Abstract

The invention relates to a pharmaceutical composition for inhibiting myocardial fibrosis, and belongs to the technical field of biological medicines. As the acatinib has relatively high kinase selectivity and relatively good safety, and in a pathological state, BTK in myocardial fibroblasts can be directly combined and phosphorylated with a TGF-beta receptor I (TbetaRI), so that activation of downstream SMAD classical and MAPK non-classical fibrosis signal channels is promoted. The Acalabrutinib can be used for inhibiting phosphorylation and activation of BTK in a targeted manner and reducing the activation of a fibrosis signal channel in a pathological state, so that the occurrence of cardiomyopathy fibrosis is prevented. Therefore, research shows that the BTK inhibitor Acalabrutinib can inhibit myocardial fibrosis reaction under cardiomyopathy conditions (such as myocardial infarction, hypertension, chronic myocardial ischemia and other pathological conditions), so that the cardiac function is protected, adverse cardiac remodeling is prevented, and the occurrence of heart failure is controlled.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a pharmaceutical composition for inhibiting myocardial fibrosis. Background technique [0002] In real life, varying degrees of myocardial fibrosis can be observed in almost all cardiac diseases. Myocardial fibrosis is an important hallmark of adverse cardiac remodeling under cardiac pathological conditions, leading to heart failure in severe cases. Although some methods found in basic research may have a certain effect on controlling the development of pathological myocardial fibrosis, the means of clinical treatment of myocardial fibrosis are still limited. Cardiac fibrosis is most typically characterized by excessive extracellular matrix (ECM) deposition and activation of fibroblasts. The accumulation of ECM between myocardial tissues leads to cardiac stiffness, decreased ventricular compliance, impaired cardiac function, and ultimately heart failure. Therefore, the ado...

Claims

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Application Information

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IPC IPC(8): A61K38/45A61K31/4985A61P9/00A61P9/12A61P9/10A61P9/04
CPCA61K38/45A61K31/4985A61P9/00A61P9/12A61P9/10A61P9/04C12Y207/10001A61K2300/00
Inventor 占贞贞汪波刘星光
Owner SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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