阅读说明：本技术 罗沙司他用于心肌保护的用途 (Use of Rosxastat for myocardial protection ) 是由 贾占军 夏薇薇 龙广风 张爱华 黄松明 陈红兵 李袁媛 吴梦颍 王倩 王皓 于 2019-11-13 设计创作，主要内容包括：本发明涉及罗沙司他用于心肌保护的用途。具体而言是涉及罗沙司他用于治疗阿霉素化疗引起的心肌功能损伤的用途。(The present invention relates to the use of rosmarintat for myocardial protection. In particular to the application of the roxasistat in treating myocardial function damage caused by adriamycin chemotherapy.)

1. Use of roxasistat for the preparation of a myocardial preservation medicament.

2. Use of roxasistat in preparation of a medicament for treating myocardial function damage caused by doxorubicin chemotherapy.

The technical field is as follows:

the invention belongs to the field of new application of medicines, and particularly relates to application of roxasistat in myocardial protection, and further particularly relates to application of roxasistat in a myocardial protection medicine in an adriamycin chemotherapy process.

Background art:

doxorubicin (DOX) is one of the most clinically effective antitumor drugs at present, but the cardiac toxicity of Doxorubicin severely limits the clinical application of Doxorubicin. Left ventricular dysfunction and heart failure are the most severe symptoms of doxorubicin cardiotoxicity. Studies have shown that doxorubicin cardiotoxicity is involved in a number of contributing factors, such as causing apoptosis, autophagy, oxygen radical damage, mitochondrial damage, and abnormal energy metabolism. In vivo and in vitro studies indicate that doxorubicin-induced cardiomyocyte apoptosis is the most direct cause of myocardial injury, while accumulation of intracellular ROS and activation of oxidative stress systems are essential factors in triggering and accelerating DOX-induced myocardial toxicity.

Dexrazoxane is the only drug approved by the U.S. Food and Drug Administration (FDA) to be used clinically to protect the heart from doxorubicin-induced cardiotoxicity, but it has been found that Dexrazoxane may interfere with doxorubicin's anti-cancer activity and potentiate doxorubicin's myelosuppressive effects. Therefore, the development of clinical drugs for treating doxorubicin cardiomyopathy is urgently needed.

Roxadustat (FG-4592/ASP 1517/Rosesata, domestic trade name Ehreizine) has the following structural formula:

is a novel oral inhibitor of a high-activity small-molecule hypoxia-inducible factor prolyl hydroxylase, can up-regulate the production of endogenous EPO so as to promote the generation of erythrocytes, and is currently on the market at home for treating chronic kidney disease anemia

Disclosure of Invention

Aiming at the problem of lack of treatment drugs for cardiotoxicity caused by the existing adriamycin treatment tumor patients, the invention provides a new application of roxamastat in myocardial preservation, which is used for developing a product for treating adriamycin cardiomyopathy and does not influence the anticancer effect of adriamycin. There are currently no reports of the use of roxasistat for the treatment of doxorubicin cardiomyopathy.

According to the invention, the mice are subjected to intraperitoneal injection of the roxasistat (10mg/kg/day) every day, after 48 hours, the mice are subjected to intraperitoneal injection of the adriamycin (12.5mg/kg/day) to construct an adriamycin acute cardiomyopathy model, and after 7 days, the heart function of the mice is detected by cardiac ultrasound, and the results show that the roxasistat can obviously improve the heart function reduction caused by the adriamycin.

The results of the study also found that rosxastat did not affect the cardiac function of normal mice. TUNEL staining of mouse left ventricular tissue sections indicated that Rosemastat reduced cardiomyocyte apoptosis. By testing for MDA in mouse heart tissue, rosxastat was found to reduce oxidative stress injury of cardiomyocytes. Rat cardiomyocyte cell line H9c2 was cultured in vitro and pretreated with Rosemastat (5. mu.M) for 24 hours, followed by doxorubicin (1. mu.M) treatment to prepare a cardiomyocyte injury model. The results indicate that rosxastat can significantly reduce doxorubicin-induced apoptosis of H9c2 cells and ROS production. Finally, whether the Rosemastat interferes with the anticancer effect of the adriamycin is detected in two adriamycin-sensitive tumor cell lines (a human liver cancer cell line HepG2 and a human breast cancer cell line MCF 7). The results show that the roxasistat does not interfere the anticancer effect of the adriamycin.

Therefore, the roxasistat has a remarkable effect of being applied to adriamycin myocardial protection, and does not interfere with adriamycin anticancer effect.

Drawings

FIG. 1 is a graph of the safety evaluation of rasagiline on cardiac function in normal mice;

FIG. 2 is a graph of the cardiac supracardiac results of Rosxastat in alleviating impairment of cardiac function of doxorubicin;

FIG. 3 is a graph of Rosxastat reducing doxorubicin-induced apoptosis in mouse cardiomyocytes;

FIG. 4 is a graph of Rosxastat alleviating doxorubicin-induced oxidative stress in mouse cardiomyocytes;

FIG. 5 is a graph of Rosxastat reducing Adriamycin induced apoptosis in rat cardiomyocyte line H9c 2;

FIG. 6 is a graph of the relief of doxorubicin-induced H9c2ROS production by the rat cardiomyocyte cell line from Rosxastat;

figure 7 is a graph of the effect of rosxastat in not interfering with doxorubicin killing of cancer cells.

Detailed Description

The process of the invention is illustrated in detail below with reference to specific examples. The content is to explain the invention and not to limit the scope of protection of the invention.