CN113855701A

CN113855701A - Pharmaceutical application of compound in treating dilated cardiomyopathy induced by adriamycin

Info

Publication number: CN113855701A
Application number: CN202111210422.8A
Authority: CN
Inventors: 张瀚文; 杨亚青; 蔡文晗; 韩蕙安; 张莱; 彭聪; 陈琪
Original assignee: Nanjing Medical University
Current assignee: Nanjing University; Nanjing Medical University
Priority date: 2021-10-18
Filing date: 2021-10-18
Publication date: 2021-12-31

Abstract

A pharmaceutical use of a compound in treating dilated cardiomyopathy induced by adriamycin, in particular to an application of a prepared fucoidin and ginsenoside Rg1 compound in preventing and treating dilated cardiomyopathy. The invention can restore the heart function reduction caused by the dilated cardiomyopathy induced by the adriamycin hydrochloride, the mixed components are given to the mice at the early stage of the development of the dilated cardiomyopathy, and the heart function of the mice is obviously restored compared with the group which is only given with the physiological saline after the model building, and the ejection fraction and the short axis shortening rate of the mice are obviously improved.

Description

Pharmaceutical application of compound in treating dilated cardiomyopathy induced by adriamycin

Technical Field

The invention relates to the technical field of medicines, in particular to a therapeutic application of a compound in dilated cardiomyopathy induced by adriamycin hydrochloride.

Background

Doxorubicin hydrochloride and its derivatives have been limited in clinical use as first-line chemotherapy drugs due to dose-dependent cardiotoxicity. This cardiotoxicity, which leads to pathological remodeling of the heart in anthracycline-sensitive cancer patients, as represented by breast cancer patients, and ultimately to heart failure, is currently the most significant focus of attention in oncological cardiology. Currently, doxorubicin hydrochloride-induced cardiomyopathy (DiCM) is mainly characterized by ventricular dilatation and left ventricular dysfunction, and can induce systolic dysfunction without abnormal load. The patient's endocardial tissue exhibits typical histopathological changes including myofibrillar loss, sarcoplasmic reticulum expansion and cytoplasmic vacuolization. Although oxidative stress is considered to be the initiating factor in dilated cardiomyopathy, intermittent inhibition of oxidative stress in dilated cardiomyopathy patients has no significant effect on the progression of the disease process. Therefore, the search for a countermeasure or an effective medicine is very important, and the clinical significance for remedying the heart injury induced by using the adriamycin hydrochloride for tumor patients is achieved.

Fucoidan (Fucoidan), also known as mixed component sulfate, Fucoidan sulfate, is a unique water-soluble polysaccharide combined with sulfate groups, is obtained by esterifying the mixed components with sulfate groups, and is mainly present in brown algae and some marine invertebrates. A large number of scientific researches prove that the fucoidin has the physiological effects of regulating the immunity in two ways, eliminating free radicals, resisting aging, blood coagulation and thrombus, resisting tumor and HIV virus, eliminating gastrointestinal system disorder, resisting allergy, enhancing the liver function, reducing hyperlipidemia and hypertension, stabilizing the blood sugar level, promoting the skin regeneration, moisturizing the skin and the like, and has more than 20 items. Ginsenoside (Ginsenoside-Rg 1, G-Rg 1): is a tetracyclic triterpene derivative, which is one of the main active ingredients of ginseng, pseudo-ginseng and other ginseng medicinal materials. The compound has the effects of promoting hippocampal neurogenesis and survival, improving neural plasticity, enhancing learning and memory, resisting aging, resisting fatigue, improving immunity, assisting in resisting tumors, repairing sexual functions and the like, and meanwhile, a plurality of researches prove that G-Rg1 has a protective effect on heart vessels, can play a role in protecting heart muscle by inhibiting apoptosis and autophagy of heart muscle cells in ischemic injury, and enhances the survival capability of heart muscle. However, whether the fucoidin and the ginsenoside have protective effects on the heart injury induced by the doxorubicin hydrochloride is not reported, and according to the reported functions of the fucoidin and the ginsenoside, by utilizing the complementary mechanisms of the fucoidin and the ginsenoside in the functions of immunoregulation, free radical elimination, protection of cardiac muscle cells in the process of myocardial injury and the like, the invention uses the mixed component of the fucoidin and the ginsenoside for observing the protective effects on the heart function in the occurrence process of dilated cardiomyopathy, and further searches for a countermeasure or an effective medicine for saving the heart injury induced by the doxorubicin hydrochloride for tumor patients.

Disclosure of Invention

The technical problem to be solved is as follows: in order to solve the problems, the invention provides a pharmaceutical application of the compound in treating dilated cardiomyopathy induced by adriamycin hydrochloride.

The technical scheme is as follows: application of fucoidin and ginsenoside G-Rg1 compound in preparing dilated cardiomyopathy preventing medicine is provided.

Application of fucoidin and ginsenoside G-Rg1 compound in preparing dilated cardiomyopathy treating medicine is provided.

When in application, through a medicament concentration pre-experiment, the optimal effective concentration is finally selected, wherein the fucoidin is 200mg/kg/d, and the ginsenoside G-Rg1 is 80 mg/kg/d.

A medicine for preventing and treating dilated cardiomyopathy contains the compound of fucoidin and ginsenoside G-Rg1 as effective component.

Has the advantages that: the invention can restore the heart failure caused by the heart injury due to the use of the adriamycin hydrochloride, comprises the step of giving the mixed components to the mouse at the early stage, and finds that the heart function of the mouse is remarkably restored compared with the normal saline after the molding, the ejection fraction and the short axis shortening rate of the mouse are both remarkably increased, which indicates that the heart function of the mouse is remarkably restored.

The invention can be clinically used for the adjuvant therapy effect of heart failure caused by using adriamycin hydrochloride for tumor patients, helps the limited use of the medicine due to the side effect of the heart failure, helps the tumor patients to have wider selection of chemotherapy medicines, and provides an effective means for the use of the adriamycin hydrochloride.

The polysaccharide component contained in the polysaccharide composition has a plurality of benefits for human bodies, such as antianaphylaxis, anti-tumor, anti-obesity, anti-diabetes, anticoagulation, antivirus, immunomodulator, cardioprotection, anti-liver disease, anti-neuropathy, anti-adrenal gland activity and the like, has small toxic and side effects, and can be taken for a long time.

Drawings

FIG. 1 is a statistical plot of cardiac functional ejection fraction and short axis shrinkage of mice in the experimental group of Fucoidan (Fucoidan) drug concentration.

FIG. 2 is a statistical chart of cardiac functional ejection fraction and short axis shrinkage of mice in a Ginsenoside-Rg1 (G-Rg 1) drug concentration experimental group.

FIG. 3 is a plan view of ultrasonic testing of cardiac function of mice.

FIG. 4 is a statistical plot of the ejection fraction and short axis shrinkage of mouse heart function.

FIG. 5 shows the detailed values and statistical analysis of the specific parameters of mouse cardiac function including ejection fraction, short axis contraction rate, diastolic and systolic ventricular septum thickness, left ventricular inner diameter and left ventricular posterior wall thickness.

Fig. 6 is a photograph showing HE staining of cardiac tissue sections of the experimental group and the control group.

FIG. 7 is a photograph of MASSON staining of cardiac tissue sections from experimental and control groups.

Fig. 8 is a photograph of TUNEL staining of cardiac tissue sections of experimental and control groups.

Detailed Description

The technical solution of the present invention will be described in detail below with reference to specific examples.

Example 1

60 male C57BL6/j mice with the body weight of 25 +/-5G and the age of 6-8 weeks are selected and randomly distributed to obtain Fucoidan (Fucoidan) medicament concentration experimental groups (which are divided into three concentration gradients: 100mg/kg/d, 200mg/kg/d and 400 mg/kg/d) and Ginsenoside (Ginsenoside-Rg 1, G-Rg 1) (which are divided into three concentration gradients: 40mg/kg/d, 80mg/kg/d and 100 mg/kg/d). Six groups of mice are injected with adriamycin hydrochloride (2.5 mg/kg) in the abdominal cavity, six times are averagely injected in two weeks to induce dilated cardiomyopathy, and simultaneously, fucoidan and ginsenoside with different concentrations are injected with 0.2mL in the abdominal cavity every day; the injection is repeated at the same time point every day to maintain the blood concentration, two-dimensional echocardiography monitoring is carried out on each group of mice before (0 w) and after (2 w) model building through echocardiography, as shown in figure 1 and figure 2, figure 1 shows the heart contractile function of the mice of a Fucoidan (Fucoidan) drug concentration experimental group, figure 2 shows the heart contractile function of the mice of a Ginsenoside (Ginsenoside-Rg 1, G-Rg 1) drug concentration experimental group, and the optimal drug concentration (Fucoidan (200 mg/kg/d) and Ginsenoside (80 mg/kg/d) compound) is selected according to the heart function for subsequent experiments.

Example 2

20 male C57BL6/j mice of 6-8 weeks old, weighing 25 + -5 g, were selected and randomly assigned to obtain experimental and control groups.

Two groups of mice were injected intraperitoneally with doxorubicin hydrochloride (2.5 mg/kg), six times per two weeks on average, to induce dilated cardiomyopathy, and experimental groups were injected intraperitoneally daily with the mixed components: fucoidin (200 mg/kg/d) and ginsenoside (80 mg/kg/d) compound 0.2mL, and the control group is injected with equal volume of normal saline into the abdominal cavity every day; injections were repeated daily at the same time points to maintain blood levels.

Performing two-dimensional echocardiogram monitoring on the experimental group and the control group through echocardiogram before (0 w) and after (2 w) modeling, as shown in fig. 3 and 4, wherein fig. 3 is a two-dimensional echocardiogram detection plane diagram of the heart of the mouse before and after modeling, and fig. 4 is statistical analysis of the heart function including the cardiac ejection fraction and the short axis shrinkage rate of the mouse before and after modeling; FIG. 5 is a detailed numerical and statistical analysis of all cardiac parameters including ejection fraction, short axis contraction, ventricular septum thickness in diastole and systole, left ventricular inner diameter, left ventricular posterior wall thickness for a mouse echocardiogram; FIGS. 6 and 7 are staining charts of heart HE and MASSON heart slices of experimental and control groups 2 weeks after model building; FIG. 8 is a positive staining diagram of cardiac apoptosis in experimental and control groups for establishing dilated cardiomyopathy models.

The results show that: after 2 weeks of establishing the mouse dilated cardiomyopathy model, compared with the control group, the heart function of the experimental group mouse is remarkably recovered, the ventricular remodeling and the myocardial cell apoptosis are also improved, and the differences have statistical significance (P is less than 0.05).

The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.

Claims

1. Application of fucoidin and ginsenoside Rg1 compound in preparing dilated cardiomyopathy preventing medicine is provided.

2. Application of fucoidin and ginsenoside Rg1 compound in preparing dilated cardiomyopathy treating medicine is provided.

3. The use of claim 1 or 2, wherein the fucoidan is 200mg/kg/d and the ginsenoside Rg1 is 80 mg/kg/d.

4. The dilated cardiomyopathy preventing or treating medicine is characterized in that the effective components are a compound consisting of fucoidin and ginsenoside Rg 1.