Application of 3-phenylglutaric acid derivative 84-B10 in preparation of myocardial protection drugs

Abstract

The invention belongs to the technical field of medicines, and particularly discloses application of a compound 84-B10 in preparation of myocardial protection medicines. In order to solve the problems that in the prior art, effective therapeutic drugs are lacked for myocardial injury caused by sepsis and chemotherapeutic drugs (cis-platinum and adriamycin), and an existing cardiac protective agent possibly interferes with the chemotherapeutic effect, 84-B10 is used for preparing the myocardial protective drug, and the 84-B10 is particularly suitable for patients suffering from cardiac function injury caused by sepsis or chemotherapeutic drugs. Experiments show that the medicine can significantly improve the cardiac ejection fraction and shortening rate, reduce the levels of serum lactic dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB), and inhibit the expression of chemotactic factors (CCL5 and CXCL1) and inflammatory factors (IL-6 and IL-17A) in cardiac muscle tissues. Meanwhile, the medicine does not interfere with the killing effect of adriamycin on tumor cells, and the curative effect of chemotherapy is guaranteed. The medicine is simple in preparation process and high in stability, can realize efficient protection in a myocardial injury model, and has clinical application potential.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical technology, and particularly relates to the application of 3-phenylglutaric acid derivative 84-B10 in the preparation of drugs for myocardial protection, and specifically relates to the application of 84-B10 in the preparation of drugs for myocardial protection during sepsis and myocardial injury caused by chemotherapeutic drugs. Background Art

[0002] Sepsis refers to life-threatening organ dysfunction caused by dysregulated host response to infection. Septic shock refers to sepsis complicated by severe circulatory, cellular, and metabolic disorders, and its risk of death is higher than that of simple sepsis. Sepsis and septic shock are important problems currently faced by critical care medicine. Each year, there are more than 19 million sepsis patients, and more than 25% of them die, with a very high fatality rate. Severe sepsis is accompanied by cardiovascular dysfunction, reduced cardiac function, and decreased blood pressure. The treatment of sepsis includes: replenishing body fluids; vasoactive drugs; controlling infection; removing the focus and other methods. However, there is still a lack of treatment methods for sepsis-induced myocardial injury, so there is an urgent need to develop clinical drugs for the treatment of septic cardiomyopathy.

[0003] Cisplatin and doxorubicin (DOX) are currently the most effective antitumor chemotherapeutic drugs in clinical practice, but their cardiotoxicity and nephrotoxicity severely limit their clinical application. Left ventricular dysfunction and heart failure are the most severe symptoms of chemotherapeutic drug cardiotoxicity. Existing studies have shown that chemotherapeutic drug cardiotoxicity involves many factors, such as causing apoptosis, autophagy, oxygen free radical damage, mitochondrial damage, and abnormal energy metabolism. In vivo and in vitro studies have shown that apoptosis of cardiomyocytes induced by chemotherapeutic drugs is the most direct cause of myocardial injury. Dexrazoxane is currently the only drug approved by the FDA for protecting the heart from doxorubicin-induced cardiotoxicity in clinical practice, but studies have found that Dexrazoxane may interfere with the anti-cancer activity of doxorubicin and enhance the myelosuppressive effect of doxorubicin. Therefore, there is an urgent need to develop clinical drugs for the treatment of chemotherapeutic drug cardiomyopathy.

[0004] 84-B10 is a new 3-phenylglutaric acid derivative (CAS No.: 698346-43-9), and its chemical formula is shown as follows.

[0005]

[0006] 84-B10 can activate the mitochondrial protease LONP1 and has a protective effect on cisplatin-induced acute kidney injury and chronic kidney injury models induced by unilateral ureteral obstruction or 5 / 6 nephrectomy. In acute kidney injury, 84-B10 may play a protective role in the kidney by restoring mitochondrial homeostasis and inhibiting ferroptosis induced by mtROS; in chronic kidney disease, 84-B10 may improve renal fibrosis and mitochondrial dysfunction by activating LONP1. There is currently no report on the use of 84-B10 for the treatment of cardiomyopathy. Summary of the Invention

[0007] To solve the above-mentioned problems in the prior art and address the lack of therapeutic drugs for cardiotoxicity caused by sepsis or chemotherapy in cancer patients, the present invention provides the application of 84-B10 in the treatment of cardiomyopathy products. 84-B10 can effectively improve sepsis and chemotherapy-induced cardiomyopathy without affecting the anti-cancer effect of chemotherapy drugs.

[0008] The present invention includes the following technical solutions:

[0009] The present invention discloses the application of the 3-phenylglutaric acid derivative 84-B10 in the preparation of a cardioprotective drug.

[0010] Further, in the above pharmaceutical application, the cardioprotective drug is a drug that reduces myocardial injury and improves cardiac function.

[0011] Further, in the above pharmaceutical application, the cardioprotective drug is a drug used to relieve / treat cardiac function injury caused by sepsis.

[0012] Further, in the above pharmaceutical application, the cardioprotective drug is a drug used to relieve / treat inflammatory injury of cardiomyocytes caused by sepsis.

[0013] Further, in the above pharmaceutical application, the cardioprotective drug is a drug used to relieve / treat cardiac function injury caused by chemotherapy drugs in cancer patients.

[0014] Further, in the above pharmaceutical application, the cardioprotective drug is a drug used to relieve / treat cardiac function injury caused by cisplatin chemotherapy drugs in cancer patients.

[0015] Further, in the above pharmaceutical application, the cardioprotective drug is a drug used to relieve / treat cardiac function injury caused by doxorubicin chemotherapy drugs in cancer patients.

[0016] Further, in the above pharmaceutical application, the cardioprotective drug does not interfere with the killing effect of doxorubicin on tumor cells while protecting the myocardium.

[0017] Further, in the above pharmaceutical application, the myocardial protection drug is a drug that alleviates the decline in myocardial cell viability caused by doxorubicin.

[0018] Further, in the above pharmaceutical application, the myocardial protection drug is a drug that achieves the protective effect by inhibiting the expression of chemokines and inflammatory factors in myocardial tissue.

[0019] Further, in the above pharmaceutical application, the chemokines include at least one of CCL5, CCL11, and CXCL1; the inflammatory factors include at least one of IL-6 and IL-17A.

[0020] The present invention also discloses a pharmaceutical composition, comprising 84-B10 and a therapeutically effective amount of a chemotherapeutic drug, wherein the chemotherapeutic drug is cisplatin or doxorubicin.

[0021] Compared with the prior art, the present invention has the following outstanding beneficial effects:

[0022] The present invention discloses the application of compound 84-B10 in the preparation of myocardial protection drugs, which is an innovative improvement on the existing treatment methods for myocardial injury. On the premise of ensuring the anti-cancer effect of chemotherapeutic drugs, the myocardial protection efficacy is significantly improved. Specifically manifested as:

[0023] 1. Precise targeted protection: For myocardial injuries caused by different etiologies such as sepsis, cisplatin, and doxorubicin, by inhibiting the expression of chemokines (CCL5, CXCL1) and inflammatory factors (IL-6, IL-17A) in myocardial tissue, the inflammatory injury of myocardial cells is effectively reduced, the cardiac ejection fraction and shortening rate are improved, and the levels of serum lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) are reduced by 40%-60%.

[0024] 2. Both efficacy and safety: The drug does not interfere with the killing effect of chemotherapeutic drugs such as doxorubicin on tumor cells, avoiding the defects of existing cardioprotective agents (such as Dexrazoxane) that interfere with the chemotherapy efficacy or aggravate myelosuppression, and ensuring that tumor treatment is not affected.

[0025] 3. High efficiency and convenience: Animal experiments show that intraperitoneal injection of 84-B10 (5-15 mg / kg / day) can significantly relieve myocardial injury within 12-48 hours, and the protective effect is steadily improved with the increase of the dose, and there is no significant cytotoxicity.

[0026] 4. Excellent stability: The pharmaceutical preparation process is simple, and the standard product can be stored refrigerated for a long time, ensuring the stability and accessibility of clinical applications.

[0027] The drug provided by the present invention combines high efficiency, specificity, and safety, providing an innovative solution for the treatment of sepsis and chemotherapy-related cardiomyopathy, and having important clinical application value. Description of the Drawings

[0028] Figure 1 It is the blood biochemical results and HE staining diagrams of 84-B10 at different concentrations in alleviating myocardial injury caused by sepsis;

[0029] Figure 2 It is the echocardiogram results of 84-B10 in alleviating myocardial injury caused by sepsis;

[0030] Figure 3 It is the blood biochemical results diagram of 84-B10 in alleviating myocardial injury caused by sepsis;

[0031] Figure 4 It is the RNA-seq omics analysis diagram of mouse myocardial tissue;

[0032] Figure 5 It is the increase diagram of chemokines in mouse myocardial tissue alleviated by 84-B10 due to sepsis;

[0033] Figure 6 It is the increase diagram of inflammatory factors in mouse myocardial tissue alleviated by 84-B10 due to sepsis;

[0034] Figure 7 It is the increase diagram of myocardial enzyme spectrum in mice caused by cisplatin alleviated by 84-B10;

[0035] Figure 8 It is the decrease diagram of mouse myocardial cell viability caused by adriamycin alleviated by 84-B10;

[0036] Figure 9 It is the effect diagram of 84-B10 not interfering with the anti-hepatocellular carcinoma effect of adriamycin. Detailed Implementation Modes

[0037] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0038] Example 1

[0039] Animal experiment: Application of 84-B10 in alleviating myocardial function injury in mice caused by sepsis.

[0040] 1 Experimental materials

[0041] The C57BL / 6j mice used in the present invention were purchased from Jicui Pharmaceutical Co., Ltd. The 84-B10 used in the present invention was purchased from Shanghai Medicilon Inc., and lipopolysaccharide LPS was purchased from Sigma-Aldrich.

[0042] 2 Experimental Methods

[0043] 2.1 Administration Method for Mice

[0044] Twenty-eight male C57BL / 6j mice (8 weeks old, weighing 22 - 25 g) were housed in a SPF-class animal room. After 1 week of adaptive feeding, they were randomly divided into a control group (n = 6), a lipopolysaccharide LPS group (n = 8), a Low 84-B10 + lipopolysaccharide LPS group (n = 7), and a High 84-B10 + lipopolysaccharide LPS group (n = 7). Mice in the Low 84-B10 + lipopolysaccharide LPS group were intraperitoneally injected with 84-B10 (5 mg / kg / day), mice in the High 84-B10 + lipopolysaccharide LPS group were intraperitoneally injected with 84-B10 (15 mg / kg / day), and mice in the control group and the lipopolysaccharide group were intraperitoneally injected with PBS. Twelve hours after intraperitoneal injection of lipopolysaccharide (10 mg / kg) in the lipopolysaccharide group and the 84-B10 + lipopolysaccharide groups two days later, blood and heart tissues were collected.

[0045] 2.2 Detection of Blood Biochemical Indexes of Mice and HE Staining of Heart Tissues

[0046] The levels of blood lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) in mice were detected using a biochemical detector, and HE staining of mouse heart tissues was performed.

[0047] 3 Experimental Results

[0048] The levels of blood lactate dehydrogenase in the four groups of mice were as Figure 1 shown in A, and the levels of blood creatine kinase isoenzyme in the four groups of mice were as Figure 1 shown in B. Statistical results showed that lipopolysaccharide could significantly increase the levels of blood lactate dehydrogenase and creatine kinase isoenzyme in mice, while both low-concentration and high-concentration 84-B10 could significantly alleviate the increase in biochemical indexes of heart function such as lactate dehydrogenase and creatine kinase isoenzyme caused by lipopolysaccharide, and there was no significant difference between the low-concentration group and the high-concentration group. The results of HE staining indicated that lipopolysaccharide could significantly increase myocardial tissue damage in mice, while both low-concentration and high-concentration 84-B10 could significantly alleviate the myocardial damage caused by lipopolysaccharide.

[0049] Example 2

[0050] Animal Experiment: Application of 84-B10 in Alleviating the Decline of Heart Function Caused by Sepsis

[0051] 1 Experimental Materials

[0052] The C57BL / 6j mice used in this invention were purchased from Jicuiyaokang Biotechnology Co., Ltd. The 84-B10 used in this invention was purchased from Shanghai Medicilon Inc., and the lipopolysaccharide LPS was purchased from Sigma-Aldrich Corporation.

[0053] 2 Experimental Methods

[0054] 2.1 Mouse Administration Method

[0055] Twenty-nine male C57BL / 6j mice (8 weeks old, weighing 22 - 25 g) were housed in a SPF-class animal room. After 1 week of adaptive feeding, they were randomly divided into four groups: control group (n = 7), 84-B10 group (n = 8), lipopolysaccharide LPS group (n = 6), and 84-B10 + lipopolysaccharide LPS group (n = 8). Mice in the 84-B10 group were intraperitoneally injected with 84-B10 (5 mg / kg / day), mice in the LPS group were intraperitoneally injected with LPS (10 mg / kg), and mice in the control group were intraperitoneally injected with PBS.

[0056] 84-B10 was administered 48 hours in advance, and echocardiography was performed 12 hours after LPS injection.

[0057] 2.2 Mouse Echocardiography and Mouse Blood Biochemical Indexes

[0058] A small animal ultrasound device (Vevo 2100) was used to detect the cardiac function of mice. A biochemical detector was used to detect the levels of mouse blood lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB).

[0059] 3 Experimental Results

[0060] Representative diagram of mouse echocardiography ( Figure 2 A), statistical chart of mouse left ventricular ejection fraction ( Figure 2 B) and mouse left ventricular shortening fraction ( Figure 2 C). It shows that 84-B10 can significantly relieve the decline in cardiac function caused by LPS.

[0061] The level of mouse blood lactate dehydrogenase is as shown in Figure 3 A, and the level of mouse blood creatine kinase isoenzyme is as shown in Figure 3 B. The statistical results show that lipopolysaccharide can significantly increase the levels of mouse blood lactate dehydrogenase and creatine kinase isoenzyme, while 84-B10 can significantly relieve the increase in the levels of biochemical indexes of cardiac function such as lactate dehydrogenase and creatine kinase isoenzyme caused by lipopolysaccharide.

[0062] Example 3

[0063] Animal experiment: 84-B10 relieves cardiac function injury in mice caused by sepsis by affecting inflammatory factors and chemotactic factors.

[0064] 1 Experimental Materials

[0065] The C57BL / 6j mice used in this invention were purchased from Jicuiyaokang Biotechnology Co., Ltd. The 84-B10 used in this invention was purchased from Shanghai Medicilon Inc., and lipopolysaccharide LPS was purchased from Sigma-Aldrich.

[0066] 2 Experimental methods

[0067] 2.1 Mouse administration method

[0068] Twenty-eight male C57BL / 6j mice (8 weeks old, body weight 22 - 25 g) were housed in a SPF-class animal room. After 1 week of adaptive feeding, they were randomly divided into a control group (n = 6), a lipopolysaccharide LPS group (n = 8), a Low 84-B10 + lipopolysaccharide LPS group (n = 7), and a High 84-B10 + lipopolysaccharide LPS group (n = 7). Mice in the Low 84-B10 + lipopolysaccharide LPS group were intraperitoneally injected with 84-B10 (5 mg / kg / day), mice in the High 84-B10 + lipopolysaccharide LPS group were intraperitoneally injected with 84-B10 (15 mg / kg / day), and mice in the control group and the LPS group were intraperitoneally injected with PBS. Twelve hours after intraperitoneal injection of lipopolysaccharide (10 mg / kg) in the LPS group and the 84-B10 + lipopolysaccharide groups two days later, heart tissues were collected.

[0069] 2.2 RNA-seq omics detection of heart tissues

[0070] Mouse myocardial tissues were collected, and three mice in each group were subjected to transcriptomic sequencing (BGI) to screen for differentially expressed genes. Through high-throughput sequencing technology, the gene expression differences between the sepsis model group and the 84-B10 treatment + sepsis model group were obtained.

[0071] 3 Experimental results

[0072] Pathway enrichment analysis of differentially expressed genes was performed using the KEGG (Kyoto Encyclopedia of Genes and Genomes) database. The experimental results showed that a total of 677 genes were identified as having changes in expression levels among all experimental groups between the LPS stimulation group and the control group, the low-dose (Low / LPS) and high-dose (High / LPS) 84-B10 treatment groups. KEGG pathway enrichment analysis showed that these differentially expressed genes were mainly enriched in cytokine-cytokine receptor interaction, NF-kappa B signaling pathway, IL-17 signaling pathway, TNF signaling pathway, and Toll-like receptor signaling pathway ( Figure 4)。The results of RNA-seq data analysis showed that, compared with the LPS group, the mRNA expression levels of chemokines CCL5, CCL11, CCL22, CXCL1, CXCL2, CXCL5, CXCL9, and CXCL19 in the myocardial tissues of septic mice were significantly decreased in the low-dose (Low / LPS) and high-dose (High / LPS) 84-B10 treatment groups ( Figure 5 )。Further analysis of the RNA-seq data showed that the mRNA expression levels of inflammatory factors IL-6, IL-17A, IL-17F, IL-22, and IL-27 were significantly downregulated in the 84-B10 treatment group ( Figure 6 )。The results suggest that 84-B10 may play an anti-inflammatory role and protect the myocardium in the septic cardiomyopathy model by inhibiting inflammatory factors.

[0073] Example 4

[0074] Animal experiment: Application of 84-B10 in alleviating the increase in myocardial enzyme spectrum caused by cisplatin in mice.

[0075] 1 Experimental materials

[0076] The C57BL / 6j mice used in this invention were purchased from Jicui Pharmaceutical Co., Ltd. The 84-B10 used in this invention was purchased from Shanghai Medicilon Inc., and cisplatin was purchased from Sigma-Aldrich.

[0077] 2 Experimental methods

[0078] 2.1 Method for administering drugs to mice

[0079] Twenty-four male C57BL / 6j mice (8 weeks old, weighing 22 - 25 g) were housed in a SPF-class animal room. After 1 week of adaptive feeding, they were randomly divided into a control group (n = 8), a cisplatin group (n = 8), and an 84-B10 + cisplatin group (n = 8). Mice in the 84-B10 + cisplatin group were intraperitoneally injected with 84-B10 (5 mg / kg / day), and mice in the control group and the cisplatin group were intraperitoneally injected with PBS. Two days later, the cisplatin group and the 84-B10 + cisplatin group were intraperitoneally injected with liposomal cisplatin (25 mg / kg). Three days later, blood was collected to detect the levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB).

[0080] 2.2 Detection of blood biochemical indexes of mice

[0081] The levels of blood lactate dehydrogenase (LDH) and creatine kinase isoenzyme (CK-MB) in mice were detected using a biochemical analyzer.

[0082] 3 Experimental results

[0083] The levels of lactate dehydrogenase (LDH) in the blood of three groups of mice were as Figure 7 shown in A, and the levels of creatine kinase isoenzyme (CK-MB) in the blood of three groups of mice were as Figure 7 shown in B. The statistical results showed that cisplatin could significantly increase the levels of lactate dehydrogenase and creatine kinase isoenzyme in the blood of mice, while 84-B10 could significantly alleviate the increase in the levels of biochemical indexes of cardiac function such as lactate dehydrogenase and creatine kinase isoenzyme caused by cisplatin.

[0084] Example 5

[0085] Animal experiment: Application of 84-B10 in alleviating the decrease in the viability of cardiomyocytes in mice caused by doxorubicin.

[0086] 1 Experimental materials

[0087] The CCK8 kit for detecting cell viability was purchased from KeyGen Biotech; the rat cardiomyocyte line H9c2 was purchased from ATCC; high-glucose DMEM and fetal bovine serum required for culturing the H9c2 cell line were purchased from Gibco; 84-B10 was purchased from Shanghai Medicilon Inc.; doxorubicin (DOX) was purchased from Sigma-Aldrich.

[0088] 2 Experimental methods

[0089] The rat cardiomyocyte line H9c2 was cultured in vitro using high-glucose DMEM containing 10% fetal bovine serum in an incubator at 37°C with 5% CO2. During the experiment, the H9c2 cells were seeded in a 96-well cell culture plate at a cell density of 2×103 / well. 1. Evaluation of the cytotoxicity of 84-B10 on H9c2 cells: After the cells were plated overnight, the experimental groups were divided into a control group and 84-B10 groups (10, 20, 40 μM). After 24 h, 10 μL of CCK8 detection solution was added to each well, and the cells were incubated in the incubator for 2 hours. The absorbance of the cells was measured at a wavelength of 450 nm using an enzyme-linked immunosorbent assay (ELISA) reader. 2. Evaluation of the effect of 84-B10 on the decrease in the viability of H9c2 cells caused by doxorubicin: After the cells were plated overnight, the experimental groups were divided into a control group, a doxorubicin group (1 μM), an 84-B10 (20 μM) + doxorubicin group, and an 84-B10 (40 μM) + doxorubicin group. H9c2 cells were pretreated with 84-B10 (20, 40 μM) for 2 h, and then treated with doxorubicin (1 μM). After 24 h, 10 μL of CCK8 detection solution was added to each well, and the cells were incubated in the incubator for 2 hours. The absorbance of the cells was measured at a wavelength of 450 nm using an ELISA reader.

[0090] 3 Experimental results

[0091] The CCK8 detection results showed that 84-B10 at 10, 20, and 40 μM had no effect on the viability of rat cardiomyocytes H9c2 ( Figure 8A), 84-B10 can significantly alleviate the decrease in the viability of H9c2 cells induced by 1 μM doxorubicin ( Figure 8 B).

[0092] Example 6

[0093] Animal experiment: 84-B10 does not interfere with the anti-hepatocellular carcinoma effect of doxorubicin.

[0094] 1 Experimental materials

[0095] The human hepatocellular carcinoma cell line HepG2 was purchased from ATCC; 84-B10 was purchased from Shanghai Medicilon Inc., and doxorubicin was purchased from Sigma-Aldrich.

[0096] 2 Experimental methods

[0097] HepG2 cells were cultured in vitro. During the experiment, the cells were seeded in a 96-well cell culture plate at a cell density of 2×103 / well. After overnight incubation, the cells were grouped for the experiment, divided into a control group, a doxorubicin group, an 84-B10 (20 μM) + doxorubicin group, and an 84-B10 (40 μM) + doxorubicin group. The cells were pretreated with 84-B10 (20, 40 μM) for 2 h, and then treated with doxorubicin (1 μM). After 24 h, 10 μL of CCK8 detection solution was added to each well, and the plate was incubated in an incubator for 2 h. The absorbance of the cells was measured at a wavelength of 450 nm using an enzyme-linked immunosorbent assay (ELISA) reader.

[0098] 3 Experimental results

[0099] The results of the CCK8 assay showed that 84-B10 at 20 and 40 μM did not affect the killing effect of doxorubicin on HepG2 cells. It was shown that 84-B10 did not interfere with the anti-hepatocellular carcinoma effect of doxorubicin ( Figure 9 ).

[0100] Summary of embodiments: In this invention, mice were intraperitoneally injected with 84-B10 (5 mg / kg / day) every day. After 48 hours, the mice were intraperitoneally injected with LPS (10 mg / kg) to establish a sepsis cardiomyopathy model. After 12 hours, echocardiography was used to detect the cardiac function of the mice. The results showed that 84-B10 could significantly improve the cardiac function decline caused by sepsis. The results of blood biochemical tests indicated that 84-B10 could significantly relieve the increase in LDH and CK-MB caused by sepsis. The results of HE staining of mouse left ventricular tissue sections showed that 84-B10 could reduce cardiomyocyte damage. By analyzing the mouse heart tissue through transcriptomics (RNA-seq), it was found that 84-B10 significantly reduced chemokines and inflammatory factors in cardiomyocytes. In addition, to examine the effect of 84-B10 on myocardial damage caused by chemotherapeutic drugs, we intraperitoneally injected mice with 84-B10 (5 mg / kg / day) every day. After 48 hours, the mice were intraperitoneally injected with cisplatin (25 mg / kg) to establish an acute cardiomyopathy model caused by chemotherapeutic drugs. After 3 days, mouse blood samples were taken. The results of blood biochemical tests showed that 84-B10 could significantly relieve the increase in myocardial enzyme spectra LDH and CK-MB caused by cisplatin. The rat cardiomyocyte line H9c2 was cultured in vitro and pretreated with 84-B10 (20, 40 μM) for 2 hours, and then treated with doxorubicin (1 μM) to prepare a doxorubicin-induced cardiomyocyte damage model. The results showed that 84-B10 could significantly reduce the decrease in H9c2 cell viability induced by doxorubicin. Finally, in doxorubicin-sensitive tumor cell lines (human hepatocellular carcinoma cell line HepG2), it was detected whether 84-B10 interfered with the anti-cancer effect of doxorubicin. The results showed that 84-B10 did not interfere with the anti-cancer effect of doxorubicin.

[0101] Therefore, 84-B10 has a significant effect in protecting the myocardium in myocardial damage caused by sepsis or chemotherapeutic drugs and does not interfere with the anti-cancer effect of doxorubicin.

[0102] The above are only several limited preferred embodiments of the present invention, and the description thereof is relatively specific and detailed. However, it should not be construed as a limitation to the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all belong to the protection scope of the present invention.

Claims

Application of 1.3-phenylglutaric acid derivative 84-B10 in the preparation of myocardial protective drugs.

2. The use according to claim 1, characterized in that: The myocardial protective drug is a drug that reduces myocardial damage and improves cardiac function.

3. The use according to claim 1 or 2, characterized in that: The myocardial protection drug is a drug used to alleviate / treat cardiac function damage caused by sepsis.

4. The use according to claim 3, characterized in that: The myocardial protective drug is a drug used to alleviate / treat inflammatory damage to myocardial cells caused by sepsis.

5. The use according to claim 1 or 2, characterized in that: The myocardial protection drug is a drug used to alleviate / treat cardiac function damage caused by chemotherapy drugs in cancer patients.

6. The use according to claim 5, characterized in that: The chemotherapy drug is cisplatin or doxorubicin.

7. The use according to claim 6, characterized in that: The myocardial protection drug protects the myocardium without interfering with the killing effect of cisplatin or doxorubicin on tumor cells.

8. The use according to claim 6, characterized in that: The myocardial protective drug is a drug that alleviates the decline in myocardial cell activity caused by doxorubicin.

9. The use according to claim 1 or 2, characterized in that: The myocardial protective drug is a drug that achieves protective effects by inhibiting the expression of chemokines and inflammatory factors in myocardial tissue.

10. A pharmaceutical composition, characterized in that The invention comprises 84-B10 and a therapeutic amount of a chemotherapeutic drug, wherein the chemotherapeutic drug is cisplatin or doxorubicin.

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