Application of deaminotyrosine in preparation of medicine for treating cardiomyopathy

Abstract

The invention belongs to the technical field of medicines, particularly relates to application of deaminotyrosine in preparation of a medicine for treating cardiomyopathy caused by anthracycline medicines, discovers that DAT can relieve cardiotoxicity caused by DOX to a great extent, and can provide a new thought for recovery of patients after chemotherapy and expansion of clinical application of DOX.

Description

Technical Field

[0001] The invention belongs to the field of medical technology, and particularly relates to the application of deaminotyrosine in preparing a drug for treating cardiomyopathy. Background Art

[0002] Doxorubicin (DOX) is the most widely used anthracycline and one of the most widely used and effective drugs for the treatment of hematological malignancies, solid tumors and lymphomas. However, it is toxic to multiple organs including the heart and has severe dose-dependent cardiotoxicity, such as hypotension, tachycardia and various arrhythmias, pericarditis, myocarditis, congestive heart failure, etc. Its cardiotoxicity greatly hinders its therapeutic value and widespread clinical application. Therefore, it is urgent to explore better drugs to prevent and treat doxorubicin cardiotoxicity.

[0003] Desaminotyrosine (DAT) is one of the products of flavonoids and amino acids degraded by symbiotic bacteria in the human intestine. Intestinal microorganisms, such as Clostridium orbiscindens, can convert dietary flavonoids such as quercetin and anthocyanins into DAT to regulate the host's natural immune response. As a small molecule produced by the metabolism of intestinal microbiota, DAT may affect immune metabolic responses by regulating the macrophage IRG-1-itaconate axis, thereby playing an important role in maintaining local or systemic immune homeostasis in the host. However, the effect of DAT on cardiomyopathy has not been reported. Summary of the invention

[0004] In order to solve the above technical problems, the present invention provides the use of deaminotyrosine in preparing a drug for treating cardiomyopathy.

[0005] Application of deaminotyrosine in the preparation of drugs for treating cardiomyopathy.

[0006] Preferably, the drug has deaminotyrosine as an active ingredient.

[0007] Preferably, the medicament comprises a pharmaceutically acceptable carrier.

[0008] Preferably, the pharmaceutically acceptable carrier is one or more of a diluent, a binder, an antioxidant, a pH adjuster, a preservative, a lubricant, and a disintegrant.

[0009] Preferably, the drug is a deaminotyrosine solution.

[0010] Preferably, water is used as solvent in the deaminotyrosine solution.

[0011] Preferably, the cardiomyopathy is anthracycline-induced cardiomyopathy.

[0012] Preferably, the drug inhibits myocardial cell proliferation and cardiac function caused by doxorubicin.

[0013] A drug for treating cardiomyopathy caused by anthracyclines, wherein the drug uses the deaminotyrosine as an active ingredient.

[0014] Preferably, a pharmaceutically acceptable carrier is also included, and the pharmaceutically acceptable carrier is one or more of a diluent, a binder, an antioxidant, a pH adjuster, a preservative, a lubricant, and a disintegrant.

[0015] The cardiomyopathy treatment comprises reducing the left ventricular end-diastolic pressure LVEDP and the maximum rate of left ventricular pressure drop -dp / dt, and increasing the left ventricular systolic pressure LVDP and the maximum rate of left ventricular pressure rise +dp / dt, so as to alleviate heart damage.

[0016] Patients receiving anthracycline chemotherapy, including doxorubicin, should be prescribed the lowest dose of anthracyclines if they are considered to be at high or very high risk for anthracycline-induced cardiotoxicity. For high-risk or very high-risk patients, or when elevated serum cardiac biomarkers are noted in patients, high-dose statin therapy and angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), or beta-blockers are currently used clinically to reduce anthracycline toxicity, LVEF impairment, and mortality, but long-term and high-volume use of these drugs has certain adverse reactions, such as water and sodium retention, increased blood potassium, bradycardia, etc.

[0017] Compared with the prior art, the present invention has the following beneficial effects:

[0018] Tumors seriously endanger human life and health. DOX, as an effective chemotherapy drug, is widely used in the treatment of various solid tumors and hematological malignancies. However, DOX causes progressive and irreversible cardiotoxicity, which limits its clinical application and is also one of the causes of death of many cancer patients receiving chemotherapy. The present invention finds that DAT can alleviate the cardiotoxicity caused by DOX to a large extent, which can provide new ideas for the recovery of patients after chemotherapy and expand the clinical application of DOX. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 For the detection of cardiac hemodynamic parameters LVSP results, the data shown are mean ± SEM, **P < 0.01.

[0020] Figure 2 To detect the results of cardiac hemodynamic parameters LVEDP, the data shown are mean ± SEM, **P < 0.01.

[0021] Figure 3For the detection of cardiac hemodynamic parameters + dp / dt results, the data shown are mean ± SEM, **P < 0.01.

[0022] Figure 4 For the detection of cardiac hemodynamic parameters-dp / dt results, the data shown are mean ± SEM, **P < 0.01.

[0023] Figure 5 The results show that DAT alleviates the inhibition of H9C2 cell proliferation by DOX. The data are mean ± SEM, *P < 0.05, **P < 0.01 DETAILED DESCRIPTION

[0024] The specific embodiments of the present invention are described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work belong to the protection scope of the present invention. The experimental methods described in the embodiments of the present invention are conventional methods unless otherwise specified.

[0025] Experimental methods:

[0026] 1. Determination of hemodynamic parameters in rats

[0027] Experimental animals: Male Sprague Dawley (SD) rats weighing 180–200 g were provided by the Experimental Animal Center of Xuzhou Medical University, China, license number: SYXK(Su)2015-0030. Rats were housed in a temperature- and humidity-controlled room with a 12-h dark-light cycle.

[0028] After 3 days of adaptive feeding, the SD rats were randomly divided into three groups: Ctrl group, DOX group, and DAT+DOX group, with 6 rats in each group.

[0029] DOX group: Rats received the same dose of 3 mg / kg DOX once every 7 days via intraperitoneal injection for 6 weeks, with a cumulative dose of 18 mg / kg.

[0030] DAT+DOX group: DOX was administered by intraperitoneal injection. Rats received the same dose of 3 mg / kg DOX once every 7 days for 6 weeks, with a cumulative dose of 18 mg / kg. At the same time, 40 mg / kg of DAT was dissolved in normal saline and injected intraperitoneally every day for 6 consecutive weeks.

[0031] Ctrl group: Rats were injected intraperitoneally with an equal volume of normal saline.

[0032] Hemodynamic parameters were measured after 6 weeks: the rats were fixed in a supine position, anesthetized, and retrogradely cannulated via the right common carotid artery to measure the corresponding clinical hemodynamic parameters LVDP, LVEDP, +dp / dt, and -dp / dt. During the entire experiment, the body temperature was maintained at 37±0.5℃ using a thermostatically controlled thermostat. After the cardiac function stabilized for 15 minutes, the Powerlab data acquisition system continuously recorded for 80 minutes.

[0033] 2. Cell CCK8 proliferation assay

[0034] The cultured cardiomyocyte cell line H9C2 cells were subcultured into 96-well cell culture plates, with 3 replicate wells per group and about 5000 cells per well. Then, 200 μl of complete medium containing 10% FBS was added to each well containing cells, and a corresponding blank control group was set up at the same time.

[0035] Place four culture plates in an incubator at 37°C with 5% CO2 for 6-8 hours to wait for cells to adhere to the wall. Give Dox 2 hours after DAT. The first measurement is taken as 0h, and the culture is continued for 24h. Take out the culture plate and perform CCK8 experiment; measure the absorbance value with a full-wavelength microplate reader at 0.5h, 1h, 2h and 3h, respectively, and select the time point with the strongest absorbance as the value of the best detection time point for analysis. Statistical analysis of the absorbance values ​​at the four time points as a reflection of the number of cells, make a line graph and analyze the changes in the number of cells.

[0036] result:

[0037] LVDP, LVEDP, +dp / dt, and -dp / dt are important indicators of cardiac function. Since cardiac dysfunction is considered to be the main manifestation of DOX-induced cardiotoxicity, we further monitored the levels of these indicators in the in vivo experiment to explore the protective effect of DAT against DOX-induced cardiac injury. Compared with the control group, LVEDP and -dp / dt in the DOX group were significantly reduced, as shown in Figure 2. Figure 1 and Figure 2 , while LVDP and +dp / dt increase, see Figure 3 and Figure 4 .

[0038] In the in vitro experiment, we gave 5μM DOX to the cardiomyocyte cell line H9C2 and different concentrations of DAT, namely 1mM, 2mM, 4mM, and 8mM, with water as the solvent, incubated for 24h, and detected the cell proliferation effect. Figure 5As shown in the figure, it was observed that DOX significantly inhibited the proliferation of cardiomyocytes, causing the cardiomyocytes to become round, the nuclei to become significantly larger, and the striations to become disordered. DAT can inhibit this damage. When DAT is 4mM, it can significantly reduce the damage caused by Dox, and the proliferation rate is increased from the original 44% to 76%. Therefore, DAT has a significant inhibitory effect on the myocardial damage caused by doxorubicin.

[0039] It should be noted that when the claims of the present invention involve numerical ranges, it should be understood that the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. In order to avoid redundancy, the present invention describes a preferred embodiment.

[0040] Although the preferred embodiments of the present invention have been described, those skilled in the art may make other changes and modifications to these embodiments once they have learned the basic creative concept. Therefore, the appended claims are intended to be interpreted as including the preferred embodiments and all changes and modifications that fall within the scope of the present invention.

[0041] Obviously, those skilled in the art can make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. Application of deaminotyrosine in the preparation of drugs for treating cardiomyopathy.

2. The use according to claim 1, characterized in that: The drug uses deaminotyrosine as an active ingredient.

3. The use according to claim 2, characterized in that: The medicament includes a pharmaceutically acceptable carrier.

4. The use according to claim 3, characterized in that: The pharmaceutically acceptable carrier is one or more of a diluent, a binder, an antioxidant, a pH adjuster, a preservative, a lubricant, and a disintegrant.

5. The use according to claim 1, characterized in that: The drug is a deaminotyrosine solution.

6. The use according to claim 3, characterized in that: The deaminotyrosine solution uses water as solvent.

7. The use according to claim 1, characterized in that: The cardiomyopathy is anthracycline-induced cardiomyopathy.

8. The use according to claim 1, characterized in that: The drug inhibits adriamycin-induced cardiomyocyte proliferation and cardiac function.

9. A drug for treating anthracycline-induced cardiomyopathy, characterized in that: The drug uses the deaminotyrosine described in claim 1 as an active ingredient.

10. The drug according to claim 9, characterized in that The pharmaceutically acceptable carrier is also included, and the pharmaceutically acceptable carrier is one or more of a diluent, a binder, an antioxidant, a pH adjuster, a preservative, a lubricant, and a disintegrant.

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