Use of deaminotyrosine for the preparation of a medicament for the treatment of cardiomyopathy

Abstract

The application belongs to the technical field of medicines, and particularly relates to application of deaminated tyrosine in preparation of medicines for treating cardiomyopathy caused by anthracycline drugs. It is found that DAT can greatly relieve the cardiotoxicity caused by DOX, and can provide a new idea for recovery of patients after chemotherapy treatment and expansion of the clinical application of DOX.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of deaminotyrosine in the preparation of drugs for treating cardiomyopathy. Background Technology

[0002] Doxorubicin (DOX) is arguably the most widely used anthracycline, and one of the most widely used and effective drugs for treating hematologic malignancies, solid tumors, and lymphomas. However, it is toxic to multiple organs, including the heart, and exhibits severe dose-dependent cardiotoxicity, such as hypotension, tachycardia and various arrhythmias, pericarditis, myocarditis, and congestive heart failure. This cardiotoxicity significantly hinders its therapeutic value and widespread clinical application; therefore, there is an urgent need to explore better drugs to prevent and treat doxorubicin cardiotoxicity.

[0003] Desaminotyrosine (DAT) is a product of the degradation of flavonoids and amino acids by symbiotic bacteria in the human gut. Gut microorganisms, such as Clostridium orbiscindens, can convert dietary flavonoids such as quercetin and anthocyanins into DAT, regulating the host's innate immune response. As a small molecule produced by gut microbiota metabolism, DAT may affect immune metabolic responses by regulating the macrophage IRG-1-itaconic acid axis, thereby playing an important role in maintaining local or systemic immune homeostasis in the host. However, the effects of DAT on cardiomyopathy have not been reported. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides the application of deaminotyrosine in the preparation of drugs for treating cardiomyopathy.

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

[0006] Preferably, the drug uses deaminotyrosine as its active ingredient.

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

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

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

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

[0011] Preferably, the cardiomyopathy is caused by anthracycline drugs.

[0012] Preferably, the drug inhibits cardiomyocyte proliferation and cardiac function induced by doxorubicin.

[0013] A medicine for treating anthracycline-induced cardiomyopathy, wherein the medicine has the deaminotyrosine mentioned above as its active ingredient.

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

[0015] The treatment of cardiomyopathy involves reducing left ventricular end-diastolic pressure (LVEDP) and the maximum rate of decrease in left ventricular pressure (-dp / dt), and increasing left ventricular systolic pressure (LVDP) and the maximum rate of increase in left ventricular pressure (+dp / dt) to alleviate cardiac damage.

[0016] Patients receiving anthracycline chemotherapy, including doxorubicin, should be prescribed the lowest possible dose of anthracycline if they are considered to be at high or very high risk of anthracycline-induced cardiotoxicity. For high-risk or very high-risk patients, or when elevated serum cardiac biomarkers are observed, statins and angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), or beta-blockers are currently used concurrently with high-dose therapy to reduce anthracycline toxicity, LVEF impairment, and mortality. However, long-term, high-dose use of these drugs has certain adverse effects, such as sodium and water retention, hyperkalemia, and bradycardia.

[0017] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0018] Cancer poses a serious threat to human life and health. DOX, as an effective chemotherapy drug, is widely used in the treatment of various solid tumors and hematological malignancies. However, the progressive and irreversible cardiotoxicity caused by DOX limits its clinical application and is one of the causes of death for many cancer patients undergoing chemotherapy. This invention discovers that DAT can greatly alleviate the cardiotoxicity caused by DOX, providing new ideas for the recovery of patients after chemotherapy and expanding the clinical application of DOX. Attached Figure Description

[0019] Figure 1 The data presented are mean ± SEM values, and **P<0.01, used to detect the cardiac hemodynamic parameters LVSP.

[0020] Figure 2 The results of LVEDP (cardiac hemodynamic parameter) are presented as mean ± SEM, **P<0.01.

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

[0022] Figure 4 To detect the cardiac hemodynamic parameter -dp / dt, the data shown are mean ± SEM, **P<0.01.

[0023] Figure 5 The results of DAT alleviating DOX inhibition of H9C2 cell proliferation are shown in the figure. Data are presented as mean ± SEM. *P<0.05, **P<0.01 Detailed Implementation

[0024] The specific embodiments of the present invention are described in detail below, but it should be understood that the scope of protection of the present invention is not limited to the specific embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention. Unless otherwise specified, the experimental methods described in the embodiments of the present invention are conventional methods.

[0025] Experimental methods:

[0026] 1. Measurement of hemodynamic parameters in rats

[0027] Laboratory animals: Male Sprague Dawley (SD) rats weighing 180-200g were selected and provided by the Laboratory Animal Center of Xuzhou Medical University, China, License No.: SYXK(Su)2015-0030. The rats were housed in a temperature- and humidity-controlled room under 12-hour dark-light cycles.

[0028] After 3 days of acclimatization 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 were administered the same dose of 3 mg / kg DOX every 7 days via intraperitoneal injection for a total of 6 weeks, with a cumulative dose of 18 mg / kg.

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

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

[0032] Six weeks later, hemodynamic parameters were measured: Rats were immobilized in a supine position, anesthetized, and ventricular cannulation was performed retrogradely via the right common carotid artery. Corresponding clinical hemodynamic parameters, LVDP, LVEDP, +dp / dt, and -dp / dt, were measured. Throughout the experiment, the body temperature was maintained at 37±0.5℃ using a thermostat. After 15 minutes of stable cardiac function, data were continuously recorded for 80 minutes using the Powerlab data acquisition system.

[0033] 2. Cell CCK8 proliferation experiment

[0034] H9C2 cardiomyocytes were cultured and passaged into 96-well cell culture plates with 3 replicates per group and approximately 5000 cells per well. 200 μl of complete culture medium containing 10% FBS was then added to each well containing cells. A corresponding blank control group was also set up.

[0035] Four culture plates were placed in an incubator at 37℃ with 5% CO2 and cultured for 6-8 hours until cell attachment. DAT was administered for 2 hours, followed by Dox. The first measurement was recorded as 0h, and the plates were cultured for another 24 hours. The culture plates were then removed and subjected to a CCK8 assay. Absorbance values ​​were measured using a full-wavelength microplate reader at 0.5h, 1h, 2h, and 3h. The time point with the highest absorbance was selected as the optimal detection time for analysis. The absorbance values ​​at the four time points were statistically analyzed to reflect cell number, and line graphs were plotted to analyze changes in cell number.

[0036] result:

[0037] LVDP, LVEDP, +dp / dt, and -dp / dt are important indicators of cardiac function. Since cardiac dysfunction is considered a major manifestation of DOX-induced cardiotoxicity, we further monitored the levels of these indicators in in vivo to explore the protective effect of DAT against DOX-induced cardiac injury. Compared with the control group, the DOX group showed significantly lower LVEDP and -dp / dt (see [reference needed]). Figure 1 and Figure 2 Meanwhile, LVDP and +dp / dt increase, see Figure 3 and Figure 4 .

[0038] In in vitro experiments, we administered 5 μM DOX to the H9C2 cardiomyocyte cell line simultaneously with different concentrations of DAT (1 mM, 2 mM, 4 mM, and 8 mM) in water as the solvent, and incubated for 24 h. Cell proliferation was then assessed. Results are as follows: Figure 5As shown, DOX significantly inhibited cardiomyocyte proliferation, causing cardiomyocytes to become rounder, with significantly enlarged nuclei and disordered striations. DAT could inhibit this damage; at 4 mM, DAT significantly reduced the damaging effect of DOX, increasing the proliferation rate from 44% to 76%. Therefore, DAT has a significant inhibitory effect on doxorubicin-induced myocardial damage.

[0039] It should be noted that when numerical ranges are mentioned in the claims of this invention, it should be understood that the two endpoints of each numerical range and any value between the two endpoints can be selected. To avoid redundancy, the present invention describes preferred embodiments.

[0040] Although preferred embodiments of the invention have been described, those skilled in the art, upon learning the basic inventive concept, can make other changes and modifications to these embodiments. Therefore, the appended claims are intended to be interpreted as including both the preferred embodiments and all changes and modifications falling within the scope of the invention.

[0041] Obviously, those skilled in the art can make various modifications and variations to this invention without departing from its spirit and scope. Therefore, if these modifications and variations fall within the scope of the claims of this invention and their equivalents, this invention also intends to include these modifications and variations.

Claims

1. The application of deaminotyrosine in the preparation of drugs for treating cardiomyopathy, characterized in that, The cardiomyopathy mentioned is cardiomyopathy caused by anthracycline drugs.

2. The application according to claim 1, characterized in that, The drug uses deaminotyrosine as its active ingredient.

3. The application according to claim 2, characterized in that, The drug includes a pharmaceutically acceptable carrier.

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

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

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

7. The application according to claim 1, characterized in that, The drug inhibits doxorubicin-induced cardiomyocyte proliferation and cardiac dysfunction.

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