Application of Zhongwinning in preparation of medicine for treating ischemic heart disease

Abstract

The invention belongs to the technical field of new application of medicines, and provides application of Zhongwinning in preparation of a medicine for treating ischemic heart disease. In a myocardial ischemia rat model test, Zhongwinning shows that the Zhongwinning can obviously improve the left ventricular ejection fraction and the left ventricular short-axis shortening rate of a myocardial ischemia rat; in addition, the rising and falling rates of the ventricular pressure of the myocardial ischemia rats can be remarkably improved, and it is indicated that Zhongutanin can effectively recover the left ventricular systolic function and can effectively repair myocardial injury caused by myocardial ischemia reperfusion. Therefore, according to the experimental research result of the application, the Zhongwinning has a certain application prospect in treating the ischemic heart disease.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of new uses of drugs, in particular, relates to the application of Zhongwuning in the preparation of a drug for treating ischemic heart disease. BACKGROUND

[0002] The World Heart Report released by the World Heart Federation shows that cardiovascular disease is the leading cause of death worldwide, and ischemic heart disease is the main cause of death from cardiovascular disease. Ischemic heart disease can be acute or chronic. According to the definition of the eleventh edition of the International Classification of Diseases, acute ischemic heart disease includes angina (stable and unstable), acute myocardial infarction, etc., and chronic ischemic heart disease includes ischemic cardiomyopathy, coronary atherosclerosis, etc.

[0003] In addition, other secondary diseases may occur after the onset of acute ischemic heart disease, such as pericarditis, arrhythmia, cardiogenic shock, heart failure, ventricular rupture, aneurysm (with thrombus), and recurrent infarction, etc.

[0004] For chronic cardiac ischemia, some patients still need to take revascularization when the drug treatment of anti-platelet, anticoagulation, lipid-lowering, beta receptor blocker, renin, angiotensin, aldosterone, system blocker, nitrate, calcium channel blocker, etc. is not good, in order to reduce the risk of cardiovascular death, myocardial infarction, etc. Timely restoration of cardiac blood perfusion is the best treatment for acute cardiac ischemia. However, reperfusion after ischemia can cause further damage to the myocardium through various mechanisms, and aggravate myocardial necrosis. The proliferative capacity of myocardial cells in adult individuals is weak, and it is difficult to repair after myocardial injury. These problems have a profound impact on the long-term prognosis improvement of patients with ischemic heart disease.

[0005] At present, most of the researches on reperfusion injury are focused on the pathological mechanism during the injury, in order to implement myocardial protection during reperfusion, but none of them have successfully translated into clinical practice. There are fewer reports on the repair after myocardial injury, and only a small part of stem cell therapy has entered clinical research, but the clinical application effect still needs further verification.

[0006] Therefore, it is of great significance to develop a drug that can promote myocardial repair after the onset of ischemic heart disease, so that patients who need revascularization can benefit more, and the quality of life and survival of patients can be improved, and the risk of complications can be reduced. SUMMARY

[0007] In view of the above shortcomings in the prior art, the purpose of the present application is to provide the application of Zhongwuning in the preparation of a drug for treating ischemic heart disease.

[0008] In order to achieve the above purpose, the solution adopted by the present application is:

[0009] Use of the midodrine or its pharmaceutically acceptable salt, ester or solvate in the preparation of a drug for treating ischemic heart disease; the structural formula of the midodrine is:

[0010]

[0011] Further, in the preferred embodiments of the present application, the ischemic heart disease includes angina pectoris, acute myocardial infarction, certain recent complications after acute myocardial infarction, other acute ischemic heart diseases and chronic ischemic heart disease.

[0012] Further, in the preferred embodiments of the present application, the chronic ischemic heart disease includes arteriosclerotic cardiovascular disease, arteriosclerotic heart disease, old myocardial infarction, cardiac aneurysm, coronary aneurysm, ischemic cardiomyopathy, and asymptomatic myocardial ischemia.

[0013] Further, in the preferred embodiments of the present application, the certain recent complications after acute myocardial infarction include pericardial effusion, atrial septal defect, ventricular septal defect, heart wall rupture without pericardial effusion, tendon rupture, papillary muscle rupture, thrombosis of atrium, auricle and cardiac plug.

[0014] Further, in the preferred embodiments of the present application, the other acute ischemic heart disease includes coronary thrombosis without causing myocardial infarction, Dressler syndrome, coronary artery failure, and coronary insufficiency.

[0015] Further, in the preferred embodiments of the present application, the drug for treating ischemic heart disease is a preparation prepared by adding pharmaceutically acceptable excipients or auxiliary ingredients to the midodrine or its pharmaceutically acceptable salt as an active ingredient.

[0016] Further, in the preferred embodiments of the present application, the pharmaceutically acceptable salt is an inorganic salt or an organic salt.

[0017] Further, in the preferred embodiments of the present application, the dosage form of the preparation includes a liquid preparation, a solid preparation or a semi-solid preparation.

[0018] The use of the midodrine or its pharmaceutically acceptable salt, ester or solvate in the preparation of a drug for treating ischemic heart disease provided by the present application has the following beneficial effects:

[0019] In the myocardial ischemia rat model test, the midodrine showed that it can significantly improve the left ventricular ejection fraction and left ventricular short axis shortening rate of myocardial ischemia rats; and can significantly improve the rate of rise and fall of intraventricular pressure of myocardial ischemia rats, indicating that the midodrine can effectively restore the left ventricular systolic function and can effectively repair the myocardial damage caused by myocardial ischemia reperfusion. Therefore, according to the experimental research results of the present application, the midodrine has certain application prospect for the treatment of ischemic heart disease. BRIEF DESCRIPTION OF DRAWINGS

[0020] Figure 1 Figure 1 is a graph showing the effect of Zhonguuning on the echocardiography of the heart of an animal with myocardial ischemic injury;

[0021] Figure 2 Figure 2 is a graph showing the effect of Zhonguuning on the left ventricular ejection fraction of an animal with myocardial ischemic injury;

[0022] Figure 3 Figure 3 is a graph showing the effect of Zhonguuning on the left ventricular fractional shortening of an animal with myocardial ischemic injury;

[0023] Figure 4 Figure 4 is a graph showing the effect of Zhonguuning on the maximum rate of rise of left ventricular pressure of an animal with myocardial ischemic injury;

[0024] Figure 4 Figure 5 is a graph showing the effect of Zhonguuning on the maximum rate of decline of left ventricular pressure of an animal with myocardial ischemic injury;

[0025] Figure 5 Figure 6 is a graph showing the effect of Zhonguuning on the myocardial infarct size TTC staining of an animal with myocardial ischemic injury. DETAILED DESCRIPTION

[0026] In order to make the purpose, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be described clearly and completely below. If specific conditions are not indicated in the embodiments, conventional conditions or conditions suggested by the manufacturer are used. If the reagents or instruments used are not indicated by the manufacturer, they are all conventional products that can be purchased on the market.

[0027] The features and performances of the present application will be described in further detail below in combination with the embodiments.

[0028] Embodiment 1

[0029] 1. Establishment of a myocardial ischemic model in rats:

[0030] SPF male SD rats (body weight 180-200 g). After the animals were anesthetized with 2-5% isoflurane, the left pectoral muscle was cut, the chest was opened, the heart was exposed, the pericardium was torn with forceps, the left anterior descending branch was temporarily ligated with a 6-0 suture needle, 30 min later, the ligature was loosened, the blood flow was restored, the chest was closed before the chest cavity was squeezed to expel air, and the chest cavity was sutured with 2-0 silk.

[0031] Successful model establishment criteria: after ligation of the left anterior descending branch, the myocardium was observed to be pale due to ischemia, and 15 min after modeling, the ST segment was elevated on the II lead electrocardiogram.

[0032] The animals in the sham operation group were closed after opening the chest, without ligation of the left anterior descending branch, and the rest of the operations were the same as in the model construction.

[0033] 2. Experimental Groups:

[0034] Rats were randomly divided into three groups based on their body weight and cardiac ejection fraction: sham-operated group, model group, and Zhongwuning group. The sham-operated group consisted of 3 rats, while the model group and Zhongwuning group each consisted of 8 rats.

[0035] 3. Dosage frequency and route of administration:

[0036] Twenty-four hours after model establishment, the Zhongwu Ning group received a tail vein injection of 0.4 mg / kg, followed by once daily for a total of 13 times. The sham-operated group and the model group received an equal volume of physiological saline.

[0037] 4. Echocardiography to assess cardiac function:

[0038] Animals were anesthetized with 2.5–5% isoflurane before modeling, and 24 h, 7 d, and 14 d after modeling. Coupling agent was applied to the chest wall. In the long axis section of the left ventricle next to the sternum, the sampling line was placed at the maximum diameter of the left ventricle in M-mode ultrasound, and a waveform was collected. The left ventricular ejection fraction (EF) and left ventricular short axis shortening rate (FS) of the rats were measured by the eight-point measurement method.

[0039] The results are as follows Figure 1 , Figure 2 , Figure 3 As shown, compared with the sham-operated group, the model group showed significantly reduced EF and FS 24 hours after modeling and maintained this level throughout the experimental period. This indicates that the cardiac output function of the model group animals was impaired. In contrast, the Zhongwu Ning group showed significantly improved EF and FS in rats after administration. This indicates that Zhongwu Ning can effectively restore the weakened cardiac output function caused by myocardial ischemia.

[0040] 5. Hemodynamic assessment:

[0041] Fourteen days after modeling, the animals were anesthetized with 2.5% isoflurane and the right carotid artery was dissected. A catheter with a pressure sensor was inserted into the left ventricle through the right carotid artery to measure the maximum rate of rise of left ventricular pressure (Max dp / dt) and the maximum rate of fall of left ventricular pressure (Min dp / dt).

[0042] The results are as follows Figure 4 A and Figure 4 As shown in Figure B, compared with the model group, the rats in the Zhongwu Ning group showed significantly improved rates of increase and decrease in intraventricular pressure after 14 days of administration. This indicates that Zhongwu Ning can effectively restore left ventricular systolic function.

[0043] 6. TTC staining analysis of infarct area:

[0044] Animals were anesthetized with isoflurane, and their hearts were collected. Five 2mm thin slices of the heart were coronally cut from the ligation point toward the apex of the heart. The slices were stained in 2% TTC solution for 20 minutes and then scanned on both sides using a scanner to analyze the infarct area.

[0045] The results are as follows Figure 5 As shown, in the Zhongwu Ning group, administration began 24 hours after reperfusion in rats, and after 14 days of continuous administration, the myocardial infarction area in the rats was significantly reduced. This indicates that Zhongwu Ning can effectively repair myocardial damage caused by myocardial ischemia-reperfusion.

[0046] In summary, the application of Zhongwu Ning provided by this invention in the preparation of drugs for treating ischemic heart disease demonstrates its effectiveness. In rat models of myocardial ischemia, Zhongwu Ning significantly increased left ventricular ejection fraction and left ventricular fractional shortening; it also significantly improved the rate of increase and decrease in intracardiac pressure, indicating that Zhongwu Ning can effectively restore left ventricular systolic function and effectively repair myocardial damage caused by myocardial ischemia-reperfusion. Therefore, based on the above experimental results, Zhongwu Ning shows promising application potential in the treatment of ischemic heart disease.

[0047] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. The use of zhongwuning or its pharmaceutically acceptable salts, esters or solvates in the preparation of drugs for treating ischemic heart disease, wherein the structural formula of zhongwuning is:

2. The application according to claim 1, characterized in that: The ischemic heart disease includes angina pectoris, acute myocardial infarction, subsequent myocardial infarction, certain recent complications following acute myocardial infarction, other acute ischemic heart disease, and chronic ischemic heart disease.

3. The application according to claim 2, characterized in that: The chronic ischemic heart disease includes arteriosclerotic cardiovascular disease, arteriosclerotic heart disease, old myocardial infarction, coronary aneurysm, coronary aneurysm, ischemic cardiomyopathy, and asymptomatic myocardial ischemia.

4. The application according to claim 2, characterized in that: Some of the short-term complications following acute myocardial infarction include hemopericardium, atrial septal defect, ventricular septal defect, rupture of the heart wall without hemopericardium, rupture of chordae tendineae, rupture of papillary muscles, and thrombosis of the atria, atrial appendages, and myocardial thrombosis.

5. The application according to claim 2, characterized in that: Other acute ischemic heart diseases include coronary thrombosis without causing myocardial infarction, Dresler syndrome, coronary artery failure, and coronary insufficiency.

6. The application according to claim 1, characterized in that: The ischemic heart disease drug is a preparation made with zhongwuning or its pharmaceutically acceptable salt as the active ingredient, plus commonly used pharmaceutical excipients or auxiliary ingredients.

7. The application according to claim 6, characterized in that: The pharmaceutically acceptable salt is either an inorganic salt or an organic salt.

8. The application according to claim 6, characterized in that: The dosage form of the preparation includes liquid preparations, solid preparations, or semi-solid preparations.

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