Application of pazufloxacin mesylate in preparation of medicine for treating acute myocardial infarction

Abstract

The invention belongs to the field of biological medicine, and particularly relates to application of pazufloxacin mesylate to preparation of medicine for treating acute myocardial infarction. The invention provides an application of pazufloxacin or a pharmaceutically acceptable salt thereof in preparation of a product for preventing and / or treating myocardial infarction, and further provides an application of pazufloxacin or a pharmaceutically acceptable salt thereof in preparation of a product for preventing and / or treating heart diseases, and the heart diseases are caused by acute myocardial infarction. The pazufloxacin or the pharmaceutically acceptable salt of the pazufloxacin is pazufloxacin mesylate. It is found for the first time that pazufloxacin mesylate can be applied to preparation of the medicine for treating acute myocardial infarction or heart diseases caused by acute myocardial infarction, and a new treatment approach is provided for treating acute myocardial infarction or acute myocardial infarction related diseases.

Description

Technical Field

[0001] The present application belongs to the field of biomedicine, and specifically relates to the use of pazufloxacin mesylate in the preparation of a drug for treating acute myocardial infarction. Background Art

[0002] According to the China Health Statistics Yearbook 2022, cardiovascular disease ranks first in the proportion of disease deaths among urban and rural residents in China. Acute myocardial infarction (AMI) is an important manifestation of cardiovascular disease, which refers to severe stenosis or blockage of the coronary arteries of the heart, leading to myocardial cell necrosis, often causing serious heart damage and complications.

[0003] The drug treatment of AMI has evolved from basic diuretics and vasodilators to combined therapy. Although these drugs play an important role in relieving symptoms and improving cardiac function, they cannot solve the high incidence and serious complications of AMI. In recent years, cardiac interventional surgery and thrombolytic therapy have saved many AMI patients, but there are still patients who fail to undergo blood flow reconstruction in time for various reasons, resulting in irreversible myocardial necrosis, ventricular remodeling and heart failure.

[0004] It is worth noting that traditional Chinese medicine has accumulated many classic and effective natural medicines. These medicines are usually milder and safer, and are gradually widely regarded as complementary or alternative therapies for AMI. However, anti-AMI drugs developed based on natural products still face many challenges in clinical use, such as the difficulty in screening and separation of active ingredients, unclear mechanisms of action related to the treatment of AMI, and few clinical research samples. Pazufloxacin mesylate (PM) is an orally active fluoroquinolone drug with broad-spectrum and potent antibacterial activity against both Gram-positive and Gram-negative bacteria. However, the specific effects and mechanisms of PM on cardiovascular disease have not been reported.

[0005] Therefore, new drugs with good efficacy in treating acute myocardial infarction need to be developed. Summary of the invention

[0006] In order to solve the defects of the above-mentioned prior art, the present application found that pazufloxacin mesylate can significantly alleviate the series of hazards of acute AMI after screening a large number of compounds for their effects on AMI. The present application found that pazufloxacin mesylate can improve cardiac function, improve cardiac morphology, improve cardiac pathological changes, reduce myocardial fibrosis, and alleviate decreased cardiac function, and has a therapeutic effect on acute myocardial infarction.

[0007] Therefore, the first aspect of the present application provides the use of pazufloxacin or a pharmaceutically acceptable salt thereof in the preparation of a product for preventing and / or treating myocardial infarction or heart disease.

[0008] The cardiac lesions are selected from any one or more of the following: decreased cardiac function, changes in cardiac state, changes in cardiac tissue morphology, and myocardial fibrosis.

[0009] The heart disease is caused by acute myocardial infarction.

[0010] The product has any one or more of the following effects:

[0011] 1) Improve heart function;

[0012] 2) Improve heart morphology;

[0013] 3) Improve cardiac tissue morphology;

[0014] 4) Improve myocardial fibrosis.

[0015] The improvement of cardiac function is selected from: any one or more of increasing left ventricular ejection fraction, increasing left ventricular minor axis shortening rate, or decreasing the ratio of early diastolic mitral blood flow peak velocity to early diastolic mitral annular peak velocity.

[0016] The improving of heart morphology includes: reducing heart volume.

[0017] The improvement of cardiac tissue morphology is selected from: any one or more of improving the disordered arrangement of myocardial cells, improving the widening of myocardial gaps, or reducing inflammatory cell infiltration.

[0018] The improvement of myocardial fibrosis includes: reducing the percentage of cardiac tissue fibrosis.

[0019] The pazufloxacin or a pharmaceutically acceptable salt thereof is pazufloxacin mesylate.

[0020] The myocardial infarction is acute myocardial infarction.

[0021] The product contains an effective dose of pazufloxacin or a pharmaceutically acceptable salt thereof.

[0022] The effective dosage of pazufloxacin or its pharmaceutically acceptable salt in the product is greater than or equal to 10 mg / kg.

[0023] The second aspect of the present application provides a product comprising an effective dose of pazufloxacin or a pharmaceutically acceptable salt thereof.

[0024] The pazufloxacin or a pharmaceutically acceptable salt thereof is pazufloxacin mesylate.

[0025] The effective dosage of pazufloxacin or its pharmaceutically acceptable salt in the product is greater than or equal to 10 mg / kg.

[0026] The beneficial effects of this application are:

[0027] The present application discovers for the first time that pazufloxacin mesylate can be used in the preparation of drugs for treating acute myocardial infarction or heart disease caused by acute myocardial infarction, and can improve the cardiac function, cardiac morphology, cardiac tissue morphology, and cardiac fibrosis of patients with acute myocardial infarction. The therapeutic effect is good, which is equivalent to or superior to the existing drug sacubitril valsartan sodium tablets (SVST) for treating acute myocardial infarction, and provides a new treatment approach for treating acute myocardial infarction or acute myocardial infarction-related diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 This is an ultrasound image of the effect of PM intervention on cardiac function in mice with acute myocardial infarction in Example 2.

[0029] Figure 2 This is a statistical analysis chart of the effect of PM intervention on cardiac function in mice with acute myocardial infarction in Example 2 (LVEF%).

[0030] Figure 3 This is a statistical analysis chart of the effect of PM intervention on cardiac function in mice with acute myocardial infarction in Example 2 (LVFS%).

[0031] Figure 4 This is a statistical analysis chart of the effect of PM intervention on cardiac function in mice with acute myocardial infarction in Example 2 (E / e').

[0032] Figure 5 This is the effect of PM intervention on the cardiac morphology of mice with acute myocardial infarction in Example 3.

[0033] Figure 6 This is the effect of PM intervention in Example 4 on the cardiac pathological morphology of mice with acute myocardial infarction.

[0034] Figure 7 This is Masson staining of myocardial fibers in mice with acute myocardial infarction after PM intervention in Example 5.

[0035] Figure 8 This is a statistical analysis chart of the effect of PM intervention on myocardial fibrosis in mice with acute myocardial infarction in Example 5. DETAILED DESCRIPTION

[0036] The following describes the implementation of the present application through specific examples, and those skilled in the art can easily understand other advantages and effects of the present application from the contents disclosed in this specification. The present application can also be implemented or applied through other different specific implementations, and the details in this specification can also be modified or changed in various ways based on different viewpoints and applications without departing from the spirit of the present application.

[0037] Before further describing the specific implementation methods of the present application, it should be understood that the scope of protection of the present application is not limited to the specific specific implementation methods described below; it should also be understood that the terms used in the examples of the present application are for describing specific specific implementation methods rather than for limiting the scope of protection of the present application; in the specification and claims of the present application, unless otherwise expressly stated herein, the singular forms "a", "an" and "the" include plural forms.

[0038] This application discovers for the first time that pazufloxacin mesylate can treat acute myocardial infarction or heart disease caused by acute myocardial infarction, with good therapeutic effect, which is superior to the existing drug sacubitril valsartan sodium tablets (SVST) for treating acute myocardial infarction, and provides a new treatment approach for treating acute myocardial infarction or acute myocardial infarction-related diseases.

[0039] In this application, myocardial infarction (MI) refers to myocardial necrosis caused by acute and persistent ischemia and hypoxia of the coronary arteries. This situation is usually caused by thrombosis in the coronary arteries, which leads to complete occlusion of the blood vessels, so that the heart muscle cannot get enough blood supply, and eventually leads to the death of myocardial cells. Myocardial infarction includes acute myocardial infarction, old myocardial infarction, and non-Q wave myocardial infarction.

[0040] In this application, prevention refers to taking measures to prevent the occurrence of a disease or reduce the risk of a disease, which can be divided into primary prevention, which is taking measures before the disease occurs, with the purpose of preventing the occurrence of the disease; secondary prevention: the purpose is to detect and treat the disease in its early stages to prevent the development and deterioration of the disease; tertiary prevention is taking measures after the disease has occurred to prevent further deterioration of the disease or complications. Specifically refers to all actions to suppress symptoms or delay specific symptoms by administering the products described in this application.

[0041] In this application, the treatment refers to a series of positive effects after the disease has begun to develop. Specifically, it can slow down the progression of the disease so that the originally rapid development trend can be controlled; it can interrupt the process of continuous deterioration of the disease and prevent the disease from evolving further in a serious direction; effectively control the severity of the disease to prevent it from exceeding the range that the body can bear; stop the adverse development trend of the disease so that it no longer continues to deteriorate; alleviate the various uncomfortable symptoms caused by the disease and relieve the patient's pain; and even reverse a specific sign, symptom, disorder, disease or the direction or severity of the progression of the disease to a certain extent. However, it should be made clear that this treatment does not necessarily mean that it can involve the complete elimination of all signs, symptoms, diseases or disorders related to the disease, but improves the state of the disease and slows down the signs, symptoms, diseases or disorders related to the disease.

[0042] In the present application, the efficacy refers to the role and effect of the product containing the compound in the body, which may include therapeutic effect, preventive effect, diagnostic effect, rehabilitation effect, regulatory effect, immunoregulatory effect, toxic and side effects, pharmacokinetic properties, and pharmacodynamic properties.

[0043] In the present application, the effective dose refers to the dose of the drug, treatment or other intervention measure that achieves the desired therapeutic effect without causing unacceptable side effects or toxicity. The effective dose is expressed as the weight of the drug administered per kilogram of body weight to each individual and is administered to the subject every day during the use period.

[0044] The present application first provides the use of pazufloxacin or a pharmaceutically acceptable salt thereof in preparing a product for preventing and / or treating myocardial infarction.

[0045] In the present application, the pharmaceutically acceptable salt refers to the salt of pazufloxacin, which is prepared by pazufloxacin and a relatively non-toxic acid or base. When pazufloxacin contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound of the present application with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable bases include salts prepared from inorganic bases and organic bases, and the salts of the inorganic bases include aluminum salts, ammonium salts, calcium salts, copper salts, iron salts, ferrous salts, lithium salts, magnesium salts, manganic salts, manganous salts, potassium salts, sodium salts, zinc salts, etc. The salts of the organic non-toxic bases include salts of primary amines, secondary amines and tertiary amines, including substituted amines and cyclic amines. For example: N, N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxocobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc. When pazufloxacin contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acid salts such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid and the like.

[0046] In a specific embodiment of the present application, the pazufloxacin or a pharmaceutically acceptable salt thereof is pazufloxacin mesylate.

[0047] Pazufloxacin mesylate (PM) is a quinolone antibacterial drug, and its chemical name is (-)-(3S)-10-(1-aminocyclopropyl)9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de]-[1,4]benzoxazine-6-carboxylic acid methanesulfonate. Its molecular formula is C 17 H 19 FN2O7S, molecular weight is 414.41. Pazufloxacin mesylate is mainly used for various infections caused by sensitive bacteria, CAS No. is 136905-87-8, and the structural formula is as follows:

[0048]

[0049] In a specific embodiment of the present application, the product has any one or more of the following effects:

[0050] 1) Improve cardiac function; 2) Improve cardiac morphology; 3) Improve cardiac tissue morphology; 4) Improve myocardial fibrosis.

[0051] The heart function refers to the ability of the heart, as the core organ of the circulatory system, to perform its pumping function to maintain blood circulation and the supply of oxygen and nutrients throughout the body. It may include pumping function, the main function of the heart is to pump blood to all parts of the body to supply oxygen and nutrients and take away metabolic waste; heart rate, the number of heart beats per minute, is an indicator of the frequency of heart activity; heart rhythm, the regularity of heart beats, including the rhythm and sequence of heartbeats, the normal heart rhythm is sinus rhythm; myocardial contractility, the ability of myocardial cells to contract, directly affects the efficiency of the heart's pumping; cardiac diastolic function, the ability of the ventricles and atria to expand during diastole, allowing Blood returns to the heart; Ejection fraction, the percentage of blood volume ejected by the ventricle to the end-stage filling volume of the ventricle each time the heart contracts, is an important indicator for evaluating the heart's pumping function; Heart reserve capacity, the heart's ability to increase the amount of blood pumped when physiological needs increase (such as during exercise); Heart valve function, the opening and closing function of the heart valve to ensure unidirectional blood flow and prevent blood from flowing back; Heart metabolic function, the ability of heart cells to use oxygen and nutrients to generate energy to support the heart's pumping function; Heart electrophysiological function, the function of the heart's electrical conduction system, including the sinoatrial node, atrioventricular node, His bundle and Purkinje fibers, etc., which are responsible for the heart's pacing and electrical signal conduction. Heart function can be evaluated through electrocardiogram (ECG), echocardiography (Echocardiography), cardiac magnetic resonance imaging (CardiacMRI), nuclear heart scanning (Nuclear Cardiology) and other examination methods.

[0052] In a specific embodiment of the present application, the improvement of cardiac function refers to restoring the reduced cardiac function of myocardial infarction patients compared with the healthy group, so that the cardiac function is restored to the direction of the cardiac function of the healthy group, which may specifically include increasing the left ventricular ejection fraction, and / or increasing the left ventricular short-axis shortening rate, and / or increasing the ratio of the left ventricular ejection fraction to the early diastolic velocity of the mitral annulus.

[0053] The left ventricular ejection fraction (LVEF) refers to the percentage of the amount of blood ejected from the left ventricle to the volume of the left ventricular end-diastolic volume during each cardiac contraction. In a normal adult at rest, the normal range of the left ventricular ejection fraction is approximately between 55% and 65%, and some data suggest that the normal range is 50% to 70%. The higher the left ventricular ejection fraction, the stronger the myocardial contractility and the more blood pumped out with each heartbeat. When the left ventricular ejection fraction is less than 50%, it usually represents a decrease in left ventricular contractile function, which is an important indicator for assessing the presence or absence of heart failure. Improving the left ventricular ejection fraction refers to improving the left ventricular ejection fraction of myocardial infarction patients compared to the healthy population. In a specific embodiment of the present application, the left ventricular ejection fraction of myocardial infarction patients is lower than that of the healthy population. Compared with not using the product of the present application, when the patient uses the product of the present application, the patient's left ventricular ejection fraction is improved.

[0054] The left ventricular fractional shortening (LVFS%) is an indicator to measure the left ventricular contractile function, which describes the degree of change in the diameter of the left ventricle in the short-axis direction during the contraction process. Specifically, LVFS% refers to the difference between the short-axis diameter of the left ventricle at the end of systole (left ventricular end-systolic diameter, LVDs) and the end of diastole (left ventricular end-diastolic diameter, LVDd), and the ratio of the short-axis diameter at the end of diastole, multiplied by 100% to obtain the percentage. The improvement of the left ventricular fractional shortening refers to improving the left ventricular fractional shortening of myocardial infarction patients compared with the healthy population. In the specific embodiment of the present application, the left ventricular fractional shortening of myocardial infarction patients is lower than that of the healthy population. Compared with the product of the present application not using the product of the present application, when the patient uses the product of the present application, the patient's left ventricular fractional shortening is improved.

[0055] In the early diastolic mitral blood flow peak velocity and the early diastolic mitral annular peak velocity (E / e'), the E peak reflects the early pressure difference between the left atrium and the left ventricle, that is, the blood flow velocity during early diastolic ventricular filling. The e' peak is the early movement velocity of the mitral annulus, which is an indicator of the myocardial relaxation rate. The E / e' indicator is used to estimate the left ventricular filling pressure and has good feasibility and repeatability; a small E / e' value usually indicates that the left ventricular filling pressure is normal. In a specific embodiment of the present application, the ratio of the early diastolic mitral blood flow peak velocity to the early diastolic mitral annular peak velocity of patients with myocardial infarction is higher than that of the healthy group, and when the patient uses the product of the present application, the ratio of the patient's early diastolic mitral blood flow peak velocity to the early diastolic mitral annular peak velocity is reduced compared to patients who do not use the product of the present application.

[0056] The heart morphology refers to the overall shape and structure of the heart, including the heart's position, size, shape and other macroscopic features. Cardiac morphology studies the external morphological features of the heart, such as the arrangement and connection of the heart's four chambers (left atrium, right atrium, left ventricle, right ventricle) and the main blood vessels in and out of the heart (aorta, pulmonary artery, superior vena cava, inferior vena cava, pulmonary vein).

[0057] In a specific embodiment of the present application, improving heart morphology refers to restoring the changed heart morphology of myocardial infarction patients compared with the healthy group, so that it recovers towards the direction of the heart morphology of the healthy group, which may specifically include reducing the volume of the heart and softening the heart texture.

[0058] The heart volume mainly refers to the capacity of the heart at different stages, which is an important indicator for evaluating heart function and structure. In the case of myocardial infarction, changes in heart volume are closely related to cardiac remodeling after myocardial infarction. Cardiac remodeling refers to changes in heart structure and function after myocardial infarction, including enlargement of the heart chamber, increase in myocardial volume, and centrifugal / concentric hypertrophy and valvular regurgitation of the heart after myocardial infarction. Left ventricular dilatation and remodeling are closely related to poor prognosis after myocardial infarction, and the end-diastolic and end-systolic volumes of the left ventricular cavity can predict the occurrence of adverse events after myocardial infarction. Therefore, in myocardial infarction, the assessment of heart volume is of great significance for judging the severity of the disease and prognosis. The reduction in heart volume shown refers to reducing the heart volume of myocardial infarction patients compared to healthy groups. In the specific embodiment of the present application, the heart volume of myocardial infarction patients is larger than that of healthy groups. Compared with the product of the present application not using the product of the present application, when the patient uses the product of the present application, the patient's heart volume is reduced.

[0059] The cardiac tissue morphology refers to the microscopic structure and tissue characteristics of the heart, such as the arrangement of cardiomyocytes, the space between cardiomyocytes, and the accumulation of inflammatory cells in the cardiac tissue.

[0060] In a specific embodiment of the present application, the improvement of cardiac tissue morphology refers to restoring the altered cardiac tissue morphology of myocardial infarction patients compared with healthy people, so that it recovers towards the cardiac tissue morphology of healthy people, which can specifically be improving the disordered arrangement of myocardial cells, and / or improving the widening of myocardial gaps, and / or reducing inflammatory cell infiltration.

[0061] The disordered arrangement of myocardial cells is usually manifested as disordered polarity of myocardial fibers or disordered arrangement of myocardial cells, which may be accompanied by myocardial cell hypertrophy, interstitial fibrosis and abnormalities of myocardial interstitial small coronary arteries (thickening of the tube wall, severe narrowing of the lumen) and other phenomena. The improvement of the disordered arrangement of myocardial cells refers to restoring the originally abnormally arranged myocardial cells to a more orderly or normal arrangement state of healthy people. In a specific embodiment of the present application, the arrangement of myocardial cells in patients with myocardial infarction is more disordered than that in healthy people. Compared with not using the product of the present application, when the patient uses the product of the present application, the patient's myocardial cells are arranged in a more orderly manner.

[0062] The widened myocardial gap refers to that the gap between myocardial cells becomes wider than normal. The widened myocardial gap is due to cardiac interstitial fibrosis, that is, a large amount of fibrous tissue in the myocardial interstitium proliferates, causing the myocardial cells to be separated to form a honeycomb structure, which may affect the normal function of the heart, including the contraction and relaxation function of the heart. The improved myocardial gap widening refers to reducing the enlarged gap between myocardial cells in patients with myocardial infarction compared with healthy people. In a specific embodiment of the present application, the myocardial gap of patients with myocardial infarction is wider than that of healthy people. Compared with not using the product of the present application, when the patient uses the product of the present application, the patient's myocardial gap is reduced.

[0063] The inflammatory cell infiltration refers to the aggregation of inflammatory cells (such as lymphocytes, macrophages, etc.) in the myocardial interstitium in myocardial inflammatory lesions. This infiltration is usually accompanied by the degeneration and necrosis of myocardial cells and is one of the histological characteristics of myocarditis. Inflammatory cells have the functions of phagocytosis, immunity and tissue damage. Different types of inflammation, different stages of inflammation and different immune states of the body have different types of infiltrating inflammatory cells. The presence of inflammatory cell infiltration is of great significance for determining the cause, assessing the prognosis and formulating treatment plans. In myocarditis, inflammatory cell infiltration is one of the basic pathological changes, including the infiltration of inflammatory cells and damage to myocardial cells. Inflammatory cell infiltration can be different types such as lymphocytic myocarditis, eosinophilic myocarditis, giant cell myocarditis, granulomatous myocarditis (such as cardiac sarcoidosis) and suppurative myocarditis. The infiltration of these inflammatory cells not only reflects the presence of inflammation, but also may be involved in the process of myocardial damage and repair. The reduction of inflammatory cell infiltration refers to reducing the number and activity of inflammatory cells in the myocardial tissue of patients with myocardial infarction, thereby reducing inflammatory reactions and tissue damage. In a specific embodiment of the present application, inflammatory cell infiltration occurs in the heart tissue of patients with myocardial infarction. Compared with patients who do not use the product of the present application, when patients with myocardial infarction use the product of the present application, the inflammatory cell infiltration in the heart tissue of the patients is reduced.

[0064] Myocardial fibrosis refers to a pathological change in which collagen fibers accumulate excessively, collagen concentration in cardiac tissue increases significantly, or collagen composition changes in the normal tissue structure of the myocardium. This pathological change is an inevitable process for the development of various cardiovascular diseases to the terminal stage, and is also the main manifestation of cardiac structural remodeling. Myocardial fibrosis is closely related to arrhythmias, cardiac dysfunction, and even sudden cardiac death. Its main characteristics include the proliferation of fibroblasts and the deposition of extracellular matrix (ECM), which cause increased hardness of the heart, reduced compliance, and affect the normal diastolic and systolic functions of the heart. Myocardial fibrosis can cause cardiac systolic and diastolic dysfunction, and is the main pathological manifestation of the development of various cardiovascular diseases to a certain stage. It destroys myocardial structure, disrupts myocardial excitation-contraction coupling, and damages its systolic and diastolic functions, causing and aggravating arrhythmias and cardiac dysfunction, thereby further developing heart disease and ultimately leading to heart failure.

[0065] In a specific embodiment of the present application, the improvement of cardiac fibrosis refers to restoring the degree of cardiac fibrosis in patients with myocardial infarction that is higher than that in healthy people, so that it recovers towards the direction of the degree of cardiac fibrosis in healthy people. Specifically, it can be to reduce the percentage of cardiac tissue fibrosis in patients with myocardial infarction.

[0066] The percentage of cardiac tissue fibrosis refers to the proportion of fibrotic tissue in cardiac tissue. The reduction of the percentage of cardiac tissue fibrosis in patients with myocardial infarction refers to reducing the percentage of cardiac tissue fibrosis in patients with myocardial infarction compared with a healthy population. In a specific embodiment of the present application, the percentage of cardiac tissue fibrosis in patients with myocardial infarction is increased compared with a healthy population, and when patients with myocardial infarction use the product of the present application, the percentage of cardiac tissue fibrosis in the patient is reduced compared with patients who do not use the product of the present application.

[0067] In a specific embodiment of the application, the myocardial infarction is specifically acute myocardial infarction.

[0068] In a specific embodiment of the present application, the product comprises an effective dose of pazufloxacin or a pharmaceutically acceptable salt thereof.

[0069] In a specific embodiment of the present application, the effective dose of pazufloxacin or its pharmaceutically acceptable salt in the product is greater than or equal to 10 mg / kg, for example, it can be 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, and >500 mg / kg.

[0070] The present application also provides use of pazufloxacin or a pharmaceutically acceptable salt thereof in preparing a product for preventing and / or treating heart disease.

[0071] Wherein, pazufloxacin or its pharmaceutically acceptable salt is as described above.

[0072] In a specific embodiment of the present application, the pazufloxacin or a pharmaceutically acceptable salt thereof is pazufloxacin mesylate.

[0073] Wherein, the pazufloxacin mesylate is as described above.

[0074] In a specific embodiment of the present application, the cardiac pathology may specifically include decreased cardiac function, changes in cardiac morphology, changes in cardiac tissue morphology, and myocardial fibrosis.

[0075] Among them, the decreased cardiac function, changes in cardiac morphology, changes in cardiac tissue morphology, and myocardial fibrosis are as described above.

[0076] In a specific embodiment of the present application, the heart disease is caused by myocardial infarction.

[0077] In a specific embodiment of the present application, the myocardial infarction is acute myocardial infarction.

[0078] In a specific embodiment of the present application, the product has any one or more of the following effects:

[0079] 1) Improve heart function;

[0080] 2) Improve heart morphology;

[0081] 3) Improve cardiac tissue morphology;

[0082] 4) Improve myocardial fibrosis.

[0083] Among them, the improvement of cardiac function, improvement of cardiac morphology, improvement of cardiac tissue morphology, and improvement of myocardial fibrosis are all as described above.

[0084] In a specific embodiment of the present application, the product comprises an effective dose of pazufloxacin or a pharmaceutically acceptable salt thereof.

[0085] In a specific embodiment of the present application, the effective dose of pazufloxacin or its pharmaceutically acceptable salt in the product is greater than or equal to 10 mg / kg, for example, it can be 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, >500 mg / kg, and the product.

[0086] The present application also provides a product comprising an effective dose of pazufloxacin or a pharmaceutically acceptable salt thereof.

[0087] The product can prevent and / or treat myocardial infarction, more specifically, the product can prevent and / or treat acute myocardial infarction.

[0088] The product is capable of preventing and / or treating cardiac lesions caused by acute myocardial infarction.

[0089] The product can improve heart function, heart morphology, heart tissue morphology, and myocardial fibrosis, specifically including increasing left ventricular ejection fraction, increasing left ventricular short-axis shortening rate, increasing the ratio of left ventricular ejection fraction to early diastolic velocity of the mitral valve annulus, reducing heart volume, arranging myocardial cells in an orderly manner, reducing myocardial gap widening, reducing inflammatory cell infiltration, and reducing the percentage of cardiac tissue fibrosis.

[0090] Wherein, the pazufloxacin or a pharmaceutically acceptable salt thereof is as described above.

[0091] In a specific embodiment of the present application, the pazufloxacin or a pharmaceutically acceptable salt thereof is pazufloxacin mesylate.

[0092] Wherein, the pazufloxacin mesylate is as described above.

[0093] In a specific embodiment of the present application, the effective dose of pazufloxacin or its pharmaceutically acceptable salt in the product is greater than or equal to 10 mg / kg, for example, it can be 10 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, 100 mg / kg, 200 mg / kg, 300 mg / kg, 400 mg / kg, 500 mg / kg, and >500 mg / kg.

[0094] In the present application, the product mentioned above can be a drug, a drug composition, a combination of drugs, a reagent, a kit, a food, or a health product.

[0095] In the present application, the dosage form or state of the product described above is not limited. For example, when the product is a medicine, or a pharmaceutical composition, or a combination of medicines, the dosage form can be one or more of a solution, injection, spray, nasal drops, aerosol, powder spray, tablet, capsule and granule; the drugs in the above-mentioned various dosage forms can be prepared according to conventional methods in the pharmaceutical field; preferably, it is a solution; for another example, when the product is a food or a health product, the state can be liquid or solid.

[0096] In the present application, the product described above has pazufloxacin mesylate as the main active ingredient and may further include pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable excipients refer to those auxiliary materials that do not affect the efficacy and safety of the main ingredients of the drug, are non-toxic in themselves, do not produce adverse, allergic or other adverse reactions, and should be compatible with the pazufloxacin mesylate, that is, can be mixed with it without significantly reducing the effect of pazufloxacin mesylate under normal circumstances. Examples of these excipients include: sterile water or saline, which is used as a solvent or diluent for the drug; stabilizers, which are used to maintain the stability of the drug and prevent decomposition; excipients, which help form a specific form of the drug, such as tablets, capsules, etc.; antioxidants, such as ascorbic acid, which prevent the drug from oxidizing; buffers: such as phosphates, citric acid, etc., which are used to maintain the pH value of the drug; preservatives, which prevent the drug from being contaminated by microorganisms during storage; surfactants, such as polyethylene glycol (PEG), Tween, etc., which are used to increase the solubility or stability of the drug; chelating agents, such as EDTA, which are used to bind to metal ions and prevent drug degradation; binders, which are used to fix drug components together. In addition, drug preparations may also contain: low molecular weight polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; amino acids, such as glycine, glutamic acid, asparagine, arginine and lysine; sugars or carbohydrates, such as polysaccharides and monosaccharides; sugar alcohols, such as mannitol or sorbitol. When preparing aqueous solutions for injection, the following may also be used: physiological saline; isotonic solutions containing glucose or other auxiliary drugs; solubilizers, such as alcohols (ethanol), polyols (such as propylene glycol, PEG) and non-ionic surfactants (such as Tween 80, HCO-50). The types and proportions of these excipients or carriers can be adjusted according to the type and requirements of the final drug preparation.

[0097] In the present application, the pazufloxacin mesylate described in the above-mentioned product can be a single active ingredient, or it can be combined with one or more other active ingredients that have therapeutic effects on myocardial infarction to form a combined preparation, and the efficacy and safety of each component do not conflict. Other active ingredients can be various other drugs that can be used to treat myocardial infarction, such as antiplatelet aggregation drugs (aspirin, clopidogrel, ticagrelor), cholesterol-lowering drugs (atorvastatin, rosuvastatin, simvastatin), beta-blockers (metoprolol, bisoprolol, carvedilol), renin-angiotensin-aldosterone system inhibitors (ACEI (such as lepril) and ARB (such as rocatrap)), nitrate drugs (nitroglycerin, isosorbide dinitrate), thrombolytic drugs (urokinase, alteplase, reteplase), anticoagulants (such as heparin, bivalirudin), PCSK9 inhibitors (Incosilan). The content of each ingredient in the combined preparation is generally a safe and effective amount, which can be adjusted based on actual usage (eg, patient weight, application type, disease condition, severity).

[0098] In the present application, the product described above is preferably in unit dosage form when used as a preparation, which means that the preparation is subdivided into unit doses containing an appropriate amount of active ingredient. The unit dosage form can be a solution, injection, injection, capsule, tablet or any dosage form; in addition, the unit dosage form can also be a packaged preparation, such as a solution, injection, tablet, capsule and powder packaged in a vial or ampoule. The amount of the active ingredient in the unit dosage preparation can be changed or adjusted from 0.1 mg to 1000 mg, depending on the specific application and efficacy of the active ingredient.

[0099] In the present application, when the product described in the previous text is used to treat myocardial infarction or heart disease caused by myocardial infarction in a subject, the product in an effective dose must be accurately administered to the subject, so that the myocardial infarction or heart disease originally suffered by the subject can be effectively inhibited, reduced or even alleviated, including the restoration of cardiac function, cardiac morphology, cardiac tissue morphology, and cardiac tissue fibrosis to the state of a healthy group.

[0100] The present application also provides a method for treating myocardial infarction or cardiac lesions caused by myocardial infarction, which comprises administering an effective dose of the above product to a subject.

[0101] In the present application, the target of the products and methods described above is an organism suffering from myocardial infarction or heart disease caused by myocardial infarction, or an organism that needs to prevent and / or treat myocardial infarction or heart disease caused by myocardial infarction, specifically various mammals, including but not limited to rodents, artiodactyls, perissodactyls, lagomorphs, primates, such as humans, monkeys, other primates, migratory birds, cattle, horses, donkeys, pigs, dogs, cats, mice, rabbits, rats, guinea pigs, hamsters, foxes, deer, etc.; in a preferred embodiment of the present application, the target of action is human or mouse.

[0102] In the present application, the products and methods described above can also be used simultaneously or sequentially with other methods for treating myocardial infarction or diseases caused by myocardial infarction, such as drug therapy (antiplatelet drugs, thrombolytic drugs, lipid-lowering drugs, beta-blockers, ACEI, ARB, nitrates, anticoagulants), interventional therapy (percutaneous coronary intervention), surgical treatment (coronary artery bypass grafting), and non-drug therapy (cardiac resynchronization therapy, intra-aortic balloon pump, mechanical ventilation, blood ultrafiltration, and ventricular mechanical assist devices).

[0103] The present application is further described below by specific examples. When the examples give numerical ranges, it should be understood that, unless otherwise specified in the present application, the two endpoints of each numerical range and any numerical value between the two endpoints can be selected. Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as those commonly understood by those skilled in the art. In addition to the specific methods, equipment, and materials used in the examples, according to the technical staff of the present art's grasp of the prior art and the records of the present application, any methods, equipment, and materials of the prior art similar or equivalent to the methods, equipment, and materials described in the examples of the present application can also be used to implement the present application. Unless otherwise specified, the instruments, reagents, and materials used in the examples can be obtained by conventional means.

[0104] Experimental animals used in the examples:

[0105] SPF-grade male C57BL / 6 mice were purchased from Shanghai Slake Laboratory Animal Co., Ltd., license number: SCKY (Shanghai) 2017-0005. The experimental animals were raised in the SPF-grade laboratory of the Experimental Animal Center of Fujian University of Traditional Chinese Medicine. The mice were given free access to water and food, the room temperature was 23±1℃, the relative humidity was about 50-60%, and the light / dark cycle was 12h. The mice were used for experiments after 5-7 days of adaptive feeding. All animal experiments were conducted under the guidance of the latest "Guidelines for the Treatment of Laboratory Animals".

[0106] Experimental drugs and main reagents used in the examples:

[0107] Pazufloxacin mesylate (MCE, HY-B0724A);

[0108] Sacubitril / valsartan sodium tablets (Beijing Novatis Pharmaceuticals Co., Ltd., HJ20170363);

[0109] Masson trichrome staining kit (Beijing Solebow Technology Co., Ltd., G1340);

[0110] Eosin staining solution (Beijing Solebow Technology Co., Ltd., g1100);

[0111] Hematoxylin staining solution (Beijing Solebow Technology Co., Ltd., g1140);

[0112] Isoflurane (Shenzhen Reward Life Science Technology Co., Ltd., 970-00026-00);

[0113] Paraformaldehyde (LA0427 from Fuzhou Feijing Biotechnology Co., Ltd.),

[0114] Anhydrous ethanol (Xilong Science Co., Ltd., 1280340101602),

[0115] Xylene (Xilong Scientific Co., Ltd., 1430030101600), and other chemical reagents.

[0116] The main instruments used in the examples are:

[0117] Pipette (Raining, USA); electronic balance scale (Shanghai Ohaus Instrument Co., Ltd.); small animal ultrasound imaging system Vevo2100 (Fujifilm Investment Co., Ltd.); inhalation small animal anesthesia machine (Shenzhen Ruiwode Life Science Technology Co., Ltd.); pathological slicer (Leica, Germany); paraffin embedding machine (Hubei Xiaogan Yaguang Medical Electronic Technology Co., Ltd.).

[0118] Example 1 Drug preparation, animal grouping, and model construction

[0119] 1. Drug configuration:

[0120] Weigh an appropriate amount of PM and sacubitril valsartansodium tablets (SVST) powder, dissolve them in a corresponding volume of distilled water at a dose of 10 mg / kg / d according to the average weight of mice, place them in an ultrasound machine for low-temperature ultrasound for about 1 hour after preparation, and store them in a 4°C refrigerator for use.

[0121] 2. Animal grouping and model construction

[0122] Male C57BL / 6 mice were randomly divided into four groups according to body weight: Sham group (n=6), AMI group (n=6), AMI+PM group (n=6), and AMI+SVST group (n=6). The chest of the experimental mice was depilated with depilatory cream the day before surgery. On the day of surgery, the mice were anesthetized with isoflurane, placed in a supine position, and the chest of the mice was disinfected with iodine 3 times. A sterile scalpel was used to make a longitudinal incision of about 2 cm on the left side of the mouse sternum, and the muscles were bluntly separated between the third and fourth ribs on the left side. The third and fourth ribs were propped open with hemostats, and the heart was quickly squeezed out. The left anterior descending branch of the coronary artery was ligated with a 6-0 suture needle. The ligation position was 1 mm below the left atrial appendage, and the needle insertion depth was 0.5 mm. During the operation, the apex of the myocardial infarction area below the ligation site turned pale to determine whether the ligation was successful. After suturing the wound, the skin incision was disinfected with iodine 3 times. Finally, the mice were placed under a 37°C heating lamp and placed in grouped cages after they woke up. Mice in the sham group underwent thoracotomy, and the left anterior descending branch of the coronary artery of the mice was pierced with a suture needle but not ligated. On the second day after surgery, the AMI+PM group was given 10 mg / kg / d of PM by gavage, and the AMI+SVST group was given 10 mg / kg / d of SVST by gavage. The Sham group and the AMI group were given an equal volume of distilled water by gavage, once a day, for 14 consecutive days.

[0123] Example 2 Effect of PM intervention on cardiac function in mice with acute myocardial infarction

[0124] In this example, small animal cardiac ultrasound was used to detect changes in cardiac function of mice in each group.

[0125] 1. Experimental Methods

[0126] The cardiac function of mice was detected by Vevo 2100 small animal ultrasound system (VisualSonics). The chest hair of mice was removed with depilatory cream in advance. After the mice were anesthetized with isoflurane at a flow rate of 1.5 ml / min, they were placed supine on the physiological information monitoring table. During this period, the mice maintained a constant flow rate of isoflurane inhalation and the heart rate of the mice was kept between 450-650 bp. The coupling agent was applied to the upper chest of the mice, and the cardiac function of the mice was recorded in B-Mode and M-Mode modes respectively. Then the left ventricular short axis section was taken, and the cardiac function of the mice was recorded in B-Mode and M-Mode modes respectively. VevoStrain Software (Vevo LAB 1.7.1) was then used to calculate the left ventricular ejection fraction (LVEF), left ventricular fraction shortening (LVFS) value and the ratio of E (early diastolic mitral blood flow peak velocity) / e' (early diastolic mitral annular peak velocity) of each group of mice according to the software manual.

[0127] 2. Experimental results

[0128] The experimental results showed that 14 days after the left anterior descending branch of the coronary artery of mice was ligated, compared with the Sham group, the ventricular contraction amplitude of the AMI group was reduced, the ventricular contraction speed was slowed down, the slope of the ventricular wall motion was reduced, the waveform was flat, and the cardiac contraction function was reduced. Compared with the AMI group, the echocardiograms of the AMI+PM group and the AMI+SVST group showed that the cardiac contraction function was improved ( Figure 1 After 14 days of PM and SVST intervention, the LVEF and LVFS of mice in the AMI+PM group were significantly increased compared with those in the AMI group ( Figure 2-3 , P<0.05), E / e'( Figure 4 , P<0.05) was significantly reduced, indicating that PM intervention can improve the decreased cardiac function in mice with acute myocardial infarction.

[0129] Example 3 Effect of PM intervention on cardiac morphology in mice with acute myocardial infarction

[0130] The heart morphology of mice in each group was observed, and it was found that the heart volume of mice in the AMI group was larger and harder than that in the Sham group. After continuous oral gavage of PM and SVST for 14 days, the heart volume of mice in the AMI+PM group and AMI+SVST group was smaller and the texture was relatively softer than that in the AMI group ( Figure 5 ), indicating that PM intervention can improve the cardiac morphology of mice with acute myocardial infarction.

[0131] Example 4 Effect of PM intervention on cardiac tissue morphology in mice with acute myocardial infarction

[0132] In this example, HE staining was further used to observe the cardiac morphological changes of mice in each group.

[0133] 1. Experimental Methods

[0134] The mice were anesthetized with isoflurane and then quickly killed by dislocating the neck. The heart was removed and divided into two parts along the infarct area. After the infarct area was fixed in 4% paraformaldehyde for 48 hours, the heart was placed in an embedding box and dehydrated according to the concentration gradient of ethanol. After being transparentized with xylene, it was immersed in paraffin and waxed. Finally, the heart tissue was embedded into a wax block on an embedding machine. The heart tissue was cut into 0.4mm slices and placed in a 60℃ oven for 1h. After the baking was completed, the slides were dewaxed in xylene and concentration gradient ethanol in turn, and the sections were stained with hematoxylin solution and then eosin solution. After the samples were dried, they were sealed with neutral gum and the pathological changes of the heart tissue were observed under a microscope.

[0135] 2. Experimental results

[0136] The experimental results are as follows Figure 6 The results showed that compared with the Sham group, the myocardial cells in the AMI group were disordered, the myocardial gap was widened, and the inflammatory cell infiltration in the heart tissue increased, indicating that the ligation of the left anterior descending coronary artery led to morphological changes in the mouse heart tissue. After 14 days of PM and SVST intervention, the disordered arrangement of myocardial cells and widened myocardial gap in the AMI+PM group and the AMI+SVST group were significantly improved compared with the AMI group, and the inflammatory cell infiltration in the heart tissue decreased, indicating that PM intervention can significantly improve the damage to the tissue morphology of mice with acute myocardial infarction.

[0137] Example 5 Effect of PM intervention on myocardial fibrosis in mice with acute myocardial infarction

[0138] In this example, in order to further explore whether PM intervention can alleviate myocardial fibrosis and improve cardiac function in mice with acute myocardial infarction, Masson staining was used to detect myocardial fibrosis in each group of mice.

[0139] 1. Experimental Methods

[0140] Mouse heart tissue was fixed in 4% paraformaldehyde for 24 hours, then dehydrated with gradient ethanol, and then the tissue block was placed in xylene to make it transparent. After wax immersion, the tissue was embedded in paraffin. The heart tissue was cut into 0.4m slices and placed in a 60℃ oven for 1 hour. After the baking, the slides were dewaxed in xylene and gradient ethanol in turn, and iron hematoxylin A and iron hematoxylin B reagents were mixed in equal amounts and stained for 5 minutes under light-proof conditions. After washing with tap water 3-4 times, differentiated in acidic ethanol for 2s, and washed with tap water again for 3-4 times. Stained in Masson blue solution for 1min, washed with tap water 3-4 times. Ponceau fuchsin staining solution for 1min, washed with tap water 3-4 times. Stained with phosphomolybdic acid for 2s, washed with tap water 3-4 times. Aniline blue for 30s, washed with tap water 3-4 times. Dry with a hair dryer and add an appropriate amount of neutral gum to seal the slide.

[0141] 2. Experimental results

[0142] The results showed that compared with the Sham group, the myocardial fibrosis of the mice in the AMI group was significantly increased, and the percentage of fibrosis in the heart tissue of the mice was significantly increased, while the myocardial fibrosis in the heart tissue was significantly reduced after PM and SVST intervention ( Figure 7-8 , P<0.05), indicating that PM intervention significantly reduced myocardial fibrosis induced by acute myocardial infarction.

[0143] In summary, PM intervention can significantly alleviate the decreased cardiac function, pathological changes in myocardial tissue and myocardial fibrosis in mice with acute myocardial infarction, and has the effect of treating myocardial infarction and heart disease caused by myocardial infarction.

[0144] The above embodiments are merely illustrative of the principles and effects of the present application and are not intended to limit the present application. Anyone familiar with the technology may modify or change the above embodiments without violating the spirit and scope of the present application. Therefore, all equivalent modifications or changes made by a person of ordinary skill in the art without departing from the spirit and technical ideas disclosed in the present application shall still be covered by the claims of the present application.

Claims

1. Use of pazufloxacin or a pharmaceutically acceptable salt thereof in the preparation of a product for preventing and / or treating myocardial infarction or heart disease.

2. The use according to claim 1, characterized in that The cardiac lesions are selected from any one or more of the following: decreased cardiac function, changes in cardiac morphology, changes in cardiac tissue morphology, and myocardial fibrosis.

3. The use according to claim 1 or 2, characterized in that The heart disease is caused by myocardial infarction.

4. The use according to claim 2, characterized in that: The product has any one or more of the following effects: 1) Improve heart function; 2) Improve heart morphology; 3) Improve cardiac tissue morphology; 4) Improve myocardial fibrosis.

5. The use according to claim 4, characterized in that The improvement of cardiac function is selected from: increasing the left ventricular ejection fraction, or increasing the left ventricular short-axis shortening rate, or reducing any one or more of the ratio of early diastolic mitral blood flow peak velocity / early diastolic mitral annular peak velocity; the improvement of cardiac morphology includes: reducing the volume of the heart; the improvement of cardiac tissue morphology is selected from: improving the disorder of myocardial cell arrangement, or improving the widening of myocardial gaps, or reducing inflammatory cell infiltration; the improvement of myocardial fibrosis includes: reducing the percentage of cardiac tissue fibrosis.

6. The use according to claim 1, characterized in that: The pazufloxacin or a pharmaceutically acceptable salt thereof is pazufloxacin mesylate.

7. The use according to claim 1 or 3, characterized in that: The myocardial infarction is acute myocardial infarction.

8. The use according to claim 1, characterized in that The product contains an effective dose of pazufloxacin or a pharmaceutically acceptable salt thereof.

9. The use according to claim 8, characterized in that The effective dosage of pazufloxacin or its pharmaceutically acceptable salt in the product is greater than or equal to 10 mg / kg.

10. A product for preventing and / or treating myocardial infarction or heart disease, comprising an effective dose of pazufloxacin or a pharmaceutically acceptable salt thereof; preferably, the pazufloxacin or a pharmaceutically acceptable salt thereof is pazufloxacin mesylate; more preferably, the effective dose of the pazufloxacin or a pharmaceutically acceptable salt thereof in the product is greater than or equal to 10 mg / kg.

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