Application of enoxacin sesquihydrate and related product

Abstract

The invention relates to the technical field of medicines, in particular to application of enoxacin sesquihydrate and related products. The invention provides application of enoxacin sesquihydrate or pharmaceutically acceptable salt thereof in preparation of products for preventing and / or treating myocardial infarction, and further provides application of enoxacin sesquihydrate or pharmaceutically acceptable salt thereof in preparation of products for preventing and / or treating heart diseases caused by myocardial infarction. It is found for the first time that enoxacin semihydrate can be applied to preparation of the medicine for treating acute myocardial infarction or heart diseases caused by acute myocardial infarction, the treatment effect is good, and a new treatment approach is provided for treating acute myocardial infarction or acute myocardial infarction related diseases.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a use of enoxacin sesquihydrate and related products. Background Art

[0002] Cardiovascular disease (CVD) refers to circulatory system diseases including heart disease, peripheral arterial disease, high cholesterol, atherosclerosis, etc. From 1990 to 2019, the number of CVD patients increased from 271 million to 523 million, and the number of deaths increased from 12.1 million to 18.6 million, bringing a huge disease burden to society.

[0003] Acute myocardial infarction (AMI) is an acute myocardial necrosis caused by persistent ischemia and hypoxia of the coronary arteries. According to statistics from 2022, there are about 1 million patients with sudden AMI in my country each year, with a mortality rate of more than 30%, which is an overall upward trend compared with previous years. Effective prevention and control measures are urgently needed to deal with it.

[0004] In recent years, Chinese medicine has played a positive role in improving the symptoms of patients with acute myocardial infarction (AMI), reducing myocardial damage and mortality through multi-target and multi-pathway intervention, which helps to improve the quality of life of patients. However, the mechanism of Chinese medicine and its extracts is currently insufficient. After screening a large number of compounds for their effects on AMI, this project found that Enoxacin hydrate (EXH) can significantly alleviate the series of hazards of acute AMI. EXH is an orally active fluoroquinolone drug that has broad-spectrum and potent antibacterial activity against both Gram-positive and Gram-negative bacteria. However, there are currently no reports on the specific effects and mechanisms of EXH on cardiovascular diseases, especially acute myocardial infarction.

[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 invention found that enoxacin sesquihydrate can significantly alleviate a series of hazards of acute AMI after screening a large number of compounds for their effects on AMI. The present invention found that enoxacin sesquihydrate can improve cardiac function, improve cardiac morphology, improve cardiac pathological changes, alleviate decreased cardiac function, and has a therapeutic effect on acute myocardial infarction.

[0007] The first aspect of the present invention provides the use of enoxacin sesquihydrate or its pharmaceutically acceptable salt in the preparation of products for preventing and / or treating myocardial infarction, and further provides the use of enoxacin sesquihydrate or its pharmaceutically acceptable salt in the preparation of products for preventing and / or treating cardiac pathology caused by myocardial infarction.

[0008] In some embodiments of the present invention, the cardiac lesions caused by myocardial infarction have at least one of the following symptoms: decreased cardiac function, changes in cardiac morphology, and changes in cardiac tissue morphology.

[0009] In some embodiments of the present invention, the product has any one or more of the following effects:

[0010] 1) Treatment of acute myocardial infarction;

[0011] 2) Improve heart function;

[0012] 3) Improve cardiac pathological changes;

[0013] 4) Alleviate decreased heart function.

[0014] In some embodiments of the present invention, the myocardial infarction is acute myocardial infarction.

[0015] In some embodiments of the present invention, the enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof is used alone or in combination with other drugs.

[0016] In some embodiments of the present invention, the enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient, or a combination thereof, constitute a pharmaceutical composition.

[0017] The third aspect of the present invention provides a product for preventing and / or treating myocardial infarction or heart disease, the product comprising enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof, and the product has any one or more of the following effects:

[0018] 1) Treatment of acute myocardial infarction;

[0019] 2) Improve heart function;

[0020] 3) Improve cardiac pathological changes;

[0021] 4) Alleviate decreased heart function.

[0022] In some embodiments of the present invention, the effective dosage of the enoxacin sesquihydrate or its pharmaceutically acceptable salt in the product is greater than or equal to 10 mg / kg.

[0023] In some embodiments of the present invention, the products include medicines, health products and foods.

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] The present invention first discovered that enoxacin hemihydrate can be used in the preparation of drugs for treating acute myocardial infarction or heart disease caused by acute myocardial infarction, with good therapeutic effects, providing a new therapeutic approach for treating acute myocardial infarction or acute myocardial infarction-related diseases. The experimental results of the present invention show that intervention with enoxacin sesquihydrate can significantly alleviate the reduction of cardiac function, myocardial tissue pathological changes and myocardial fibrosis in mice with acute myocardial infarction, and has the effect of treating myocardial infarction and heart disease caused by myocardial infarction. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The ultrasonic graph shows the effect of enoxacin sesquihydrate intervention on the cardiac function of mice with acute myocardial infarction in Example 2 of the present invention.

[0027] Figure 2 It shows the statistical analysis chart of the effect of enoxacin sesquihydrate intervention on cardiac function of mice with acute myocardial infarction (LVEF%) in Example 2 of the present invention.

[0028] Figure 3 It shows the statistical analysis chart (LVFS%) of the effect of enoxacin sesquihydrate intervention on the cardiac function of mice with acute myocardial infarction in Example 2 of the present invention.

[0029] Figure 4 The figure shows the statistical analysis of the effect of enoxacin sesquihydrate intervention on the cardiac function of mice with acute myocardial infarction in Example 2 of the present invention (E / e').

[0030] Figure 5 The figure shows the effect of enoxacin sesquihydrate intervention on the cardiac morphology of mice with acute myocardial infarction in Example 3 of the present invention.

[0031] Figure 6 The figure shows the effect of enoxacin sesquihydrate intervention on the cardiac index of mice with acute myocardial infarction in Example 3 of the present invention.

[0032] Figure 7 The results show the effect of enoxacin sesquihydrate intervention on cardiac pathological morphology in mice with acute myocardial infarction in Example 4 of the present invention. DETAILED DESCRIPTION

[0033] The following describes the embodiments of the present invention through specific examples, and those skilled in the art can easily understand other advantages and effects of the present invention from the contents disclosed in this specification. The present invention can also be implemented or applied through other different specific embodiments, 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 invention.

[0034] Before further describing the specific embodiments of the present invention, it should be understood that the scope of protection of the present invention is not limited to the specific embodiments described below; it should also be understood that the terms used in the examples of the present invention are for describing the specific embodiments rather than for limiting the scope of protection of the present invention; in the present specification and claims, unless otherwise expressly stated herein, the singular forms "a", "an" and "the" include plural forms.

[0035] The present invention discovers for the first time that enoxacin sesquihydrate can treat acute myocardial infarction or heart disease caused by acute myocardial infarction, has a good therapeutic effect, and is superior to the existing drug sacubitril valsartan sodium tablets (SVST) for treating acute myocardial infarction, providing a new therapeutic approach for treating acute myocardial infarction or acute myocardial infarction-related diseases.

[0036] In the present invention, myocardial infarction (MI) refers to an acute disease in which the blood supply to a part of the myocardial area is interrupted due to coronary artery obstruction, resulting in ischemic necrosis of myocardial cells. Its pathogenesis is mainly due to the rupture of atherosclerotic plaques in the coronary arteries, which triggers platelet aggregation to form thrombi, further blocking blood flow, causing myocardial hypoxia and malnutrition, and ultimately leading to irreversible damage and death of myocardial cells.

[0037] In the present invention, cardiac pathology caused by myocardial infarction includes the death and necrosis of myocardial cells, which in turn leads to decreased cardiac function, changes in cardiac morphology, changes in cardiac tissue morphology, myocardial fibrosis and scar formation, and further leads to a series of complex pathological changes such as heart failure, arrhythmia, heart failure and ventricular dilatation. These lesions will significantly affect the heart's pumping function and overall heart health.

[0038] In the present invention, the myocardial infarction is specifically acute myocardial infarction, which refers to an emergency medical condition in which a part of the myocardium is rapidly ischemic and necrotic due to sudden blockage of the coronary artery, and must be treated promptly.

[0039] The first aspect of the present invention provides the use of enoxacin sesquihydrate or its pharmaceutically acceptable salt in the preparation of products for preventing and / or treating myocardial infarction, and further provides the use of enoxacin sesquihydrate or its pharmaceutically acceptable salt in the preparation of products for preventing and / or treating cardiac pathology caused by myocardial infarction.

[0040] In the present invention, the enoxacin sesquihydrate is a broad-spectrum quinolone antibiotic that inhibits bacterial DNA gyrase and topoisomerase IV, interferes with the bacterial DNA replication process, and thus achieves an antibacterial effect. It is commonly used to treat a variety of bacterial infections, such as respiratory tract, urinary tract, gastrointestinal tract and skin infections. Its chemical name is 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-1,8-naphthylidene-3-carboxylic acid sesquihydrate, and its molecular formula is C 15 H 17 FN4O3·1.5H2O, CAS No. 84294-96-2, has the following structural formula:

[0041]

[0042] In the present invention, the pharmaceutically acceptable salt refers to a salt prepared from a pharmaceutically acceptable non-toxic acid or base, wherein the acid or base includes an inorganic acid or base or an organic acid or base. The inorganic acid is selected from hydrochloric acid, hydrobromic acid, phosphoric acid, hydroiodic acid or sulfuric acid. The inorganic base is selected from calcium, magnesium, lithium, sodium, zinc, aluminum or potassium. The organic acid is selected from formic acid, glycolic acid, propionic acid, acetic acid, succinic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, glutamic acid, benzoic acid, stearic acid, alginic acid, benzenesulfonic acid, glucuronic acid, pamoic acid or galacturonic acid. The organic base is selected from diethanolamine, choline, procaine, lysine or 1,2-ethylenediamine.

[0043] In the present invention, the product must contain enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof, and enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof is used as an effective ingredient for preventing or treating myocardial infarction.

[0044] In the present invention, the active ingredient of the product for preventing or treating myocardial infarction may be only enoxacin sesquihydrate, or may contain other chemicals that can play a similar role.

[0045] In the present invention, the product may be a single-component substance or a multi-component substance.

[0046] In the present invention, the enoxacin sesquihydrate or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, or a combination thereof, form a pharmaceutical composition.

[0047] In the present invention, the pharmaceutically acceptable excipient is selected from one or more of diluents, adhesives, lubricants and wetting agents. The pharmaceutically acceptable means that when the molecular entities and compositions are properly administered to animals or humans, they will not produce adverse, allergic or other adverse reactions.

[0048] In the present invention, the pharmaceutically acceptable carrier or excipient should be compatible with enoxacin sesquihydrate, that is, it can be mixed with it without significantly reducing the effect of the pharmaceutical composition under normal circumstances. Specific examples of some substances that can be used as pharmaceutically acceptable carriers or excipients are sugars, such as lactose, glucose and sucrose; binders, in particular starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium methylcellulose, ethylcellulose and methylcellulose; tragacanth powder; malt; gelatin; lubricants, in particular talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and cocoa butter; polyols, such as propylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid; emulsifiers, such as Tween; wetting agents, such as sodium lauryl sulfate; colorants; flavoring agents; tableting, stabilizers; antioxidants; preservatives; diluents, such as pyrogen-free water; isotonic saline solution; and phosphate buffer, etc. These substances are used as needed to help the stability of the formulation or to help improve the activity or its biological effectiveness or to produce an acceptable taste or smell in the case of oral administration.

[0049] In the present invention, unless otherwise specified, the dosage form of the pharmaceutical composition is not particularly limited. In some embodiments of the present invention, the pharmaceutical composition is one or more of a solution, an injection, a spray, a nasal drop, an aerosol, a powder spray, a tablet, a capsule and a granule, and can be prepared by a conventional method. Preferably, it is a solution.

[0050] In the present invention, the dosage form of the pharmaceutical composition should be matched with the mode of administration. The pharmaceutical composition of the present invention can be introduced into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue by injection, spraying, nasal drops, eye drops, penetration, absorption, physical or chemical mediation; or introduced into the body after being mixed or wrapped with other substances. Preferably, it is introduced into the body subcutaneously. The pharmaceutical composition can also be used in combination with other treatment methods, including surgery, radiotherapy, chemotherapy, and targeted therapy.

[0051] In the present invention, the product has any one or more of the following effects:

[0052] 1) Treatment of acute myocardial infarction;

[0053] 2) Improve heart function;

[0054] 3) Improve cardiac pathological changes;

[0055] 4) Alleviate decreased heart function.

[0056] In a specific embodiment of the present invention, the acute myocardial infarction mainly includes rapidly restoring blood flow to the damaged myocardium, reducing cardiac load, controlling related symptoms and preventing subsequent cardiac events. The treatment focuses on stabilizing cardiac function, reducing myocardial oxygen demand, alleviating pain, controlling blood pressure and heart rate, and preventing thrombosis and reducing further damage to the heart.

[0057] In a specific embodiment of the present invention, 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 in 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.

[0058] Left Ventricular Ejection Fraction (LVEF) refers to the percentage of blood pumped out each time the left ventricle of the heart contracts. It is an important indicator for evaluating the heart's pumping function and reflects the efficiency of the left ventricle in pumping blood into the systemic circulation. LVEF is calculated by dividing the stroke volume (the amount of blood pumped out by the heart in one contraction) by the end-diastolic volume (the total amount of blood filled with the left ventricle at the end of diastole) and then multiplying by 100 to get the percentage. The normal range is generally between 50% and 70%. An LVEF below this range may indicate impaired left ventricular function and require further medical evaluation and treatment.

[0059] The Left Ventricular Shortening Fraction (LVSF) refers to the percentage of shortening of the inner diameter (short axis) of the left ventricle during contraction. This indicator reflects the contractile function of the left ventricle and the myocardial pumping capacity. Improving the left ventricular short-axis shortening fraction means that the inner diameter of the left ventricle shortens more during heart contraction, indicating that the contractility of the myocardium is enhanced and the heart's pumping function is stronger.

[0060] The ratio of left ventricular ejection fraction to the early diastolic velocity of the mitral annulus (E / e' ratio) is an important echocardiographic index used to evaluate left ventricular diastolic function and left atrial pressure. Specifically, it is calculated by measuring the ratio of the left ventricular early diastolic blood flow velocity (E wave) to the mitral annular early diastolic movement velocity (e' wave). The E wave reflects the filling velocity of the left ventricle in early diastole, while the e' wave reflects the relaxation velocity of the left ventricular diastolic function. A higher E / e' ratio usually indicates impaired left ventricular diastolic function and increased left atrial pressure, which may indicate increased left ventricular filling pressure and is often used to diagnose and evaluate left ventricular function in patients with heart failure.

[0061] In the present invention, the improvement of reduced cardiac function includes enhancing myocardial contractility, increasing cardiac output, improving cardiac electrical activity, optimizing cardiac structure, promoting myocardial regeneration and repair, etc. The reduced cardiac function can be reflected by the cardiac ejection fraction (LVEF), the left ventricular shortening fraction (LVSF), and the ratio of the left ventricular ejection fraction to the early diastolic velocity of the mitral ring (E / e' ratio). The improvement of reduced cardiac function refers to increasing the cardiac ejection fraction or the left ventricular shortening fraction to the cardiac ejection fraction and the left ventricular shortening fraction of the subject to be acted on, close to or reaching the score of a healthy heart, and reducing the E / e' ratio. In a specific embodiment of the present invention, the product can significantly increase the cardiac ejection fraction and the left ventricular shortening fraction of the subject to be acted on, at least reaching at least 70%, 80%, 90% or 100% of the healthy heart score, and the expression of E / e' is reduced, which means that the pumping function and filling pressure of the heart are improved.

[0062] In the present invention, the improvement of cardiac pathological changes refers to repairing or alleviating the structural and functional abnormalities of the heart, including reducing inflammatory reactions, preventing the formation of atherosclerotic plaques, promoting the regeneration and repair of myocardial cells, and improving the functions of heart valves and coronary arteries, thereby restoring the normal morphology and function of the heart. In a specific embodiment of the present invention, the product can significantly improve the disordered arrangement of myocardial cells and widening of myocardial spaces in the subject, and reduce the infiltration of inflammatory cells in cardiac tissue.

[0063] The second aspect of the present invention provides a product, comprising enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof, and the product has at least one of the following functions:

[0064] 1) Treatment of acute myocardial infarction;

[0065] 2) Improve heart function;

[0066] 3) Improve cardiac pathological changes;

[0067] 4) Alleviate decreased heart function.

[0068] Among them, the treatment of acute myocardial infarction; improvement of cardiac function; improvement of cardiac pathological changes; and relief of decreased cardiac function are all as described above.

[0069] In the present invention, the product can prevent and / or treat myocardial infarction, and more specifically, the product can prevent and / or treat acute myocardial infarction.

[0070] The product can treat acute myocardial infarction; improve heart function; improve cardiac pathological changes; and relieve decreased heart function, specifically including increasing left ventricular ejection fraction, increasing left ventricular short-axis shortening rate, increasing the ratio of left ventricular ejection fraction to the early diastolic velocity of the mitral 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.

[0071] In the present invention, the pharmaceutical composition composed of the pharmaceutically acceptable salt, the enoxacin sesquihydrate or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, or a combination thereof is as described above.

[0072] In the present invention, the effective dose of the enoxacin sesquihydrate 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,

[0073] In some specific embodiments of the present invention, 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.

[0074] The present invention also provides a method for treating myocardial infarction or heart disease caused by myocardial infarction, which comprises administering an effective dose of the above product to a subject.

[0075] In the present invention, 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 invention, the target of action is human or mouse.

[0076] In the present invention, 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 counterpulsation, mechanical ventilation, blood ultrafiltration, and ventricular mechanical assist devices).

[0077] The present invention is further described below by specific examples. When the examples give numerical ranges, it should be understood that, unless otherwise specified in the present invention, 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 invention 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 art's grasp of the prior art and the record of the present invention, 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 invention can also be used to realize the present invention. Unless otherwise specified, the instruments, reagents, and materials used in the examples can be obtained by conventional means.

[0078] Experimental animals used in the examples:

[0079] 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".

[0080] Experimental drugs and main reagents used in the examples:

[0081] Enoxacin sesquihydrate (MCE, HY-B0268A);

[0082] Sacubitril / valsartan sodium tablets (Beijing Novatis Pharmaceuticals Co., Ltd., HJ20170363);

[0083] Masson trichrome staining kit (Beijing Solebow Technology Co., Ltd., G1340);

[0084] Eosin staining solution (Beijing Solebow Technology Co., Ltd., g1100);

[0085] Hematoxylin staining solution (Beijing Solebow Technology Co., Ltd., g1140);

[0086] Isoflurane (Shenzhen Reward Life Science Technology Co., Ltd., 970-00026-00);

[0087] Paraformaldehyde (LA0427 from Fuzhou Feijing Biotechnology Co., Ltd.),

[0088] Anhydrous ethanol (Xilong Science Co., Ltd., 1280340101602),

[0089] Xylene (Xilong Scientific Co., Ltd., 1430030101600), and other chemical reagents.

[0090] The main instruments used in the examples are:

[0091] 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.).

[0092] Statistical analysis

[0093] All data analysis in the experiment was performed using SPSS 26.0 software. The Shapiro-Wilk test was first used to test the normality of each group of data. For data with normal distribution and homogeneity of variance, ANOVA multiple group comparison was used. For data with non-normal distribution or unequal variance, Kruskal-Wallis test was used. All analyses were defined as statistically significant when P < 0.05. Example 1 Drug preparation, animal grouping, and model construction

[0094] 1. Drug configuration:

[0095] Weigh an appropriate amount of Enoxacin hydrate (EXH) 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.

[0096] 2. Animal grouping and model construction

[0097] Male C57BL / 6 mice were randomly divided into four groups according to body weight: Sham group (n=3), AMI group (n=3), AMI+EXH group (n=3), and AMI+SVST group (n=3). 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 3 times with iodine tincture. Finally, the mice were placed under a 37°C heating lamp, and after they woke up, they were placed in grouped cages. Mice in the Sham group underwent thoracotomy, and the left anterior descending branch of the mouse coronary artery was pierced with a suture needle but not ligated. On the second day after surgery, the AMI+EXH group was given EXH 10 mg / kg / d by gavage, and the AMI+SVST group was given SVST 10 mg / kg / d 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. Example 2 Effects of Enoxacin Sesquihydrate Intervention on Cardiac Function in Mice with Acute Myocardial Infarction

[0098] In this example, small animal cardiac ultrasound was used to detect changes in cardiac function in each group of mice.

[0099] 1. Experimental Methods

[0100] 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.

[0101] 2. Experimental results

[0102] 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+EXH group and the AMI+SVST group showed that the cardiac contraction function was improved ( Figure 1 ). After 14 days of intervention with EXH and SVST, the LVEF and LVFS of mice in the AMI+EXH group were significantly increased compared with those in the AMI group, and the expression of E / e' was decreased, indicating that EXH intervention can improve the decreased cardiac function of mice with acute myocardial infarction ( Figure 2-4 , P<0.05).

[0103] Example 3 Effect of Enoxacin Sesquihydrate on Cardiac Index in Mice with Acute Myocardial Infarction

[0104] The cardiac morphology of mice in each group was observed and it was found that compared with the Sham group, the heart volume of mice in the AMI group was larger, the texture became harder, and the cardiac index was significantly increased ( Figure 5 After continuous oral administration of EXH and SVST for 14 days, compared with the AMI group, the heart volume of mice in the AMI+EXH group and the AMI+SVST group was reduced, the texture was relatively soft, and the cardiac index was significantly decreased ( Figure 6 , P<0.05), indicating that EXH intervention can improve the cardiac index of mice with acute myocardial infarction.

[0105] Example 4 Effect of Enoxacin Sesquihydrate on the Morphology of Heart Tissue in Mice with Acute Myocardial Infarction

[0106] In this example, hematoxylin-eosin (HE) staining was further used to observe the cardiac morphological changes of mice in each group.

[0107] 1. Experimental Methods

[0108] 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 0.4 mm slices and placed in a 60°C oven for 1 hour. 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.

[0109] 2. Experimental results

[0110] The experimental results are as follows Figure 7 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 intervention with EXH and SVST, the disordered arrangement of myocardial cells and widened myocardial gap in the AMI+EXH 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 EXH intervention can significantly improve the damage to the tissue morphology of mice with acute myocardial infarction.

[0111] In summary, intervention with enoxacin sesquihydrate 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.

[0112] The above embodiments are merely illustrative of the principles and effects of the present invention, and are not intended to limit the present invention. Anyone familiar with the art may modify or alter the above embodiments without departing from the spirit and scope of the present invention. Therefore, all equivalent modifications or alterations made by a person of ordinary skill in the art without departing from the spirit and technical ideas disclosed by the present invention shall still be covered by the claims of the present invention.

Claims

1. Use of enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof in preparing a product for preventing and / or treating myocardial infarction.

2. Use of enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof in the preparation of a product for preventing and / or treating cardiac pathology caused by myocardial infarction.

3. The use according to claim 2, characterized in that The heart disease caused by myocardial infarction has at least one of the following symptoms: decreased heart function, changes in heart morphology, and changes in heart tissue morphology.

4. The use according to claim 3, characterized in that The product has any one or more of the following effects: 1) Treatment of acute myocardial infarction; 2) Improve heart function; 3) Improve cardiac pathological changes; 4) Alleviate decreased heart function.

5. The use according to any one of claims 1 to 3, wherein the myocardial infarction is acute myocardial infarction.

6. The use according to claim 1, characterized in that The enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof is used alone or in combination with other drugs.

7. The use according to claim 6, characterized in that The enoxacin sesquihydrate or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier or excipient, or a combination thereof, form a pharmaceutical composition.

8. A product for preventing and / or treating myocardial infarction or heart disease, characterized in that: The product comprises enoxacin sesquihydrate or a pharmaceutically acceptable salt thereof, and the product has any one or more of the following effects: 1) Treatment of acute myocardial infarction; 2) Improve heart function; 3) Improve cardiac pathological changes; 4) Alleviate decreased heart function.

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

10. The product according to claim 9, characterized in that The products include medicines, health products and food.

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