Use of pefloxacin mesylate for the preparation of a medicament for the treatment of acute myocardial infarction

Abstract

The application belongs to the field of biological medicine, and particularly relates to the use of peflacine mesylate in the preparation of a drug for treating acute myocardial infarction. The application provides the use of peflacine or a pharmaceutically acceptable salt thereof in the preparation of a product for preventing and / or treating myocardial infarction, and the use of peflacine or a pharmaceutically acceptable salt thereof in the preparation of a product for preventing and / or treating a heart lesion caused by acute myocardial infarction, wherein the peflacine or the pharmaceutically acceptable salt thereof is peflacine mesylate. The application first finds that peflacine mesylate can be applied in the preparation of a drug for treating acute myocardial infarction or a heart lesion caused by acute myocardial infarction, and provides a new treatment approach for treating acute myocardial infarction or diseases related to acute myocardial infarction.

Description

Technical Field

[0001] This application belongs to the field of biomedicine and specifically relates to the use of pazufloxacin mesylate in the preparation of drugs for the treatment of acute myocardial infarction. Background Technology

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

[0003] Drug treatment for acute myocardial infarction (AMI) has evolved from basic diuretics and vasodilators to combination therapies. While these drugs play an important role in relieving symptoms and improving cardiac function, they cannot address the high incidence and serious complications of AMI. In recent years, interventional cardiac surgery and thrombolytic therapy have saved many AMI patients, but some patients still fail to undergo timely revascularization for various reasons, leading to irreversible myocardial necrosis, ventricular remodeling, and heart failure.

[0004] It is worth noting that Traditional Chinese Medicine (TCM) has accumulated many classic and effective natural medicines. These medicines are generally milder and safer, and are gradually being widely regarded as complementary or alternative therapies for acute myocardial infarction (AMI). However, the clinical application of anti-AMI drugs based on natural products still faces many challenges, such as difficulties in screening and isolating the active ingredients, unclear mechanisms of action related to AMI, and limited clinical research samples. Pazufloxacin mesylate (PM) is an orally administered 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 yet been reported.

[0005] Therefore, there is currently a need to develop new drugs with good efficacy for the treatment of acute myocardial infarction. Summary of the Invention

[0006] In order to overcome the shortcomings of the prior art, this application found that pazufloxacin methanesulfonate can significantly alleviate the series of harms of acute myocardial infarction after screening a large number of compounds for their effects on acute myocardial infarction. This application found that pazufloxacin methanesulfonate can improve cardiac function, improve cardiac morphology, improve cardiac pathological changes, reduce myocardial fibrosis, and alleviate the decline in cardiac function, and has a therapeutic effect on acute myocardial infarction.

[0007] Therefore, the first aspect of this application provides the use of pazufloxacin or a pharmaceutically acceptable salt thereof in the preparation of products for the prevention and / or treatment of myocardial infarction or heart disease.

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

[0009] The heart condition was caused by an acute myocardial infarction.

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

[0011] 1) Improves heart function;

[0012] 2) Improves heart morphology;

[0013] 3) Improves the morphology of cardiac tissue;

[0014] 4) Improve myocardial fibrosis.

[0015] The improvement in cardiac function is selected from any one or more of the following: increasing left ventricular ejection fraction, increasing left ventricular fractional shortening, or decreasing the ratio of peak diastolic mitral valve velocity to peak diastolic mitral valve annular velocity.

[0016] The improvement in heart morphology includes: reducing heart volume.

[0017] The improvement in cardiac tissue morphology is selected from any one or more of the following: improving disordered arrangement of cardiomyocytes, improving widening of intermyocardial spaces, or reducing inflammatory cell infiltration.

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

[0019] The aforementioned pazufloxacin or its pharmaceutically acceptable salt is pazufloxacin mesylate.

[0020] The myocardial infarction mentioned refers to acute myocardial infarction.

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

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

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

[0024] The aforementioned pazufloxacin or its pharmaceutically acceptable salt is pazufloxacin mesylate.

[0025] The effective dose of the 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 as follows:

[0027] This application is the first to discover that pazufloxacin mesylate can be used in the preparation of drugs for treating acute myocardial infarction or cardiac lesions caused by acute myocardial infarction. It can improve cardiac function, cardiac morphology, cardiac tissue morphology, and cardiac fibrosis in patients with acute myocardial infarction, with good therapeutic effects that are equivalent to or superior to existing drugs for treating acute myocardial infarction, sacubitril / valsartan sodium tablets (SVST). This provides a new treatment approach for the treatment of acute myocardial infarction or related diseases. Attached Figure Description

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

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

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

[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 on the pathomorphology of the heart in mice with acute myocardial infarction in Example 4.

[0034] Figure 7 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 graph showing the effect of PM intervention on myocardial fibrosis in mice with acute myocardial infarction in Example 5. Detailed Implementation

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

[0037] Before further describing the specific embodiments of this application, it should be understood that the scope of protection of this application is not limited to the specific embodiments described below; it should also be understood that the terminology used in the embodiments of this application is for describing specific embodiments and not for limiting the scope of protection of this application; in the specification and claims of this application, unless otherwise expressly stated in the text, the singular forms "a", "an" and "this" include the plural forms.

[0038] This application is the first to discover that pazufloxacin mesylate can treat acute myocardial infarction or cardiac lesions caused by acute myocardial infarction, with good therapeutic effects, which are superior to existing drugs for treating acute myocardial infarction, sacubitril / valsartan sodium tablets (SVST), providing a new treatment approach for acute myocardial infarction or 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 condition is usually caused by thrombus formation within the coronary arteries, leading to complete occlusion of the vessel, which deprives the heart muscle of sufficient blood supply, ultimately resulting in 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 disease or reduce the risk of disease occurrence. It can be divided into primary prevention, which involves taking measures before the disease occurs to prevent its onset; secondary prevention, which aims to detect and treat the disease in its early stages to prevent its development and worsening; and tertiary prevention, which involves taking measures after the disease has occurred to prevent further deterioration or complications. Specifically, it refers to all behaviors that suppress symptoms or delay specific stress through the application of the product described in this application.

[0041] In this application, the treatment refers to a series of positive effects that occur after a disease has already begun to develop. Specifically, it can slow the progression of the disease, controlling its rapid progression; it can interrupt the continuous deterioration of the disease, preventing it from evolving further into a more severe state; it can effectively control the severity of the disease, preventing it from exceeding the body's tolerance; it can stop the adverse development of the disease, preventing it from continuing to worsen; it can alleviate various uncomfortable symptoms caused by the disease, relieving the patient's suffering; and it can even, to some extent, reverse a specific sign, symptom, disorder, condition, or the direction or severity of the disease's progression. However, it should be clarified that this treatment does not necessarily mean the complete elimination of all disease-related signs, symptoms, conditions, or disorders, but rather the improvement of the disease's state and the alleviation of disease-related signs, symptoms, conditions, or disorders.

[0042] In this application, the efficacy refers to the effects and functions of a product containing a compound in the body, which may include therapeutic effects, preventive effects, diagnostic effects, rehabilitative effects, regulatory effects, immunomodulatory effects, toxic side effects, pharmacokinetic properties, and pharmacodynamic properties.

[0043] In this application, the effective dose refers to the dose of a drug, treatment or other intervention that achieves the expected 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 daily during the period of use.

[0044] This application first provides the use of pazufloxacin or a pharmaceutically acceptable salt thereof in the preparation of products for the prevention and / or treatment of myocardial infarction.

[0045] In this application, the pharmaceutically acceptable salt refers to the salt of pazufloxacin, prepared by reacting pazufloxacin with 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 in this application with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable bases include salts prepared from inorganic and organic bases. The inorganic base salts include aluminum, ammonium, calcium, copper, iron, ferrous, lithium, magnesium, manganese, manganese, potassium, sodium, and zinc salts. The organic non-toxic base salts include salts of primary, secondary, and tertiary amines, including substituted amines and cyclic amines. Examples include: N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidine, guanidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc. When pazufloxacin contains relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds 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, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid.

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

[0047] Pazufloxacin mesylate (PM) is a quinolone antibacterial drug with the chemical name (-)-(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 mesylate. Its molecular formula is C2. 17 H 19 FN2O7S, with a molecular weight of 414.41. Pazufloxacin mesylate is mainly used for various infections caused by susceptible bacteria. Its CAS number is 136905-87-8, and its structural formula is as follows: [Formula I]

[0048]

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

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

[0051] The cardiac function refers to the heart's ability, as the core organ of the circulatory system, to perform its pumping function to maintain systemic blood circulation and the supply of oxygen and nutrients. This includes the pumping function, the heart's primary function being to pump blood to all parts of the body to supply oxygen and nutrients and remove metabolic waste; heart rate, the number of times the heart beats per minute, an indicator of cardiac activity frequency; heart rhythm, the regularity of heartbeats, including the rhythm and sequence of heartbeats; a normal heart rhythm is sinus rhythm; myocardial contractility, the ability of myocardial cells to contract, directly affecting the efficiency of the heart's pumping; and 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 pumped by the ventricles during each heart contraction, is an important indicator of cardiac pumping function; cardiac reserve capacity, the heart's ability to increase pumping volume when physiological demands increase (such as during exercise); valvular function, the opening and closing function of heart valves to ensure unidirectional blood flow and prevent backflow; cardiac metabolic function, the ability of heart cells to use oxygen and nutrients to produce energy to support the heart's pumping function; and cardiac electrophysiological function, the function of the heart's electrical conduction system, including the sinoatrial node, atrioventricular node, His bundle, and Purkinje fibers, which are responsible for pacing and electrical signal transmission. Cardiac function can be assessed using methods such as electrocardiography (ECG), echocardiography, cardiac magnetic resonance imaging (MRI), and nuclear cardiology.

[0052] In a specific embodiment of this application, improving cardiac function refers to restoring the reduced cardiac function of myocardial infarction patients compared to healthy individuals, bringing it back to the level of healthy individuals. Specifically, this may include increasing left ventricular ejection fraction, and / or increasing the left ventricular fractional shortening rate, and / or increasing the ratio of left ventricular ejection fraction to early diastolic velocity of the mitral valve annulus.

[0053] The left ventricular ejection fraction (LVEF) refers to the percentage of blood ejected from the left ventricle during each cardiac contraction, relative to the left ventricular end-diastolic volume. In normal adults at rest, the normal range for LVEF is approximately 55% to 65%, with some sources suggesting a range of 50% to 70%. A higher LVEF indicates stronger myocardial contractility and a larger volume of blood ejected with each heartbeat. A LVEF below 50% typically indicates decreased left ventricular systolic function, a crucial indicator for assessing heart failure. Improving LVEF refers to increasing the reduced LVEF in patients with myocardial infarction compared to healthy individuals. In the specific embodiments of this application, the LVEF of patients with myocardial infarction is lower than that of healthy individuals. Compared to those not using the product of this application, patients using the product of this application show an increase in their LVEF.

[0054] The left ventricular fractional shortening (LVFS%) is an indicator of left ventricular systolic function, describing the degree of change in the diameter of the left ventricle along its short axis during systole. Specifically, LVFS% is the percentage obtained by multiplying the difference between the left ventricular short-axis diameter at end-systole (LVDs) and end-diastole (LVDd) by the end-diastolic short-axis diameter, to 100%. Improving the left ventricular fractional shortening refers to increasing the reduced left ventricular fractional shortening rate in myocardial infarction patients compared to healthy individuals. In the specific embodiments of this application, the left ventricular fractional shortening rate is lower in myocardial infarction patients compared to healthy individuals. Compared to those who did not use the product of this application, patients who used the product of this application showed an increase in their left ventricular fractional shortening rate.

[0055] In the early diastolic mitral valve peak velocity and early diastolic mitral valve annular peak velocity (E / e'), the E peak reflects the early pressure difference between the left atrium and left ventricle, i.e., the blood flow velocity during early diastolic ventricular filling. The e' peak is the early motion velocity of the mitral valve annulus, an indicator of myocardial relaxation velocity. The E / e' index is used to estimate left ventricular filling pressure and has good feasibility and repeatability; a small E / e' value usually indicates normal left ventricular filling pressure. In the specific embodiments of this application, the ratio of early diastolic mitral valve peak velocity to early diastolic mitral valve annular peak velocity is higher in patients with myocardial infarction compared to healthy individuals. Compared to those who did not use the product of this application, when patients used the product of this application, the ratio of early diastolic mitral valve peak velocity to early diastolic mitral valve annular peak velocity was lower.

[0056] The term "cardiac morphology" refers to the overall shape and structure of the heart, including its macroscopic features such as location, size, and shape. Cardiac morphology studies the external morphological features of the heart, such as the arrangement and connection of the four chambers (left atrium, right atrium, left ventricle, and right ventricle) and the major blood vessels entering and leaving the heart (aorta, pulmonary artery, superior vena cava, inferior vena cava, and pulmonary veins).

[0057] In a specific embodiment of this application, improving heart morphology refers to restoring the altered heart morphology of myocardial infarction patients compared to healthy individuals, making it return to the heart morphology of healthy individuals. Specifically, this may include reducing heart volume and softening heart texture.

[0058] The heart volume mentioned primarily refers to the heart's capacity at different stages and is an important indicator for assessing cardiac 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 cardiac structure and function after myocardial infarction, including enlargement of cardiac chambers, increase in myocardial volume, and eccentric / concentric hypertrophy and valvular regurgitation. Left ventricular dilation and remodeling are closely related to poor prognosis after myocardial infarction, and the end-diastolic and end-systolic volumes of the left ventricle can predict the occurrence of adverse events after myocardial infarction. Therefore, in myocardial infarction, the assessment of heart volume is of great significance for determining the severity of the condition and prognosis. The reduction of heart volume shown refers to reducing the increased heart volume of myocardial infarction patients compared to healthy individuals. In the specific embodiments of this application, the heart volume of myocardial infarction patients is larger than that of healthy individuals. Compared to not using the product of this application, when patients use the product of this application, their heart volume is reduced.

[0059] The cardiac tissue morphology refers to the microstructure 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 the specific embodiments of this application, the improvement of cardiac tissue morphology refers to restoring the altered cardiac tissue morphology of myocardial infarction patients compared to healthy individuals, making it return to the direction of cardiac tissue morphology in healthy individuals. Specifically, this can be achieved by improving disordered arrangement of myocardial cells, and / or improving widening of intermyocardial spaces, 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. This may be accompanied by phenomena such as myocardial cell hypertrophy, interstitial fibrosis, and abnormalities in small coronary arteries of the myocardium (thickening of the vessel wall and severe narrowing of the lumen). Improving the disordered arrangement of myocardial cells means restoring the originally abnormally arranged myocardial cells to a more orderly or normal arrangement state like that of healthy people. In the specific embodiments of this application, the myocardial cells of patients with myocardial infarction are more disordered than those of healthy people. Compared with those who have not used the product of this application, when patients use the product of this application, the myocardial cells of patients are arranged more orderly.

[0062] The widening of the myocardial interstitial space refers to the widening of the gaps between myocardial cells compared to normal conditions. This widening is due to cardiac interstitial fibrosis, i.e., the excessive proliferation of fibrous tissue in the myocardial interstitium, which leads to the separation of myocardial cells and the formation of a honeycomb structure. This may affect the normal function of the heart, including its systolic and diastolic functions. Improving the widening of the myocardial interstitial space refers to reducing the increased gaps between myocardial cells in patients with myocardial infarction compared to healthy individuals. In the specific embodiments of this application, the myocardial interstitial space in patients with myocardial infarction is wider than that in healthy individuals. Compared to those who have not used the product of this application, when patients use the product of this application, the myocardial interstitial space of the patients is reduced.

[0063] Inflammatory cell infiltration refers to the aggregation of inflammatory cells (such as lymphocytes and macrophages) in the myocardial interstitium during myocardial inflammatory lesions. This infiltration is usually accompanied by degeneration and necrosis of cardiomyocytes and is one of the histological features of myocarditis. Inflammatory cells have phagocytic, immune, and tissue-damaging functions; the types of infiltrating inflammatory cells vary depending on the type of inflammation, the stage of inflammation, and the body's immune state. The presence of inflammatory cell infiltration is important for determining the etiology, assessing prognosis, and developing treatment plans. In myocarditis, inflammatory cell infiltration is one of the basic pathological changes, including the infiltration of inflammatory cells and damage to cardiomyocytes. Inflammatory cell infiltration can occur in different types, such as lymphocytic myocarditis, eosinophilic myocarditis, giant cell myocarditis, granulomatous myocarditis (such as cardiac sarcoidosis), and purulent myocarditis. This infiltration of inflammatory cells not only reflects the presence of inflammation but may also participate in the process of myocardial injury and repair. Reducing inflammatory cell infiltration refers to decreasing the number and activity of inflammatory cells in the myocardial tissue of patients with myocardial infarction, thereby alleviating the inflammatory response and tissue damage. In a specific embodiment of this application, inflammatory cell infiltration occurs in the cardiac tissue of patients with myocardial infarction. Compared with those who have not used the product of this application, when patients with myocardial infarction use the product of this application, the inflammatory cell infiltration in the cardiac tissue of the patients is reduced.

[0064] Myocardial fibrosis refers to a pathological change in the normal tissue structure of the myocardium, characterized by excessive accumulation of collagen fibers, a significant increase in collagen concentration in the heart tissue, or alterations in collagen composition. This condition is an inevitable process in the terminal stage of many cardiovascular diseases and a major manifestation of cardiac structural remodeling. Myocardial fibrosis is closely related to arrhythmias, cardiac dysfunction, and even sudden cardiac death. Its main characteristics include fibroblast proliferation and extracellular matrix (ECM) deposition, which leads to increased cardiac stiffness, decreased compliance, and impaired normal diastolic and systolic functions. Myocardial fibrosis can cause cardiac systolic and diastolic dysfunction and is a major pathological manifestation of many cardiovascular diseases at a certain stage. It damages myocardial structure, disrupts the excitation-contraction coupling of the myocardium, and impairs its systolic and diastolic functions, leading to and aggravating arrhythmias and cardiac dysfunction, thus further developing heart disease and ultimately causing heart failure.

[0065] In a specific embodiment of this application, improving cardiac fibrosis refers to restoring the increased degree of cardiac fibrosis in patients with myocardial infarction compared to healthy individuals, bringing it back towards the level of cardiac fibrosis in healthy individuals. Specifically, this can be achieved by reducing 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 the heart tissue. Reducing the percentage of cardiac tissue fibrosis in patients with myocardial infarction refers to reducing the increased percentage of cardiac tissue fibrosis in patients with myocardial infarction compared to healthy individuals. In a specific embodiment of this application, the percentage of cardiac tissue fibrosis in patients with myocardial infarction is higher than that in healthy individuals. Compared to not using the product of this application, when patients with myocardial infarction use the product of this application, the percentage of cardiac tissue fibrosis in the patients decreases.

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

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

[0069] In specific embodiments of this application, the effective dose of the 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, or >500 mg / kg.

[0070] This application also provides the use of pazufloxacin or a pharmaceutically acceptable salt thereof in the preparation of products for the prevention and / or treatment of heart disease.

[0071] Among them, pazufloxacin or its pharmaceutically acceptable salts are as described above.

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

[0073] The pazufloxacin mesylate is as described above.

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

[0075] The aforementioned decline in cardiac function, changes in cardiac morphology, changes in cardiac tissue morphology, and myocardial fibrosis are as described above.

[0076] In a specific embodiment of this application, the cardiac lesion is caused by myocardial infarction.

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

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

[0079] 1) Improves heart function;

[0080] 2) Improves heart morphology;

[0081] 3) Improves the morphology of cardiac tissue;

[0082] 4) Improve myocardial fibrosis.

[0083] The improvements in cardiac function, cardiac morphology, cardiac tissue morphology, and myocardial fibrosis are as described above.

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

[0085] In specific embodiments of this application, the effective dose of the 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, or >500 mg / kg, and the product.

[0086] This 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, and more specifically, the product can prevent and / or treat acute myocardial infarction.

[0088] The product can prevent and / or treat heart disease caused by acute myocardial infarction.

[0089] The product can improve cardiac function, cardiac morphology, cardiac tissue morphology, and myocardial fibrosis. Specifically, it can increase left ventricular ejection fraction, increase left ventricular short-axis shortening rate, increase the ratio of left ventricular ejection fraction to early diastolic velocity of the mitral valve annulus, reduce heart volume, make myocardial cells more orderly arranged, reduce myocardial interstitial widening, reduce inflammatory cell infiltration, and reduce the percentage of cardiac tissue fibrosis.

[0090] The pazufloxacin or its pharmaceutically acceptable salt is as described above.

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

[0092] The pazufloxacin mesylate is as described above.

[0093] In specific embodiments of this application, the effective dose of the 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, or >500 mg / kg.

[0094] In this application, the products mentioned above can be pharmaceuticals, pharmaceutical compositions, combinations of pharmaceuticals, reagents, reagent kits, food, or health products.

[0095] In this application, the dosage form or state of the product described above is not limited. For example, when the product is a drug, a drug composition, or a combination of drugs, the dosage form can be one or more of the following: solution, injection, spray, nasal drops, aerosol, powder, tablet, capsule, and granule. Drugs of all the above dosage forms can be prepared according to conventional methods in the pharmaceutical field. Preferably, it is a solution. For example, when the product is food or health product, the state can be liquid or solid.

[0096] In this application, the product described above uses pazufloxacin mesylate as the main active ingredient and may also include pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable excipients refer to those non-toxic materials that do not affect the efficacy and safety of the main drug ingredient, do not produce adverse, allergic, or other adverse reactions, and should be compatible with the pazufloxacin mesylate, meaning they can be mixed with it without significantly reducing the efficacy of pazufloxacin mesylate under normal circumstances. Examples of these excipients include: sterile water or saline solution, used as a solvent or diluent for the drug; stabilizers, used to maintain the stability of the drug and prevent decomposition; excipients, used to help form the drug in a specific form, such as tablets or capsules; antioxidants, such as ascorbic acid, to prevent the drug from oxidizing; buffers, such as phosphates and citric acid, used to maintain the pH value of the drug; preservatives, used to prevent the drug from being contaminated by microorganisms during storage; surfactants, such as polyethylene glycol (PEG) and Tween, used to increase the solubility or stability of the drug; chelating agents, such as EDTA, used to bind to metal ions and prevent drug degradation; and binders, used to hold the drug components together. In addition, pharmaceutical formulations may also contain: low molecular weight peptides; 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; and sugar alcohols, such as mannitol or sorbitol. In preparing aqueous solutions for injection, the following may also be used: physiological saline; isotonic solutions containing glucose or other excipients; solubilizers, such as alcohols (ethanol), polyols (such as propylene glycol, PEG), and nonionic surfactants (such as Tween 80, HCO-50). The type and proportion of these excipients or carriers can be adjusted depending on the type and requirements of the final drug formulation.

[0097] In this application, the pazufloxacin mesylate described in the aforementioned 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 formulation, wherein the efficacy and safety of the components 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 (ACEIs (such as lepril) and ARBs (such as locateprazole)), nitrates (nitroglycerin, isosorbide dinitrate), thrombolytic drugs (urokinase, alteplase, reteplase), anticoagulants (such as heparin, bivalirudin), and PCSK9 inhibitors (incoslan). The content of each component in a combination formulation is usually a safe and effective amount, which can be adjusted based on actual usage (e.g., patient weight, type of application, disease condition, severity).

[0098] In this application, when the product described above is used as a formulation, it is preferably in unit dosage form, meaning that the formulation is further divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a solution, injection, syringe, capsule, tablet, or any dosage form; alternatively, the unit dosage form can also be a packaged formulation, such as solutions, injections, tablets, capsules, and powders packaged in vials or ampoules. The amount of active ingredient in the unit dose formulation can be varied or adjusted from 0.1 mg to 1000 mg, depending on the specific application and potency of the active ingredient.

[0099] In this application, when the product described herein is used to treat myocardial infarction or heart disease caused by myocardial infarction, the product must be accurately administered to the subject at an effective dose 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 a healthy state.

[0100] This application also provides a method for treating myocardial infarction or cardiac lesions caused by myocardial infarction, comprising administering an effective dose of the above-mentioned product to a subject.

[0101] In the present application, the objects of the products and methods described above are organisms suffering from myocardial infarction or heart diseases caused by myocardial infarction, or organisms that need to prevent and / or treat myocardial infarction or heart diseases caused by myocardial infarction. Specifically, they can be various mammals, including but not limited to rodents, artiodactyls, perissodactyls, lagomorphs, and primates, such as humans, monkeys, other primates, sheep, cattle, horses, donkeys, pigs, dogs, cats, mice, rabbits, rats, guinea pigs, hamsters, foxes, deer, etc.; in the preferred embodiment of the present application, the object is a human or a mouse.

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

[0103] The present application will be further described below through specific examples. When the examples give numerical ranges, it should be understood that unless otherwise specified in the present application, any value at both ends of each numerical range and any value between the two ends can be selected. Unless otherwise defined, all technical and scientific terms used in the present application have the same meaning as commonly understood by those skilled in the art of this technology. In addition to the specific methods, devices, and materials used in the examples, according to the knowledge of those skilled in the art of this technology and the records of the present application, any methods, devices, and materials of the prior art similar or equivalent to those described in the embodiments 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 through conventional channels.

[0104] Experimental animals used in the examples:

[0105] SPF-grade male C57BL / 6 mice were purchased from Shanghai SLAC Laboratory Animal Co., Ltd., with the license number: SCKY(Shanghai)2017-0005. The experimental animals were housed 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, at a room temperature of 23±1°C, a relative humidity of about 50-60%, and a 12h light / dark cycle. The mice were used in the experiment after 5-7 days of adaptive feeding. All animal experiments were carried out under the guidance of the latest "Guide for the Care and Use 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 Novartis Pharmaceutical Co., Ltd., HJ20170363);

[0109] Masson Trichrome Staining Kit (Beijing Solarbio Science & Technology Co., Ltd., G1340);

[0110] Eosin staining solution (Beijing Solarbio Science & Technology Co., Ltd., G1100);

[0111] Hematoxylin staining solution (Beijing Solarbio Science & Technology Co., Ltd., G1140);

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

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

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

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

[0116] Main instruments used in the examples:

[0117] Pipettes (Renin, USA); Electronic balances (Shanghai Ohaus Instruments Co., Ltd.); Vevo2100 small animal ultrasound imaging system (Fujifilm Investment Co., Ltd.); Inhalation-type small animal anesthesia machine (Shenzhen Ruiwode Life Technology Co., Ltd.); Pathological sectioning machine (Leica GmbH, Germany); Paraffin embedding machine (Xiaogan Yaguang Medical Electronics Technology Co., Ltd., Hubei).

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

[0119] 1. Drug preparation:

[0120] Weigh an appropriate amount of PM and Sacubitril valsartan sodium tablets (SVST) powder, dissolve them in the corresponding volume of distilled water at a dose of 10 mg / kg / day according to the average weight of the mice, place the solution in an ultrasonic instrument and sonicate at low temperature for about 1 hour, and store it in a refrigerator at 4°C for later 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). Hair was removed from the chest of the mice with depilatory cream the day before surgery. On the day of surgery, the mice were anesthetized with isoflurane and placed in a supine position. The chest of the mice was disinfected three times with povidone-iodine. A 2cm longitudinal incision was made on the left side of the sternum using a sterile scalpel. The muscles were bluntly separated between the third and fourth ribs on the left side. Hemostatic forceps were used to open the third and fourth ribs, and the heart was quickly expelled. The left anterior descending coronary artery was ligated with a 6-0 suture needle, 1mm below the left atrial appendage, with a needle depth of 0.5mm. Successful ligation was determined by the apex of the heart below the ligation site turning pale. After suturing the wound, the skin incision was disinfected three times with povidone-iodine. Finally, the mice were placed under a 37°C heat lamp and, after waking up, were placed in their pre-grouped cages. The Sham group mice underwent open-chest surgery, with a suture needle inserted through the left anterior descending coronary artery but not ligated. On the second day post-surgery, the AMI+PM group received 10 mg / kg / day of PM via gavage, the AMI+SVST group received 10 mg / kg / day of SVST via gavage, and the Sham and AMI groups received an equal volume of distilled water via gavage, once daily for 14 consecutive days.

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

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

[0125] 1. Experimental Methods

[0126] Cardiac function in mice was assessed using the Vevo 2100 VisualSonics small animal ultrasound system. Mice were dehaired on their chests beforehand using hair removal cream. After anesthetizing with isoflurane at a flow rate of 1.5 ml / min, the mice were placed supine on a physiological information monitoring table. During this time, the mice were kept inhaled with isoflurane at a constant flow rate, and their heart rate was maintained between 450-650 bp. Coupling agent was applied to the upper chest of the mice, and cardiac function was recorded in both B-Mode and M-Mode. Left ventricular short-axis views were then taken, and cardiac function was recorded again in both B-Mode and M-Mode. Then, using VevoStrain Software (Vevo LAB 1.7.1), the left ventricular injection fraction (LVEF), left ventricular fraction shortening (LVFS), and the ratio of E (peak diastolic mitral valve velocity) / e' (peak diastolic mitral valve annular velocity) were calculated for each group of mice according to the software manual.

[0127] 2. Experimental Results

[0128] Experimental results showed that, 14 days after ligation of the left anterior descending coronary artery in mice, compared with the Sham group, the AMI group exhibited reduced ventricular contraction amplitude, slower ventricular contraction velocity, decreased ventricular wall slope, smoother waveform, and decreased cardiac contractile function. However, compared with the AMI group, echocardiography in both the AMI+PM group and the AMI+SVST group showed improved cardiac contractile function. Figure 1 After 14 days of intervention with PM and SVST, compared with the AMI group, the LVEF and LVFS of mice in the AMI+PM group were significantly increased. Figure 2-3 (P<0.05), E / e'( Figure 4 The levels (P<0.05) were significantly reduced, suggesting that PM intervention can improve the decreased cardiac function in mice with acute myocardial infarction.

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

[0130] Observation of the heart morphology of mice in each group revealed that, compared with the Sham group, the hearts of mice in the AMI group were larger and harder. However, after 14 days of continuous gavage intervention with PM and SVST, compared with the AMI group, the hearts of mice in both the AMI+PM group and the AMI+SVST group were smaller and relatively softer. Figure 5 The results indicate that PM intervention can improve cardiac morphology in mice with acute myocardial infarction.

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

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

[0133] 1. Experimental Methods

[0134] Mice were anesthetized with isoflurane and rapidly euthanized by cervical dislocation. The heart was removed and divided into two parts along the infarct area. The infarct area was fixed in 4% paraformaldehyde for 48 hours. The heart was then placed in an embedding cassette for dehydration with ethanol at a concentration gradient, cleared with xylene, and then immersed in paraffin for waxing. Finally, the heart tissue was embedded into a paraffin block using an embedding machine. The heart tissue was cut into 0.4 mm thin slices and baked in a 60°C oven for 1 hour. After baking, the slides were dewaxed sequentially with xylene and ethanol at a concentration gradient. The sections were stained with hematoxylin solution and then eosin solution. After the samples were dried, they were mounted with neutral resin and the pathological changes in the heart tissue were observed under a microscope.

[0135] 2. Experimental Results

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

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

[0138] In this embodiment, 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 the myocardial fibrosis status in each group of mice.

[0139] 1. Experimental Methods

[0140] Mouse heart tissue was fixed in 4% paraformaldehyde for 24 hours, then dehydrated using a gradient of ethanol. The tissue blocks were then cleared in xylene, impregnated with paraffin, and embedded in paraffin. Heart tissue was cut into 0.4 μm slices and baked in a 60°C oven for 1 hour. After baking, the slides were dewaxed sequentially through xylene and a gradient of ethanol concentrations. Equal volumes of iron hematoxylin A and iron hematoxylin B reagents were mixed and stained for 5 minutes in the dark. After rinsing 3-4 times with tap water, the slides were differentiated in acidic ethanol for 2 seconds, followed by 3-4 more rinses with tap water. Masson's blue solution was stained for 1 minute, followed by 3-4 rinses with tap water. Ponceau fuchsin was stained for 1 minute, followed by 3-4 rinses with tap water. Phosphomolybdic acid was stained for 2 seconds, followed by 3-4 rinses with tap water. Aniline blue was stained for 30 seconds, followed by 3-4 rinses with tap water. The slides were dried with a hairdryer and mounted with a suitable amount of neutral resin.

[0141] 2. Experimental Results

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

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

[0144] The above embodiments are merely illustrative of the principles and effects of this application and are not intended to limit this application. Any person skilled in the art can modify or alter the above embodiments without departing from the spirit and scope of this application. Therefore, all equivalent modifications or alterations made by those skilled in the art without departing from the spirit and technical concept disclosed in this application should still be covered by the claims of this application.

Claims

1. Use of pazufloxacin or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or treatment of myocardial infarction or heart disease caused by myocardial infarction.

2. The use according to claim 1, characterized in that, The cardiac lesions are selected from 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 2, characterized in that, The drug has one or more of the following effects: 1) Improves heart function; 2) Improves heart morphology; 3) Improves the morphology of cardiac tissue; 4) Improves myocardial fibrosis.

4. The use according to claim 3, characterized in that, The improvement in cardiac function is selected from any one or more of the following: increasing left ventricular ejection fraction, increasing left ventricular short-axis shortening rate, or reducing the ratio of peak diastolic mitral valve velocity to peak diastolic mitral valve annular velocity; the improvement in cardiac morphology includes: reducing cardiac volume; the improvement in cardiac tissue morphology is selected from any one or more of the following: improving cardiomyocyte disorder, improving intermyocardial interstitial space widening, or reducing inflammatory cell infiltration; the improvement in myocardial fibrosis includes: reducing the percentage of cardiac tissue fibrosis.

5. The use according to claim 1, characterized in that, The pharmaceutically acceptable salt of pazufloxacin is pazufloxacin mesylate.

6. The use according to claim 1, characterized in that, The myocardial infarction mentioned refers to acute myocardial infarction.

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

8. The use according to claim 7, characterized in that, The effective dose of the pazufloxacin or its pharmaceutically acceptable salt in the drug is greater than or equal to 10 mg / kg.

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