Use of oxymatrine in preparation of medicine for treating hypertension

Abstract

The application belongs to the technical field of medicine, and particularly relates to the use of oxymatrine A in the preparation of a drug for treating hypertension. The application provides the use of oxymatrine A or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or relieving and / or treating hypertension or a complication thereof, wherein the complication is selected from one or more of abdominal aortic sclerosis, heart disease, mesenteric arterial disease, stroke, and renal failure. The application finds that oxymatrine A has the effect of treating hypertension and its complications, and provides a new treatment scheme for treating hypertension and its complications.

Description

Technical Field

[0001] This application belongs to the field of pharmaceutical technology, specifically relating to the use of oroxylon ammodendronin A in the preparation of antihypertensive drugs. Background Technology

[0002] With socio-economic development and changes in national lifestyles, especially the accelerated aging of the population and urbanization, unhealthy lifestyles are becoming increasingly prominent, and cardiovascular disease risk factors are having a more significant impact on residents' health. Hypertension, a clinical syndrome characterized by persistently elevated arterial blood pressure, is the most common and major risk factor for cardiovascular and cerebrovascular diseases, affecting more than 1 billion people worldwide. A nationwide sampling survey of hypertension prevalence from 1958 to 2022 showed an overall upward trend, particularly among young and middle-aged adults and in rural areas. The prevalence of hypertension among residents aged 18 and above was 31.6%, with men (36.8%) having a higher prevalence than women (26.3%), and rural areas (33.7%) having a higher prevalence than urban areas (29.1%). Although awareness, treatment, and control rates of hypertension are continuously improving, the blood pressure control rate remains low at only 26.8%. Improperly controlled hypertension can lead to related complications such as stroke, kidney failure, cardiac hypertrophy, myocardial infarction, and heart failure, primarily affecting vital organs such as the heart, brain, kidneys, and eyes. Therefore, it is necessary to explore more effective treatments for hypertension with fewer side effects.

[0003] Oroxin A (OA), also known as oroxin A-7-O-glucose, is an active flavonoid component isolated from the seeds of *Oroxylumindicum*, a plant in the Bignoniaceae family. Oroxin A possesses antioxidant, anti-inflammatory, antibacterial, and antitumor effects. Current research indicates that total flavonoids from *Oroxylumindicum* can increase the viability of H9C2 cardiomyocytes in rats, as well as the activities of SOD and GSH-Px. Furthermore, studies have shown that *Oroxylumindicum* can lower systolic blood pressure in rats and increase serum superoxide dismutase, thus improving the serum microenvironment. However, there are currently no reports regarding the potential effects of oroxin A on hypertension. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this application has discovered that oroxylum indicum glycoside A has the effect of treating hypertension and its complications. It can lower the blood pressure of the subjects, reduce the thickened abdominal aortic wall of the subjects, improve the pathological morphology of myocardial tissue of the subjects, increase the decreased left ventricular ejection fraction and left ventricular fractional shortening rate of the subjects, and decrease the increased mesenteric artery pulsatility index and mesenteric artery resistance index of the subjects.

[0005] Therefore, the first aspect of this application provides the use of oroxylin A or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or relief and / or treatment of hypertension or its complications.

[0006] The complications are selected from one or more of the following: abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and kidney failure.

[0007] The drug is used for one or more of the following:

[0008] 1) Lower blood pressure;

[0009] 2) Improves the thickness of the abdominal aorta;

[0010] 3) Improves abnormal pathological morphology of cardiac tissue;

[0011] 4) Improves abnormal cardiac function;

[0012] 5) Improves abnormal mesenteric artery function.

[0013] The drug comprises an effective amount of oroxylon ammodendronin A or a pharmaceutically acceptable salt thereof, wherein the effective amount of oroxylon ammodendronin A or a pharmaceutically acceptable salt thereof in the drug is greater than or equal to 10 mg / kg.

[0014] A second aspect of this application provides a medicament for the prevention and / or relief and / or treatment of hypertension and its complications, comprising an effective amount of oroxylin and oxyphylla glycoside A or a pharmaceutically acceptable salt thereof.

[0015] The complications are selected from one or more of the following: abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and kidney failure.

[0016] The effective amount of the oroxylon ammodendronin A or its pharmaceutically acceptable salt in the drug is greater than or equal to 10 mg / kg.

[0017] The beneficial effects of this application are as follows:

[0018] This application discovers that oroxylum indicum glycoside A has a therapeutic effect on hypertension and its complications. In animal experiments, a dose of only 10 mg / kg / day was sufficient to reduce elevated blood pressure, thickened abdominal aortic wall, elevated mesenteric artery pulsatility index and mesenteric artery resistance index, increase decreased left ventricular ejection fraction and left ventricular fractional shortening, and improve myocardial tissue pathology. The therapeutic effect is superior to the existing antihypertensive drug valsartan, providing a new treatment option for hypertension and its complications. Attached Figure Description

[0019] Figure 1The SBP results are for mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2.

[0020] Figure 2 The results of DBP in mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2 are shown.

[0021] Figure 3 The MAP results are for mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2.

[0022] Figure 4 The weight of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 2.

[0023] Figure 5 Ultrasound images of the abdominal aortic thickness in mice from the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 3.

[0024] Figure 6 The results show the abdominal aortic thickness of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 3.

[0025] Figure 7 The pathological morphology of the abdominal aorta in mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 4.

[0026] Figure 8 The heart tissue pathology of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 5.

[0027] Figure 9 The results of LVEF in mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 6 are shown.

[0028] Figure 10 The results of LVFS in mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 6 are shown.

[0029] Figure 11 Ultrasound images of the mesenteric arteries of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 7.

[0030] Figure 12 The results are the superior mesenteric artery pulsatility index of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 7.

[0031] Figure 13 The results are for the superior mesenteric artery resistance index of mice in the Control group, AngII group, AngII+Oroxin A group, and AngII+Valsartan group in Example 7. Detailed Implementation

[0032] 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.

[0033] 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.

[0034] When numerical ranges are given in the embodiments, it should be understood that, unless otherwise stated in this application, both endpoints of each numerical range and any value between the two endpoints may be selected. Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by one of ordinary skill in the art. In addition to the specific methods, apparatus, and materials used in the embodiments, based on the knowledge of the prior art possessed by one of ordinary skill in the art and the description in this application, any prior art methods, apparatus, and materials similar to or equivalent to those described, apparatus, and materials in the embodiments of this application may be used to implement this application.

[0035] This application first provides the use of oroxylin A or a pharmaceutically acceptable salt thereof in the preparation of medicaments for the prevention and / or relief and / or treatment of hypertension or its complications.

[0036] The molecular formula of oroxylin A is C. 21 H 20 O 10 The molecular weight is 432.378, the CAS number is 57396-78-8, and the structural formula is shown in Formula I below:

[0037]

[0038] In this application, the pharmaceutically acceptable salt refers to the salt of oroxylon ammodendronin A, prepared by oroxylon ammodendronin A with a relatively non-toxic acid or base. When oroxylon ammodendronin A contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of the compound of 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 resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, etc. When ornithoside A contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of this compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, 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.

[0039] In this application, prevention refers to taking measures to prevent the occurrence of a disease or reduce the risk of its 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 drugs described in this application.

[0040] In this application, remission refers to a significant reduction or disappearance of disease symptoms and an improvement in the patient's health status. Examples include: complete remission (all measurable signs and symptoms disappear completely, typically lasting for a period of time, e.g., one month or longer); partial remission (symptoms lessen but do not meet the criteria for complete remission); clinical remission (significant improvement in symptoms and signs, and improved quality of life, although some mild symptoms or signs may still be present); biochemical remission (reduction in disease activity as shown by laboratory tests, such as blood and urine biochemical indicators, but without significant improvement in clinical symptoms); and molecular remission (in some diseases, such as certain types of cancer, no evidence of disease can be found even under a microscope, and disease marker levels drop to undetectable levels). Remission signifies effective treatment and improved patient prognosis. However, disease remission does not always mean a complete cure, as some diseases may relapse. In some chronic diseases, such as diabetes and hypertension, remission may indicate effective control of the condition, but requires continued management to maintain the remission state.

[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 complication is selected from one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and kidney failure.

[0043] In a specific embodiment of this application, the abdominal aortic sclerosis is characterized by an increase in the thickness of the abdominal aorta.

[0044] In a specific embodiment of this application, the cardiac lesions manifest as cardiac hypertrophy, and / or myocardial infarction, and / or heart failure. Specifically, cardiac hypertrophy, and / or myocardial infarction, and / or heart failure can manifest as abnormal cardiac tissue pathological morphology and / or abnormal cardiac function.

[0045] In a specific embodiment of this application, the mesenteric artery lesion is characterized by abnormal mesenteric artery function.

[0046] In specific embodiments of this application, the drug is used to lower blood pressure, specifically by lowering mean arterial pressure, and / or lowering systolic blood pressure, and / or lowering diastolic blood pressure; more specifically, by lowering elevated mean arterial pressure, and / or lowering elevated systolic blood pressure, and / or lowering elevated diastolic blood pressure; or by inhibiting the increase in mean arterial pressure, and / or inhibiting the increase in systolic blood pressure, and / or inhibiting the increase in diastolic blood pressure.

[0047] In some embodiments of this application, patients with hypertension or its complications have elevated mean arterial pressure, systolic pressure, and diastolic pressure compared to healthy individuals. When oroxylum indicum A is administered to these patients, their mean arterial pressure, systolic pressure, and diastolic pressure decrease compared to when oroxylum indicum A is not administered.

[0048] In a specific embodiment of this application, the drug is used to improve the thickness of the abdominal aorta, specifically by reducing the thickness of the abdominal aorta; more specifically, by reducing the thickness of the thickened abdominal aorta in the target body.

[0049] In some embodiments of this application, the abdominal aorta of patients with hypertension or its complications is thicker than that of healthy individuals. When the patients are given orchidine A, the thickness of their abdominal aorta is reduced compared to when orchidine A is not given.

[0050] In a specific embodiment of this application, the drug is used to improve abnormal pathological morphology of cardiac tissue, specifically by making cardiomyocytes neatly arranged, and / or making the nuclei of cardiomyocytes clear, and / or making the cytoplasm of cardiomyocytes uniformly stained with HE, and / or reducing cardiomyocyte degeneration and necrosis; more specifically, by transforming disordered or poorly arranged cardiomyocytes into tightly arranged ones, and / or by transforming the nuclei of cardiomyocytes that appear blurred in HE staining into clearly visible ones in HE staining, and / or by transforming the cytoplasm of cardiomyocytes that are unevenly stained in HE staining into uniformly stained ones in HE staining, and / or reducing cardiomyocyte degeneration and necrosis.

[0051] In some embodiments of this application, compared to healthy individuals, cardiomyocytes in patients with hypertension or its complications show blurred nuclei, uneven cytoplasmic staining, disordered arrangement, or reduced regularity in HE staining. When oroxylin A is administered to these patients, their cardiomyocytes show clearer nuclei, more uniform cytoplasmic staining, and more regular or improved arrangement in HE staining compared to when oroxylin A is not administered. Furthermore, there is less cardiomyocyte degeneration and necrosis.

[0052] In specific embodiments of this application, the drug is used to improve abnormal cardiac function, specifically by increasing left ventricular ejection fraction and / or increasing left ventricular short-axis shortening rate; more specifically, by increasing the reduced left ventricular ejection fraction and / or increasing the reduced left ventricular short-axis shortening rate of the target; or by inhibiting the reduction of left ventricular ejection fraction and / or inhibiting the reduction of left ventricular short-axis shortening rate of the target.

[0053] In some embodiments of this application, patients with hypertension or its complications have lower left ventricular ejection fraction and left ventricular fractional shortening compared to healthy individuals. When the patients are given orchidinoside A, their left ventricular ejection fraction and left ventricular fractional shortening are increased compared to when orchidinoside A is not administered.

[0054] In specific embodiments of this application, the drug is used to improve abnormal mesenteric artery function, specifically by reducing the mesenteric artery pulsatility index and / or reducing the mesenteric artery resistance index; more specifically, by reducing the elevated mesenteric artery pulsatility index and / or reducing the elevated mesenteric artery resistance index in the target body; or by inhibiting the elevation of the mesenteric artery pulsatility index and / or inhibiting the elevation of the mesenteric artery resistance index in the target body.

[0055] In some embodiments of this application, the mesenteric artery pulsatility index and mesenteric artery resistance index are elevated in patients with hypertension or its complications compared to healthy individuals. When the patients are given orchidine A, their mesenteric artery pulsatility index and mesenteric artery resistance index are reduced compared to when orchidine A is not administered.

[0056] In this application, the target group can be a group that has had, is currently having, or may have hypertension or its complications.

[0057] In this application, the healthy group refers to a group that does not suffer from hypertension or its complications, and whose indicators involved in this application are normal.

[0058] In a specific embodiment of this application, the drug comprises an effective amount of oroxylon ammodendronin A or a pharmaceutically acceptable salt thereof.

[0059] In this application, the effective dose refers to the dose at which a drug, treatment or other intervention 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, such as an effective dose of ≥10 mg / kg / day.

[0060] In specific embodiments of this application, the effective amount of the oroxylon ammodendronin A or its pharmaceutically acceptable salt in the drug is greater than or equal to 10 mg / kg, for example, it can be 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, or greater than 40 mg / kg.

[0061] This application also provides a medicament for the prevention and / or relief and / or treatment of hypertension and its complications, comprising an effective amount of oroxylin and oxyphylla glycoside A or a pharmaceutically acceptable salt thereof.

[0062] In the specific embodiments of this application, the complications are selected from one or more of abdominal aortic sclerosis, heart disease, mesenteric artery disease, stroke, and renal failure, which are the same as those described above and will not be repeated here.

[0063] In a specific embodiment of this application, the drug is used for any one or more of the following: 1) lowering blood pressure; 2) improving abdominal aortic thickening; 3) improving abnormal cardiac tissue pathology; 4) improving abnormal cardiac function; 5) improving abnormal mesenteric artery function; the specifics are the same as those described above, and will not be repeated here.

[0064] In specific embodiments of this application, the effective amount of the oroxylon ammodendronin A or its pharmaceutically acceptable salt in the drug is greater than or equal to 10 mg / kg, for example, it can be 10 mg / kg, 15 mg / kg, 20 mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg, 40 mg / kg, or greater than 40 mg / kg.

[0065] The dosage form of the drug in this application is not limited, and may be one or more of the following: spray, nasal drops, solution, granules, aerosol, powder, tablet, injection, and capsule.

[0066] The medicament in this application may also include pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable excipients refer to those non-toxic excipients that do not affect the efficacy and safety of the main ingredient, oroxylin A, and do not produce adverse, allergic, or other adverse reactions. They should also be compatible with oroxylin A, meaning they can be mixed with it without significantly reducing its efficacy 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 its decomposition; 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; excipients, used to help form the drug into a specific form, such as tablets or capsules; 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; binders, used to hold the drug components together; suspending agents, such as ethoxylated isooctadecyl alcohol, polyoxyethylene sorbitol, dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures of these substances; and chelating agents, such as EDTA, used to bind to metal ions and prevent drug degradation. In addition, pharmaceutical formulations may also contain: low molecular weight peptides; proteins, such as immunoglobulins, serum albumin, or gelatin; amino acids, such as glycine, glutamic acid, arginine, asparagine, and lysine; sugars or carbohydrates, such as polysaccharides and monosaccharides; and sugar alcohols, such as sorbitol or mannitol. When 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); wetting agents; sweeteners; flavoring agents; emulsifiers; suspending agents; and flavorings. The types and proportions of these excipients or carriers can be adjusted according to the type and requirements of the final pharmaceutical formulation.

[0067] In the drug of this application, the oroxylon ammodendronin A can be a single active ingredient, or it can be combined with one or more other active ingredients that have therapeutic effects on hypertension or its complications to form a combined preparation, and the efficacy and safety of each component do not conflict. Other active ingredients can be various other drugs that can be used to treat hypertension or its complications, such as other drugs for treating hypertension, other drugs for treating abdominal aortic sclerosis, other drugs for treating heart disease, other drugs for treating mesenteric artery disease, other drugs for treating stroke, and other drugs for treating renal failure. Specific examples include: drugs for treating hypertension, such as calcium channel blockers (e.g., amlodipine, nifedipine, nifedipine), angiotensin-converting enzyme inhibitors (e.g., enalapril, ramipril, captopril), angiotensin receptor blockers (e.g., valsartan, losartan, candesartan, irbesartan, olmesartan medoxomil), diuretics (e.g., furosemide, hydrochlorothiazide, spironolactone, furosemide), beta-blockers (e.g., metoprolol, atenolol, bisoprolol), and angiotensin receptor neprilysin inhibitors (e.g., sacubitril / valsartan sodium); and drugs for treating abdominal aortic sclerosis, such as antiplatelet drugs (e.g., aspirin, clopidogrel, ticagrelor). Drugs containing nitrates include: lipid-lowering drugs (such as statins like atorvastatin and rosuvastatin), hypoglycemic drugs (such as metformin and acarbose), vasodilators (such as isosorbide mononitrate, nifedipine sustained-release tablets, and diltiazem), triglyceride-lowering drugs (such as fenofibrate and atorvastatin), cholesterol-lowering drugs (such as simvastatin and pravastatin), anticoagulants (such as unfractionated heparin, low molecular weight heparin, dabigatran, and xaban), and medications for treating heart disease, such as nitrates. Ester drugs (such as nitroglycerin, isosorbide dinitrate), renin-angiotensin-aldosterone system inhibitors (including angiotensin-converting enzyme inhibitors (ACEIs) such as perindopril), statins (such as lovastatin, fluvastatin), antiarrhythmic drugs (such as lidocaine, amiodarone, propafenone, ivabradine), cardiotonic drugs (such as fructose diphosphate sodium, coenzyme Q10, levocarnitine, or creatine phosphate sodium for injection), and cardiotonic drugs (such as digoxin, digoxin). The content of each component in the combination preparation 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).

[0068] When the drug in the present application is used as a preparation, it is preferably a unit dosage form, which refers to that the preparation is further divided into unit doses containing an appropriate amount of the active ingredient. The unit dosage form can be a solution, an injection, a syringe, a capsule, a tablet or any dosage form; in addition, the unit dosage form can also be a packaged preparation, such as a solution, an injection, a tablet, a capsule and a powder packaged in a vial or an ampoule, etc. The amount of the active ingredient in the unit dosage preparation can be changed or adjusted between 0.1 mg and 1000 mg, depending on the specific application and potency of the active ingredient.

[0069] When the drug described in the present application is used to treat hypertension or its complications in a subject, the product at an effective dose must be accurately administered to the subject so that the hypertension or its complications originally suffered by the subject can be effectively inhibited, reduced and even alleviated.

[0070] The present application also provides a method for treating hypertension or its complications, which is to administer an effective dose of the above-mentioned drug to a subject.

[0071] In the specific embodiments of the present application, the complications are selected from any one or more of abdominal aortic sclerosis, heart lesions, mesenteric artery lesions, stroke, and renal failure, which are the same as those described above and will not be elaborated here.

[0072] The subjects of the drug and method in the present application can specifically be various mammals, including but not limited to rodents, artiodactyls, perissodactyls, lagomorphs, 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 embodiments of the present application, the subject is a human or a mouse.

[0073] The present application will be further illustrated by the following examples, but the scope of the present application is not limited thereby. Unless otherwise stated, the experimental methods, detection methods, and preparation methods disclosed in the present application all adopt the conventional molecular biology, biochemistry, chromatin structure and analysis, analytical chemistry, cell culture, recombinant DNA technology and related conventional technologies in the technical field. These technologies have been well described in the existing literature. Unless otherwise specified, the instruments, reagents, and materials used in the embodiments of the present application can be obtained through conventional channels.

[0074] Experimental animals used in the examples:

[0075] In the embodiments of the present application, the material information used is as follows:

[0076] Experimental animals: SPF-grade C57BL / 6 male mice were purchased from Slake Experimental Animal Co., Ltd., and the experimental animal use license number: SYXK(Fujian)2020-0002.

[0077] Experimental drugs and main reagents: osmotic micropump (Alzet, 2004D); angiotensin II (AngII; Abcam, ab120183); oroxylin A (Shanghai Yuanye Biotechnology Co., Ltd., B20880); eosin staining solution (Beijing Solarbio Science & Technology Co., Ltd., g1100); hematoxylin staining solution (Beijing Solarbio Science & Technology Co., Ltd., g1140); isoflurane (Shenzhen Ruiwode Life Science & Technology Co., Ltd., 970-00026-00); paraformaldehyde (Fuzhou Feijing Biotechnology Co., Ltd., LA0427); anhydrous ethanol (Xilong Scientific Co., Ltd., 1280340101602); xylene (Xilong Scientific Co., Ltd., 1430030101600), and other chemical reagents.

[0078] Main instruments used in the experiment: pipettes (Renin, USA); electronic balance (Shanghai Ohaus Instruments Co., Ltd.); non-invasive rat tail sphygmomanometer (Kent, USA); Vevo2100 small animal ultrasound imaging system (Fujifilm Investment Co., Ltd.); inhalation anesthesia machine for small animals (Shenzhen Ruiwode Life Technology Co., Ltd.); pathology slide machine (Leica, Germany); paraffin embedding machine (Xiaogan Yaguang Medical Electronics Technology Co., Ltd., Hubei).

[0079] Statistical analysis:

[0080] Statistical analysis was performed using IBM SPSS Statistics (version 29.0.1.0). The Shapiro-Wilk test was used to test the normality of the data. The data were presented as mean and standard deviation. If the data met the condition of normality, ANOVA (one-way ANOVA) was used to assess the differences. In this case, depending on the homogeneity of the variances, the LSD (Least Significant Difference) method was chosen for post-hoc testing (when variances are homogeneous), or the Games-Howell method was used for post-hoc testing (when variances are unequal). For datasets that did not conform to a normal distribution, the nonparametric Kruskal-Wallis test was used to compare the differences between groups. A p-value less than 0.05 was considered statistically significant between groups.

[0081] Example 1: Drug preparation, experimental animal feeding, animal grouping, and model construction

[0082] Animal feeding: 12 healthy male C57BL / 6 mice (weight 19±1 g) were purchased from Slake Laboratory Animal Co., Ltd. (License number: SYXK(Fujian)2020 - 0002). All animals were housed in the SPF - level laboratory of the Experimental Animal Center of Fujian University of Traditional Chinese Medicine, provided with sufficient food and water, under a 12 - h light / dark cycle, at a temperature of 23±1 °C, and the humidity was controlled at 50%, all within the acceptable range for experimental animals. After 5 - 7 days of adaptive feeding, the mice were used for experiments. All animal experiments were conducted in accordance with the regulations of experimental animal ethics and the Animal Management Association of Fujian University of Traditional Chinese Medicine, and the experimental animal ethics review form has been approved, with the approval number 2W2024005.

[0083] Drug preparation:

[0084] Weigh an appropriate amount of oroxindin A powder, dissolve it in the corresponding volume of distilled water according to the average body weight of the mice at a dose of 10 mg / kg / d. After preparation, place it in an ultrasonic instrument and keep it under low - temperature ultrasonic treatment for about 1 h, then store it in a 4 °C refrigerator for later use to obtain oroxindin A solution.

[0085] Weigh an appropriate amount of AngII powder and dissolve it in high - pressure water to prepare a stock solution with a concentration of 1 mM. After preparation, store it in an - 80 °C refrigerator for later use to obtain AngII solution.

[0086] At the same time, weigh an appropriate amount of valsartan powder, dissolve it in the corresponding volume of distilled water according to the body weight of the mice at a dose of 10 mg / kg / d. After preparation, store it in a 4 °C refrigerator for later use to obtain valsartan solution.

[0087] Animal grouping: 12 male C57BL / 6 mice were randomly divided into 4 groups according to their basal blood pressure: Control group, AngII group, AngII + Oroxin A (10 mg / kg / d) group, and AngII + Valsartan (10 mg / kg / d) group. Each group had 3 mice.

[0088] Preparation of osmotic minipumps: One day before surgery, take out the osmotic minipumps in a laminar flow hood, and inject 200 μL of AngII solution into the osmotic minipumps of the AngII group, AngII + Oroxin A (10 mg / kg / d) group, and AngII + Valsartan (10 mg / kg / d) group respectively to obtain pre - set osmotic minipumps containing AngII.

[0089] Inject 200 μL of normal saline solution into the osmotic minipump of the Control group to obtain an osmotic minipump containing normal saline.

[0090] All groups of osmotic micropumps were immersed in physiological saline overnight in a cell culture incubator at 37°C and used for pump implantation surgery the next day.

[0091] Model Construction and Processing: On the day of surgery, the operating table was routinely disinfected. Mice were anesthetized with isoflurane, placed in a prone position, and the hair on the head, neck, and back was removed. After disinfection with povidone-iodine, the skin was cut with scissors, and the subcutaneous tissue was bluntly dissected. Mice in the AngII group, AngII+Oroxin A (10 mg / kg / d), and AngII+Valsartan (10 mg / kg / d) groups were subcutaneously implanted with pre-placed osmotic micropumps containing AngII. Simultaneously, mice in the Control group were subcutaneously implanted with pre-placed osmotic micropumps containing physiological saline. After implantation of the corresponding osmotic micropumps in each group, the skin was sutured and disinfected.

[0092] The day after the pump was implanted, mice in the AngII+Oroxin A (10 mg / kg / d) group were given 10 mg / kg / d of Oroxin A solution by gavage, mice in the AngII+Valsartan group were given 10 mg / kg / d of Valsartan solution by gavage, and mice in the Control group and AngII group were given an equal volume of distilled water by gavage. The treatment was administered once a day for a total of 4 weeks.

[0093] Example 2: Effects of oroxylon ammodendronin A on blood pressure and body weight in mice

[0094] Blood pressure measurement:

[0095] During the experimental period, CODA was used. TM A non-invasive precision blood pressure monitor was used to regularly monitor key blood pressure parameters in laboratory mice, including mean arterial pressure (MAP), systolic blood pressure (SBP), and diastolic blood pressure (DBP), once a week. The obtained data underwent detailed statistical analysis. The specific operating procedure is detailed below:

[0096] (1) Ensure the correct assembly and connection of equipment such as mouse heating plate, sensor and computer to make full preparations for the experiment.

[0097] (2) Gently place the experimental mice in the restraints and place them steadily on the mouse heating plate. Turn on the heating plate to maintain a constant body temperature of the mice and promote smooth blood flow in the tail artery.

[0098] (3) Carefully attach the occlusion kit and volumetric pressure sensor to the tail of the mouse to ensure the accuracy and stability of the measurement process.

[0099] (4) Launch the Coda 4.1 software and set the corresponding measurement parameters according to the experimental requirements. Each measurement cycle contains 15 cycles. Before the formal measurement, allow the mice to rest quietly on the heating plate for 10 minutes to reduce the influence of external interference on the measurement results. At the same time, keep the surrounding environment quiet and stable throughout the measurement process. After the measurement is completed, the volumetric pressure sensor will automatically transmit the data of each measurement to the computer for storage and analysis.

[0100] (5) Record the systolic blood pressure, diastolic blood pressure, mean arterial pressure and body weight of each mouse in detail each week, and calculate their mean and standard deviation for subsequent statistical analysis.

[0101] The effect of oroxylin A on blood pressure is shown in the following results. Figure 1 , Figure 2 and Figure 3 .

[0102] like Figure 1 As shown, SBP in mice increased significantly after AngII intervention, with a statistically significant difference compared to the Control group (P<0.05). After oroxylin A intervention, SBP in the AngII+Oroxin A group decreased significantly compared to the AngII group. These results indicate that oroxylin A intervention can significantly inhibit the increase in SBP in the AngII group.

[0103] like Figure 2 As shown, DBP in mice increased significantly after AngII intervention, with a statistically significant difference compared to the Control group (P<0.05). After oroxylin A intervention, DBP in the AngII+Oroxin A group decreased significantly compared to the AngII group. These results indicate that oroxylin A intervention can significantly inhibit the increase in DBP in the AngII group.

[0104] like Figure 3 As shown, MAP in mice increased significantly after AngII intervention, with a statistically significant difference compared to the Control group (P<0.05). After oroxylin A intervention, MAP in the AngII+Oroxin A group decreased significantly compared to the AngII group. These results indicate that oroxylin A intervention can significantly inhibit the increase in MAP in the AngII group.

[0105] Simultaneously, body weight measurements revealed that intervention with oroxylum indicum A had no significant effect on mouse body weight. Figure 4 ).

[0106] Example 3: Investigation of the effect of oroxylon ammodendronin A on the thickness of the abdominal aorta in mice.

[0107] Mice were first induced with AngII, and then treated with oroxylum indicum A for 4 weeks. The blood vessel thickness of each group of mice was detected and analyzed by small animal ultrasound.

[0108] Abdominal aortic thickness measurement:

[0109] (1) Echocardiography detection period: The abdominal aortic vascular function of mice in each experimental group was comprehensively detected using the Vevo 2100 small animal ultrasound imaging system.

[0110] (2) Abdominal hair removal and animal anesthesia procedure: First, the hair on the mouse's abdomen was carefully removed using depilatory cream to ensure clear contact with the ultrasound probe. Then, the mouse was anesthetized by inhalation with 1.5% isoflurane and securely fixed in a supine position on a 37°C constant temperature heating plate in preparation for the subsequent ultrasound examination.

[0111] (3) Acquisition of abdominal aortic imaging sections: Ultrasound coupling agent was evenly applied to the anterior chest and abdomen of mice to fully expose the abdominal aortic region. High-quality abdominal aortic section images were acquired by adjusting the probe position and angle. The probe operating frequency was set to 30MHz to ensure the clarity and accuracy of the imaging.

[0112] (4) Ultrasound data analysis and calculation methods: After the examination, Vevo Strain Software (Vevo LAB 1.7.1) was used to perform in-depth analysis of the acquired ultrasound data. The abdominal aortic wall thickness of each group of mice was calculated, and each index was based on the average of three independent measurements to ensure the reliability of the data.

[0113] from Figure 5 and Figure 6 It was found that, compared with the Control group, the thickness of the abdominal aorta in the AngII group mice was significantly increased (P<0.05), while the thickness of the abdominal aorta in mice after intervention with oroxylum indicum A was significantly decreased (P<0.05).

[0114] Example 4: Investigation of the pathological morphology of the abdominal aorta in mice by oroxylum indicum A

[0115] HE staining was used to observe the changes in the morphology of the abdominal aorta in mice caused by oroxylum indicum glycoside A.

[0116] HE staining:

[0117] (1) Fixed:

[0118] Mouse abdominal aortic and heart tissue samples were fixed in 4% paraformaldehyde for 48 hours, then placed in tissue embedding cassettes and labeled.

[0119] (2) Dehydration and wax impregnation:

[0120] Heart tissue samples were dehydrated in the following order: 70% anhydrous ethanol (60 min) → 80% anhydrous ethanol (60 min) → 90% anhydrous ethanol (60 min) → 95% anhydrous ethanol (60 min) → 100% anhydrous ethanol I (20 min) → 100% anhydrous ethanol II (20 min) → 100% anhydrous ethanol III (50 min) → xylene I (5 min) → xylene II (20 min) → paraffin I (10 min) → paraffin II (20 min) → paraffin III (30 min).

[0121] (3) Embedding:

[0122] Preheat the embedding mold, place the tissue upright in the center of the bottom of the embedding mold, add melted paraffin wax, and gently place the embedding cassette on top of the mold. Transfer the mold to a cooling table and wait for the paraffin wax to solidify. Place the wax block in a -20°C refrigerator overnight, then separate the wax block from the mold and store at room temperature.

[0123] (4) Slicing:

[0124] Pre-cool the tissue blocks in a -20°C freezer. Fix the blocks onto a paraffin microtome and perform initial tissue trimming at a coarse thickness of 10 μm until the complete tissue structure is visible. Then adjust the section thickness to 4 μm for fine trimming. Place the cut tissue sections in 39°C warm water. After the sections flatten, retrieve them using an adhesive slide. Bake at 60°C for 1 hour, then bake for 3 hours. Store the sections at room temperature.

[0125] (5) Dewaxing:

[0126] Dewaxing was performed by immersing the reagents in the following order: Xylene I (25 min) → Xylene II (25 min) → Xylene III (15 min) → 100% anhydrous ethanol I (5 min) → 100% anhydrous ethanol II (5 min) → 95% anhydrous ethanol (5 min) → 80% anhydrous ethanol (5 min) → 70% anhydrous ethanol (5 min) → ultrapure water I (5 min) → ultrapure water II (5 min).

[0127] (6) Hematoxylin staining:

[0128] Immerse the slide in hematoxylin solution for 30 seconds to stain, then rinse three times with pure water.

[0129] (7) Eosin staining:

[0130] Immerse the glass slide in eosin solution for 15 seconds, then rinse with pure water three times.

[0131] (8) Sealing:

[0132] After staining, allow the tissue sections to air dry, then add neutral resin for mounting.

[0133] (9) Microscopic observation:

[0134] The pathological changes of each group of samples were observed using an intelligent tissue section analysis system. The whole sample image of each sample was taken at 12.5× field of view, and 6 areas were randomly selected for imaging at 400× field of view.

[0135] See results Figure 7 Compared with the control group, the abdominal aortic wall of mice in the AngII group was thickened, while the thickening of the abdominal aortic wall of mice was reduced after intervention with oroxylum indicum A.

[0136] Example 5: Investigation of the effect of oroxylon ammodendronin A on the pathological morphology of mouse heart.

[0137] The effect of oroxylon ammodendronin A on the pathological morphology of cardiac tissue in AngII-induced mice was assessed by HE staining. The HE staining method was the same as in Example 4.

[0138] See results Figure 8 In the Control group, the nuclei of the cardiomyocytes were clear, the cytoplasm was uniformly stained, and the cells were arranged tightly and neatly without degeneration or necrosis. Compared with the Control group, the morphology of the heart tissue in the AngII group was significantly changed: the neatness of the cardiomyocyte arrangement was significantly reduced. In contrast, the pathological morphology of the myocardial tissue in mice after intervention with oroxylum indicum A was significantly improved.

[0139] Example 6: Investigation of the effect of oroxylon ammodendronin A on cardiac function in mice

[0140] Mice were first induced with AngII, and then treated with oroxylum indicum A for 4 weeks. Small animal ultrasound was used to detect and analyze the left ventricular ejection fraction and left ventricular fractional shortening rate of each group of mice.

[0141] Specifically, following the "Abdominal Hair Removal and Animal Anesthesia Procedure" in Example 3 of the mouse anesthesia protocol, the ultrasound probe was placed vertically on the left chest of the mouse, and the probe was adjusted so that its notch faced the mouse's head. In B-Mode, the probe was slowly adjusted until a clear cardiac image was obtained. Then, the mode was switched to M-Mode to acquire the mouse's cardiac cycle. Data from at least three cardiac cycles were measured for each mouse, and the average value was taken after the ultrasound scan for subsequent statistical analysis. The measured cardiac function parameters were left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and stroke volume (SV).

[0142] The heart’s main function is to pump blood. The amount of blood ejected by one ventricle in one heartbeat is called stroke volume, or simply stroke volume.

[0143] from Figure 9 and Figure 10 It was found that, compared with the Control group, the LVEF and LVFS of mice in the AngII group were significantly reduced (P<0.05), while the LVEF and LVFS of mice increased after intervention with oroxylum indicum A (P<0.05).

[0144] Example 7: Investigation of the effect of oroxylon ammodendronin A on the function of the mesenteric artery in mice.

[0145] Mesenteric artery pulsatility index and resistance index measurement:

[0146] The hair removal and animal anesthesia procedures are the same as in Example 3, "Abdominal Hair Removal and Animal Anesthesia Procedure." The probe is positioned at the midline of the abdomen, displaying the abdominal aorta along a longitudinal section. The mesenteric artery is then located downwards. A pulsed Doppler ultrasound is used to display the blood flow spectrum. After adjusting the angle between the blood flow and the sound beam, a cross-sectional image of the mesenteric artery is acquired. The average values ​​of each indicator are used to calculate and analyze the changes in mesenteric artery blood flow, calculated according to the following formula:

[0147] Pulsatility Index: PI = (Peak systolic velocity - Average diastolic velocity) / Average velocity;

[0148] Resistance index: RI = (peak systolic velocity - end diastolic velocity) / peak systolic velocity.

[0149] The function of the mesenteric artery was assessed using ultrasound in small animals. For example... Figure 11 , Figure 12 and Figure 13 As shown, compared with the Control group, the superior mesenteric artery pulsatility index (SMA PI) and superior mesenteric artery resistance index (SMA RI) of mice in the AngII group were significantly increased (P<0.05); compared with the AngII group, after intervention with oroxylum indicum A, both the superior mesenteric artery pulsatility index and the superior mesenteric artery resistance index were significantly decreased (P<0.05).

[0150] In summary, oroxylum indicum glycoside A significantly reduced blood pressure in AngII model mice, improved vascular function, alleviated abdominal aortic thickening and pathological changes, and improved cardiac function. It also improved myocardial cell hypertrophy and vascular wall thickening caused by hypertension.

[0151] 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 oroxylin A or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and / or relief and / or treatment of complications of hypertension; said complications being selected from abdominal aortic sclerosis, heart disease, and mesenteric artery disease; The abdominal aortic sclerosis is characterized by an increase in the thickness of the abdominal aorta. The mesenteric artery lesions are characterized by abnormal mesenteric artery function; The cardiac lesions are manifested as abnormal pathological morphology of cardiac tissue and / or abnormal cardiac function.

2. The use according to claim 1, characterized in that, The drug is used for one or more of the following: 1) Lower blood pressure; 2) Improves the thickness of the abdominal aorta; 3) Improves abnormal pathological morphology of cardiac tissue; 4) Improves abnormal cardiac function; 5) Improves abnormal mesenteric artery function.

3. The use according to claim 2, characterized in that, The reduction of blood pressure refers to reducing mean arterial pressure, and / or reducing systolic blood pressure, and / or reducing diastolic blood pressure; The improvement of abdominal aortic thickness refers to reducing the thickness of the abdominal aorta. The improvement of cardiac tissue pathological morphology refers to making cardiomyocytes neatly arranged, and / or making the cell nuclei of cardiomyocytes clear, and / or making the cytoplasm of cardiomyocytes uniformly stained with HE, and / or reducing cardiomyocyte degeneration and necrosis. The improvement of cardiac function refers to increasing the left ventricular ejection fraction and / or increasing the left ventricular fractional shortening. The improvement of mesenteric artery function refers to reducing the mesenteric artery pulsatility index and / or reducing the mesenteric artery resistance index.

4. The use according to claim 1, characterized in that, The drug comprises an effective amount of oroxylon ammodendronin A or a pharmaceutically acceptable salt thereof.

5. The use according to claim 4, characterized in that, The effective amount of the oroxylon ammodendronin A or its pharmaceutically acceptable salt in the drug is greater than or equal to 10 mg / kg.

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