Application of chest stuffiness relieving composition in preparation of medicine for treating and / or preventing heart failure

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of a chest stuffiness relieving composition in preparation of a medicine for treating and / or preventing heart failure. According to the application, the chest stuffiness relieving composition is used for treating the heart failure, especially the ejection fraction reduction type heart failure, action mechanism research and animal experiment verification of the chest stuffiness relieving composition show that the curative effect is remarkable, the symptoms of the heart failure can be improved from multiple levels, the treatment effect is improved, and a new scheme is provided for clinical treatment of the ejection fraction reduction type heart failure.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to the use of a chest-widening composition in the preparation of a medicine for treating and / or preventing heart failure. Background Art

[0002] Heart failure (HF) is a serious manifestation or late stage of various heart diseases, characterized by impaired cardiac pump function, which cannot meet the body's metabolic needs. It is mainly manifested by dyspnea, fatigue and fluid retention (pulmonary congestion, systemic congestion and peripheral edema), etc. It has the characteristics of high morbidity, high mortality and high re-hospitalization rate. Its 5-year survival rate is similar to that of malignant tumors. The mortality rate of patients with heart function grade IV (NYHA classification) can reach 40%-50%; for patients with uncontrolled heart failure, the 5-year mortality rate can reach 62%. The "World Heart Report 2023" released by the World Heart Federation shows that the number of heart failure patients worldwide has reached 64 million.

[0003] Heart failure can be divided into acute heart failure (AHF) and chronic heart failure (CHF) according to the course of the disease; it can be divided into heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) according to the ejection fraction (EF). Heart failure with reduced ejection fraction (HFrEF) is a common type of heart failure, which is mainly characterized by a left ventricular ejection fraction (LVEF) < 40%, and cardiac systolic dysfunction is its main pathophysiological mechanism.

[0004] The main purpose of treating heart failure is to alleviate the symptoms of heart failure, prolong survival, improve the quality of life, and prevent disease progression. For example, the current treatment goals of chronic HFrEF are mainly to improve clinical symptoms and quality of life, prevent or reverse cardiac remodeling, reduce rehospitalization, and reduce mortality. Although modern medicine has made significant progress in the treatment of heart failure, for example, the "quadruple therapy" represented by angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor antagonists (ARB), β-blockers and aldosterone antagonists, and SGLT-2 inhibitors is the cornerstone of HFrEF treatment. When the patient's symptoms are alleviated through treatment, it is necessary to consider how to prolong the patient's survival, but long-term use of these drugs will cause certain adverse reactions, as well as poor tolerance in some patients and high treatment costs. Specifically, HFrEF patients usually need long-term medication, but some Western medicines (such as ARNI, spironolactone) have adverse reactions such as renal damage, hyperkalemia, and hypotension, which affect patient tolerance.

[0005] Traditional Chinese medicine believes that heart failure belongs to the category of "palpitations", "asthma", "edema", etc., and the pathogenesis involves qi deficiency and blood stasis, water retention, yang deficiency, etc. The treatment principle is based on "tonifying qi and warming yang, promoting qi and removing blood stasis, promoting diuresis and reducing swelling". However, the existing Chinese medicines used to treat heart failure are mainly based on the ideas of promoting blood circulation and removing blood stasis, regulating qi and relieving pain. Although they have certain therapeutic effects, they are slow to take effect due to the preparation or prescription composition, and there are still problems such as unsatisfactory long-term efficacy and incurable diseases, and the treatment mechanism has not been explored.

[0006] The wide-chest composition is a modern Chinese medicine preparation developed based on the theory of traditional Chinese medicine. Its main ingredients include sandalwood oil, piper longum oil, asarum oil, galangal oil and borneol. It was originally used to treat angina pectoris caused by coronary heart disease, and exerts its efficacy by dilating coronary arteries, improving myocardial blood supply, and relieving angina symptoms. Among them, ingredients such as sandalwood oil and piper longum oil can dilate blood vessels and promote coronary circulation; asarum oil and galangal oil can warm the yang and dispel cold, relieve vasospasm; borneol can enhance drug permeability and improve bioavailability. On this basis, the applicant also explored the therapeutic effects of the wide-chest composition or drugs containing it in stroke and myocardial injury, such as patent application 2020112531539 and patent 2023114615138.

[0007] Based on the treatment goal of chronic HFrEF and the shortcomings of existing drugs for the treatment of heart failure, it is urgent to study Chinese medicine with effective therapeutic effects. At present, there is no report on the study of the wide-chest composition in heart failure, especially heart failure with reduced ejection fraction. This study has important clinical significance for the treatment of chronic HFrEF and the expansion of new uses of the wide-chest composition. Summary of the invention

[0008] In order to overcome the shortcomings of the prior art, the present invention provides an application of a wide-chest composition in the preparation of a drug for treating and / or preventing heart failure, which is significantly effective in improving heart failure with reduced ejection fraction, improves the therapeutic effect, provides a new solution for the clinical treatment of heart failure with reduced ejection fraction, and solves the problems existing in the prior art.

[0009] The present invention provides the following technical solutions:

[0010] The invention discloses an application of a chest-opening composition in preparing a medicine for treating and / or preventing heart failure. The chest-opening composition is prepared from the following effective ingredients: 50-80 parts by volume of sandalwood oil, 8-22 parts by volume of piper longum oil, 10-30 parts by volume of asarum oil, 20-40 parts by volume of galangal oil and 10-30 parts by weight of borneol.

[0011] Furthermore, the heart failure is heart failure with reduced ejection fraction.

[0012] Furthermore, the asarum oil, sandalwood oil, galangal oil and piper longum oil are all volatile oils extracted separately from the corresponding medicinal materials through steam distillation.

[0013] Furthermore, the effective ingredients and dosages of the above-mentioned chest-widening composition are preferably: 70 parts by volume of sandalwood oil, 15 parts by volume of piper longum oil, 23 parts by volume of asarum oil, 32 parts by volume of galangal oil, and 22.5 parts by weight of borneol.

[0014] Furthermore, the above-mentioned chest-widening composition also includes pharmaceutically acceptable excipients.

[0015] Furthermore, the auxiliary materials are conventional auxiliary materials for preparing the wide-chest composition into different pharmaceutical preparations; the pharmaceutical preparations are liquid preparations, solid preparations or gas preparations.

[0016] Furthermore, the chest-widening composition is in the form of a liquid preparation, and the content of the active ingredient in the liquid preparation is 0.2-0.25 mL / mL.

[0017] Furthermore, the auxiliary material of the liquid preparation of the wide-chest composition is ethanol.

[0018] The effective ingredient content of the liquid preparation is preferably 0.22mL / mL. That is, 1mL of the wide-chest composition liquid preparation is composed of two parts: effective drug ingredients and excipients. The effective drug ingredients are sandalwood oil, piper longum oil, asarum oil, galangal oil and borneol, accounting for 22%, which is approximately equal to 0.22mL; the excipient ethanol accounts for 78%, which is approximately equal to 0.78mL.

[0019] Furthermore, the preparation of the above-mentioned chest-widening composition includes the following steps: mixing the above-mentioned sandalwood oil, galangal oil, asarum oil, and piper longum oil in the above-mentioned weight parts, placing in a 40°C water bath, adding borneol, slightly heating to dissolve, adjusting the total amount to 22%-25% of the active ingredient content with anhydrous ethanol, and mixing well to obtain the composition.

[0020] The beneficial effects of the present invention include but are not limited to:

[0021] 1. The wide-chest composition of the present invention has a good therapeutic effect on heart failure with reduced ejection fraction (HFrEF). Its mechanism of action is different from the simple improvement of coronary blood supply in the treatment of angina pectoris. Instead, it plays a protective role by enhancing myocardial contractility, improving cardiac energy metabolism, and reducing inflammation and oxidative damage. It complements the mechanism of action of existing Western medicines and can become a new choice for the treatment of HFrEF. It has outstanding innovation and clinical transformation value.

[0022] 2. The chest-widening composition of the present invention is derived from the theory of traditional Chinese medicine "promoting qi and blood circulation, warming yang and unblocking collaterals, and aromatic invigorating the orifices". The various components work synergistically and can improve cardiac function through multiple mechanisms such as regulating calcium ion homeostasis, resisting oxidative stress, reducing inflammatory response, and dilating blood vessels, and multi-target intervention in the pathological process of heart failure. It has unique advantages in improving cardiac function, regulating hemodynamics, and protecting myocardial cells. It can improve the symptoms of patients with heart failure from multiple levels and improve the treatment effect.

[0023] 3. Compared with existing Western medicines for the treatment of heart failure, the wide-chest composition of the present invention can reduce adverse reactions such as kidney damage, hyperkalemia, and hypotension caused by long-term medication in HFrEF patients, and has relatively small toxic and side effects. It is suitable for long-term use, can improve patient compliance, and reduce drug intolerance problems in patients with chronic heart failure. Therefore, the development of the wide-chest composition as a new treatment for HFrEF provides a safer, long-term, and economical new option for patients with heart failure.

[0024] 4. Animal experiments of the present invention show that the wide-chested composition can significantly inhibit the dilatation of the left ventricular cavity in HFrEF rats, thereby improving the ejection fraction (EF) and the left ventricular shortening fraction (FS), enhancing the myocardial contractility, reducing myocardial hypertrophy, and improving the cardiac function level of rats with heart failure; it can significantly improve the myocardial tissue lesions and myocardial fibrosis in rats with heart failure, reduce myocardial cell apoptosis and collagen deposition, and prevent cardiac remodeling. Pathological analysis showed that HE staining revealed that it reduced myocardial cell damage, and Masson staining confirmed that it inhibited myocardial fibrosis, indicating that the composition can not only relieve symptoms, but also prevent the progression of HFrEF from a pathological level. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 Design of experimental process for the wide-chest composition of the present invention to prevent and treat heart failure with reduced ejection fraction;

[0026] Figure 2 The ultrasonic cardiogram test results and statistical analysis of rats in each experimental group of the present invention;

[0027] Figure 3 Analysis of the serum biochemical test results of rats in each experimental group of the present invention;

[0028] Figure 4 This is the detection and comparative analysis of the myocardial tissue pathological morphology of rats in each experimental group of the present invention.

[0029] in, Figure 2 In a, from left to right, there are myocardial ultrasound images of the sham operation group (sham group), model group (HF), wide chest combination low-dose group (KXL), and wide chest combination high-dose group (KXH); b is the statistics of left ventricular ejection fraction of each group; c is the statistics of short axis shortening rate of each group;

[0030] Figure 3 ae in the middle are the test results of serum biochemical indexes creatine kinase (CK), creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-ProBNP) of rats in each group;

[0031] Figure 4 a is the myocardial tissue image of each group stained with HE, b is the myocardial tissue image of each group stained with Masson, c is the heart body mass index (HW / BW) statistics of each group, and d is the statistics of the degree of myocardial fibrosis of each group. DETAILED DESCRIPTION

[0032] In order to clearly illustrate the technical features of this solution, the present invention is described in detail below through specific implementation methods in conjunction with the accompanying drawings. The scope of the present invention is not limited to the following embodiments. Professionals in the field can understand that various changes and modifications can be made to the present invention without departing from the spirit and scope of the present invention. In the embodiments of the present invention, unless otherwise specified, all parts and percentages are weight units, and the equipment and raw materials used can be purchased from the market or are commonly used in the field. The experimental methods, detection methods, etc. involved in the following embodiments, unless otherwise specified, are all conventional experimental methods, detection methods, etc. existing in the prior art.

[0033] This embodiment provides a therapeutic application of a wide-chest composition for improving heart failure with reduced ejection fraction (HFrEF). The raw material composition and preparation of the wide-chest composition are as follows:

[0034] 50-80 parts by volume of sandalwood oil, 8-22 parts by volume of piper longum oil, 10-30 parts by volume of asarum oil, 20-40 parts by volume of galangal oil and 10-30 parts by weight of borneol.

[0035] Preparation steps: Mix the above volumes of sandalwood oil, galangal oil, asarum oil and piper longum oil, place in a 40°C water bath, add borneol, heat slightly to dissolve, adjust the total amount to 22% of the active ingredient content with anhydrous ethanol, mix well, and obtain.

[0036] The therapeutic effect and efficacy of the above wide-chest composition in heart failure with reduced ejection fraction (HFrEF) were specifically verified through the following animal experiments.

[0037] The therapeutic drugs and their specific preparations used in animal experiments are as follows:

[0038] 70mL sandalwood oil, 15mL piper longum oil, 23mL asarum oil, 32mL galangal oil, 22.5g borneol; auxiliary material ethanol. Mix the above amounts of sandalwood oil, galangal oil, asarum oil, and piper longum oil, place in a 40℃ water bath, add borneol, heat slightly to dissolve, adjust the total amount to 625mL with anhydrous ethanol, mix well, and you have it.

[0039] The prepared wide-chest combination liquid was taken and administered at 200 μL / kg and 100 μL / kg for the wide-chest combination high-dose group and the wide-chest combination low-dose group.

[0040] 1. Experimental Materials and Animals

[0041] 1.1 Main experimental materials

[0042] Masson trichrome staining kit (Biyuntian, C0189M); HE staining kit (Biyuntian, C0105M); rat creatine kinase MB isoenzyme (CKMB) ELISA kit (ELISA, ml107008); rat lactate dehydrogenase (LDH) ELISA kit (ELISA, ml106660); rat brain natriuretic peptide (BNP) ELISA kit (ELISA, ml003039); rat amino-terminal pro-brain natriuretic peptide (NT-ProBNP) ELISA kit (ELISA, ml028489).

[0043] 1.2 Experimental animals

[0044] Male SD rats were purchased from Beijing Weitonglihua Experimental Animal Technology Co., Ltd. and housed in the SPF barrier environment of the Animal Experiment Center of Zhejiang Suken Pharmaceutical Co., Ltd. Rats were fed with standard rodent food and water in an animal room with a constant temperature and a 12-12h day and night rhythm for one week. All protocols involving animal use were approved by the Ethics Committee of Zhejiang Suken Pharmaceutical Co., Ltd.

[0045] 2. Experimental Methods

[0046] 2.1 Preparation and grouping of rat heart failure model

[0047] The SD rats were weighed and anesthetized by intraperitoneal injection of 1% sodium pentobarbital at a dose of 5 ml / kg. The rats were fixed on a mouse board in a supine position. The skin on the left edge of the sternum was prepared and disinfected, and the muscles were separated. The 3rd to 5th ribs were cut off on the left chest. After opening the chest, the pericardium was torn to fully expose the heart. The left anterior descending coronary artery (LAD) was used as a landmark, and the needle was inserted 1-2 mm below the left atrial appendage. The needle was threaded across the LAD with a depth of 1.0-1.5 mm and a width of 2.0-3.0 mm. After the ligation was completed, the blood supply area of ​​the anterior descending coronary artery became pale, indicating that the rat myocardial infarction model was successfully established. The wound was sutured layer by layer, and the rat's breathing was stable, the cannula was removed, and the rat was moved to a warming blanket to maintain body temperature. After the anterior descending coronary artery of the rat was ligated, the blood supply area of ​​the anterior descending coronary artery became pale.

[0048] One week after the operation, the patient's mental state was poor, he ate little, felt weak and less active, his fur was dull, and cyanosis was visible on the lips and bottom of his paws.

[0049] Four weeks after rat modeling, all modeling rats were tested, and after screening according to EF < 40%, they were divided into sham operation group, model group (equal volume of normal saline), low-dose group of wide-chest combination (100 μL / kg), and high-dose group of wide-chest combination (200 μL / kg), with 10 rats in each group. The administration period was 4 weeks, and cardiac ultrasound was performed again after the end. The experimental process design is shown in Figure 1 .

[0050] 2.2 Echocardiography

[0051] On the second day after the last administration, all rats were anesthetized by isoflurane inhalation. The 10S probe equipped on the Mindray M9 small animal ultrasound instrument was used for detection. The parasternal left ventricular short-axis section was taken, and the M-type curve was guided by two-dimensional ultrasound and measured. The measurement indicators included: left ventricular end-diastolic diameter LVIDd, left ventricular end-systolic diameter LVIDs, left ventricular ejection fraction LVEF, and left ventricular shortening fraction LVFS. Each indicator was measured over 3 consecutive cardiac cycles and the average value was taken.

[0052] 2.3 Heart weight detection

[0053] After euthanasia, the rats were euthanized by blood sampling from the abdominal aorta, and the thoracic cavity was quickly opened to remove the heart. The heart was cleaned with 4°C saline, and the fascia, left and right atria and other tissues were cut off. The water was absorbed with filter paper, and the whole heart weight (HW) was weighed and recorded on a precision electronic balance. The ratio of heart mass (HW) / body mass (BW) (g / kg) was used as the heart mass index (HWI).

[0054] 2.4 Serum biochemical index detection

[0055] Biochemical indexes tested include creatine kinase (CK), creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH), brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-ProBNP), which are used to assess the degree of myocardial damage and cardiac function.

[0056] Serum was collected and the levels of CK, CK-MB, LDH, BNP and NT-proBNP in serum were determined.

[0057] 2.5 Observation of myocardial tissue pathology

[0058] Pathological analysis Hematoxylin-eosin (HE) staining and Masson staining were used to observe the pathological changes and degree of fibrosis in myocardial tissue.

[0059] The heart tissue was fixed in 4% paraformaldehyde for 24 hours, dehydrated with gradient ethanol, transparentized with xylene, embedded in paraffin, sliced ​​(3-5 μm), and stained with HE. The morphological changes of myocardial tissue were observed under a microscope at 200 times. Myocardial fibrosis detection: Myocardial tissue was fixed, and the preparation process of pathological sections was the same as HE staining, and staining was performed according to the Masson staining kit.

[0060] 3. Experimental Results

[0061] 3.1 High-frequency echocardiography to detect myocardial hypertrophy and heart failure development

[0062] High-frequency echocardiography was used to detect cardiac function in rats 8 weeks after TAC. Figure 2 In a, compared with the control group, the model group showed significant myocardial hypertrophy and the heart chamber was significantly enlarged; see Figure 2 In middle b, the cardiac function was significantly lower than that in the Sham group, indicating that the establishment of the heart failure model was effective.

[0063] At the same time, it can be observed that after 4 weeks of administration of wide chest high and low dose, the dilatation of the left ventricle in rats with heart failure can be significantly inhibited, myocardial hypertrophy can be reduced, and the cardiac function is significantly better than that of the model group rats. Figure 2 As shown in a, b, and c, the left ventricular ejection fraction (EF) and fractional shortening (FS) increased by 10%-20% in a dose-dependent manner, indicating that the ventricular cavity's blood discharge function was restored.

[0064] 3.2 Effects of Kuanxiong Composition on Serum Biochemical Indexes in Rats with Heart Failure

[0065] The improvement effect of the wide-chest composition on myocardial damage and the progression of heart failure was further verified by detecting serum biochemical indicators of rats with heart failure with reduced ejection fraction (HFrEF).

[0066] The results showed that compared with the model group, the high- and low-dose (200 μL / kg, 100 μL / kg) administration groups of the wide-chest composition could reduce the levels of CK, CK-MB, LDH, BNP and NT-proBNP in serum to varying degrees. Figure 3 , indicating that it has a protective effect on myocardial cells and can improve cardiac function decline.

[0067] Among them, creatine kinase (CK) and creatine kinase isoenzyme (CK-MB) are key indicators reflecting myocardial damage. This experiment found that the wide chest composition significantly reduced these two indicators, such as Figure 3 Figures a and b indicate that it can reduce myocardial cell damage, which may be related to its antioxidant, anti-inflammatory and myocardial energy metabolism-improving mechanisms.

[0068] In addition, the reduction in lactate dehydrogenase (LDH) levels further indicated that the composition had a certain protective effect in alleviating myocardial cell necrosis, such as Figure 3 As shown in c.

[0069] B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) are cardiac neurohormones released by the ventricles. They are secreted from the ventricles reactively only when blood volume increases and pressure is overloaded. They are specific and sensitive indicators of ventricular dysfunction. When myocardial cells are insufficiently supplied with blood oxygen or when ventricular volume undergoes pathological changes, their levels increase significantly and are often used as biomarkers for patients with heart failure. Experimental results show that the wide-chest composition can reduce the levels of BNP and NT-proBNP, see Figure 3 Figures d and e in the middle indicate that it can reduce left ventricular remodeling and improve ventricular diastolic function, possibly through mechanisms such as dilating coronary arteries and improving myocardial blood and oxygen supply.

[0070] 3.3 Effect of Kuanxiong Composition on Myocardial Histopathology in Rats with Heart Failure

[0071] like Figure 4 The results in Figure a showed that HE staining showed that the myocardial fibers of rats in the Sham group were arranged regularly and had a complete structure, while the myocardial fibers of rats in the Model group were arranged in disorder and the ventricular wall was thinned. Compared with the Model group, the ventricular wall thickness of rats in the group administered with the wide-chest composition increased, the myocardial fibers were arranged relatively regularly, and the tissue pathological damage was reduced. Figure 4 Middle b, Masson staining showed that there was no obvious fibrosis in the rats in the Sham group, while large pieces of blue collagen fibers were visible in the myocardial tissue of the rats in the Model group, and the degree of myocardial fibrosis was aggravated ( Figure 4 (d)

[0072] Compared with the Model group, the myocardial fibrosis degree of rats in the Kuanxiong composition group was alleviated, and the myocardial tissue structure was significantly improved. Figure 4Results in b and d.

[0073] The body weight (BW) and heart weight (HW) were recorded and the HW / BW index was calculated. It was found that the heart weight index of the model group rats was significantly higher than that of the sham group. Figure 4 Figure c in the middle shows that this group of rats had obvious myocardial hypertrophy, while the heart body mass index of the rats in the wide-chest high-dose administration group was significantly decreased compared with the sham group, indicating that the wide-chest composition can alleviate ventricular remodeling in rats with heart failure, reduce left ventricular enlargement, and inhibit myocardial tissue hypertrophy.

[0074] In summary, the experimental results show that both the high and low dose groups of the wide-chest composition of this embodiment can alleviate the progression of heart failure, enhance myocardial contractility, increase coronary blood flow, reduce myocardial damage and fibrosis area, and protect myocardial cells to varying degrees, thereby improving cardiac function. The above results verify the effectiveness of the wide-chest composition in the treatment of HFrEF and provide an innovative treatment plan with clinical application potential.

[0075] Based on the wide-chest composition drug used in the aforementioned animal experiments, corresponding wide-chest compositions prepared with other amounts within the weight range of each component of the wide-chest composition were also subjected to animal experiments, which confirmed their effectiveness, and the results all achieved the above-mentioned significant beneficial effects in treating HFrEF.

[0076] The above is only the embodiment of the present application, and the protection scope of the present application is not limited by these specific embodiments, but is determined by the claims of the present application. For those skilled in the art, the present application can have various changes and variations. Any modification, equivalent replacement, improvement, etc. made within the technical ideas and principles of the present application should be included in the protection scope of the present application.

Claims

1. Use of a chest-opening composition in the preparation of a drug for treating and / or preventing heart failure, wherein the chest-opening composition is prepared from the following effective ingredients: 50-80 parts by volume of sandalwood oil, 8-22 parts by volume of piper longum oil, 10-30 parts by volume of asarum oil, 20-40 parts by volume of galangal oil and 10-30 parts by weight of borneol.

2. The use according to claim 1, characterized in that: The heart failure is heart failure with reduced ejection fraction.

3. The use according to claim 1 or 2, characterized in that: The wide-chest composition further comprises a pharmaceutically acceptable auxiliary material.

4. The use according to claim 3, characterized in that: The auxiliary materials are auxiliary materials for preparing the wide-chest composition into different pharmaceutical preparations; the pharmaceutical preparations are liquid preparations, solid preparations or gas preparations.

5. The use according to claim 4, characterized in that: The chest-widening composition is in the form of a liquid preparation, and the content of the active ingredient in the liquid preparation is 0.2-0.25 mL / mL.

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