A pharmaceutical composition for treating heart failure and use thereof

Abstract

This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition for treating heart failure and its application. The pharmaceutical composition comprises aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3. This pharmaceutical composition can effectively improve cardiac function and cardiac tissue pathology, and the components exhibit synergistic effects, achieving excellent therapeutic response at lower dose levels, demonstrating the clinical advantage of dose-reduction synergistic effects. Furthermore, its dosage regimen is simple, improving long-term treatment adherence. Therefore, this pharmaceutical composition can be used to prepare drugs for treating or preventing heart failure, showing promising clinical application prospects.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a pharmaceutical composition for treating heart failure and its application. Background Technology

[0002] Heart failure is a clinical syndrome caused by abnormalities in the structure or function of the heart, resulting in impaired ventricular filling or ejection capacity. It is the end stage of many cardiovascular diseases.

[0003] The multifactorial and complex nature of heart failure dictates that combination therapy is a fundamental treatment strategy. The current "Chinese Guidelines for the Diagnosis and Treatment of Heart Failure 2024" recommends a treatment regimen based on the "new quadruple therapy," which combines four classes of drugs: renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors. Further combining this with soluble guanylate cyclase stimulators constitutes the "five-in-one" treatment model. Clinical studies have confirmed that the above multi-drug combination regimens can bring clear survival benefits to heart failure patients; however, they involve frequent medication, complex drug combinations, high treatment costs, and poor patient adherence during long-term treatment. Therefore, developing novel anti-heart failure drugs with simple administration methods and significant therapeutic effects has important clinical and social value. Summary of the Invention

[0004] To address the above-mentioned technical problems, this invention provides a pharmaceutical composition for treating heart failure and its application. This pharmaceutical composition can effectively improve cardiac function and cardiac tissue pathology, and its administration regimen is simple, overcoming the shortcomings of existing multi-drug combination regimens in the treatment of heart failure, and has good clinical application prospects.

[0005] To achieve the above-mentioned objectives, the present invention adopts the following technical solution:

[0006] The first aspect of the present invention provides a pharmaceutical composition for treating heart failure, comprising aconitine (CAS No.: 509-24-0), ginsenoside Rg1 (CAS No.: 22427-39-0), ginsenoside Rb1 (CAS No.: 41753-43-9) and ginsenoside Rb3 (CAS No.: 68406-26-8).

[0007] This invention, through preliminary experimental studies, found that all four components significantly improved cardiomyocyte hypertrophy. However, in a mouse model of pressure-induced heart failure constructed using the transverse aortic arch constriction (TAC) method, at the experimental dose, aconitine increased left ventricular ejection fraction and fractional shortening, while the other three compounds did not show significant effects; ginsenoside Rb1 and ginsenoside Rb3 reduced the heart-to-body weight ratio in the heart failure mouse model, while the other two compounds did not show significant effects; ginsenoside Rb1 reduced the heart-to-tibia length ratio in the heart failure mouse model, while the other three compounds did not show significant effects.

[0008] This invention, through research, has for the first time discovered that a pharmaceutical composition containing aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 can significantly increase left ventricular ejection fraction and fractional shortening in a mouse model of heart failure, reduce the ratio of heart mass to body mass and the ratio of heart mass to tibia length, alleviate ventricular dilation in mice with heart failure, enhance cardiac contractile function, reduce the degree of cardiomyocyte necrosis and fibrosis, and improve cardiac dysfunction. Furthermore, the above four compounds exhibit a significant synergistic effect in improving cardiac function in mice with heart failure. When used in combination, they produce significant therapeutic effects at lower dosages, thereby reducing the risk of toxic side effects that may be caused by high doses of single components and reducing the metabolic burden in the body, while further reducing the raw material consumption cost per unit treatment course.

[0009] There are currently no reports of combining the above four compounds for the treatment of heart failure. This drug composition provides a new option for the treatment of heart failure and has good prospects for clinical application.

[0010] Preferably, the mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is (2~40):(30~600):(30~600):(3~60).

[0011] More preferably, the mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is (6~40):(30~400):(60~600):(10~60).

[0012] More preferably, the mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is (6~32):(60~400):(100~400):(10~60).

[0013] More preferably, the mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is 22:170:376:18.

[0014] The second aspect of the present invention provides a method for preparing the above-mentioned pharmaceutical composition, specifically comprising the following steps: mixing and grinding the prescribed amounts of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 until uniform, thereby obtaining the pharmaceutical composition.

[0015] A third aspect of the present invention provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating or preventing heart failure.

[0016] Preferably, the heart failure is heart failure with reduced ejection fraction.

[0017] Preferably, the dosage form of the drug includes oral preparations and injections.

[0018] More preferably, the dosage form of the drug is an oral preparation, including but not limited to tablets, capsules, granules, oral liquids, suspensions, pills, powders, ointments, and elixirs.

[0019] Preferably, the drug further includes pharmaceutically acceptable excipients.

[0020] The beneficial effects of the present invention are as follows: (1) The drug composition has clearly defined components, requires fewer daily doses, and has a simple medication regimen, which greatly simplifies the medication process for patients. For patients who need long-term or even lifelong medication, it reduces the psychological and memory burden caused by frequent medication, thereby effectively avoiding missed doses or refusal to take them, fundamentally improving the compliance of long-term treatment, and providing a reliable guarantee for stable disease control. (2) The drug composition can effectively improve cardiac function and cardiac tissue pathological changes, and the components have a synergistic effect, enabling it to achieve excellent therapeutic response at a low dose level. This not only reduces the risk of toxic side effects that may be caused by high doses of a single component, but also reduces the metabolic burden in the body. At the same time, it further reduces the raw material consumption cost per unit course of treatment, and has the clinical advantage of reduced dosage and increased efficacy. It is especially suitable for patients who need to balance efficacy and safety. Attached Figure Description

[0021] Figure 1The figures show the detection results of cardiac function in different groups of mice in Example 10 of this invention. Figure A shows representative B-mode and M-mode echocardiograms of mice in the sham-operated group, model group, positive control group, and each drug combination group; Figure B is a bar chart of left ventricular ejection fraction; Figure C is a bar chart of left ventricular short-axis shortening fraction; Figure D is a bar chart of the ratio of heart mass to body mass; and Figure E is a bar chart of the ratio of heart mass to tibia length. In the figures, "#" indicates p < 0.05 compared to the model group, "##" indicates p < 0.01 compared to the model group, "*" indicates p < 0.05 compared to the positive control group / drug combination group and the model group, and "**" indicates p < 0.01 compared to the positive control group / drug combination group and the model group. The sham surgery group n = 8, the model group n = 8, the positive drug group n = 5, the drug composition 1 group n = 8, the drug composition 2 group n = 8, the drug composition 3 group n = 8, the drug composition 4 group n = 8, the drug composition 5 group n = 8, the drug composition 6 group n = 8, the drug composition 7 group n = 8, and the drug composition 8 group n = 7.

[0022] Figure 2 The images show the pathological staining results of mouse heart tissue from different groups in Example 10 of this invention. Figure A shows a representative HE staining image of mouse heart tissue; Figure B shows a representative Masson staining image of mouse heart tissue.

[0023] Figure 3The results of cardiac function testing in different groups of mice in Example 11 of this invention are shown. Figure A shows representative B-mode and M-mode echocardiograms of mice in the sham-operated group, model group, positive control group, high-dose drug composition group, medium-dose drug composition group, low-dose drug composition group, aconitine group, ginsenoside Rg1 group, ginsenoside Rb1 group, and ginsenoside Rb3 group; Figure B is a bar chart of left ventricular ejection fraction; Figure C is a bar chart of left ventricular short-axis shortening fraction; Figure D is a bar chart of the ratio of mouse heart mass to body mass; and Figure E is a bar chart of the ratio of mouse heart mass to tibia length. Wherein, "#" indicates p < 0.05 compared to the model group, "##" indicates p < 0.01 compared to the model group, "*" indicates p < 0.05 compared to the positive control group, drug composition group, and single component group compared to the model group, and "**" indicates p < 0.01 compared to the positive control group, drug composition group, and single component group compared to the model group. The sham surgery group n = 10, the model group n = 10, the positive control group n = 6, the high-dose drug composition group n = 10, the medium-dose drug composition group n = 10, the low-dose drug composition group n = 9, the aconitine group n = 7, the ginsenoside Rg1 group n = 7, the ginsenoside Rb1 group n = 7, and the ginsenoside Rb3 group n = 7.

[0024] Figure 4 The images show the pathological staining results of mouse heart tissue from different groups in Example 11 of this invention. Figure A shows a representative HE staining image of mouse heart tissue; Figure B shows a representative Masson staining image of mouse heart tissue. Detailed Implementation

[0025] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to specific embodiments. It should be understood that the specific embodiments described herein are for illustrative purposes only and are not intended to limit the invention. All other embodiments obtained by those skilled in the art based on the implementation methods of this invention without creative effort fall within the protection scope of this invention.

[0026] Current treatment options for heart failure primarily involve the combined use of drugs such as renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors. While multidrug regimens can provide clear survival benefits for heart failure patients, they require frequent medication, involve a complex array of drugs, are costly, and lead to poor patient adherence during long-term treatment.

[0027] Based on the research results, an embodiment of the present invention provides a pharmaceutical composition for treating heart failure, comprising songorine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3. The pharmaceutical composition can effectively improve cardiac function and histopathological changes of the heart, has a simple medication regimen, and overcomes the deficiencies of existing multi-drug combination regimens in the treatment of heart failure.

[0028] An embodiment of the present invention also provides a preparation method of the above pharmaceutical composition.

[0029] An embodiment of the present invention also provides use of the above pharmaceutical composition in preparation of a medicament for treating or preventing heart failure.

[0030] Further description is given below with reference to specific examples.

[0031] In the following examples, songorine (batch number: PRF24121245, purity: 99.80%) was purchased from Chengdu Puruifa Technology Development Co., Ltd., and ginsenoside Rg1 (batch number: AZCA1111, purity: 98.08%), ginsenoside Rb1 (batch number: AZCJ3003, purity: 99.06%) and ginsenoside Rb3 (batch number: AFCK2007, purity: 98.48%) were purchased from Chengdu Alfa Biotechnology Co., Ltd.

[0032] In the following examples, the C57BL / 6J mice used are male, with a body weight of 22~24 g, SPF grade, purchased from Beijing Vital River Laboratory Animal Technology Co., Ltd., with the license number SCXK (Beijing) 2021-0006.

[0033] Unless otherwise specified, the reagents, drugs or instruments used in the following examples are all conventional commercially available products obtained through commercial channels. Unless otherwise specified, the methods used in the following examples are all conventional methods in the art.

[0034] Example 1

[0035] This example provides a pharmaceutical composition for treating heart failure, which consists of songorine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 in a mass ratio of 40:30:60:20.

[0036] The preparation method is as follows: mixing songorine powder, ginsenoside Rg1 powder, ginsenoside Rb1 powder and ginsenoside Rb3 powder according to the above mass ratio and grinding the mixture until uniform, thereby obtaining the product.

[0037] Example 2

[0038] This embodiment provides a pharmaceutical composition for treating heart failure, comprising aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in a mass ratio of 32:60:200:60. The preparation method is the same as in Example 1.

[0039] Example 3

[0040] This embodiment provides a pharmaceutical composition for treating heart failure, comprising aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in a mass ratio of 24:100:400:10. The preparation method is the same as in Example 1.

[0041] Example 4

[0042] This embodiment provides a pharmaceutical composition for treating heart failure, comprising aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in a mass ratio of 15:200:600:50. The preparation method is the same as in Example 1.

[0043] Example 5

[0044] This embodiment provides a pharmaceutical composition for treating heart failure, comprising aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in a mass ratio of 10:300:30:6. The preparation method is the same as in Example 1.

[0045] Example 6

[0046] This embodiment provides a pharmaceutical composition for treating heart failure, comprising aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in a mass ratio of 6:400:100:40. The preparation method is the same as in Example 1.

[0047] Example 7

[0048] This embodiment provides a pharmaceutical composition for treating heart failure, comprising aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in a mass ratio of 4:500:300:3. The preparation method is the same as in Example 1.

[0049] Example 8

[0050] This embodiment provides a pharmaceutical composition for treating heart failure, comprising aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in a mass ratio of 2:600:500:30. The preparation method is the same as in Example 1.

[0051] Example 9

[0052] This example provides a pharmaceutical composition for treating heart failure, which consists of songorine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 in a mass ratio of 22:170:376:18. The preparation method thereof is the same as that in Example 1.

[0053] Example 10

[0054] This example evaluates the pharmacodynamics of the pharmaceutical compositions of Examples 1 to 8 in a TAC-induced heart failure mouse model.

[0055] 1. Experimental animals

[0056] C57BL / 6J mice were raised in the Experimental Animal Center of Tianjin University of Traditional Chinese Medicine, with the feeding license number SYXK (Jin) 2025-0012. Standard feeding conditions were adopted: room temperature 20-25 ℃, relative humidity 40%-60%, and 12-hour alternation of light and dark environment. All operations on experimental animals complied with the specifications approved by the Experimental Animal Ethics Committee of Tianjin University of Traditional Chinese Medicine.

[0057] 2. Experimental methods

[0058] 2.1 Construction of pressure overload-induced heart failure mouse model by transverse aortic constriction (TAC)

[0059] Mice were fasted for 12 h before surgery with free access to water. Anesthesia was performed by intraperitoneal injection of 15 mg / mL tribromoethanol (0.01 mL / g). After anesthesia, the surgical field on the neck and anterior chest was depilated, the four limbs and head were fixed in the supine position, and the surgical area was disinfected. Under aseptic operation, a median cervical incision was made on the mouse, intercostal muscles were bluntly separated, and retraction was performed with a retractor to expose the thoracic cavity. The thymus was separated with atraumatic microforceps to expose the aortic arch, and the surrounding tissues of the aortic arch were bluntly separated. A No. 5 cotton thread was passed from the upper edge of the aorta to the posterior and lower edge of the aorta. A 27G needle was used for padding, and double knots were ligated on the aorta and the padding needle. After confirmed ligation, the knot was lifted with atraumatic forceps, and the padding needle was pulled out horizontally. After confirming no active bleeding, the upper edge of the sternum was sutured in a figure-of-eight pattern with 5-0 suture, then the chest was closed layer by layer and the skin was sutured.

[0060] A sham operation group was set up in parallel at the same time: mice were fasted for 12 h before surgery with free access to water. Anesthesia was performed by intraperitoneal injection of 15 mg / mL tribromoethanol (0.01 mL / g). After anesthesia, the surgical field on the neck and anterior chest was depilated, the four limbs and head were fixed in the supine position, and the surgical area was disinfected. Under aseptic operation, a median cervical incision was made on the mouse, intercostal muscles were bluntly separated, and retraction was performed with a retractor to expose the thoracic cavity. The thymus was separated with atraumatic microforceps to expose the aortic arch, and the surrounding tissues of the aortic arch were bluntly separated. A No. 5 cotton thread was passed from the upper edge of the aorta to the posterior and lower edge of the aorta. After confirming no active bleeding, the upper edge of the sternum was sutured in a figure-of-eight pattern with 5-0 suture, then the chest was closed layer by layer and the skin was sutured.

[0061] 2.2 Animal grouping and administration

[0062] Four weeks after TAC surgery, the model animals were randomly divided into a model group, a positive drug group, and a drug composition group according to their left ventricular ejection fraction. Mice in the model group and sham-operated group were given distilled water. The positive drug group was given valsartan at a dose of 10.4 mg / kg. Drug composition group 1 was given the drug composition of Example 1 at a dose of 15 mg / kg. Drug composition group 2 was given the drug composition of Example 2 at a dose of 35.2 mg / kg. Drug composition group 3 was given the drug composition of Example 3 at a dose of 53.4 mg / kg. Drug composition group 4 was given the drug composition of Example 4 at a dose of 86.5 mg / kg. Drug composition group 5 was given the drug composition of Example 5 at a dose of 34.6 mg / kg. Drug composition group 6 was given the drug composition of Example 6 at a dose of 54.6 mg / kg. Drug composition group 7 was given the drug composition of Example 7 at a dose of 80.7 mg / kg. Drug composition group 8 was given the drug composition of Example 8 at a dose of 113.2 mg / kg. Mice in all groups were administered the drug by gavage at a volume of 0.1 mL / 10 g, once daily for 28 consecutive days.

[0063] 2.3 Echocardiography

[0064] The day after the last administration, changes in cardiac function in mice were detected using the Vevo 2100 ultra-high resolution small animal ultrasound real-time imaging system. Parasternal long-axis and short-axis sections were observed, and cardiac cycles were recorded using B-mode and M-mode ultrasound. Left ventricular ejection fraction, left ventricular fractional shortening, and left ventricular mass were also recorded.

[0065] 2.4 Cardiac Mass Index

[0066] After echocardiography, mice were anesthetized by intraperitoneal injection of 15 mg / mL tribromoethanol (0.01 mL / g), and the heart was exposed via thoracotomy. The heart was then perfused with pre-cooled DPBS buffer. Subsequently, the mouse heart was harvested, surface moisture and residual fluid were aspirated, the heart mass was measured using an electronic balance, and the maximum tibial length was measured using calipers. The ratio of heart mass to body mass and the ratio of heart mass to tibial length were calculated to assess the degree of cardiac hypertrophy.

[0067] 2.5 Cardiac Pathological Evaluation

[0068] Mouse heart tissue was fixed in 10% neutral formalin. The fixed heart was dehydrated, cleared, paraffin-embedded, and embedded, then cut into 5 μm thick sections. HE staining and Masson staining were performed, and histopathological features such as cardiomyocyte morphology, nuclear aggregation, collagen distribution, and myocardial fibrosis were observed under an electron microscope.

[0069] 3. Experimental Results

[0070] like Figure 1 As shown, TAC-induced cardiac function in mice was significantly impaired. Compared with the sham-operated group, the left ventricular ejection fraction and fractional shortening of the model group mice were both significantly reduced (p < 0.01). Compared with the model group, the drug composition of Example 5 significantly increased the left ventricular ejection fraction of mice (p < 0.05), and the drug compositions of Examples 1-4 and Examples 6-8 significantly increased the left ventricular ejection fraction of mice (p < 0.01); the drug compositions of Examples 2 and 5 significantly increased the fractional shortening of the left ventricular fraction of mice (p < 0.05), and the drug compositions of Examples 3, 4, and Examples 6-8 significantly increased the fractional shortening of the left ventricular fraction of mice (p < 0.01). Furthermore, compared with the model group, the drug compositions of Examples 2-4, 6, and 8 significantly reduced the ratio of heart weight to body weight in mice (p < 0.01); the drug composition of Example 8 significantly reduced the ratio of heart weight to tibia length in mice (p < 0.05), and the drug compositions of Examples 1-6 significantly reduced the ratio of heart weight to tibia length in mice (p < 0.01). These results indicate that the drug compositions provided by this invention can significantly improve cardiac function in mice and effectively alleviate ventricular hypertrophy.

[0071] HE staining results of cardiac tissue showed ( Figure 2 (Figure A) In the model group mice, cardiomyocytes were irregularly arranged, with localized cardiomyocyte degeneration and necrosis, accompanied by inflammatory cell infiltration. The cardiomyocyte morphology in each drug combination group was improved compared to the model group, with significantly reduced cell necrosis and degeneration. Masson staining results of cardiac tissue showed (…). Figure 2 (Figure B) Diffuse interstitial fibrosis was observed in the model group mice, with blue collagen fiber networks proliferating between cardiomyocytes, widening the septa, and locally visible patchy replacement fibrosis areas. In each drug combination group, the area of ​​collagen fibers in the myocardium of mice decreased to varying degrees, the interstitial collagen network was relatively sparse, and myocardial fibrosis was significantly improved.

[0072] The above experimental results show that the pharmaceutical composition of the present invention can reduce ventricular dilation in mice with heart failure, enhance cardiac contractile function, reduce the degree of myocardial cell necrosis and fibrosis, and improve cardiac dysfunction.

[0073] Example 11

[0074] This embodiment evaluates the pharmacodynamics of the pharmaceutical composition of Example 9 in a TAC-induced heart failure mouse model and compares it with the pharmacodynamics of each component used alone.

[0075] 1. Laboratory animals

[0076] The feeding method is the same as in Example 10.

[0077] 2. Experimental Methods

[0078] 2.1 Establishment of a mouse model of stress-induced heart failure using the TAC method

[0079] The method is the same as 2.1 in Example 10.

[0080] 2.2 Animal grouping and administration

[0081] Four weeks after TAC surgery, the model animals were randomly divided into the model group, positive drug group, high-dose drug composition group, medium-dose drug composition group, low-dose drug composition group, aconitine group, ginsenoside Rg1 group, ginsenoside Rb1 group and ginsenoside Rb3 group according to their left ventricular ejection fraction.

[0082] Mice in the model group and sham-operated group were given distilled water. The positive control group was given valsartan at a dose of 10.4 mg / kg. The high-dose group was given the drug composition of Example 9 at a dose of 58.6 mg / kg. The medium-dose group was given the drug composition of Example 9 at a dose of 29.3 mg / kg. The low-dose group was given the drug composition of Example 9 at a dose of 11.72 mg / kg. The aconitine group was given aconitine at a dose of 2.2 mg / kg, the ginsenoside Rg1 group at a dose of 17 mg / kg, the ginsenoside Rb1 group at a dose of 37.6 mg / kg, and the ginsenoside Rb3 group at a dose of 1.8 mg / kg. All mice were administered the drug via gavage at a volume of 0.1 mL / 10 g, once daily for 28 consecutive days.

[0083] 2.3 Echocardiography

[0084] The method is the same as 2.3 in Example 10.

[0085] 2.4 Cardiac Mass Index

[0086] The method is the same as 2.4 in Example 10.

[0087] 2.5 Cardiac Pathological Evaluation

[0088] The method is the same as 2.5 in Example 10.

[0089] 3. Experimental Results

[0090] like Figure 3 As shown, compared with the model group, the left ventricular ejection fraction and fractional shortening of mice in the low-dose group of the drug composition were significantly increased (p < 0.05), while the left ventricular ejection fraction and fractional shortening of mice in the high- and medium-dose groups of the drug composition were extremely significantly increased (p < 0.01). Among the single-component groups, only the aconitine group showed a significant increase in left ventricular ejection fraction and fractional shortening of mice (p < 0.05). Furthermore, compared with the model group, the low-dose drug composition significantly reduced the heart mass to body mass ratio in mice (p < 0.05), while the high- and medium-dose drug compositions significantly reduced the heart mass to body mass ratio (p < 0.01). The medium- and low-dose drug compositions significantly reduced the heart mass to tibia length ratio in mice (p < 0.05), while the high-dose drug composition significantly reduced the heart mass to tibia length ratio (p < 0.01). In the single-component groups, the ratio of heart weight to body weight in mice was significantly reduced in the ginsenoside Rb3 group (p < 0.05), and the ratio was extremely significantly reduced in the ginsenoside Rb1 group (p < 0.01), while the other two groups showed no significant changes. Similarly, the ratio of heart weight to tibia length in mice was extremely significantly reduced in the ginsenoside Rb1 group (p < 0.01), while the other three groups showed no significant changes. These results indicate that the pharmaceutical composition of Example 9 of this invention can significantly improve cardiac function in mice, effectively alleviate ventricular hypertrophy, and its efficacy is superior to that of any single component used alone.

[0091] Further analysis based on cardiac tissue pathology results ( Figure 4 As can be seen, the morphology of cardiomyocytes in mice in the high, medium, and low dose groups of the drug composition was significantly improved compared with that in the model group, and the degree of cell necrosis and degeneration was significantly reduced. Simultaneously, the collagen fiber area in the myocardium of mice in the drug composition groups was significantly reduced, and myocardial fibrosis was improved to varying degrees. The pathological improvement of cardiac tissue in mice treated with each component alone was comparable to that in the low dose group of the drug composition.

[0092] To further evaluate the synergistic effect of the four drugs in the pharmaceutical composition of this invention, the Model-Free Test (MFT) method was used to calculate the combination drug index, i.e., the combination drug index γ = a / A + b / B + c / C + d / D, where A, B, C, and D are the doses that produce the same effect when used alone and in combination, and a, b, c, and d are the individual doses when used in combination. When γ > 1, the drug interaction is antagonistic; when γ = 1, the drug interaction is additive; and when γ < 1, the drug interaction is synergistic.

[0093] In this embodiment, the dosage of each component used alone is equivalent to the dosage of each component in the high-dose group of the drug composition. In the TAC-induced heart failure animal model, the high-dose drug composition showed the best effect on improving cardiac function in mice, while the efficacy of the medium- and low-dose drug compositions decreased with decreasing dosage. Simultaneously, the low-dose drug composition showed better improvement on cardiac function in mice than the individual components used alone, and its effect on improving cardiac tissue pathology was comparable to that of the individual components used alone. Therefore, substituting the dosage of each component used alone and the lowest dosage of the combined drug use into the above formula for calculating the combined drug use index yields: γ = 0.44 / 2.2 + 3.4 / 17 + 7.52 / 37.6 + 0.36 / 1.8 = 0.8, i.e., γ < 1, further demonstrating that the combined use of aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 in the drug composition of this invention has a synergistic effect.

[0094] As can be seen from the above experimental results, the drug composition of Example 9 can produce a better effect than the individual components when used alone, and the four drugs in the drug composition can exert a synergistic effect.

[0095] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition for treating heart failure, characterized in that, It includes aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3.

2. The pharmaceutical composition according to claim 1, characterized in that, The mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is (2~40):(30~600):(30~600):(3~60).

3. The pharmaceutical composition according to claim 2, characterized in that, The mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is (6~40):(30~400):(60~600):(10~60).

4. The pharmaceutical composition according to claim 3, characterized in that, The mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is (6~32):(60~400):(100~400):(10~60).

5. The pharmaceutical composition according to claim 4, characterized in that, The mass ratio of aconitine, ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Rb3 is 22:170:376:

18.

6. A method for preparing the pharmaceutical composition according to any one of claims 1 to 5, characterized in that, Specifically, the following steps are involved: mixing and grinding the prescribed amounts of aconitine, ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Rb3 until homogeneous to obtain the pharmaceutical composition.

7. Use of the pharmaceutical composition according to any one of claims 1 to 5 in the preparation of a medicament for treating or preventing heart failure.

8. The application according to claim 7, characterized in that, The heart failure referred to here is heart failure with a reduced ejection fraction.

9. The application according to claim 7 or 8, characterized in that, The dosage forms of the drug include oral preparations and injections; and / or The drug also includes pharmaceutically acceptable excipients.

10. The application according to claim 9, characterized in that, The drug is an oral formulation.

Images