A composition for treating ischemic heart disease and use thereof

Abstract

This invention belongs to the field of biomedical technology, specifically relating to a composition for treating ischemic heart disease and its application. This invention combines two or more of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1, which can significantly downregulate the levels of myocardial enzymes, aspartate aminotransferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH) in myocardial coronary effusion, with an inhibitory effect significantly higher than that of a single saponin component and the positive control drug verapamil. Simultaneously, the composition exhibits better recovery capabilities for coronary flow (CF), left ventricular developmental pressure (LVDP), maximum rate of decrease in left ventricular pressure (-dp / dtmax), and heart rate (HR) in myocardial coronary effusion. Therefore, the composition can alleviate and treat myocardial ischemia-reperfusion injury through multiple targets and mechanisms, fundamentally inhibiting the development of ischemic heart disease.

Description

Technical Field

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

[0002] Ischemic heart disease (IHD) is a heart disease caused by myocardial ischemia and hypoxia due to changes in coronary artery circulation. It is also known as coronary heart disease. Atherosclerotic lesions of the coronary artery wall lead to narrowing of the vascular lumen, obstruction of coronary blood flow, insufficient blood supply to the myocardium, and in severe cases, myocardial infarction. Currently, the main strategy for treating ischemic heart disease is to restore blood flow (i.e., reperfusion) as quickly as possible and alleviate insufficient nutrition and oxygen supply. Clinically, conventional treatments for myocardial ischemia in IHD include thrombolysis, percutaneous coronary intervention, and coronary artery bypass grafting. However, these treatments have not completely solved the problems associated with reperfusion, such as arrhythmias, myocardial infarction, microvascular obstruction, and myocardial injury. This phenomenon is called myocardial ischemia-reperfusion injury (MIRI), and MIRI accounts for 50% of ischemic heart disease. Therefore, developing multi-target drugs to treat myocardial ischemia-reperfusion injury is of great value and significance for the prevention and treatment of heart disease.

[0003] Studies have found that the pathogenesis of myocardial ischemia-reperfusion injury may be related to oxygen free radicals, calcium overload, inflammatory response, apoptosis, and protein kinase pathways. Some key regulatory molecules, including intercellular adhesion molecule (ICAM), nitric oxide synthase (NOS), mitochondrial ATP-sensitive potassium channel (mitoKATP), and mitochondrial permeability transition pore (mPTP), are closely related to its molecular mechanism. Currently, small molecule drugs developed targeting these mechanisms include mitochondrial ATP-sensitive potassium channel openers (such as nicodil, pinacidil, clokalin, and diazoxide), calcium channel blockers (verapamil), myocardial cell membrane ATP-sensitive potassium channel inhibitors (HMR1883), mPTP inhibitors (HMR1883), cyclosporine A, and small interfering RNA (siRNA) inhibitors (miR-1, miR-26, and miR-133). On the other hand, traditional Chinese medicine monomer inhibitors and... Significant progress has been made in the development of compound inhibitors, among which ginsenosides and notoginsenosides show particularly significant effects in repairing myocardial ischemia-reperfusion injury (MIRI). Notoginsenosides contain notoginsenoside R1, while ginsenosides contain Rg1, ginsenoside Re, ginsenoside Rb1, and ginsenoside Rd, among other saponin components. These have been shown to exert effective inhibitory effects on MIRI through anti-oxidative stress, inhibition of neutrophil activation and adhesion, blockade of calcium overload, inflammatory response, regulation of energy metabolism, inhibition of apoptosis, regulation of vascular endothelial cell function, and protein kinase pathways. However, while the mechanisms by which single Chinese herbal medicines repair myocardial ischemia-reperfusion injury are relatively clear, their effects and targets are relatively limited, and they are expensive, placing a significant pathological and economic burden on patients. Summary of the Invention

[0004] The purpose of this invention is to provide a composition for treating ischemic heart disease and its application. The components in the composition of this invention have a synergistic effect and can effectively inhibit myocardial ischemia-reperfusion injury.

[0005] The present invention provides a composition for treating ischemic heart disease, the composition comprising a saponin composition or a substance containing a saponin composition;

[0006] The saponin composition includes two or more of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1;

[0007] When the composition comprises two components, the two components are ginsenoside Rg1 and notoginsenoside R1.

[0008] Preferably, when the composition includes ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1, the mass ratio of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1 is (1-4):(1-4):(1-4):(1-4).

[0009] Preferably, when the composition comprises three components selected from ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1, the mass ratio of any three components is (1-4):(1-4):(1-4).

[0010] Preferably, when the composition includes ginsenoside Rb1, ginsenoside Re and notoginsenoside R1, the mass ratio of ginsenoside Rb1, ginsenoside Re and notoginsenoside R1 is (1-3):(1-4):(1-3).

[0011] Preferably, when the composition includes ginsenoside Rb1, ginsenoside Re and notoginsenoside R1, the mass ratio of ginsenoside Rb1, ginsenoside Re and notoginsenoside R1 is 1:1:2.

[0012] Preferably, when the composition includes ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Re, the mass ratio of ginsenoside Rg1, ginsenoside Rb1 and ginsenoside Re is 1:1:1.

[0013] Preferably, when the composition consists of two components, ginsenoside Rg1 and notoginsenoside R1, the mass ratio of ginsenoside Rg1 to notoginsenoside R1 is 4:1.

[0014] Preferably, the substance containing the saponin composition includes two or more of Panax notoginseng extract, ginseng extract, and American ginseng extract.

[0015] The present invention also provides the use of the composition described above in the preparation of a medicament for treating ischemic heart disease.

[0016] The present invention also provides a medicament for treating ischemic heart disease, comprising the composition described in the above technical solution.

[0017] Beneficial effects:

[0018] This invention provides a composition for treating ischemic heart disease, comprising a saponin composition or a substance containing a saponin composition. This invention combines two or more of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1, which can significantly downregulate the levels of myocardial enzymes, aspartate aminotransferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH) in myocardial coronary effluent. Its inhibitory effect on these components is significantly higher than that of a single saponin component and the positive control drug verapamil. Simultaneously, the composition exhibits better recovery capabilities for coronary flow (CF), left ventricular developmental pressure (LVDP), maximum rate of decrease in left ventricular pressure (-dp / dtmax), and heart rate (HR) in myocardial coronary effluent. Therefore, the composition can alleviate and treat myocardial ischemia-reperfusion injury through multiple targets and mechanisms, fundamentally inhibiting the development of ischemic heart disease, thereby achieving a safe and effective treatment objective. This provides a new treatment strategy for clinical practice and is less expensive than existing first-line positive control drugs, reducing the economic burden on patients. The results of the examples show that the composition provided by the present invention has a synergistic effect of compatibility and efficacy. Its pharmacological effect of inhibiting myocardial ischemia-reperfusion injury can replace the total saponins of Panax notoginseng and / or the saponins of American ginseng in the medicinal materials, and exerts the maximum pharmacological effect superior to that of positive verapamil. Attached Figure Description

[0019] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the embodiments will be briefly described below.

[0020] Figure 1 Effects of ischemia-reperfusion on the pathological morphology of isolated rat myocardial tissue (HE×200): (a) Sham group; (b) MIRI group; (c) Verapamil group;

[0021] Figure 2 The effects of ginsenosides Rg1, Rb1, Re and notoginsenoside R1 on the pathological morphology of isolated rat myocardial tissue (HE staining ×200). Detailed Implementation

[0022] The present invention provides a composition for treating ischemic heart disease, the composition comprising a saponin composition or a substance containing a saponin composition; the saponin composition comprising two or more of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1; when the composition comprises two components, the two components are ginsenoside Rg1 and notoginsenoside R1.

[0023] In this invention, the saponin composition comprises two or more of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1, preferably two or three, and more preferably three. The purity of all four monomers—ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1—is preferably greater than 98%. This invention does not specifically limit the source of the four monomers—ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1—and any commercially available product conventional in the art can be used. When the composition of the present invention includes ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1, the mass ratio of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re and notoginsenoside R1 is preferably (1-4):(1-4):(1-4):(1-4), more preferably (1-3):(1-2):(1-2):(1-4), and even more preferably 1:1:1:1. When the composition of the present invention comprises three components selected from ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1, any combination of three components from the above four compositions is within the scope of protection of the present invention, and the mass ratio of any three components is preferably (1-4):(1-4):(1-4), more preferably (1-3):(1-4):(1-3); more preferably 1:1:2; when the composition comprises ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Re, the human The preferred mass ratio of ginsenoside Rg1, ginsenoside Rb1, and ginsenoside Re is (1-4):(1-4):(1-4), more preferably (1-3):(1-4):(1-3), and even more preferably 1:1:1. When the composition of the present invention consists of two components, the composition is ginsenoside Rg1 and notoginsenoside R1, and the preferred mass ratio of ginsenoside Rg1 and notoginsenoside R1 is (1-4):(1-4), more preferably (1-4):(1-2), and even more preferably 4:1.

[0024] In this invention, the substance containing the saponin composition can also be used to prepare the composition of this invention. The substance containing the saponin composition preferably includes two or more of Panax notoginseng extract, ginseng extract, and American ginseng extract, more preferably including Panax notoginseng extract and American ginseng extract. The Panax notoginseng extract, ginseng extract, and American ginseng extract of this invention preferably include stem and leaf extracts or flower extracts of Panax notoginseng, ginseng, and American ginseng. The total mass of ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1 in the substance containing the saponin composition of this invention is preferably 1–1000 mg.

[0025] This invention also provides the application of the composition described above in the preparation of a medicament for treating ischemic heart disease. The medicament of this invention preferably includes a drug for treating myocardial ischemia-reperfusion injury, a drug for heart failure, or a drug for myocardial infarction, and more preferably includes a drug for treating myocardial ischemia-reperfusion injury. The composition of this invention can significantly downregulate the levels of myocardial enzymes aspartate aminotransferase (AST), creatine kinase (CK), and lactate dehydrogenase (LDH) in myocardial coronary effluent, and its inhibitory effect on these components is significantly higher than that of a single saponin component and the positive control drug verapamil. Simultaneously, the composition has a better recovery ability on coronary flow (CF), left ventricular developmental pressure (LVDP), maximum rate of decrease of left ventricular pressure (-dp / dtmax), and heart rate (HR) in myocardial coronary effluent. Therefore, the composition can alleviate and treat myocardial ischemia-reperfusion injury through multiple targets and mechanisms, fundamentally inhibiting the development of ischemic heart disease, thereby achieving a safe and effective therapeutic goal.

[0026] This invention also provides a medicament for treating ischemic heart disease, comprising the composition described in the above-described technical solution. Preferably, the medicament of this invention also includes pharmaceutically acceptable excipients. This invention does not have special requirements for the excipients of the medicament described in the above-described technical solution; conventional excipients in the art can be used. For example, the composition of this invention can be combined with antioxidants, pigments, and enzyme preparations to formulate a medicament or health product with therapeutic effects on ischemic heart disease; alternatively, no excipients can be added, and the saponin composition or substances containing saponin compositions can be directly used as a therapeutic drug. The dosage forms of this invention preferably include oral dosage forms, injectable dosage forms, and topical dosage forms; the oral dosage forms preferably include tablets, powders, capsules, granules, pills, liquids, and syrups; the injectable dosage forms preferably include aqueous solutions, suspensions, liposomes, and solutions; the topical dosage forms preferably include ointments, solids, suspensions, aqueous solutions, liniments, powders, pastes, suppositories, aerosols, mud dressings, films, lotions, and emulsions.

[0027] To further illustrate the present invention, the technical solutions provided by the present invention will be described in detail below with reference to the accompanying drawings and embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0028] Example 1

[0029] Establishment and validation of an in vitro rat MIRI pharmacodynamic model

[0030] 1.1 Establishing a Langendorff rat model of ischemia-reperfusion injury in isolated myocardium, the steps are as follows:

[0031] 1) Isolation and modeling of isolated animal hearts

[0032] The experimental animals were healthy adult male SD rats (weighing 250–300 g, provided by the Experimental Animal Research Center of Fujian Medical University, certificate number: 2010000516322). The animals were housed in a clean-grade laboratory at a room temperature of 20℃–25℃ and a relative humidity of 55%–70%. Animals were first anticoagulated by intraperitoneal injection of 0.25% heparin at a dose of 10 mL / kg, followed by anesthesia with intraperitoneal injection of 3% sodium pentobarbital at a dose of 30 mg / kg. The rats were then fixed to a dissection table, the chest skin was cut open, the thoracic cavity was opened to expose the heart, and the heart was gently lifted. At the root of the aorta, 0.5–1 cm from its origin, the aorta, other blood vessels, and surrounding tissues were quickly cut with scissors. The animals were immediately placed in pre-oxygenated, 4°C calcium-free KH solution (Krebs-Henseleits solution): NaCl 118g, KCl 4.7g, KH₂PO₄ 1.2g, NaHCO₃ 25g, MgSO₄ 1.2g, CaCl₂ 2.5g of glucose and 11.1g of blood glucose were prepared with double-distilled water to a final volume of 1L, adjusting the pH to 7.3–7.4 (filtered through a 0.45μm microporous membrane). The aortic stump was located below the liquid level. The aortic stump opening was lifted with forceps, and the aorta was quickly connected to the aortic cannula on the Langendorff equipment, securing it with an arterial clamp. The Langendorff ex vivo heart perfusion device (ADI, Australia) was then connected, and retrograde perfusion was immediately initiated with KH solution pre-saturated with a mixture of 95% oxygen and 5% carbon dioxide. The cardiac perfusion pressure was adjusted to 70 mmHg, and the heart quickly resumed beating. The tissue attached to the heart was further removed, and the left atrial appendage was located. A small incision was made in the left atrial appendage, and a pressure measuring tube with a latex water balloon was inserted into the left ventricle through the mitral valve. The pressure transducer was connected to a PowerLab multichannel physiological monitor. Using a water-filled syringe connected to a three-way valve, the volume of the water balloon in the left ventricle was adjusted to achieve a left ventricular end-diastolic pressure (LVEDP) of 4–6 mmHg. Left ventricular functional parameters—heart rate (HR), left ventricular developmental pressure (LVDP), maximum rate of rise of left ventricular pressure, and maximum rate of fall of left ventricular pressure (±dp / dtmax)—were observed and recorded in real time using Chart software. Animals with HR > 180 bpm and LVDP > 85 mmHg after equilibration perfusion using the Langendorff model were considered successfully modeled for MIRI.

[0033] 2) Establishment of pharmacodynamic experimental model and index testing

[0034] ① Grouping of pharmacological experiment models

[0035] The animal model was established using the method in step 1). The animals were grouped as follows: Nine MIRI / SD rats were randomly divided into three groups of three. The following methods and drug dosages were used to establish the specific pharmacodynamic models: A. Sham group: continuous perfusion with KH solution for 80 min. B. Myocardial ischemia / reperfusion group (MIRI): stable perfusion with KH solution for 20 min, followed by a 30 min interruption (warming and moisturizing), and then a 30 min resumption of KH solution perfusion. C. Verapamil positive drug group: stable perfusion with KH solution for 20 min, followed by a 30 min interruption, and then reperfusion with 0.5 mg / L verapamil / KH solution for 30 min.

[0036] The data, expressed as mean and standard deviation as X±SD, were analyzed using DAS3.0 software, including t-test, orthogonal design ANOVA, modeling, efficacy prediction and its predicted error (PE), model evaluation and plotting.

[0037] ②MIRI Animal Efficacy Model Index Testing

[0038] Biochemical indicators: Coronary effluent was collected, and the degree of myocardial damage was reflected by detecting the release of AST, CK, and LDH (units (U / L) of enzyme activity, L, volumetric liters) in the coronary effluent. Three mL of coronary effluent was collected at six time points: before perfusion cessation, and at 5, 10, 15, 20, and 30 minutes after ischemia-reperfusion. The results were analyzed using a fully automated biochemical analyzer (BS-200 model, Shenzhen Mindray Bio-Medical Electronics Co., Ltd.). The results are shown in Tables 1-3.

[0039] Table 1. Effects of ischemia-reperfusion on AST levels in coronary effusion from isolated rat hearts.

[0040]

[0041] Note: Compared with the Sham group, *P<0.05, **P<0.01; compared with the MIRI group, Verapamil, ▲ P < 0.05 ▲▲ P < 0.01

[0042] Table 2. Effects of ischemia-reperfusion on CK levels in coronary effusion from isolated rat hearts.

[0043]

[0044] Note: Compared with the Sham group, *P<0.05, **P<0.01; compared with the MIRI group, Verapamil, ▲ P < 0.05▲▲ P < 0.01

[0045] Table 3. Effects of ischemia-reperfusion on LDH in coronary effusion of isolated rat hearts.

[0046]

[0047] Note: Compared with the Sham group, *P<0.05, **P<0.01; compared with the MIRI group, Verapamil, ▲ P < 0.05 ▲▲ P < 0.01

[0048] As shown in Tables 1-3, compared with the Sham group, the levels of AST, CK, and LDH in the myocardial coronary effusion of the model group MIRI were significantly increased after ischemia-reperfusion (P<0.05 or P<0.01). After intervention with the positive drug verapamil, the levels of AST, CK, and LDH were significantly reduced (P<0.05 or P<0.01), with the intervention on AST enzyme being the most significant. The level of CK decreased after drug intervention, while the intervention on LDH was weaker. This indicates that the drug intervention on MIRI is selective, and the drug intervention on the model group MIRI is significant, showing that the modeling was successful.

[0049] To further verify the intervention effect of the drug on the model's kinetic parameters, the following methods were used:

[0050] Measurement of hemodynamic parameters: Changes in hemodynamic cardiac parameters in each group before and after perfusion arrest were recorded and measured using a pressure transducer connected to a left ventricular balloon catheter. Coronary effluent was collected in test tubes for 1 minute before cardiac arrest and 30 minutes after reperfusion. Each sample was observed and analyzed in real time using Chart software. The coronary flow rate (CF), left ventricular development pressure (LVDP), maximum rate of increase of left ventricular pressure (+dp / dtmax), maximum rate of decrease of left ventricular pressure (-dp / dtmax), and heart rate (HR) before cardiac arrest were used as 100%. The recovery rates of cardiac CF, LVDP, ±dp / dtmax, and HR 30 minutes after reperfusion were used as indicators to compare the changes in hemodynamic parameters in the pharmacodynamic animal model. The results are shown in Table 4 below.

[0051] Table 4. Effects of ischemia-reperfusion on hemodynamic parameters in coronary effusion of isolated rat hearts.

[0052]

[0053] Note: Compared with the Sham group, *P<0.05, **P<0.01; compared with the MIRI group, Verapamil, ▲ P < 0.05▲▲ P < 0.01

[0054] As shown in Table 4, compared with the Sham group, the levels of CF, LVDP, and ±dp / dtmax in the myocardial coronary effusion of the model group were significantly reduced after ischemia-reperfusion (P < 0.05). After intervention with the positive drug verapamil, the levels of CF, LVDP, and ±dp / dtmax were increased (P < 0.05 or P < 0.01), with the intervention effect on +dp / dtmax being the most significant. The CK level increased rapidly after drug intervention, while the intervention effect on HR was weak. This indicates that the drug intervention effect on MIRI is selective, and the drug intervention effect on MIRI in the model group is significant, indicating that the modeling was successful.

[0055] To further verify the intervention effect of the drug on pathological morphological indicators, the following methods were used:

[0056] ③ Pathological morphological observation and results

[0057] Immediately after model establishment and verification, the heart was removed, the left ventricle was excised, and myocardial tissue from the same location along the coronary plane at the apex of the heart was harvested and cut into small pieces 2–3 mm thick. The cut myocardial tissue was immediately immersed in 10% neutral formalin fixative for 24 hours. Routine graded ethanol dehydration, xylene clearing, paraffin embedding, sectioning, dewaxing, and HE staining were performed, and the pathological morphological changes of the myocardium were observed under a light microscope. Grading of cardiomyopathy: Under light microscopy, the degree of pathological damage is divided into grades 0 to III according to the grading criteria of Rona et al.: Grade 0 is no lesion; Grade I is not obvious myocardial fiber rupture, myocardial cells are swollen and enlarged, cytoplasmic turbidity or vacuolar degeneration, perinuclear effusion with perinuclear halos, but cell outlines are still clear, interstitial edema, and a few cells are necrotic; Grade II is localized myocardial rupture of a certain area, necrosis is in the form of small-scale fusion, myocardial cell necrosis is manifested as cell disintegration, membrane rupture, nuclear condensation or dissolution or even disappearance, myocardial cell outline disappears, and small blood vessels in the necrotic area also rupture, rupture, and cell leakage; Grade III is large-scale myocardial fiber rupture and disintegration, network support is destroyed, and a larger area of ​​myocardial confluent necrosis lesions appear.

[0058] Table 5 shows the myocardial pathological morphology scores after modeling. The effects of drugs on the pathological morphology of isolated MIRI rat myocardial tissue are shown in Table 5. Figure 1 As shown:

[0059] Table 5. Myocardial pathological morphology score

[0060]

[0061] From Table 5 and Figure 1 As can be seen from this, the Sham group ( Figure 1In group a), the myocardial section score was 0. The myocardial cells were morphologically normal, without hypertrophy or atrophy. The myocardial fibers were neatly arranged in bundles, with clear structure and uniform staining. The cell nuclei were elongated oval and evenly distributed. (MIRI group) Figure 1 (b) Myocardial slice scores were grade III and II, showing myocardial fiber rupture, structural disorder, wavy curvature, fragmented and absent nuclei, widened interfibrillary spaces, extensive myocardial fiber rupture, and punctate myocardial cell necrosis. Verapamil group ( Figure 1 In the middle (c) group, the myocardial slice score recovered to grades II and I, the myocardial fibers were relatively intact, the arrangement was relatively neat, the staining was relatively uniform, the interfascicular spaces were widened, and some myocardial fibers were broken. However, the degree of myocardial pathological damage was less than that in the MIRI group, which indicates that the drug intervention effect on MIRI is selective, and the drug intervention effect on the model group of MIRI is significant, indicating that the modeling was successful.

[0062] The above data confirm the successful establishment of a rat isolated myocardial ischemia-reperfusion injury model and a verapamil-positive drug model using the Langendorff isolated heart perfusion system. Results from the Sham group indicate that after 1 hour of perfusion using the Langendorff model in isolated rat hearts, the decrease in various hemodynamic parameters was not significant; after 30 minutes of perfusion, the decrease in hemodynamic parameters did not exceed 20% of the baseline value. The drug's intervention on MIRI was selective, and the drug's intervention on MIRI in the model group was significant, indicating successful model establishment. This confirms that the pharmacodynamic animal model is stable and reliable, meeting experimental requirements.

[0063] Example 2

[0064] Verification of the protective effects of ginsenosides Rg1, Rb1, Re and notoginsenoside R1 on isolated MIRI in rats

[0065] Ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1 were selected as test drugs, and verapamil was selected as a positive control drug. The Langendorff isolated heart perfusion model was used as an animal model. The effects of each monomer component on repairing myocardial ischemia-reperfusion injury were quantitatively analyzed. The experimental drugs were grouped as follows: In this example, L represents low dose 2.5 mg / L, M represents medium dose 5.0 mg / L, and H represents 5 mg / L, and the same applies below.

[0066] a. Low-dose group of ginsenoside Rg1 (Rg1L): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 2.5 mg / L ginsenoside Rg1 / KH solution for 30 min.

[0067] b. Ginsenoside Rg1 medium dose group (Rg1M): After stabilizing perfusion with KH solution for 20 min, the perfusion was stopped for 30 min, and then perfused again with 5 mg / L ginsenoside Rg1 / KH solution for 30 min.

[0068] c. High-dose group of ginsenoside Rg1 (Rg1H): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 10 mg / L ginsenoside Rg1 / KH solution for 30 min.

[0069] d. Low-dose group of ginsenoside Rb1 (Rb1L): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 2.5 mg / L ginsenoside Rb1 / KH solution for 30 min.

[0070] e. Ginsenoside Rb1 medium dose group (Rb1M): After stabilizing perfusion with KH solution for 20 min, the perfusion was stopped for 30 min, and then perfused again with 5 mg / L ginsenoside Rb1 / KH solution for 30 min.

[0071] f. High-dose group of ginsenoside Rb1 (Rb1H): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 10 mg / L ginsenoside Rb1 / KH solution for 30 min.

[0072] g. Low-dose group of ginsenoside Re (ReL): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 2.5 mg / L ginsenoside Re / KH solution for 30 min.

[0073] h. Ginsenoside Re medium dose group (ReM): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 5 mg / L ginsenoside Re / KH solution for 30 min.

[0074] i. High-dose group of ginsenoside Re (ReH): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 10 mg / L ginsenoside Re / KH solution for 30 min.

[0075] j. Low-dose group of Panax notoginseng saponin R1 (R1L): After stabilizing perfusion with KH solution for 20 min, perfusion was stopped for 30 min, and then perfused again with 2.5 mg / L Panax notoginseng saponin R1 / KH solution for 30 min.

[0076] k. Medium dose group of Panax notoginseng saponin R1 (R1M): After stabilizing perfusion with KH solution for 20 min, the perfusion was stopped for 30 min, and then perfused again with 5 mg / L Panax notoginseng saponin R1 / KH solution for 30 min.

[0077] l. High-dose group of Panax notoginseng saponin R1 (R1H): After stabilizing perfusion with KH solution for 20 min, the perfusion was stopped for 30 min, and then perfused again with 10 mg / L Panax notoginseng saponin R1 / KH solution for 30 min.

[0078] Among them, ginsenosides Rg1, Re, Rb1 and notoginsenoside R1 were all tested using Chinese pharmaceutical standards (HPLC ≥ 98, purchased from Chengdu Purifa Technology Co., Ltd.).

[0079] The pharmacodynamic modeling and analysis methods for detection indicators are the same as in Example 1, and the specific results are shown in Tables 6-8:

[0080] Table 6. Effects of four saponins on biochemical parameters in coronary effusion of isolated rat heart after 30 min.

[0081]

[0082] Note: Compared with the MIRI group, *P<0.05, **P<0.01, compared with the verapamil group ▲ P < 0.05 ▲▲ P < 0.01.

[0083] As shown in Table 6, compared with the MIRI model group, the ginsenosides Rg1, Rb1, Re, and notoginsenoside R1 in each dose group of the present invention and the positive drug group can significantly reduce the levels of myocardial enzymes AST, CK, and LDH in myocardial coronary effluent (P < 0.05 or P < 0.01). Among them, the inhibitory effects of Rg1H, Rb1H, Re1H, and R1L were the most significant. The R1L group had the most significant effect in downregulating AST and CK levels (P < 0.05), while the Rg1H group had the most significant effect in downregulating LDH levels (P < 0.01). The drug effects of the two groups were significantly higher than those of the verapamil group (P < 0.05 or P < 0.01). Rb1H and Re1H only showed higher levels of regulation on AST levels than the verapamil group (P < 0.05). Their inhibitory effects and levels of regulation on CK and LDH levels were similar to those of the verapamil group. This indicates that the inhibitory effects of various saponins on the levels of myocardial enzymes AST, CK, and LDH in myocardial coronary effluent are different. The R1L group showed the most significant effect in downregulating AST and CK levels, while the Rg1H group showed the most significant effect in downregulating LDH levels, demonstrating a certain advantage.

[0084] Table 7. Effects of various saponins on hemodynamic parameters in coronary effusion of isolated rat heart after 30 min.

[0085]

[0086] Note: Compared with the MIRI group, *P<0.05, **P<0.01, compared with the verapamil group ▲ P < 0.05 ▲▲ P < 0.01.

[0087] As shown in Table 7, compared with the MIRI model group, the ginsenosides Rg1, Rb1, Re, and notoginsenoside R1 in each dose group of this invention, as well as the positive drug group, can significantly improve the recovery rate of hemodynamic related indicators: CF, LVDP, ±dp / dtmax, and HR (P<0.05 or P<0.01). The drug effects of each group on regulating CF, LVDP, and -dp / dtmax are similar to those of the positive drug group. For CF and LVDP, the drug effects of various doses are similar, but the ginsenosides Rg1H, Rb1H, ReH, and R1L groups have the most significant effect on increasing the recovery rate of +dp / dtmax (P<0.05). All dose groups of notoginsenoside R1 can increase the HR level, with the R1L group having the most significant effect on increasing the HR level (P<0.01). The drug effects of the two groups are significantly higher than those of the verapamil group (P<0.05 or P<0.01). This indicates that various saponins have different effects on improving the levels of myocardial enzymes CF, LVDP, ±dp / dtmax, and HR recovery rate in myocardial coronary effusion. Ginsenosides Rg1H, Rb1H, ReH, and Panax notoginseng saponin R1L showed the most significant upregulation effect on +dp / dtmax recovery rate. All doses of Panax notoginseng saponin R1 could upregulate HR levels, with the R1L group showing the most significant upregulation effect on HR levels, demonstrating a certain advantage.

[0088] Further verification of the effects of ginsenosides Rg1, Rb1, Re and notoginsenoside R1 on the pathological morphology of isolated rat myocardial tissue was conducted, and the results are shown in Table 8 and 9. Figure 2 As shown.

[0089] Table 8. Myocardial Pathological Morphology Scoring

[0090]

[0091]

[0092] As shown in Table 8, in the sham group, the myocardial slice score was 0, the myocardial cell morphology was basically normal, without hypertrophy or atrophy, the myocardial fibers were neatly arranged in bundles, the structure was clear, the staining was uniform, and the cell nuclei were elongated oval and evenly distributed. In the MIRI group, after modeling, the myocardial slice score was III and II, the myocardial fibers were broken, the structure was disordered, wavy, the nuclei were fragmented or disappeared, the interfibrillary spaces were widened, and some myocardial fibers were broken. After drug intervention with ginsenosides Rg1, Rb1, and Re, and notoginsenoside R1, the myocardial slice score recovered to II and I. Among them, ginsenosides Rg1H, Rb1H, and ReH, and notoginsenoside R1L showed significant improvement in the pathological morphology of the myocardial tissue, the myocardial fibers were more intact, the arrangement was more neat, the staining was more uniform, the interfibrillary spaces were widened, and some myocardial fibers were broken. The degree of myocardial pathological damage was significantly reduced compared to the MIRI group, indicating a significant effect of drug intervention.

[0093] Analysis of the results from Example 1 shows that ginsenosides Rg1H, Rb1H, and ReH, along with notoginsenoside R1L, significantly improved the pathological morphology of myocardial tissue. Myocardial fibers were more intact, arranged more neatly, and stained more evenly. Interfascicular spaces widened, and some myocardial fibers were broken. The degree of pathological myocardial damage was significantly reduced compared to the MIRI group, demonstrating a significant therapeutic effect.

[0094] Compared with the MIRI model group, the ginsenosides Rg1, Rb1, Re, and notoginsenoside R1 in all dosage groups of this invention, as well as the positive control group, significantly reduced the levels of myocardial enzymes AST, CK, and LDH in the coronary effluent (P < 0.05 or P < 0.01). Among the various dosages, the inhibitory effects of Rg1H, Rb1H, Re1H, and R1L were the most significant. The R1L group showed the most significant effect in downregulating AST and CK levels (P < 0.05), while the Rg1H group showed the most significant effect in downregulating LDH levels (P < 0.01). The effects of these two groups were significantly higher than those of the verapamil group (P < 0.05 or P < 0.01). This indicates that the inhibitory effects of various saponins on the levels of myocardial enzymes AST, CK, and LDH in the coronary effluent are different. The R1L group showed the most significant effect in downregulating AST and CK levels, while the Rg1H group showed the most significant effect in downregulating LDH levels, demonstrating a certain advantage.

[0095] Compared with the MIRI model group, the ginsenosides Rg1, Rb1, Re, and notoginsenoside R1 in each dose group of this invention, as well as the positive control group, can significantly improve the recovery rate of hemodynamic related indicators: CF, LVDP, ±dp / dtmax, and HR (P<0.05 or P<0.01). The drug effects of each group on regulating CF, LVDP, and -dp / dtmax are similar to those of the positive control group. For CF and LVDP, the drug effects of various doses are similar, but the ginsenosides Rg1H, Rb1H, ReH, and R1L groups have the most significant effect on increasing the recovery rate of +dp / dtmax (P<0.05). All dose groups of R1 can increase the level of HR, with the R1L group having the most significant effect on increasing the level of HR (P<0.01). The drug effects of the two groups are significantly higher than those of the verapamil group (P<0.05 or P<0.01). This indicates that the effects of various saponins on improving the levels of myocardial enzymes CF, LVDP, ±dp / dtmax, and HR recovery rate in myocardial coronary effusion vary. The ginsenosides Rg1H, Rb1H, ReH, and R1L groups showed the most significant effect in upregulating the +dp / dtmax recovery rate, while all R1 dose groups could upregulate HR levels, with the R1L group showing the most significant effect and demonstrating a certain advantage.

[0096] Given the varying inhibitory effects of different saponins on the levels of myocardial enzymes AST, CK, and LDH in myocardial coronary effluent, and considering that the CF and LVDP levels of certain saponins, at various doses, are similar to those of the verapamil group, further optimization was achieved by selecting ginsenosides Rg1H, Rb1H, ReH, and Panax notoginseng saponin R1L as preferred saponins. The dosages were ginsenoside Rg1 10 mg / L, ginsenoside Rb1 10 mg / L, ginsenoside Re 10 mg / L, and Panax notoginseng saponin R1 2.5 mg / L, respectively. Compatibility experiments were conducted with different saponins to demonstrate the synergistic drug effects of different saponin combinations.

[0097] Example 3

[0098] The protective effects of different combinations of ginsenosides Rg1, Rb1, Re and notoginsenoside R1 against in vitro MIRI in rats:

[0099] Ginsenoside Rg1, ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1 were selected as detection drugs, and verapamil was selected as a positive control drug. The Langendorff isolated heart perfusion model was used as the animal model. The pharmacodynamic modeling and analysis methods for detection indicators were the same as in Examples 1 and 2. To accurately screen synergistic and antagonistic compositions, mathematical modeling was used to screen synergistic and antagonistic compositions. The modeling and screening methods are as follows:

[0100] Each saponin component was set to two levels according to dosage (drug use 1 and no drug use 2), where A is ginsenoside Rg1, B is ginsenoside Rb1, C is ginsenoside Re, and D is notoginsenoside R1. The optimal dosages were ginsenoside Rg1 10 mg / L, ginsenoside Rb1 10 mg / L, ginsenoside Re 10 mg / L, and notoginsenoside R1 2.5 mg / L. The compositions were divided into 8 groups according to the L8(24) orthogonal array design.

[0101] Since AST, CK, LDH, and other indicators have a negative relationship with drug efficacy, and among the cardiac hemodynamic parameters, the +dp / dtmax recovery rate is the most stable and sensitive, this study selected the +dp / dtmax recovery rate as the main pharmacodynamic parameter. The experimental results of the effects of each saponin drug group on the +dp / dtmax recovery rate are shown in Table 9.

[0102] Table 9. Effects of each saponin combination on the recovery rate of +dp / dtmax 30 min after reperfusion.

[0103]

[0104] Note: Level 1 indicates medication use, and Level 2 indicates no medication use; compared with the positive drug verapamil group, *P<0.05, **P<0.01.

[0105] The +dp / dtmax recovery rate (%) was used as a parameter; the higher the parameter value, the better the efficacy. Table 9 shows the +dp / dtmax recovery rates of each group of ginsenosides in the MIRI efficacy model, all of which showed varying degrees of improvement. Compared with verapamil, groups 3 and 5 (ginsenoside Rg1 + notoginsenoside R1, or ginsenoside Rb1 + notoginsenoside R1) had similar efficacy to the verapamil group, while the efficacy of all other groups was superior to that of the positive control drug verapamil group (P < 0.05, or P < 0.01).

[0106] Furthermore, the parameters were calculated using the DAS3.0 compound pharmacodynamic model to determine the antagonistic and compatibility relationships of the composition. The results are shown in Table 10.

[0107] Table 10 Parameters of the Compound Pharmacodynamic Model

[0108]

[0109] As shown in Table 10, since larger parameter values ​​indicate stronger efficacy, the contribution values ​​of each component to the efficacy of the compound are ranked as follows: C > D > B > A, and ginsenoside Re > notoginsenoside R1 > ginsenoside Rb1 > ginsenoside Rg1. The combination with the maximum effect (Emax) of the compound is BCD, and the combination with the minimum effect (Emin) is A.

[0110] Furthermore, the interactions between the various saponin combinations are shown in Table 11 (with medication 1 and without medication 2):

[0111] Table 11 Interactions and component interactions of the combined saponins

[0112]

[0113]

[0114] Table 11 shows that the combination with the strongest synergistic effect is BCD. This invention is the first to discover that the combination of ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L achieves the best synergistic effect. It is not necessary to use all saponin monomers together. Appropriate simplification of the compound can also achieve good results.

[0115] When ginsenoside Rg1H, ginsenoside Rb1H, and ginsenoside ReH are combined, or when ginsenoside Rg1H and notoginsenoside R1 are combined, the compound exhibits a synergistic effect; however, when ginsenoside Rg1H, ginsenoside ReH, Rg1H, ginsenoside Rb1H, ginsenoside ReH, notoginsenoside R1, or ginsenoside Rb1 and notoginsenoside R1 are combined, the compound exhibits an antagonistic effect.

[0116] Therefore, the preferred compositions of the present invention are BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L), ABC (ginsenoside Rg1H + ginsenoside Rb1H + ginsenoside ReH) and AD (ginsenoside Rg1H + notoginsenoside R1L).

[0117] To further verify the pharmacological effects of the preferred composition, the specific experimental methods were the same as in Examples 1 and 2, and the results are shown in Tables 12-13:

[0118] Table 12 Effects of various saponin compositions on biochemical parameters in coronary effusion of isolated rat heart after 30 min.

[0119]

[0120] Note: Compared with the MIRI group, *P<0.05, **P<0.01, compared with the verapamil group ▲ P < 0.05 ▲▲ P < 0.01; compared with R1L # P < 0.05 ## P < 0.01, compared with Rg1H ○ P < 0.05 ○○ P < 0.01.

[0121] Table 12 shows that 30 minutes after cardiac reperfusion, compared with the model group, all compositions significantly reduced the levels of AST, CK, and LDH (P < 0.01 or P < 0.05). Compared with the single preferred saponin R1L, the AD (ginsenoside Rg1H + notoginsenoside R1L) group had a similar inhibitory effect. The compositions BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) and ABC (ginsenoside Rg1H + ginsenoside Rb1H + ginsenoside ReH) had a greater effect in reducing AST and CK than the single saponin group (P < 0.05). Among them, the optimal combination BCD reduced AST by 1.10 times, CK by 1.29 times, and LDH by 1.28 times, showing a significant advantage.

[0122] Compared with the positive control drug verapamil group, the BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L), ABC (ginsenoside Rg1H + ginsenoside Rb1H + ginsenoside ReH), and AD (ginsenoside Rg1H + notoginsenoside R1L) groups showed more significant effects (P < 0.01 or P < 0.05). The combined drug groups had a greater drug effect than the verapamil group. Among them, the optimal combination of ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L had certain advantages. Its inhibitory effect reduced AST content by 1.45 times, CK content by 1.60 times, and LDH content by 1.48 times. Its drug effect in inhibiting biochemical indicators in coronary effusion was better than that of verapamil.

[0123] Analysis shows that the optimal composition BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) significantly inhibits the levels of AST, CK, and LDH in the coronary effusion of isolated rat hearts for 30 minutes compared to the single-saponin group and the verapamil group. The composition of this invention represents a substantial improvement in efficacy and possesses certain advantages.

[0124] Table 13 Effects of various saponin compositions on hemodynamics of isolated rat hearts

[0125]

[0126] Note: Compared with the MIRI group, *P<0.05, **P<0.01, compared with the verapamil group ▲ P < 0.05 ▲▲ P < 0.01; compared with R1L # P < 0.05 ## P < 0.01, compared with Rg1H ○ P < 0.05 ○○ P < 0.01.

[0127] As shown in Table 13, after 30 minutes of cardiac reperfusion, compared with the model group, all the combination drugs significantly increased cardiac hemodynamic parameters: CF, LVDP, ±dp / dtmax, and HR recovery rate (P<0.01 or P<0.05). Compared with the single preferred saponin Rg1H or R1L, the AD (ginsenoside Rg1H + notoginsenoside R1L) group had a similar enhancing effect. The combination drugs BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) and ABC (ginsenoside Rg1H + ginsenoside Rb1H + ginsenoside ReH) had a greater effect on enhancing ±dp / dtmax and HR recovery rate than the single saponin group (P<0.05 or P<0.01). Among them, the best combination BCD enhanced the ±dp / dtmax content by 1.25 times and HR by 1.28 times, which is a significant advantage.

[0128] Compared with the positive control drug verapamil group, the optimal combination of ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L can comprehensively improve CF, LVDP, ±dp / dtmax and HR recovery rate. The drug effect of the combination is greater than that of the verapamil group. The improvement effect is that the CF content increased by 1.11 times, the LVDP content increased by 1.12 times, the +dp / dtmax content increased by 1.52 times, the -dp / dtmax content increased by 1.56 times, and the HR content increased by 1.32 times. Its drug effect in inhibiting biochemical indicators in coronary effusion is better than that of verapamil. In the ABC (ginsenoside Rg1H + ginsenoside Rb1H + ginsenoside ReH) and AD (ginsenoside Rg1H + notoginsenoside R1L) groups, except for CF and LVDP which were similar to the effects of the positive drug verapamil, the drug effects of other indicators, including ±dp / dtmax and HR recovery rate, were better than those of the positive drug verapamil group (P < 0.01 or P < 0.05).

[0129] The optimal combination of ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L in this invention has certain advantages. Compared with single saponins, the drug effect of increasing +dp / dtmax and HR recovery rate is greater than that of the single saponin group. Compared with the positive drug verapamil, it can comprehensively improve CF, LVDP, ±dp / dtmax and HR recovery rate. The drug effect of the combination group is greater than that of the verapamil group. In its improvement effect, the CF content increased by 1.11 times, the LVDP content increased by 1.12 times, the +dp / dtmax content increased by 1.52 times, the -dp / dtmax content increased by 1.56 times, and the HR content increased by 1.32 times. Its drug effect of inhibiting biochemical indicators in coronary effusion is better than that of verapamil. Its inhibitory effect on isolated rat MIRI is stronger. Analysis shows that the optimal composition BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) inhibits the biochemical indicators CF, LVDP, ±dp / dtmax, and HR in the coronary effusion of isolated rat hearts for 30 min more effectively than the single-saponin group and the verapamil group. The composition of this invention represents a substantial improvement in efficacy and has certain advantages.

[0130] Example 4

[0131] Optimal ratio of the best saponin composition

[0132] Examples 1, 2, and 3 have demonstrated that the optimal composition BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) represents a substantial improvement in efficacy, exceeding that of the single saponin group and the verapamil group, exhibiting certain advantages. The optimal composition BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) has a ratio of 1:1:1. To further confirm whether this mass ratio is optimal, this invention employs the pharmacodynamic models and detection indicators of Examples 1 and 2, respectively using different ratios of the optimal composition BCD, a total notoginseng saponin group, a total American ginseng saponin group, a notoginseng saponin and total American ginseng saponin group, and a Verapamil positive control group. The experimental results are as follows:

[0133] The dosage for the single saponin group was 10 mg / L;

[0134] The total saponins of Panax notoginseng were purchased from the National Drug Standard Material Resource Platform. They contain various saponins including R1, 8.6%, ginsenoside Rg1, 35.0%, ginsenoside Re, 5.0%, ginsenoside Rb1, 28.8%, and ginsenoside Rd, 3.7%, with a dosage of 10 mg / L.

[0135] The total saponins of American ginseng were purchased from the National Drug Standard Material Resource Platform. It contains various saponins, including ginsenoside Rg1, 42.0%, ginsenoside Re, 8.0%, ginsenoside Rb1, 32.8%, and ginsenoside Rd, 17.2%, at a dose of 10 mg / L.

[0136] The total saponins of Panax notoginseng and Panax quinquefolius were combined, with each saponin being 10 mg / L and in a mass ratio of 1:1.

[0137] The optimal saponin composition with different mass ratios of ginsenoside Re, ginsenoside Rb1, and notoginsenoside R1, total notoginseng saponins, total American ginseng saponins, and total notoginseng and American ginseng saponins were selected as test drugs, and verapamil was used as a positive control. Using the Langendorff isolated heart perfusion model as an animal model, the effects of each component in repairing myocardial ischemia-reperfusion injury were quantitatively analyzed. The analytical methods for the detection indicators were the same as in Examples 1 and 2. The specific results are analyzed as follows:

[0138] Table 14 Effects of different BCD compositions on biochemical parameters in coronary effusion of isolated rat hearts

[0139]

[0140]

[0141] Note: Compared with the MIRI group, *P<0.05, **P<0.01, compared with the verapamil group ▲ P < 0.05 ▲▲ P < 0.01; compared with the optimal ratio composition BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L, mass ratio 1:1:2) # P < 0.05 ## P < 0.01.

[0142] Table 14 shows that 30 minutes after cardiac reperfusion, compared with the model group, all compositions significantly reduced the levels of AST, CK, and LDH (P < 0.01 or P < 0.05). Compared with the positive control drug verapamil group, the BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) drug groups at each ratio showed significant inhibitory effects (P < 0.01 or P < 0.05), with greater drug effects than the verapamil group. Among them, the optimal ratio of the best BCD composition (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L, mass ratio 1:1:2) was more advantageous, with its inhibitory effects reducing AST by 1.78 times, CK by 2.00 times, and LDH by 2.92 times. Its drug effect in inhibiting biochemical indicators in coronary effusion was superior to verapamil.

[0143] On the other hand, compared with the optimal ratio of BCD composition, the inhibitory effect of the group of Panax notoginseng total saponins + American ginseng saponins was similar, while the inhibitory effect of the single group of Panax notoginseng total saponins or American ginseng saponins was weaker than that of the optimal ratio of BCD composition (P < 0.01 or P < 0.05). The analysis showed that the optimal ratio of BCD composition (ginsenoside Rb1H + ginsenoside ReH + Panax notoginseng saponin R1L) had the best inhibitory effect on the biochemical indicators AST, CK, and LDH in the coronary effusion of isolated rat heart for 30 min. This indicates that the effective components of traditional Chinese medicine do not only contain one single component, but are a mixture of several single saponins. Because the number of target sites is increased compared with single components, the overall efficacy is improved compared with single components, greatly enhancing its drug effect.

[0144] To this end, this invention explores the synergistic interactions between components to form an optimal composition. The most preferred composition is a BCD combination (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L, mass ratio 1:1:2), which replaces the total notoginseng saponins and / or American ginsenosides in the medicinal materials, thereby maximizing the drug effect. Furthermore, the synergistic saponin composition replaces medicinal materials containing total notoginseng saponins and / or American ginsenosides, achieving enhanced efficacy. This provides a novel technical method and innovation for developing innovative drugs from ginseng, notoginseng, and American ginseng for the treatment of myocardial ischemia-reperfusion injury.

[0145] Table 15 Effects of different BCD compositions on hemodynamic parameters in coronary effusion of isolated rat hearts

[0146]

[0147] Note: Compared with the MIRI group, *P<0.05, **P<0.01, compared with the verapamil group ▲ P < 0.05 ▲▲ P < 0.01; compared with the optimal ratio composition BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L, volume ratio 1:1:2) # P < 0.05 ## P < 0.01.

[0148] As shown in Table 15, 30 minutes after cardiac reperfusion, compared with the model group, all compositions significantly increased the levels of CF, LVDP, ±dp / dtmax, and HR (P < 0.01 or P < 0.05). Compared with the positive control drug verapamil group, the BCD (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L) ratio groups showed significant effects (P < 0.01 or P < 0.05), with greater drug effects than the verapamil group. Among them, the optimal ratio of the best BCD composition (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L, mass ratio 1:1:2) was more advantageous, with CF content increasing by 1.26 times, LVDP content increasing by 1.24 times, ±dp / dtmax content increasing by 1.91 times, and HR content increasing by 2.01 times. Its drug effect in improving hemodynamic parameters in coronary effusion was superior to verapamil.

[0149] On the other hand, compared with the optimal ratio of BCD composition, the drug-enhancing effect of the group of total Panax notoginseng saponins + American ginseng saponins was similar, while the drug-enhancing effect of the groups of total Panax notoginseng saponins or American ginseng saponins alone was weaker than that of the optimal ratio of BCD composition (P < 0.01 or P < 0.05). Analysis shows that the optimal ratio of BCD composition (ginseng saponin Rb1H + ginseng saponin ReH + Panax notoginseng saponin R1L) improves hemodynamic parameters including CF, LVDP, and +dp / dtmax. The optimal HR effect indicates that the effective components of traditional Chinese medicine (TCM) are not merely single-component drugs, but rather a mixture of several TCM saponin monomers. Due to the increased number of target sites compared to single-component drugs, the efficacy is enhanced. Exploring the synergistic interactions between components and forming the optimal composition for the best effect—the optimal BCD composition (ginsenoside Rb1H + ginsenoside ReH + notoginseng saponin R1L, mass ratio 1:1:2)—is necessary to replace total notoginseng saponins and / or American ginseng saponins in the medicinal materials, thereby maximizing efficacy. Replacing medicinal materials containing total notoginseng saponins and / or American ginseng saponins with a synergistic saponin composition achieves enhanced efficacy. This provides a novel technical method and innovation for developing innovative drugs from ginseng, notoginseng, and American ginseng for the treatment of myocardial ischemia-reperfusion injury.

[0150] Therefore, the BCD composition of the present invention (ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L, mass ratio 1:1:2) has a synergistic effect of compatibility and efficacy. Its pharmacological effect of inhibiting myocardial ischemia-reperfusion injury can replace the total saponins of notoginseng and / or the ginsenoside group in the medicinal materials, and exerts a greater pharmacological effect than verapamil, which is a substantial and inventive progress.

[0151] As can be seen from the above embodiments, the composition provided by the present invention can significantly inhibit myocardial ischemia-reperfusion injury. In particular, when the mass ratio of ginsenoside Rb1H + ginsenoside ReH + notoginsenoside R1L in the composition is 1:1:2, it has a synergistic effect. Its drug effect in inhibiting myocardial ischemia-reperfusion injury can replace the total saponins of notoginseng and / or the ginsenoside group in the medicinal materials, and exerts a greater drug effect than verapamil, which is a substantial and inventive progress.

[0152] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. The use of a composition in the preparation of a medicament for treating myocardial ischemia-reperfusion injury, characterized in that, The composition comprises ginsenoside Rb1 at a concentration of 10 mg / L, ginsenoside Re at a concentration of 10 mg / L, and notoginsenoside R1 at a concentration of 2.5 mg / L, wherein the volume ratio of ginsenoside Rb1, ginsenoside Re, and notoginsenoside R1 is 1:1:2.

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