Pharmaceutical composition for improving cardiac function as well as preparation method and application thereof

Abstract

The invention relates to the technical field of traditional Chinese medicine compounds for treating coronary heart disease, in particular to a medicine composition for improving cardiac function and a preparation method and application thereof.The medicine composition is prepared from cassia twig, rhizoma acori graminei, codonopsis pilosula, pulp of dogwood fruit, rhodiola rosea, poria cocos, ruddle and honey-fried licorice root. The radix codonopsis and the pulp of dogwood fruit are combined to activate yang and strengthen yang, and the effect is quick. Cassia twigs, acorus calamus and poria cocos are combined to reduce phlegm and blood stasis and fully exert the functions of activating yang, freeing arthralgia, reducing phlegm and removing blood stasis, rhodiola rosea is used for eliminating collateral blood, codonopsis pilosula and pulp of dogwood fruit are used for strengthening the body resistance to make up for the defect of injury, and the traditional Chinese medicine formula highlights the difference of deficiency in root and excess in superficies. Different from a plurality of pure phlegm-reducing and blood-activating prescriptions, the medicine composition disclosed by the invention is precise and appropriate in compatibility of various medicines, has a synergistic effect together, has the effects of warming yang and freeing arthralgia, promoting the circulation of qi, activating blood and dredging collaterals, can remarkably improve the heart function, and has a good treatment effect on the'phlegm-blood stasis stagnation 'type coronary heart disease.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine compound for treating coronary heart disease, and is a drug combination for improving cardiac function and a preparation method thereof, and also includes application of the drug combination for improving cardiac function in preparing a drug for improving cardiac function, application of the drug combination for improving cardiac function in preparing a drug for preventing or / and treating coronary heart disease, and application of the drug combination for improving cardiac function in preparing a drug for preventing or / and treating "phlegm and blood stasis" type coronary heart disease. Background Art

[0002] Coronary heart disease is a heart disease caused by atherosclerotic lesions in the coronary arteries, which leads to narrowing or obstruction of the blood vessel lumen, myocardial ischemia, hypoxia or necrosis. It mainly includes stable angina pectoris, unstable angina pectoris and myocardial infarction. Studies have shown that by 2040, coronary heart disease will be the highest cause of death in 105 countries and regions, among which myocardial ischemia is the main cause. At present, the mortality rate of cardiovascular disease in China ranks first, higher than tumors and other diseases.

[0003] At present, Western medicine mainly treats patients with coronary heart disease with long-term drug treatment to control ischemic symptoms, reduce the occurrence of myocardial infarction and death, including taking dual antiplatelet drugs for at least 12 months, other drugs include B receptor blockers, statins and angiotensin converting enzyme inhibitors (ACEI) / angiotensin receptor antagonists (ARB), strictly control risk factors, carry out planned and appropriate exercise, and perform coronary revascularization when necessary, including percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG). However, there are many adverse reactions to Western medicine secondary prevention drug treatment, such as long-term use of statins can cause skeletal muscle lesions, which in turn cause muscle pain; long-term use of antiplatelet aggregation drugs can cause gastrointestinal bleeding; the combined use of multiple drugs will increase the risk of abnormal liver function. Traditional Chinese medicine theory has its unique perspective and advantages. Traditional Chinese medicine can treat according to the syndrome differentiation and give full play to the unique advantages of traditional Chinese medicine in multi-target and overall regulation. It has achieved excellent results in the clinical treatment of this type of cardiovascular disease, especially in improving the heart function of patients with coronary heart disease.

[0004] A Chinese patent application document with publication number CN114767816A discloses a Chinese medicine composition for treating coronary heart disease and a preparation method thereof, which comprises: 5-35 parts of salvia miltiorrhiza, 5-30 parts of ilex pubescens, 5-30 parts of motherwort, 5-10 parts of curcuma, 5-10 parts of pig's hoof, 4-7 parts of amomum, 5-10 parts of santalin, 5-10 parts of rose and 4-7 parts of panax notoginseng.

[0005] Chinese patent application document with publication number CN116036220A discloses a traditional Chinese medicine preparation for treating coronary heart disease, its preparation method and application, comprising: 18-25 parts of rhodiola rosea, 7-20 parts of hawthorn, 5-15 parts of angelica, 5-15 parts of codonopsis pilosula, 10-20 parts of astragalus, 5-15 parts of safflower, 5-12 parts of liquorice, 5-15 parts of cyperus rotundus, 8-20 parts of salvia miltiorrhiza, 10-20 parts of orientalis, 8-20 parts of poria, 7-20 parts of pinellia, 5-15 parts of atractylodes, 5-15 parts of polygonum multiflorum, 5-20 parts of turmeric, and 5-15 parts of white peony root.

[0006] The Chinese patent application document with publication number CN118767063A discloses a Chinese medicine composition for treating cardiovascular diseases, a preparation method and an application thereof, wherein the Chinese medicine composition comprises astragalus, notoginseng, salvia miltiorrhiza, peach kernel, trichosanthes, rhubarb, smilax glabra and radix glabra. The preparation method comprises first extracting astragalus, notoginseng, salvia miltiorrhiza, peach kernel and smilax glabra to obtain an extract; then enzymolyzing trichosanthes, rhubarb and radix glabra to obtain an enzymolyzate; finally, mixing the extract and the enzymolyzate, concentrating and drying. The combination of smilax glabra and rhubarb in a proper proportion with other medicinal ingredients in the prescription has obvious synergistic effects, has obvious effects on regulating blood lipids and improving blood rheology, has significant therapeutic effects, is simple to combine, and provides a new solution for the treatment of patients with cardiovascular diseases, which has practical application value.

[0007] Coronary heart disease belongs to the category of "chest pain" and "heart pain" in traditional Chinese medicine. Traditional Chinese medicine believes that coronary heart disease is a syndrome of deficiency of the root and excess of the symptoms. The "Golden Chamber" proposed that the main pathogenesis of chest pain is "weak yang and stringy yin", and You Zaijing explained it as "Yang is responsible for opening, yin is responsible for closing, yang is deficient and yin is dry, then there is chest pain and pain". "Suwen·Yin Yang Ying Xiang Da Lun" says: "At the age of forty, the yin qi is halved", and "Lei Zheng Zhi Cai" says: "Chest pain is caused by the weak yang in the chest. After a long time, the yin takes over the yang position and becomes a knot". Discussions in various dynasties have highlighted that insufficient yang is the dominant factor in coronary heart disease, and phlegm and blood stasis as pathological products should be "excess of symptoms". The northwest region is prone to cold and dampness, and warming and promoting yang is a common treatment method, especially for coronary heart disease. The classic prescriptions for chest pain in the past, "Zhi Shi Xie Bai Gui Zhi Tang" and "Gua Lou Xie Bai Bai Jiu Tang" are indeed ingenious, but there are still some problems in clinical application: (1) Baijiu has many inconveniences in clinical and scientific research applications. (2) Trichosanthes fruit, sweet, slightly bitter, cold. It enters the lung, stomach, and large intestine meridians. If it is not taken with white wine, it will inevitably damage the yang. The "New Compendium of Materia Medica" says: "The fruit of Trichosanthes fruit is the best at depleting the vital energy of the human body. It is used as a last resort for treating chest congestion caused by colds." The "Shi Jin Mo Yao Dui" also says: "The texture of Trichosanthes fruit is oily and sticky, and it can move and protect, but it can easily promote dampness and hinder the stomach from lingering evil."

[0008] Therefore, the present invention intends to implement a group of drug combinations that can improve heart function by adjusting the Chinese medicine dosage regimen and using the method of warming and promoting the flow of Yang Qi. Summary of the invention

[0009] The present invention provides a drug combination for improving cardiac function, a preparation method and an application thereof, which overcome the deficiencies of the above-mentioned prior art and can effectively solve the drawbacks of using white wine and Trichosanthes kirilowii in the existing classic prescriptions for chest pain during clinical and scientific research applications.

[0010] One of the technical solutions of the present invention is achieved through the following measures: a drug combination for improving cardiac function, wherein the raw materials, measured by weight, include 20 to 120 parts of cinnamon twig, 10 to 60 parts of calamus, 20 to 120 parts of codonopsis pilosula, 30 to 180 parts of cornus fruit, 20 to 120 parts of rhodiola rosea, 16 to 96 parts of poria, 6 to 36 parts of magnetite, and 7 to 28 parts of roasted liquorice.

[0011] In the present invention, cinnamon twig ( Cinnamomi Ramulus ), belongs to the Cinnamales, Lauraceae medium-sized tree; has the effects of sweating and relieving muscles, warming and unblocking the meridians, assisting yang and transforming qi, and balancing and descending qi. It is commonly used for colds, cold pain in the abdomen, amenorrhea due to cold blood, joint pain, phlegm and fluid retention, edema, palpitations, etc. Pharmacological studies have shown that cinnamon twigs have antibacterial, antiviral and diuretic effects. In the present invention, cinnamon twigs are used as the main drug to promote yang and relieve arthralgia, focusing on warming and unblocking, rather than dispersing.

[0012] In the present invention, Acorus calamus (Acori Tatarinowii Rhizoma), It is a grass-like perennial herb belonging to the Araceae family and the genus Acorus. Its rhizome has an odor and is often used as medicine. It has the effects of opening the mind and refreshing the spirit, removing dampness and harmonizing the stomach, and calming the mind and benefiting the mind. It is often used to treat phlegm blocking the clear mind, coma; dampness blocking the middle jiao, fullness in the abdomen, distension and pain; dysentery; forgetfulness, insomnia, tinnitus, and deafness. Pharmacological studies have shown that Acorus tatarinowii has the functions of calming the mind, relieving spasms, anticonvulsant, improving abnormal central excitement, improving learning and memory, and regulating blood pressure. In the present invention, Acorus tatarinowii is used as a ministerial drug to open the chest, focusing on opening the mind and removing phlegm, regulating qi and activating blood circulation.

[0013] In the present invention, Codonopsis pilosula ( Codonopsis Radix ) is a plant of the genus Codonopsis in the Campanulaceae family, which has the effects of tonifying the spleen and lungs, promoting the production of body fluids and nourishing blood. It is commonly used to treat spleen and stomach weakness, asthma and cough due to lung deficiency, thirst due to loss of body fluids, and weakness due to blood deficiency. Pharmacological studies have shown that Codonopsis has the functions of enhancing the body's immune function, regulating the central nervous system, resisting thrombosis, resisting hypoxia, improving microvascular circulation disorders, resisting inflammation, and protecting gastric mucosa. In the present invention, Codonopsis as an adjuvant focuses on replenishing qi to help cinnamon twigs to warm and promote circulation.

[0014] In the present invention, Fructus Corni ( Corni Fructus) is the dried mature pulp of the plant Cornus officinalis of the Cornaceae family. It has the effects of nourishing the liver and kidney, astringing and consolidating. It is commonly used to treat dizziness and tinnitus, soreness of the waist and knees, impotence and spermatorrhea, enuresis and frequent urination, metrorrhagia and leukorrhea, sweating and collapse, internal heat and thirst. Pharmacological studies have shown that Cornus officinalis has the effects and effects of enhancing the body's immune function, anti-inflammatory, anti-aging, and antibacterial. In addition, it has also been confirmed that it has the effects of inhibiting platelet aggregation and anti-thrombosis, as well as the effects of lowering blood sugar, blood lipids, strengthening the heart, and resisting hemorrhagic shock. In the present invention, Cornus officinalis is a ministerial drug that focuses on nourishing the kidney and replenishing essence, assisting Acorus tatarinowii in communicating the heart and kidney, and assisting Cinnamomum cassia to soothe the liver to strengthen the effect of warming, unblocking, and relieving numbness.

[0015] In the present invention, Poria cocos ( Poria ) is the dried sclerotium of the fungus Poria cocos of the genus Poria of the family Polyporaceae. It has the effects of promoting diuresis and reducing swelling, removing dampness, strengthening the spleen, and calming the mind. It is commonly used to treat edema, phlegm and fluid retention, diarrhea due to spleen deficiency, palpitations, and insomnia. Pharmacological studies have shown that Poria cocos has the functions of antibacterial, improving the digestive system, regulating blood sugar, and increasing myocardial contraction. In the present invention, Poria cocos as an adjuvant focuses on promoting diuresis and removing dampness to help cinnamon twigs to promote yang qi.

[0016] In the present invention, Rhodiola rosea ( Rhodiolae Crenulatae Radix ) is the rhizome of Rhodiola rosea or Rhodiola rosea, a plant of the Crassulaceae family. It has the effects of strengthening the spleen and replenishing qi, clearing the lungs and relieving cough, and promoting blood circulation and removing blood stasis. It is often used to treat spleen deficiency syndrome, lung yin deficiency, and lung heat cough. Pharmacological studies have shown that Rhodiola rosea has the effects of anti-hypoxia, anti-fatigue, antibacterial, analgesic, anti-radiation, anti-aging, and bidirectional regulation of the endocrine system. In the present invention, Rhodiola rosea as an adjuvant focuses on eliminating old blood and promoting blood circulation and removing blood stasis.

[0017] In the present invention, the hematite ( Hematite ) is an oxidized corundum mineral hematite Haematitum Mineral. It has the effects of calming the liver and suppressing yang, calming down the adverse, cooling blood and stopping bleeding. It is commonly used to treat hyperactivity of liver yang, dizziness, vomiting, hiccups, belching, gas reversal and wheezing, vomiting and bleeding due to blood heat, and metrorrhagia. Pharmacological studies have shown that Daizheshi has the effects of promoting digestion and increasing white blood cells. In the present invention, Daizheshi is used as an adjuvant drug, with red color entering the heart, on the one hand, nourishing blood and qi, calming blood heat, and continuously complementing with Rhodiola rosea to promote blood circulation and remove blood stasis. On the other hand, by virtue of its heavy nature, it plays the role of ascending and descending with cinnamon twigs, and the qi is smooth, and the yang is unblocked without forgetting to nourish the yin.

[0018] In the present invention, Radix Glycyrrhizae Preparata ( honey-fried licorice root ) is a processed product of licorice. The herbal property of licorice is sweet and flat, and it enters the heart, lung, spleen, and stomach meridians. It has the effects of tonifying the spleen and stomach, replenishing qi and restoring pulse. It is used for spleen and stomach weakness, fatigue, palpitations, and irregular pulse.

[0019] The following is a further optimization and / or improvement of one of the above-mentioned technical solutions: The above-mentioned 20 parts of cinnamon twigs, 10 parts of calamus gramineus, 20 parts of codonopsis pilosula, 30 parts of cornus fruit, 20 parts of rhodiola rosea, 16 parts of poria, 6 parts of magnetite, and 7 parts of roasted liquorice.

[0020] The above-mentioned cinnamon twig 50 parts, Acorus calamus 30 parts, Codonopsis pilosula 80 parts, Cornus officinalis 90 parts, Rhodiola rosea 80 parts, Poria 48 parts, Hematite 18 parts, and Radix Glycyrrhizae Preparata 14 parts.

[0021] The above-mentioned cassia twig 120 parts, Acorus calamus 60 parts, Codonopsis pilosula 120 parts, Fructus corni 180 parts, Rhodiola rosea 120 parts, Poria 96 parts, Hematite 36 parts, and Radix glycyrrhizae preparata 28 parts.

[0022] The above-mentioned drug combination for improving cardiac function is prepared according to the following method: soak the required amount of raw materials in distilled water to obtain an soaking mixture, heat the soaking mixture to reflux, cool, and filter to obtain a decoction, concentrate the decoction to obtain a concentrated solution, the volume of which is one-fourth to one-third of the volume of the decoction, and dry the concentrated solution to powder to obtain a drug combination for improving cardiac function.

[0023] The second technical solution of the present invention is achieved by the following measures: a method for preparing a drug combination for improving cardiac function, comprising: The required amount of raw materials is soaked in distilled water to obtain a soaking mixture, the soaking mixture is heated to reflux, cooled, filtered to obtain a decoction, the decoction is concentrated to obtain a concentrated solution, the volume of which is one-fourth to one-third of the volume of the decoction, and the concentrated solution is dried to powder to obtain a drug combination for improving cardiac function.

[0024] The following is a further optimization and / or improvement of the second technical solution of the above invention: The soaking time of the above-mentioned raw materials is 2.5 h to 3.0 h.

[0025] The above heating reflux time is 2.0 h to 2.5 h.

[0026] The above concentration is carried out by vacuum distillation.

[0027] The above drying adopts freeze drying method.

[0028] The third technical solution of the present invention is achieved through the following measures: use of a drug combination for improving cardiac function in the preparation of a drug for improving cardiac function.

[0029] The fourth technical solution of the present invention is achieved through the following measures: use of a drug combination for improving cardiac function in the preparation of a drug for preventing and / or treating coronary heart disease.

[0030] The fifth technical solution of the present invention is achieved through the following measures: the use of a drug combination for improving cardiac function in the preparation of a drug for preventing and / or treating "phlegm and blood stasis" type coronary heart disease.

[0031] The present invention mainly adopts a clear method of promoting yang, with cinnamon twig as the main drug and calamus as the minister, promoting yang and opening the mind, effectively solving the drawbacks of clinical liquor and trichosanthes, and combining codonopsis and cornus to promote yang and promote yang, and taking effect quickly. Cinnamon twig, calamus, and Poria can also resolve phlegm and blood stasis, give full play to the ability of promoting yang and relieving numbness, resolving phlegm and removing blood stasis, and assisting with rhodiola to eliminate old blood. Codonopsis and cornus can also make up for the disadvantages of hurting the body, highlighting that this prescription solves the difference between the severity of deficiency (lack of yang) and excess (phlegm and blood stasis). Different from many simple phlegm-resolving and blood-activating prescriptions, the drug combination of the present invention is precisely matched with each medicinal flavor, and jointly exerts a synergistic effect, has the effects of warming yang and relieving numbness, promoting qi, activating blood circulation, and unblocking collaterals, can significantly improve heart function, and has a good therapeutic effect on "phlegm and blood stasis" type coronary heart disease. In addition, the drug combination of the present invention has few raw materials, is easy to prepare, convenient to use, has good patient compliance, and has a good application prospect. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Attached Figure 1 This is a representative ultrasound image of the effect of a Chinese herbal compound on cardiac function in rats with "phlegm and blood stasis" type coronary heart disease.

[0033] Attached Figure 2 It is a Chinese herbal compound that affects the left ventricular ejection fraction of the hearts of rats with "phlegm and blood stasis" type coronary heart disease.

[0034] Attached Figure 3 It is a Chinese herbal compound that affects the left ventricular short-axis shortening rate in the hearts of rats with "phlegm and blood stasis" type coronary heart disease.

[0035] Attached Figure 4 This is a representative diagram of the effect of a Chinese herbal compound on ST segment changes in the heart of rats with "phlegm and blood stasis" type coronary heart disease.

[0036] Attached Figure 5 is based on Figure 4 Statistical graph of mid-ST segment elevation.

[0037] Attached Figure 6 It is the heart rate generated during the electrocardiogram detection process.

[0038] Attached Figure 7 It is aspartate aminotransferase (AST).

[0039] Attached Figure 8 It is the creatine phosphokinase isoenzyme (CK-MB).

[0040] Attached Fig. 9 It is lactate dehydrogenase (LDH).

[0041] Attached Fig.10It is triglyceride (TC).

[0042] Attached Fig.11 It is total cholesterol (TG).

[0043] Attached Fig.12 The survival rate on the second day after surgery.

[0044] Attached Fig.13 It is the ratio of heart weight to tibia length.

[0045] Attached Fig.14 It's about weight.

[0046] Attached Fig.15 is the eosin-hematoxylin staining of the hearts of rats in each group.

[0047] Attached Fig.16 is Sirius red staining of the hearts of rats in each group.

[0048] Attached Fig.17 yes Fig.16 Analysis of collagen volume fraction in each group.

[0049] Attached Fig.18 Masson staining of the hearts of rats in each group.

[0050] Attached Fig.19 yes Fig.18 Analysis of collagen volume fraction in each group.

[0051] Attached Fig. 20 It is a positive base peak ion flow chart of the analysis of the effective components of the traditional Chinese medicine compound of the present invention.

[0052] Attached Fig.21 It is a negative base peak ion flow chart of the analysis of the effective components of the traditional Chinese medicine compound of the present invention.

[0053] Appendix 1 is a nLC-MS identification table of the effective components of the Chinese herbal compound of the present invention.

[0054] Figure 2 , Figure 3 , Figure 5 , Figure 6 , Figures 7 to 14 , Fig.19 Compared with the normal group, # P <0.05; ## P <0.01; ### P <0.001; compared with the model group; * P <0.05, ** P <0.01, ***P <0.001; ns, no statistical difference. DETAILED DESCRIPTION

[0055] The present invention is not limited by the following embodiments, and specific implementation methods can be determined based on the technical solution of the present invention and actual conditions.

[0056] The invention provides a drug combination for improving cardiac function. The raw materials include, by weight, 20 to 120 parts of cassia twig, 10 to 60 parts of calamus calamus, 20 to 120 parts of codonopsis pilosula, 30 to 180 parts of cornus fruit, 20 to 120 parts of rhodiola rosea, 16 to 96 parts of tuckahoe, 6 to 36 parts of magnetite and 7 to 28 parts of roasted liquorice.

[0057] Preferably, the drug combination for improving cardiac function, the raw materials, by weight, include 20 parts of cinnamon twig, 10 parts of calamus, 20 parts of codonopsis pilosula, 30 parts of cornus fruit, 20 parts of rhodiola rosea, 16 parts of poria, 6 parts of magnetite, and 7 parts of roasted liquorice.

[0058] Preferably, the drug combination for improving cardiac function, the raw materials, by weight, include 50 parts of cinnamon twig, 30 parts of calamus calamus, 80 parts of codonopsis pilosula, 90 parts of cornus fruit, 80 parts of rhodiola rosea, 48 parts of poria, 18 parts of magnetite, and 14 parts of roasted liquorice.

[0059] Preferably, the drug combination for improving cardiac function, the raw materials, by weight, include 120 parts of cinnamon twig, 60 parts of calamus gramineus, 120 parts of codonopsis pilosula, 180 parts of cornus fruit, 120 parts of rhodiola rosea, 96 parts of poria, 36 parts of magnetite, and 28 parts of roasted liquorice.

[0060] The present invention will be further described below in conjunction with embodiments: Example 1: 20g of cinnamon twig, 10g of calamus gramineus, 20g of codonopsis pilosula, 30g of cornus fruit, 20g of rhodiola rosea, 16g of poria, 6g of magnetite, and 7g of roasted liquorice root.

[0061] Example 2: 50g cinnamon twig, 30g Acorus gramineus, 80g Codonopsis pilosula, 90g Cornus officinalis, 80g Rhodiola rosea, 48g Poria cocos, 18g magnetite, and 14g roasted liquorice.

[0062] Example 3: 120g cinnamon twig, 60g calamus, 120g codonopsis, 180g cornus fruit, 120g rhodiola rosea, 96g poria, 36g magnetite, and 28g roasted liquorice.

[0063] The research contents of the drug combination for improving cardiac function described in the present invention are as follows: In the following research contents, Chinese medicine compound and drug combination all refer to the drug combination for improving cardiac function described in the present invention. The animal model of coronary heart disease is a "phlegm and blood stasis" type of coronary heart disease animal model.

[0064] 1. Drug preparation and administration regimen Thirty male SD rats weighing 90 g to 110 g were purchased from the Animal Experiment Center of Xinjiang Medical University and housed in its SPF environment, with room temperature maintained at 20 ± 2 °C, humidity 50 ± 2%, 12 h / 12 ​​h light-dark cycle, and free access to water and food. This study was approved by the Animal Ethics Committee of Xinjiang Medical University (ethics review approval number: IACUC-20230321-09). The rats were randomly divided into 6 groups, namely, normal group, model group, Example 1 group, Example 2 group, Example 3 group, and metoprolol group, with 5 rats in each group.

[0065] After SD rats were adaptively fed for 7 days, each rat in the normal group was fed with 15g of ordinary feed per day; each rat in the model group, Example 1 group, Example 2 group, Example 3 group and metoprolol group was fed with 15g of high-fat feed per day (purchased from Guangdong Medical Experimental Animal Center, processing number: 20230503) for 56 days. From the 28th day of feeding, corresponding drug interventions were given to Example 1 group, Example 2 group, Example 3 group and metoprolol group respectively, and maintained for 28 days. Starting from the 57th day, the rats in the normal group underwent sham surgery, that is, thoracotomy without ligation of the left anterior descending branch of the coronary artery; the rats in the model group, Example 1 group, Example 2 group, Example 3 group and metoprolol group underwent left anterior descending branch ligation of the coronary artery to create an animal model of coronary heart disease that conforms to clinical pathological manifestations. In this study, blood samples and heart tissues of rats were collected 1 day after surgery and stored in a -80°C refrigerator.

[0066] 2. Drug preparation and administration regimen Experimental drugs: Cassia twig (Hebei Hehuachi Pharmaceutical Co., Ltd., batch number: C2852304003); Acorus calamus (Anhui Yuankang Chinese Medicine Pieces Co., Ltd., batch number: 221101); Codonopsis pilosula (Anguo Qi'ao Chinese Medicine Pieces Co., Ltd., batch number: 2398271111); Cornus officinalis (Anguo Qi'ao Chinese Medicine Pieces Co., Ltd., batch number: 2309811101); Hematite (Hebei Lily Health Pharmaceutical Co., Ltd., batch number: 8230422901); Roasted licorice (Sichuan Guoqiang Chinese Medicine Pieces Co., Ltd., batch number: 221201), Rhodiola rosea (Xinjiang Renyu Chinese Medicine Pieces Co., Ltd., batch number: 23021001); Poria cocos (Pu'er Liangpin Yikan Pharmaceutical Co., Ltd., batch number: 230702); Metoprolol tablets (specification: 50 mg, Yantai Juxian Pharmaceutical Co., Ltd., batch number: CN52-398A-3536).

[0067] The API ratios and administration methods of Example 1, Example 2, and Example 3 The Example 1 group adopted the raw material drug ratio described in Example 1, the Example 2 group adopted the raw material drug ratio described in Example 2, and the Example 3 group adopted the raw material drug ratio described in Example 3.

[0068] The formulations of the raw materials for Example 1, Example 2, and Example 3 are as shown above.

[0069] The raw materials in the proportions described in Examples 1 to 3 above are all prepared according to the following preparation method to prepare a drug combination for improving cardiac function.

[0070] Weigh the Chinese herbal medicine slices, soak them in 600 mL of distilled water for 3 h, and then add the solution volume to 600 mL. Transfer the liquid and solid in the beaker to a round-bottom flask, heat and reflux for 2 h, cool, and filter to obtain 600 mL of soup. Concentrate the soup to 100 mL using a rotary evaporator (Gongyi Yuhua Instrument Co., Ltd. RE-2010), freeze dry it in a freeze dryer (Thermo X16S-6564439-XS) at -40 °C for 20 to 24 h to obtain a Chinese herbal medicine freeze-dried powder (i.e., a drug combination for improving cardiac function), and the mass ratio of Chinese herbal medicine freeze-dried powder to raw materials is 0.1 to 0.2:1.

[0071] According to the preparation method, the freeze-dried powder of traditional Chinese medicine obtained in Example 1 was 13.66 g, the freeze-dried powder of traditional Chinese medicine obtained in Example 2 was 49.20 g, and the freeze-dried powder of traditional Chinese medicine obtained in Example 3 was 114.00 g.

[0072] According to the dosage of clinical Chinese medicine compound, the drug combination for improving cardiac function obtained in Example 1, Example 2 and Example 3 is converted into drug dosage by body surface area between human and rat as shown below: The following uses the drug combination for improving cardiac function prepared in Example 1 as an example to illustrate the daily dosage for rats.

[0073] The daily dose for rats = the daily dose for adults [g / (kg·d)] × 70kg × 0.018 / 0.2kg = 13.66g / 70kg × 70kg × 0.018 / 0.2≈1.23[g / (kg·d)].

[0074] Preparation and administration method of metoprolol According to the clinical dosage of metoprolol, adults take 200 mg per day. Grind the metoprolol tablets into fine powder in a mortar and dissolve in 2 mL of distilled water. The method for converting the drug dosage of metoprolol between humans and rats based on body surface area is as follows: The rat dosage [mg / (kg·d)] = adult dosage [mg / (kg·d)] × 70kg × 0.018 / 0.2kg = 200mg / 70kg × 70kg × 0.018 / 0.2kg = 18[mg / (kg·d)].

[0075] nLC-MS Identification of Active Components in Traditional Chinese Medicine Compounds Take the freeze-dried traditional Chinese medicine compound sample, add steel beads, put it into the grinder, grind it 6 times until it is powdered, accurately weigh 50 mg, add 500 ul, 75% methanol water, and ultrasonically treat it for 30 minutes (with ice packs). Centrifuge at 20°C, 17000g, 15min, take 100 ul of supernatant into the injection bottle, and detect it with ultra-high pressure liquid chromatography (EasynLC1000, THERMO) combined with ultra-high pressure liquid chromatography (EasynLC1000, THERMO).

[0076] Mobile phase conditions: A chromatographic column (75um*25cm, C18, 1.9um, THERMO) was used with a column temperature of 40°C and a sample volume of 3μl. The positive ion mode used 0.1% formic acid water and 0.1% formic acid acetonitrile. The negative ion mode used a 2mM ammonium acetate solution and acetonitrile. Acetonitrile and methanol were purchased from Merck (Darmstadt, Germany), and formic acid and ammonium acetate were purchased from CNW (Shanghai, China).

[0077] 3. Testing indicators Effect of Chinese herbal medicine on cardiac ultrasound function in rats with coronary heart disease of "phlegm and blood stasis" type Cardiac ultrasound is a non-invasive examination method that can observe the structure and function of the heart through ultrasonic imaging technology, which is of great significance for the diagnosis and monitoring of heart diseases. The present invention uses an ultra-high resolution small animal ultrasound imaging system (Visualsonics, vevo2100) to detect the coronary heart disease rat model to observe the effect of the Chinese medicine compound on the cardiac function of rats with "phlegm and blood stasis" type coronary heart disease.

[0078] Figure 1 This is a representative ultrasound image of the effect of a Chinese herbal compound on the cardiac function of rats with coronary heart disease of the "phlegm and blood stasis" type. Figure 2 and Figure 3 It is based on the analysis of echocardiographic data. Figure 2 It is a Chinese herbal compound that affects the left ventricular ejection fraction of rats with coronary heart disease of the "phlegm and blood stasis" type. Figure 3 It is a Chinese herbal compound that affects the left ventricular short-axis shortening rate in the hearts of rats with "phlegm and blood stasis" type coronary heart disease.

[0079] from Figure 2 and Figure 3It can be seen that compared with the normal group, the left ventricular ejection fraction and left ventricular short axis shortening rate in the model group were significantly reduced ( P <0.001), weakened heart function. Figure 2 It can be seen that after the treatment with the drug combination described in each embodiment of the present invention, Example 1 ( P <0.001)、Example 2( P <0.01)、Example 3( P <0.01) and metoprolol group ( P <0.01) can effectively alleviate the left ventricular ejection fraction of rats with "phlegm and blood stasis" type of coronary heart disease.

[0080] from Figure 3 It can be seen that after the treatment with the drug combination described in each embodiment of the present invention, Example 1 ( P <0.001)、Example 2( P <0.001)and Example 3( P <0.01) can effectively alleviate the left ventricular short-axis shortening rate in rats with "phlegm and blood stasis" type of coronary heart disease.

[0081] In summary, the drug combinations described in Examples 1, 2 and 3 of the present invention can effectively improve the cardiac function of rats with coronary heart disease of the "phlegm and blood stasis" type.

[0082] Effects of Chinese herbal medicine on myocardial ischemia in rats with coronary heart disease of "phlegm and blood stasis" type When a person has acute myocardial ischemia (or infarction), the characteristic electrocardiogram changes that appear are mainly ST segment elevation, abnormal Q wave and coronary T wave. Similar to the human electrocardiogram, the characteristic electrocardiogram changes of rats with "phlegm and blood stasis" type coronary heart disease after ligation of the left anterior descending coronary artery are mainly QRS wave group increase, ST segment elevation, and abnormal Q wave. Since these three characteristics do not appear at the same time, but at different stages of myocardial infarction, different characteristics will appear or appear in combination. Generally, during LAD surgery in rat models of "phlegm and blood stasis" type coronary heart disease, the main focus is on "ST segment elevation". The present invention uses the BL-420S biofunction experimental system (Chengdu Taimeng Software Company) to detect the ST segment of the electrocardiogram of the coronary heart disease rat model to observe the effect of the Chinese medicine compound on myocardial ischemic damage in rats with "phlegm and blood stasis" type coronary heart disease.

[0083] Figure 4 This is a representative diagram of the effect of a Chinese herbal compound on ST segment changes in rats with coronary heart disease of the "phlegm and blood stasis" type. Figure 5 is based on Figure 4 Statistical graph of mid-ST segment elevation.

[0084] from Figure 4 and Figure 5It can be seen that compared with the normal group, the ST segment of the model group was significantly elevated ( P <0.001), indicating significant ischemia in the heart. After treatment with the drug combination described in each embodiment of the present invention, Example 1 ( P <0.001)、Example 2( P <0.05)、Example 3( P <0.05) and metoprolol group ( P <0.05) can effectively reduce the elevation of ST segment in rats with "phlegm and blood stasis" type of coronary heart disease.

[0085] In summary, the drug combinations described in Examples 1, 2 and 3 of the present invention can effectively improve myocardial ischemia in the hearts of rats with coronary heart disease of the "phlegm and blood stasis" type.

[0086] Figure 6 It is the heart rate generated during the electrocardiogram test. From the data, it can be seen that compared with the normal group, the heart rate of rats in the model group was significantly reduced during surgery ( P＜ 0.001); compared with the model group, Example 1 ( P <0.001)、Example 2( P <0.001)、Example 3( P <0.05) and metoprolol group ( P The above data show that the drug combinations described in Examples 1, 2 and 3 of the present invention can increase heart rate and protect heart function.

[0087] Effects of Chinese herbal compound on serum myocardial enzymes and blood lipids in rats with coronary heart disease of "phlegm and blood stasis" type Myocardial enzymes are a general term for a variety of enzymes present in the myocardium, including aspartate aminotransferase, lactate dehydrogenase, creatine phosphokinase isoenzymes, etc. These enzymes increase to varying degrees after myocardial damage or necrosis, among which creatine phosphokinase isoenzymes and lactate dehydrogenase have the highest specificity. Therefore, the determination of myocardial enzymes in serum has a certain value in diagnosing acute myocardial infarction and evaluating the effect of thrombolysis. Total cholesterol is the sum of cholesterol contained in various lipoproteins in the blood, and triglycerides are lipids formed by the reaction of glycerol molecules and fatty acids. They can be used clinically to help diagnose diseases such as coronary heart disease and ischemic cardiovascular disease. The present invention uses a fully automatic biochemical analyzer (BECKMANCOULTER AU2700) to detect serum myocardial enzymes and blood lipid levels in a rat model of coronary heart disease to observe the effect of a Chinese medicine compound on myocardial serum indicators in rats with "phlegm and blood stasis" type coronary heart disease.

[0088] Figure 7 is aspartate aminotransferase (AST), Figure 8 is the creatine phosphokinase isoenzyme (CK-MB), Fig. 9 is lactate dehydrogenase (LDH), Fig.10 is triglyceride (TC), Fig.11 It is total cholesterol (TG).

[0089] from Figures 7 to 11 It can be seen that compared with the normal group, the AST content in the model group increased significantly ( P <0.001), CK-MB content increased significantly ( P <0.01), LDH content increased significantly ( P <0.001), TC content increased significantly ( P <0.01), TG content increased significantly ( P <0.001). Compared with the model group, Example 1 ( P <0.01)、Example 2( P <0.05)、Example 3( P <0.01), metoprolol group ( P <0.001) significantly reduced the AST content; Example 1 ( P <0.01)、Example 2( P <0.05)、Example 3( P <0.05), metoprolol group ( P <0.05) significantly reduced the CK-MB content; Example 1 ( P <0.01)、Example 2( P <0.05), metoprolol group ( P <0.05) significantly reduced the LDH content; Example 1 ( P <0.05)、Example 2( P <0.05)、Example 3( P <0.05), metoprolol group ( P <0.05) significantly reduced the TC content; Example 1 ( P <0.05)、Example 2( P <0.05)、Example 3( P <0.05), metoprolol group ( P <0.05) was significantly reduced.

[0090] In summary, the drug combinations described in Examples 1, 2 and 3 of the present invention can effectively improve myocardial damage in the hearts of rats with "phlegm and blood stasis" type coronary heart disease, and can effectively alleviate dyslipidemia.

[0091] Effects of Chinese herbal compound on survival rate, HW / TL and body weight of rats with coronary heart disease of "phlegm and blood stasis" type The survival rate of the animal model of left anterior descending coronary artery ligation is an important parameter for studying the pathogenesis of coronary heart disease. By comparing the survival rates of animals in different experimental groups, we can understand the influence of different factors (such as genes, drugs, environmental factors, etc.) on the development of coronary heart disease, which is also a key indicator for evaluating the therapeutic effect of drugs. In the process of drug development, it is necessary to verify the effectiveness and safety of drugs on animal models. By comparing the survival rates of animals in the drug administration group and the model group, the therapeutic effect of drugs on coronary heart disease can be evaluated. The present invention uses the survival rate of each group of animals within 24 hours after left anterior descending coronary artery ligation to evaluate the effectiveness, safety and therapeutic effect of the Chinese medicine compound on the treatment of rats with "phlegm and blood stasis" type coronary heart disease.

[0092] The ratio of heart weight (HW) to tibia length (TL) (HW / TL) is of great significance in medical research, especially in assessing the degree of cardiac hypertrophy, such as hypertension, myocardial infarction, etc., which can lead to pathological hypertrophy of the myocardium. In animal experiments, the HW / TL ratio is also often used as an important indicator for assessing the cardiac state of experimental animals. In addition, HW / TL needs to be comprehensively judged in combination with other indicators and clinical manifestations, such as combining electrocardiograms, echocardiograms, and the patient's clinical symptoms and signs for comprehensive evaluation and diagnosis. The present invention measures the HW / TL ratio to objectively assess whether the heart of rats with "phlegm and blood stasis" type coronary heart disease is damaged, and further evaluates whether the important compound can effectively alleviate heart damage.

[0093] Fig.12 The survival rate on the second day after surgery is Fig.13 is the ratio of heart weight to tibia length, Fig.14 It's about weight.

[0094] from Fig.12 It can be seen that the survival rate of the model group was significantly reduced compared with the normal group ( P <0.01); compared with the model group, Example 1 ( P <0.01), metoprolol group ( P <0.01) had a significant increase in survival rate.

[0095] from Fig.13 It can be seen that compared with the normal group, the heart weight to tibia length ratio of the model group increased significantly ( P <0.01); compared with the model group, Example 1 ( P <0.05)、Example 2( P <0.01)、Example 3( P <0.05), metoprolol group ( P <0.01) was significantly improved.

[0096] from Fig.14It can be seen that compared with the normal group, the body weight of rats in the model group increased significantly ( P <0.001); compared with the model group, Example 1 ( P <0.001)、Example 2( P <0.01)、Example 3( P <0.01), metoprolol group ( P <0.01) had a significant decrease in body weight.

[0097] In summary, the drug combinations described in Examples 1, 2 and 3 of the present invention can effectively improve the cardiac dysfunction in rats with "phlegm and blood stasis" type coronary heart disease.

[0098] Effects of Chinese herbal compound on cardiac pathological changes in rats with coronary heart disease of "phlegm and blood stasis" type Hematoxylin-eosin (H&E), Sirius red and Masson staining are important pathological and cytological staining methods with wide application value and significance in the study of myocardial injury. They can observe and analyze the pathological changes of myocardial tissue from different angles, providing an important basis for evaluating the severity of myocardial injury, studying the injury mechanism and formulating effective treatment strategies. H&E staining can deeply understand the pathogenesis of myocardial injury by observing the morphological and structural changes of myocardial cells during the injury process, and provide a theoretical basis for finding effective treatment methods and preventive measures. Sirius red staining is a common method for observing collagen fibers, which can clearly show the distribution and morphology of collagen fibers in the myocardium. In myocardial injury, the deposition and reconstruction of collagen fibers are one of the important pathological changes. Masson staining can observe the boundary between the infarct area and the normal myocardial area, as well as the area and depth of the infarct area, which helps to evaluate the degree and range of myocardial infarction and provides an important basis for clinical treatment. The present invention adopts H&E, Sirius red and Masson staining kits to detect the myocardial pathological changes in the rat model of coronary heart disease, so as to observe the influence of the Chinese herbal compound on the myocardial pathological changes in rats of "phlegm and blood stasis" type coronary heart disease.

[0099] Fig.15 is the eosin-hematoxylin staining of the hearts of rats in each group. Fig.16 is Sirius red staining of the hearts of rats in each group. Fig.17 yes Fig.16 Analysis of collagen volume fraction in each group, Fig.18 Masson staining of the hearts of rats in each group. Fig.19 yes Fig.18 Analysis of collagen volume fraction in each group.

[0100] from Fig.15It can be seen that the myocardial fibers in the normal group were stained pink, the cytoplasm and nucleus were clearly displayed, the cell membrane was intact, the cells were arranged regularly, and the intercellular spaces were moderate. In the model group, myocardial fibers showed coagulative necrosis, nuclear condensation, fragmentation, and disappearance, and the cytoplasm was irregular and coarse granular, interstitial edema, and a small amount of neutrophil infiltration and other pathological manifestations. Compared with the model group, the pathological changes in Example 1, Example 2, Example 3, and the metoprolol group were improved.

[0101] from Fig.16 It can be seen that the myocardial cells in the normal group have normal morphology, size and structure; in the model group, there is a large amount of red type I collagen deposition, and disordered arrangement of myocardial fibers and partial myocardial fiber rupture can be seen. Compared with the model group, the pathological changes in Example 1, Example 2, Example 3 and the metoprolol group were improved.

[0102] from Fig.17 It can be seen that compared with the normal group, the volume fraction of Sirius red collagen in the model group increased significantly ( P <0.001); compared with the model group, Example 1 ( P <0.001)、Example 2( P <0.001)、Example 3( P <0.001), metoprolol group ( P <0.001) was significantly reduced in the volume fraction of Sirius Red collagen.

[0103] from Fig.18 It can be seen that the collagen fibers of myocardial cells in the normal group are usually uniform in thickness and neatly arranged in a filamentous structure. In the model group, myocardial cells were obviously damaged, the cell structure was severely damaged, the collagen fibers were disordered, the morphology was irregular, and the collagen fiber density was significantly higher than that of the normal myocardial area, forming an obvious blue area. Compared with the model group, the Masson pathological changes in Example 1, Example 2, Example 3, and the metoprolol group were improved.

[0104] from Fig.19 It can be seen that compared with the normal group, the Masson collagen volume fraction in the model group increased significantly ( P <0.001); compared with the model group, Example 1 ( P <0.001)、Example 2( P <0.001)、Example 3( P <0.001), metoprolol group ( P <0.001) is significantly reduced.

[0105] In summary, the drug combinations described in Examples 1, 2 and 3 of the present invention can effectively improve the cardiac pathological changes in rats with "phlegm and blood stasis" type coronary heart disease.

[0106] Identification and analysis of the active ingredients in traditional Chinese medicine compound prescriptions The base peak ion chromatograms of the Chinese medicine compound in the positive and negative modes are as follows Fig. 20 and Fig.21 As shown in Table 1, a total of 126 compounds were obtained through comparative analysis of mass spectrometry information and structural identification using a self-built mass spectrometry database, including flavonoids, saponins, alkaloids, and organic acids.

[0107] The drug combination of the present invention has the characteristics of low cost, no pollution, and suitability for industrialization. The obtained traditional Chinese medicine compound has good cardioprotective effect, can significantly improve heart function, reduce serum myocardial enzyme levels, alleviate dyslipidemia, increase the survival rate of coronary heart disease rat models, improve myocardial pathological changes, and significantly alleviate the cardiac dysfunction of rats with "phlegm and blood stasis" type coronary heart disease, and can be used to prepare myocardial protective drugs for preventing and treating coronary heart disease.

[0108] The above technical features respectively constitute various embodiments of the present invention, which have strong adaptability and implementation effect. Non-essential technical features can be added or reduced according to actual needs to meet the requirements of different situations.

Claims

1. A drug combination for improving cardiac function, characterized in that The raw materials are calculated by weight and include 20 to 120 parts of cinnamon twig, 10 to 60 parts of calamus, 20 to 120 parts of codonopsis pilosula, 30 to 180 parts of cornus fruit, 20 to 120 parts of rhodiola rosea, 16 to 96 parts of poria, 6 to 36 parts of magnetite, and 7 to 28 parts of roasted liquorice.

2. The drug combination for improving cardiac function according to claim 1, characterized in that 20 parts of cinnamon twigs, 10 parts of calamus gramineus, 20 parts of codonopsis pilosula, 30 parts of cornus fruit, 20 parts of rhodiola rosea, 16 parts of poria, 6 parts of magnetite, and 7 parts of roasted liquorice.

3. The drug combination for improving cardiac function according to claim 1, characterized in that 50 parts of cinnamon twigs, 30 parts of calamus calamus, 80 parts of codonopsis pilosula, 90 parts of cornus fruit, 80 parts of rhodiola rosea, 48 parts of tuckahoe, 18 parts of magnetite, and 14 parts of roasted liquorice.

4. The drug combination for improving cardiac function according to claim 1, characterized in that 120 parts of cinnamon twigs, 60 parts of calamus gramineus, 120 parts of codonopsis pilosula, 180 parts of cornus fruit, 120 parts of rhodiola rosea, 96 parts of tuckahoe, 36 parts of magnetite, and 28 parts of roasted liquorice.

5. The drug combination for improving cardiac function according to any one of claims 1 to 4, characterized in that The preparation method is as follows: soak the required amount of raw materials in distilled water to obtain a soaking mixture, heat the soaking mixture to reflux, cool, filter to obtain a decoction, concentrate the decoction to obtain a concentrated solution, the volume of which is one-fourth to one-third of the volume of the decoction, and dry the concentrated solution to powder to obtain a drug combination for improving heart function.

6. The drug combination for improving cardiac function according to claim 5, characterized in that The soaking time of the raw material drug is 2.5 h to 3.0 h; or / and, the heating reflux time is 2.0 h to 2.5 h; or / and, the concentration is carried out by reduced pressure distillation; or / and, the drying is carried out by freeze drying.

7. A method for preparing the drug combination for improving cardiac function according to claim 1 or 2 or 3 or 4 or 6, characterized in that include: The required amount of raw materials is soaked in distilled water to obtain a soaking mixture, the soaking mixture is heated to reflux, cooled, filtered to obtain a decoction, the decoction is concentrated to obtain a concentrated solution, the volume of which is one-fourth to one-third of the volume of the decoction, and the concentrated solution is dried to powder to obtain a drug combination for improving cardiac function.

8. Use of the drug combination for improving cardiac function according to any one of claims 1 to 6 in the preparation of a drug for improving cardiac function.

9. Use of the drug combination for improving cardiac function according to any one of claims 1 to 6 in the preparation of a drug for preventing and / or treating coronary heart disease.

10. Use of the drug combination for improving cardiac function according to any one of claims 1 to 6 in the preparation of a drug for preventing and / or treating "phlegm and blood stasis" type coronary heart disease.

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