Use of traditional chinese medicine composition in preparation of drug for treating heart failure

Abstract

The present invention provides the use of a traditional Chinese medicine composition in the preparation of a drug for treating heart failure. The traditional Chinese medicine composition comprises the following components in parts by weight: 46-53.6 parts of nutmeg, 42.4-49.2 parts of radix vladimiriae, 98.4-111.6 parts of fructus chebulae, 50.8-65.2 parts of stigma croci, 17.2-26 parts of calculus bovis and 9.2-13.6 parts of bear gall powder. By means of ingenious combination of a plurality of traditional Chinese medicine components, the traditional Chinese medicine composition has enhanced drug efficacy and an expanded treatment range, can regulate qi and blood as well as yin and yang and treat internal organs, and can effectively treat heart failure.

Description

Application of a traditional Chinese medicine composition in preparing a medicine for treating heart failure Technical Field

[0001] The present invention belongs to the technical field of traditional Chinese medicine, and particularly relates to an application of a traditional Chinese medicine composition in preparing a medicine for treating heart failure. Background Art

[0002] Heart failure is the endpoint of many cardiovascular diseases and has a high prevalence. Once diagnosed, patients typically require lifelong medication, severely impacting their quality of life. Currently, the drugs commonly used to treat heart failure include angiotensin-converting enzyme inhibitors, beta-blockers, aldosterone receptor antagonists, and diuretics. However, long-term use can lead to adverse reactions such as hypotension, fluid depletion, and electrolyte imbalances, and can even increase mortality.

[0003] Traditional Chinese Medicine (TCM) classifies heart failure as "edema" and "asthma," referring to it as "heart failure" in TCM terminology. TCM believes that while heart failure originates in the heart and manifests as myocardial contractility, its primary pathogenesis is heart and kidney yang deficiency, which in turn leads to qi deficiency and fatigue. This reduced cardiac blood circulation leads to blood vessel stasis. Heart failure is most common in the elderly. Due to their declining physical function, patients often develop a vicious cycle of chronic illness, qi deficiency, yang deficiency, blood circulation impairment, and blood vessel stasis.

[0004] In recent years, modern pharmacology has confirmed that traditional Chinese medicines that invigorate qi, warm yang, activate blood circulation, and promote diuresis have the effects of invigorating qi, promoting blood circulation, and increasing myocardial oxygen consumption. These herbs are particularly effective in treating coronary heart disease and heart failure. These herbs are composed of ginseng, motherwort, salvia miltiorrhiza, astragalus, cinnamon twig, atractylodes macrocephala, licorice, Panax notoginseng, angelica sinensis, and liquorice. Numerous studies have shown that these herbs have a role in treating heart failure. However, with continued use, resistance to these herbs can develop, potentially leading to poor therapeutic outcomes.

[0005] Therefore, whether it is possible to find a Chinese medicine composition that can effectively treat heart failure from other types of Chinese medicine is a new research difficulty in this field.

[0006] Summary of the Invention

[0007] In order to solve the problems and shortcomings in the prior art, the present invention provides an application of a traditional Chinese medicine composition in the preparation of a medicament for treating heart failure. In this application, the traditional Chinese medicine composition used can effectively treat heart failure and improve the patient's cardiac function by using a variety of traditional Chinese medicine ingredients in combination.

[0008] According to a first aspect of the present invention, a Chinese medicine composition is used for preparing a medicine for treating heart failure. The Chinese medicine composition comprises the following components, calculated in parts by weight: 46-53.6 parts of nutmeg, 42.4-49.2 parts of costus root, 98.4-111.6 parts of terminalia chebula, 50.8-65.2 parts of saffron, 17.2-26 parts of bezoar, and 9.2-13.6 parts of bear bile powder.

[0009] Nutmeg is the dried seed kernel of Myristica fragrans Houtt., a plant of the Myristicaceae family. First recorded in Leigong Paozhi Lun (Thoughts on the Exploitation of the Thunder God), it is pungent and warm in nature, and enters the spleen, stomach, and large intestine meridians. Nutmeg has the properties of warming the middle and promoting qi circulation, astringing the intestines and stopping diarrhea, and is used to treat spleen and stomach deficiency and cold, persistent diarrhea, abdominal distension and pain, loss of appetite, and vomiting. Chemical composition studies have shown that nutmeg primarily contains a variety of chemical components, including volatile oils, phenylpropanoids, lignans, diarylalkanes, and flavonoids. Modern pharmacological studies have demonstrated that nutmeg exhibits a variety of pharmacological activities, including anti-inflammatory, analgesic, antioxidant, antibacterial, anti-tumor, and hypoglycemic activities. Consequently, nutmeg has traditionally been used to treat rheumatism, cholera, anxiety, stomach cramps, nausea, and diarrhea. It has also been used for its aphrodisiac and abortion properties. Nutmeg also has a certain effect in treating heart disease or heart failure, but there are few related reports and research mechanisms. In this regard, nutmeg is usually used in combination with other Chinese medicines to treat heart failure or many heart diseases such as heart pain, heart pain, delirium, syncope, and palpitations.

[0010] Dolomiaea souliei (Franch) Shih, a species of the genus Dolomiaea, belongs to the Asteraceae family and is primarily found on the border between Sichuan and Tibet, growing in alpine meadows and shrublands above 3,000 meters above sea level. The Pharmacopoeia of the People's Republic of China lists the dried root as the medicinal part of Dolomiaea. Dolomiaea is warm in nature, pungent and bitter in flavor, and has the effects of promoting qi circulation and relieving pain. Clinically, it is used to treat chest, flank, and abdominal distension and pain, intestinal rumbling, diarrhea, and tenesmus. A diverse range of small molecule compounds have been isolated from Dolomiaea plants, with the primary chemical components being sesquiterpenes, as well as other compounds such as lignans, triterpenes, and steroids. Modern pharmacological studies have shown that the pharmacological activities of this genus are primarily anti-inflammatory, antibacterial, anti-tumor, and gastric ulcer inhibition. However, there are relatively few reports on its use in the treatment of heart disease or heart failure, and similarly, it often requires combination with other traditional Chinese medicines to achieve a therapeutic effect.

[0011] The plant Terminalia chebulariae (Terminalia chebular Retz.) belongs to the genus Terminalia, in the family Combretaceae. Its dried, mature fruit, Chebulae Fructus, is a commonly used Chinese medicinal herb. Bitter, sour, and astringent, it is neutral in nature and enters the lung and large intestine meridians. It has the effects of astringing the intestines to stop diarrhea, astringing the lungs to relieve cough, and treating chronic diarrhea, dysentery, bloody stools, rectal prolapse, lung deficiency, wheezing, coughing, persistent cough, sore throat, and hoarseness. It is widely used in Chinese folk medicine and is even considered the "king of medicines" in Tibetan medicine, treating a variety of ailments. Terminalia chebulariae contains a diverse range of chemical components, primarily phenolic acids, tannins, and triterpenes, such as gallic acid, chebulic acid, and arjunol. Modern pharmacological research has found that Terminalia chebula extracts, such as Terminalia chebula water extract and some of its single components, exhibit biological activities such as antibacterial, antioxidant, anti-tumor, anti-inflammatory, detoxification, analgesic, cardiotonic, hepatoprotective, hypoglycemic, inhibition of gastric emptying and small intestinal motility, promotion of angiogenesis, and protection of the brain and liver.

[0012] Crocus sativus L. is a Crocus L. plant of the genus Crocus of the family Iridaceae. It is cultivated in countries such as Iran, Greece, Italy, Spain, India, China, and Japan. Its main medicinal part is the style, which has the effects of promoting blood circulation and removing blood stasis, cooling blood and detoxifying, relieving depression and tranquilizing the mind. It can be used for amenorrhea, postpartum stasis, fever, rash, depression, palpitations and other diseases. Modern pharmacological studies have shown that saffron has the effect of strengthening the body. At present, more than 100 compounds have been isolated from saffron both at home and abroad, mainly containing terpenes, flavonoids, anthraquinones etc., and have the multiple activities such as treating mental illness, neurodegenerative diseases, learning and memory disorders, cardiovascular diseases, atherosclerosis, hyperlipidemia, diabetes, hypertension, gastric ulcer, fatty liver and anti-epileptic, anticonvulsant.

[0013] Bezoar, the dried gallstones of cattle (Bovidae), is a traditional and precious Chinese medicine. Currently, there are four commercial varieties of bezoar: natural, cultured, artificial, and in vitro-cultured. Natural bezoar is in short supply and expensive, and the production of cultured bezoar is very limited, so in vitro-cultured and artificial bezoar are mostly used in clinical practice. Bezoar was first mentioned in the Shennong's Herbal Classic. Traditional Chinese Medicine believes that natural bezoar has the effects of clearing heat and resolving phlegm. Modern pharmacological research has shown that natural bezoar has anti-inflammatory, antispasmodic, anti-hypoxic, antidepressant, sedative, blood pressure-lowering, fever-reducing, and promotes normal gallbladder function.

[0014] Bear bile powder is the dried bile produced by the black bear after gallbladder drainage surgery. It has the effects of clearing heat and detoxifying, calming the liver and improving eyesight, and killing insects and stopping bleeding. It is a rare traditional Chinese medicinal ingredient, used in many ancient prescriptions and clinically for the treatment of liver, gallbladder, and ophthalmological diseases. The main components of bear bile powder are bile acids, including the conjugated bile acids tauroursodeoxycholic acid and taurochenodeoxycholic acid, and the free bile acids ursodeoxycholic acid and chenodeoxycholic acid, as well as small amounts of cholic acid and deoxycholic acid. Non-bile acid components include cholesterol, amino acids, bile pigments, proteins, and peptides, as well as small amounts of trace metal elements. Modern pharmacological research has shown that bear bile powder has hepatoprotective and choleretic effects, antipyretic and analgesic effects, antiviral effects, and anti-tumor effects.

[0015] Heart failure falls under the Traditional Chinese Medicine (TCM) categories of "asthma," "heart paralysis," "heart water retention," and "heart failure." Its etiology and pathogenesis are complex, and the condition is ever-changing, making it a difficult and persistent disease. Traditional Chinese Medicine considers the basic pathogenesis of this disease to be a combination of underlying deficiency and superficial excess, with the underlying deficiency primarily affecting the heart, spleen, and kidneys, while the superficial excess is characterized by water retention and blood stasis. In particular, heart and kidney yang deficiency and water retention and blood stasis permeate the disease. Treatment focuses on strengthening the body's vital energy and dispelling pathogenic factors, with strengthening the body's vital energy and warming yang, while dispelling pathogenic factors emphasize promoting diuresis and removing blood stasis.

[0016] The present invention enhances the efficacy of the drug and expands the therapeutic range by cleverly combining multiple Chinese medicinal ingredients simultaneously, achieving the goal of regulating qi, blood, yin and yang, and treating both internal organs, thereby effectively treating heart failure. Specifically, each Chinese medicinal ingredient used in the present invention contains multiple active ingredients, which complement each other and, in specific ratios, can synergize to achieve better efficacy, effectively preventing or treating heart failure, as shown below:

[0017] (1) Enhance myocardial contractility and reduce cardiac load, increase cardiac output, and improve pumping function, which can prevent and treat heart failure and improve cardiac function;

[0018] (2) Improve blood rheology, thereby reducing cardiac load, increasing myocardial oxygen supply, improving cardiac function and reducing ventricular hypertrophy;

[0019] (3) Regulate immune function, enhance the immunity of patients with heart failure, improve left ventricular systolic and diastolic function, delay ventricular remodeling, improve microcirculation and resist myocardial ischemia;

[0020] (4) Prevent the production of endothelin and tumor necrosis factor, dilate blood vessels, slow down heart rate, reduce myocardial oxygen consumption, improve myocardial blood supply, and protect heart function.

[0021] Preferably, calculated by weight, the Chinese medicine composition includes the following components: 51.6 parts of nutmeg, 44.8 parts of costus root, 103.6 parts of terminalia chebula, 53.2 parts of saffron, 22 parts of bezoar, and 11.6 parts of bear bile powder.

[0022] Preferably, the above-mentioned heart failure includes chronic heart failure.

[0023] Preferably, the preparation method of the traditional Chinese medicine composition comprises the following steps: mixing all raw materials with a solvent, heating and refluxing 2 to 3 times for 1 to 3 hours, filtering, combining the filtrates, and concentrating the filtrates.

[0024] According to another aspect of the present invention, a traditional Chinese medicine composition for treating heart failure is provided. Calculated in parts by weight, the traditional Chinese medicine composition includes the following components: 46 to 53.6 parts of nutmeg, 42.4 to 49.2 parts of costus root, 98.4 to 111.6 parts of terminalia chebula, 50.8 to 65.2 parts of saffron, 17.2 to 26 parts of bezoar, and 9.2 to 13.6 parts of bear bile powder.

[0025] Preferably, the Chinese medicine composition comprises the following components, calculated by weight:

[0026] 51.6 parts of nutmeg, 44.8 parts of Sichuan costus root, 103.6 parts of terminalia chebula, 53.2 parts of saffron, 22 parts of bezoar, and 11.6 parts of bear gall powder. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG1 shows the results of the model cardiomyocyte activity test in Example 2 of the present invention.

[0028] FIG2 shows the relative ejection fraction test results of mice in Example 3 of the present invention.

[0029] FIG3 shows the left ventricular thickness test results of mice in Example 3 of the present invention. DETAILED DESCRIPTION

[0030] In order to enable those skilled in the art to better understand the solutions of the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.

[0031] Example 1 Preparation of Chinese medicine composition

[0032] The preparation of the Chinese medicine composition is carried out according to the following steps:

[0033] All raw materials were mixed with a solvent, heated under reflux for 3 times with a reflux time of 2 hours, filtered, the filtrates were combined, and the filtrates were concentrated to obtain a traditional Chinese medicine composition.

[0034] In the above process, the raw materials include 51.6 parts of nutmeg, 44.8 parts of Sichuan costus root, 103.6 parts of terminalia chebula, 53.2 parts of saffron, 22 parts of bezoar, and 11.6 parts of bear bile powder.

[0035] Example 2 Cell function test of Chinese medicine composition

[0036] Select model cardiomyocytes induced to day 15 and culture them for at least one month, or resuscitate model cardiomyocytes in a T75 culture flask and culture them for at least one month.

[0037] To prepare the myocardial model, wash the cells twice with 1640 medium, add 8 mL of digestion buffer, and digest at 37°C. After perfusion, pipette until the cells detach from the bottom of the T75 flask. Add 1640 basal medium, the end digestion buffer, and collect the cell suspension in a 50 mL centrifuge tube. Centrifuge at 210 g for 5 minutes. Discard the supernatant, resuspend the cells in resuspension buffer, and count 10 μL of the suspension. Plate 20,000 cells per well in a 96-well plate, adding 90 μL of resuspension buffer to each well. Leave three wells untreated and add an equal amount of resuspension buffer.

[0038] After the third day of culture, the resuscitation fluid was discarded, and the cells were washed twice with 1640 medium. Medium containing the drug was added at three drug concentrations: high (10 μM), medium (3 μM), and low (1 μM). An equal volume of cardiomyocyte culture medium served as a negative control, and dexamethasone injection (10 μM) served as a positive control. 028 represents the traditional Chinese medicine composition described in Example 1, while 049 and 056 represent the commercially available first-line drugs digoxin and spironolactone, respectively.

[0039] Model cardiomyocyte activity test: After 4 days of cell culture, the activity test reagent was added, and the temperature was lowered to room temperature before the use of the Prestoblue reagent. Prestoblue reagent was added to a 96-well plate under light-proof conditions, and then incubated in the dark at 37°C for 1 hour. The activity of the model cardiomyocytes was then measured using an enzyme marker, and the specific test results are shown in Figure 1. Among them, before using the enzyme marker for measurement, it is necessary to open it for 0.5 hours in advance and preheat the machine. First, turn on the instrument to check that everything is normal; then check the parameters of the selected test items, test the wavelength settings (excitation and emission wavelengths 560mm, 590mm), file output method, format, and default save path and other parameters to ensure that the instrument can operate normally and that the parameters are set correctly.

[0040] As shown in Figure 1, at high (10 μM), medium (3 μM), and low (1 μM) concentrations, the model cardiomyocytes treated with the Chinese herbal extract of the present invention exhibited significantly better cell viability than those treated with digoxin or spironolactone. This demonstrates that the Chinese herbal composition provided by the present invention can effectively enhance cardiomyocyte activity, thereby promoting myocardial oxygen supply, improving microcirculation, and combating myocardial ischemia, effectively treating heart failure and improving cardiac function.

[0041] Example 3 Animal experiment on mouse aortic arch stenosis model

[0042] Male KM mice were weighed and anesthetized with an intraperitoneal injection of sodium pentobarbital (40 mg / kg). After anesthesia, the mice were secured in the supine position on a mouse board. The skin was prepared with the clavicle as the upper boundary, the xiphoid process as the lower boundary, the left midline of the left groin as the left boundary, and the anterior midline as the right boundary. The mouth was secured with fine wire to maintain airway patency. The mouse board was placed horizontally on a table, and the neck was illuminated by a cold light gooseneck lamp. The tongue was gently pulled out of the mouth with a tongue depressor. The tongue depressor was then placed against the base of the tongue and gently lifted upward. A distinct circular bright spot in the pharynx under cold light illumination was visible, indicating the tracheal opening. A homemade endotracheal tube was inserted into the trachea, and the ventilator was then connected. The respiratory rate was 90-100 breaths / min, and the tidal volume was 0.3-0.4 ml. After successful endotracheal intubation, the mouse was re-secured in the right lateral decubitus position with the left upper limb pointing toward the head to fully expose the thorax.

[0043] The thorax was disinfected with iodine, and the mouse was opened layer by layer in the second intercostal space on the left side. The thoracotomy incision was approximately 7 mm in size. The aortic arch, innominate artery, and bifurcation of the left common carotid artery were exposed layer by layer. A 5-0 silk braided suture was passed through the bifurcation of the innominate artery and the left common carotid artery to tie the aortic arch around a homemade L-shaped 26G ligature. After tying the knot, the ligature needle was gently withdrawn, and the excess suture around the knot was cut to complete the aortic arch constriction. Animals in the sham-operated group underwent only the thoracotomy procedure without constriction. The remaining procedures were the same as those in the model group.

[0044] Use a 4-0 suture needle to close the chest and skin layer by layer. Disinfect the incision. After suturing, perform a trial weaning from the ventilator while retaining the endotracheal tube. If the mouse's breathing is stable and normal after weaning, complete weaning can be performed. If the mouse's breathing is slow, the weaning time can be extended appropriately.

[0045] To prevent hypothermia after surgery, mice were placed on an electric blanket and, after waking, placed in a cage and given water. The number of animals that died during and after surgery in both groups was recorded, and the cause of death was recorded during autopsy.

[0046] In this experiment, the blood flow velocity value at the aortic arch constriction greater than 2400 mm / s was used as the model screening standard. The model group animals that met the screening standard were included in further research, and the model group animals that did not meet the standard were not included in further research.

[0047] Dosage:

[0048] 60 4-week-old SPF male Kunming (KM) mice were placed in an ambient temperature of 20 to 25 degrees and fed on a 12h / 12h day and night basis. The experimental animals were tested weekly after surgery, and there were no less than 10 experimental animals in each group at each time point. The sham-operated mice were given a blank solvent (control group), and the postoperative mice in the surgical group were randomly divided into 3 groups, and the Chinese medicine composition of Example 1 (denoted as Drug B) and the above-mentioned first-line heart failure drugs digoxin and spironolactone were administered. According to the clinical dose conversion, the concentration of Drug B was 25 mg / mL, the concentration of digoxin was 6.5 μg / mL, and the concentration of spironolactone was 100 μg / mL, and 200 μL was gavaged every day.

[0049] Observation and testing:

[0050] The survival time of the mice was observed, and electrocardiogram and ultrasound examinations were performed on the living mice.

[0051] An ultrasound machine with a 30 MHz center frequency and a standard frame rate of 449 fps was used. Prior to examination, the animals underwent chest hair removal, isoflurane inhalation anesthesia, and supine immobilization. Left ventricular M-mode echocardiograms and two-dimensional images of the left ventricle were obtained from the left parasternal short-axis and left long-axis views. At each measurement point in the long- and short-axis views, the cardiac cycle was recorded. Left ventricular end-systolic diameter, left ventricular end-diastolic diameter, left ventricular posterior wall systolic thickness, left ventricular posterior wall diastolic thickness, left ventricular anterior wall end-diastolic thickness, and left ventricular anterior wall end-systolic thickness were obtained. Left ventricular body mass index, left ventricular fractional shortening, left ventricular ejection fraction, left ventricular diastolic volume, left ventricular systolic volume, and left ventricular mass were calculated. The relative ejection fraction of the mice was calculated based on these data. The relative ejection fraction is shown in Figure 2. The left ventricular thickness of the mice was also measured. The results of the left ventricular thickness test are shown in Figure 3.

[0052] According to Figure 2, it can be seen that compared with the mice using spironolactone and digoxin drugs, the ejection fraction of the mice after using the traditional Chinese medicine composition of the present invention is closer to the ejection fraction of the normal heart of the mice in the control group (the control group is a sham operation group, and the mice have normal heart function). This shows that the traditional Chinese medicine composition of the present invention can effectively increase the cardiac ejection fraction and improve the cardiac systolic and diastolic function.

[0053] According to Figure 3, it can be seen that compared with mice using spironolactone and digoxin drugs, the left ventricular thickness of mice was reduced more significantly after using the traditional Chinese medicine composition of the present invention, which indicates that the traditional Chinese medicine composition of the present invention can more effectively treat heart failure and improve heart function.

[0054] The above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to the above embodiments, those skilled in the art should understand that the technical solutions of the present invention may be modified or replaced by equivalents, but these modifications or replacements are all within the scope of protection of the present invention.

Claims

1. Use of a Chinese medicine composition in preparing a medicament for treating heart failure, characterized in that: Calculated by weight, the traditional Chinese medicine composition includes the following components: 46-53.6 parts of nutmeg, 42.4-49.2 parts of costus root, 98.4-111.6 parts of terminalia chebula, 50.8-65.2 parts of saffron, 17.2-26 parts of bezoar, and 9.2-13.6 parts of bear bile powder.

2. Use of the Chinese medicine composition according to claim 1 in preparing a medicament for treating heart failure, characterized in that: Calculated by weight, the traditional Chinese medicine composition includes the following components: 51.6 parts of nutmeg, 44.8 parts of costus root, 103.6 parts of terminalia chebula, 53.2 parts of saffron, 22 parts of bezoar, and 11.6 parts of bear bile powder.

3. Use of the Chinese medicine composition according to claim 1 in preparing a medicament for treating heart failure, characterized in that: The heart failure includes chronic heart failure.

4. The use of the Chinese medicine composition according to claim 1 in preparing a medicament for treating heart failure, characterized in that: The preparation method of the traditional Chinese medicine composition comprises the following steps: mixing all raw materials with a solvent, heating and refluxing 2 to 3 times with a reflux time of 1 to 3 hours, filtering, combining the filtrates, and concentrating the filtrates.

5. A Chinese medicine composition for treating heart failure, characterized in that: Calculated by weight, the traditional Chinese medicine composition includes the following components: 46-53.6 parts of nutmeg, 42.4-49.2 parts of costus root, 98.4-111.6 parts of terminalia chebula, 50.8-65.2 parts of saffron, 17.2-26 parts of bezoar, and 9.2-13.6 parts of bear bile powder.

6. The Chinese medicine composition for treating heart failure according to claim 5, characterized in that: Calculated by weight, the traditional Chinese medicine composition includes the following components: 51.6 parts of nutmeg, 44.8 parts of costus root, 103.6 parts of terminalia chebula, 53.2 parts of saffron, 22 parts of bezoar, and 11.6 parts of bear bile powder.

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