A traditional Chinese medicine composition for treating diuretic resistance in heart failure and its application

Abstract

The present invention provides a Chinese medicine composition for diuretic resistance in heart failure and its application, and relates to the technical field of Chinese medicine pharmaceutical manufacturing. The present invention provides a Chinese medicine composition for diuretic resistance in heart failure composed of multiple Chinese medicines such as processed aconite (pre-decocted), astragalus, white imperata root, wax gourd peel, atractylodes, Poria, tangerine peel, rehmannia root, ophiopogon japonicus, wolfberry fruit, tangerine peel, zedoaria, codonopsis pilosula, and licorice root, which has the effect of warming yang and promoting diuresis. The Chinese medicine combination of the present invention has a significant diuretic effect, can significantly increase the urine excretion of chronic heart failure rat models, and reduce water and sodium retention. The Chinese medicine combination of the present invention has a significant therapeutic effect on patients with diuretic resistance in heart failure, can significantly improve the symptoms of patients, and has the effects of significantly increasing urine volume, reducing body weight, reducing BNP, and improving LVEF in patients. A new treatment method is provided for patients with diuretic resistance in heart failure.

Description

Technical Field

[0001] The present invention relates to the technical field of traditional Chinese medicine pharmaceutical preparation, and in particular to a traditional Chinese medicine composition for diuretic resistance in heart failure and application thereof. Background Art

[0002] Heart failure (hereinafter referred to as HF) refers to a clinical syndrome of abnormal cardiac structure or function caused by various reasons, and is the final stage of many heart diseases. Although the treatment of HF has made remarkable progress in recent years, its morbidity and mortality remain high, seriously threatening human life and health, and bringing a heavy burden to the social economy. Diuretics can reduce water and sodium retention in patients with HF, relieve symptoms such as dyspnea, and increase exercise tolerance. They are the cornerstone drugs for the treatment of HF. However, some patients who have been using diuretics for a long time gradually become less sensitive to diuretics, resulting in a weakening or even disappearance of the diuretic effect, and the body edema cannot be effectively controlled. This phenomenon is clinically called diuretic resistance (DR). Diuretic resistance will aggravate the patient's clinical symptoms, increase the patient's re-hospitalization rate, and have a great impact on the patient's quality of life. In severe cases, it may even threaten the patient's life safety. Studies have confirmed that diuretic resistance is independently correlated with the mortality rate of patients with HF. At present, the pathogenesis of DR has not been fully clarified, and Western medicine has no clear and effective solution for this. Even if new diuretics such as tolvaptan are used, the efficacy is still unsatisfactory.

[0003] Although there is no term "diuretic resistance" in traditional Chinese medicine, heart failure with diuretic resistance can be classified into the categories of "asthma", "palpitations" and "edema" based on the clinical manifestations and TCM syndromes of patients. The disease is located in the heart, and also involves organs such as the spleen, liver and kidney. It is a syndrome of deficiency of the root and excess of the superficial symptoms. The main syndrome type is qi deficiency, blood stasis and water obstruction. Blood circulation depends on the stimulation of heart yang and the promotion of heart qi. If heart yang is weak, spleen yang and kidney yang will be affected, qi cannot be transformed into fluid, and it will attack the heart and lungs. If heart qi is deficient, heart yang will be consumed, and long-term damage will lead to exhaustion, aggravating the loss of kidney yang and spleen yang. If yang cannot be transformed into water, it will overflow into the skin and cause edema. Clinical treatment is based on the basic principles of promoting blood circulation and removing blood stasis, warming yang and transforming qi, and promoting water and removing dampness. It has achieved certain therapeutic effects in clinical application, but there is currently no Chinese medicine composition with high universality and definite efficacy for diuretic resistance in heart failure. Summary of the invention

[0004] 1. Technical issues to be resolved

[0005] In view of the deficiencies in the prior art, the present invention provides a traditional Chinese medicine composition for diuretic resistance in heart failure and its application.

[0006] (II) Technical solution

[0007] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0008] A traditional Chinese medicine composition for diuretic resistance in heart failure, the traditional Chinese medicine composition is composed of the following raw materials by weight: 1-20g of processed aconite (pre-decocted), 10-30g of astragalus, 10-30g of Imperata root, 20-40g of wax gourd peel, 5-25g of atractylodes, 15-35g of Poria, 5-25g of dried tangerine peel, 10-30g of Rehmannia root, 1-20g of Ophiopogon japonicus, 10-30g of Lycium barbarum, 1-20g of Citrus grandis peel, 5-20g of Zedoariae rhizome, 5-25g of Codonopsis pilosula, and 5-25g of roasted liquorice.

[0009] Preferably, the Chinese medicine composition is composed of the following raw materials by weight: processed aconite (pre-decocted) 5-15g, astragalus 15-25g, white imperata root 15-25g, wax gourd peel 25-35g, white atractylodes 10-20g, Poria 20-30g, tangerine peel 10-20g, rehmannia glutinosa 15-25g, ophiopogon 5-15g, wolfberry 15-25g, tangerine peel 5-15g, zedoaria 10-20g, codonopsis pilosula 10-20g, and licorice root 10-20g.

[0010] Preferably, the Chinese medicine composition is composed of the following raw materials by weight: 9g of processed aconite (pre-decocted), 20g of astragalus, 20g of Imperata root, 30g of wax gourd peel, 12g of Atractylodes macrocephala, 24g of Poria, 15g of tangerine peel, 20g of Rehmannia root, 10g of Ophiopogon japonicus, 20g of Lycium barbarum, 10g of Citrus grandis peel, 12g of Zedoaria, 15g of Codonopsis pilosula, and 12g of roasted liquorice.

[0011] The Chinese medicine composition provided by the present invention is used to prepare a drug for treating diuretic resistance in heart failure. The Chinese medicine composition can be prepared into any medically acceptable oral dosage form, including but not limited to granules, oral liquids, decoctions, and powders.

[0012] Pharmacological effects of each component in the Chinese medicine composition of the present invention:

[0013] Processed Aconite: It tastes pungent and sweet, is very hot in nature, and is poisonous. After processing, its toxicity is greatly reduced. It has the effects of restoring yang, replenishing fire and assisting yang, and expelling wind, cold and dampness. It is mainly used to treat various diseases such as yang loss, collapse, cold limbs and weak pulse, impotence, cold uterus, cold pain in the heart and abdomen, vomiting and diarrhea due to deficiency and cold, edema due to yin and cold, etc. Modern research has found that its composition is complex, and the main components are aconite alkaloids, polysaccharides, saponins, etc.; it has a wide range of effects such as strengthening the heart, protecting myocardial cells, anti-arrhythmia, anti-inflammatory and analgesic, and anti-tumor.

[0014] Astragalus: sweet in taste, slightly warm in nature; enters the spleen and lung meridians; has the effects of tonifying qi and strengthening the exterior, expelling toxins and draining pus, diuresis, and tissue regeneration; used to treat qi deficiency and fatigue, chronic diarrhea and prolapse of the anus, spontaneous sweating, edema, uterine prolapse, proteinuria of chronic nephritis, diabetes, and non-healing wounds; the main chemical components of Astragalus include polysaccharides, saponins, flavonoids, amino acids, trace elements, sterols, etc.; the pharmacological effects of Astragalus include anti-tumor, protection of cardiovascular and cerebrovascular vessels, improving immune function, protecting lung function, protecting kidney tissue, protecting intestinal function, regulating blood pressure, anti-aging, preventing and treating osteoporosis, and anti-oxidative stress protection.

[0015] Imperata root: sweet in taste, cold in nature, enters the lung, stomach and bladder meridians; has the effects of cooling blood and stopping bleeding, clearing away heat and promoting diuresis; used for blood heat and vomiting blood, hematuria, thirst due to fever, edema, and painful stranguria due to heat; it contains triterpenes, phenylpropanoids, organic acids, sugars, sterols, flavonoids and other active ingredients, mainly with multiple pharmacological effects such as hemostasis, immunomodulation, diuresis and blood pressure reduction, antibacterial, anti-inflammatory and analgesic, anti-tumor, hypoglycemic and hypolipidemic.

[0016] Winter melon peel: sweet in taste, cold in nature, enters the spleen and small intestine meridians; has diuretic and anti-edema effects, used for edema, difficulty urinating, thirst due to heat stroke, short and red urine, etc.; contains polyphenols, pigments, polysaccharides, dietary fiber and other effective ingredients; mainly has multiple pharmacological effects such as antioxidant, hypoglycemic, antihypertensive and diuretic.

[0017] Atractylodes: bitter, sweet, and warm in nature, it enters the spleen and stomach meridians; it has the effects of strengthening the spleen and replenishing Qi, drying dampness and promoting diuresis, stopping sweating, and calming the fetus; it is often used for symptoms such as spleen deficiency, poor appetite, diarrhea, loose stools, and fetal movement disorder; its main chemical components include volatile oils, polysaccharides, and lipids, which have anti-tumor, anti-inflammatory, and digestive system regulation effects.

[0018] Poria: sweet, light, neutral in nature, enters the heart, lung, spleen, and kidney meridians; has the effects of promoting diuresis and eliminating dampness, strengthening the spleen, and calming the mind; used to treat edema, oliguria, phlegm and fluid, dizziness, palpitations, spleen deficiency, poor appetite, and restlessness; Poria mainly contains triterpenes and polysaccharide compounds, which have pharmacological effects such as diuresis, anti-inflammatory, and liver protection.

[0019] Tangerine peel: bitter and spicy in taste, warm in nature, and enters the lung and spleen meridians; it has the effects of regulating qi and strengthening the spleen, drying dampness and resolving phlegm; it is used to treat symptoms such as abdominal distension, loss of appetite, vomiting and diarrhea, cough and excessive sputum; tangerine peel mainly contains volatile oils, flavonoids, organic amines and trace elements; it has pharmacological effects such as insecticidal and inhibition of microbial activity, anti-aging and antioxidant.

[0020] Rehmannia root: It is cold in nature, bitter and sweet in taste; it enters the heart, liver and kidney meridians; it has the effects of clearing away heat and cooling blood, nourishing yin and promoting the production of body fluids, and is used to treat symptoms such as red tongue and thirst caused by fever, internal heat due to yin deficiency, old heat in the bones, internal heat and thirst, vomiting blood, and spots and rashes; it mainly contains compounds such as cyclopentane ether terpenes, ionones, phenylethanol compounds, triterpenes, flavonoids, lignans, phenolic acids, etc.; modern pharmacological studies have shown that Rehmannia root has significant effects on the human blood system, cardiovascular and cerebrovascular system, central nervous system and immune system, and also has the effects of regulating blood sugar and blood lipids, anti-aging, anti-tumor, antibacterial and anti-gastric ulcer, and protecting gastric mucosa.

[0021] Ophiopogon japonicus: sweet, slightly bitter, slightly cold. It moistens the lungs and clears the heart, relieves heat and produces body fluid, resolves phlegm and stops vomiting, treats cough and promotes fluid secretion. It can enter the stomach to nourish gastric juice, stimulate appetite, and enter the spleen to help the spleen disperse essence to the lungs, calm asthma and cough. According to traditional Chinese medicine, Ophiopogon japonicus is sweet, slightly bitter, slightly cold in nature, and belongs to the stomach, lung, and heart meridians. It has the effects of nourishing yin and moistening the lungs, benefiting the stomach and producing body fluid, clearing the heart and relieving restlessness. It is used for dry cough due to lung dryness, tuberculosis due to yin deficiency, sore throat due to throat numbness, thirst due to loss of body fluid, internal heat and thirst, restlessness and insomnia, dry intestines and constipation.

[0022] Lycium barbarum: a Chinese medicinal material that is both a medicine and a food, it has the effects of nourishing yin and invigorating yang, relieving thirst, and replenishing fatigue; it is rich in Lycium barbarum polysaccharides, Lycium barbarum total flavonoids, carotenoids, amino acids and other effective ingredients. Modern pharmacological studies have shown that Lycium barbarum and its active ingredients have multiple pharmacological effects such as anti-tumor, regulating blood lipids and blood sugar, protecting eyesight, anti-depression and anxiety, anti-inflammatory and antibacterial.

[0023] Phellodendron chinense bark: spicy in taste, slightly warm in nature, enters the spleen, stomach, large intestine and small intestine meridians; has the effects of promoting qi and relieving fullness, promoting water circulation and reducing swelling, and can be used to treat edema, beriberi, edema, difficulty urinating and other symptoms; mainly contains alkaloids, phenols, oils and other chemical components, and has pharmacological activities such as regulating gastrointestinal function and anti-oxidation.

[0024] Ze Lan: bitter and pungent in taste, slightly warm in nature; it enters the liver and spleen meridians; it has the effects of promoting blood circulation and regulating menstruation, removing blood stasis and eliminating carbuncles, promoting diuresis and reducing swelling. It is used to treat irregular menstruation, amenorrhea, dysmenorrhea, abdominal pain due to blood stasis after childbirth, sores, carbuncles, swelling and toxins, edema and ascites, etc.

[0025] Codonopsis: sweet in taste, neutral in nature; enters the spleen and lung meridians; has the effects of tonifying the middle and replenishing qi, strengthening the spleen and benefiting the lungs; used to treat spleen and lung weakness, shortness of breath and palpitations, poor appetite and loose stools, asthma and cough, internal heat and thirst; Codonopsis mainly contains chemical components such as alkaloids, acetylenes, terpenes, flavonoids, sugars, etc.; Codonopsis mainly acts on the nervous system, endocrine system, immune system, etc., and has the effects of protecting nerves, anti-tumor, anti-oxidation, anti-inflammatory, anti-stress, and liver protection.

[0026] Roasted licorice: sweet in taste, warm in nature, and enters the heart, lung, stomach, and spleen meridians; it has the effects of tonifying the spleen and stomach, replenishing qi and restoring the pulse, regulating yin and yang, and replenishing qi and blood; it is used to treat spleen and stomach weakness, fatigue, palpitations, and irregular pulse; roasted licorice contains flavonoids, triterpenes, polysaccharides, alkaloids and other effective ingredients. Modern medical research shows that roasted licorice has anti-depression, improves immune function, regulates arrhythmias, anti-tumor, and anti-inflammatory effects.

[0027] (III) Beneficial effects

[0028] Yang deficiency of the heart and kidney is the root of the pathogenesis of heart failure, and blood stasis and water retention are the symptoms. Body fluid does not flow through the blood vessels and seeps out of the vessels, becoming water and dampness and causing edema. Blood stasis and water retention block the blood vessels, and over time they gather and form "stagnation in the heart meridians", which is the result of worsening of the disease. Based on this, the present invention provides a Chinese medicine composition for diuretic resistance in heart failure composed of processed aconite (pre-decocted), astragalus, white grass root, wax gourd peel, white atractylodes, poria, tangerine peel, rehmannia, ophiopogon, wolfberry, dried tangerine peel, zedoaria, codonopsis, roasted liquorice and other Chinese medicines, which has the effect of warming yang and promoting diuresis. The processed aconite in the formula has the functions of restoring yang, rescuing adverse conditions, replenishing fire and assisting yang, dispersing cold and relieving pain. The main ingredient aconitine has the functions of strengthening the heart, strengthening the exterior, promoting diuresis and removing toxins, and is the main medicine; Astragalus is sweet in taste and warm in nature, and has the functions of replenishing qi and consolidating the exterior, promoting diuresis and removing toxins, while Atractylodes macrocephala strengthens the spleen and replenishes qi, as well as drying dampness and promoting diuresis, while Imperata root, Wax gourd peel, Ophiopogon japonicus clears heat and promotes diuresis, while Poria promotes diuresis and eliminates swelling and removes dampness. The ministerial medicines nourish the soil and control water, and together promote the effects of dispersing those who disperse and strengthening those who strengthen; tangerine peel acid can drain the liver wood to disperse water; Citrus aurantium peel and Zedoariae rhizome promote diuresis and reduce swelling; Rehmannia root strengthens the heart, promotes diuresis, relieves fever and reduces inflammation; Lycium barbarum nourishes the liver and kidneys, and can help the body's body fluids to gasify and evaporate; Codonopsis pilosula replenishes the middle and replenishes qi, and when qi flows, blood flows; and roasted licorice harmonizes all the medicines.

[0029] Animal experiments show that the Chinese medicine combination of the present invention has a significant diuretic effect, can significantly increase the urine excretion of chronic heart failure rat models, reduce water and sodium retention, and has a significant therapeutic effect.

[0030] The Chinese medicine combination of the present invention has significant therapeutic effect on patients with heart failure and diuretic resistance, can significantly improve the symptoms of patients, and has the effects of significantly increasing urine volume, reducing body weight, lowering BNP, and improving LVEF for patients, providing a new treatment method for patients with heart failure and diuretic resistance. DETAILED DESCRIPTION

[0031] In order to make the purpose, technical solution and advantages of the embodiments of the present invention clearer, the technical solution in the embodiments of the present invention will be clearly and completely described below in combination with the embodiments of the present invention. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0032] Example 1

[0033] A traditional Chinese medicine composition for diuretic resistance in heart failure, the traditional Chinese medicine composition is composed of the following weight components: 5g of processed aconite (pre-decocted), 10g of astragalus, 10g of Imperata root, 20g of wax gourd peel, 5g of atractylodes, 15g of Poria, 5g of tangerine peel, 10g of Rehmannia root, 3g of Ophiopogon japonicus, 10g of wolfberry, 5g of dried tangerine peel, 5g of Zedoariae rhizome, 5g of Codonopsis pilosula, and 5g of roasted liquorice.

[0034] The Chinese medicine composition can be prepared into any medically acceptable oral dosage form, including but not limited to granules, oral liquids, decoctions, and powders.

[0035] Example 2

[0036] The difference between this embodiment and embodiment 1 is that:

[0037] The Chinese medicine composition is composed of the following components by weight: 10g of processed aconite (pre-decocted), 15g of astragalus, 15g of Imperata root, 25g of wax gourd peel, 10g of atractylodes, 20g of Poria, 10g of tangerine peel, 15g of Rehmannia root, 5g of Ophiopogon japonicus, 15g of Lycium barbarum, 5g of Citrus grandis peel, 10g of Zedoariae rhizome, 10g of Codonopsis pilosula, and 10g of roasted liquorice.

[0038] Example 3

[0039] The difference between this embodiment and embodiment 1 is that:

[0040] The Chinese medicine composition is composed of the following components by weight: 15g of processed aconite (pre-decocted), 20g of astragalus, 20g of Imperata root, 30g of wax gourd peel, 20g of atractylodes, 25g of Poria, 20g of tangerine peel, 20g of Rehmannia root, 10g of Ophiopogon japonicus, 20g of Lycium barbarum, 10g of Citrus grandis peel, 15g of Zedoariae rhizome, 15g of Codonopsis pilosula, and 10g of roasted liquorice.

[0041] Example 4

[0042] The difference between this embodiment and embodiment 1 is that:

[0043] The Chinese medicine composition is composed of the following components by weight: 5g of processed aconite (pre-decocted), 15g of astragalus, 15g of Imperata root, 25g of wax gourd peel, 10g of atractylodes, 20g of Poria, 10g of tangerine peel, 15g of Rehmannia root, 5g of Ophiopogon japonicus, 15g of Lycium barbarum, 5g of Citrus grandis peel, 10g of Zedoariae rhizome, 10g of Codonopsis pilosula, and 10g of roasted liquorice.

[0044] Example 5

[0045] The difference between this embodiment and embodiment 1 is that:

[0046] The Chinese medicine composition is composed of the following components by weight: 10g of processed aconite (pre-decocted), 25g of astragalus, 25g of Imperata root, 35g of wax gourd peel, 20g of atractylodes, 30g of Poria, 20g of tangerine peel, 25g of Rehmannia root, 15g of Ophiopogon japonicus, 25g of Lycium barbarum, 15g of Citrus grandis peel, 20g of Zedoariae rhizome, 20g of Codonopsis pilosula, and 10-20g of roasted liquorice.

[0047] Example 6

[0048] The difference between this embodiment and embodiment 1 is that:

[0049] The Chinese medicine composition is composed of the following components by weight: 12g of processed aconite (pre-decocted), 18g of astragalus, 18g of Imperata root, 30g of wax gourd peel, 14g of Atractylodes macrocephala, 26g of Poria, 18g of dried tangerine peel, 18g of Rehmannia root, 15g of Ophiopogon japonicus, 18g of Lycium barbarum, 12g of Citrus grandis peel, 14g of Zedoariae rhizome, 12g of Codonopsis pilosula, and 16g of roasted liquorice.

[0050] Example 7

[0051] The difference between this embodiment and embodiment 1 is that:

[0052] The Chinese medicine composition is composed of the following components by weight: 9g of processed aconite (pre-decocted), 20g of astragalus, 20g of Imperata root, 30g of wax gourd peel, 12g of atractylodes, 24g of Poria, 15g of tangerine peel, 20g of Rehmannia root, 10g of Ophiopogon japonicus, 20g of Lycium barbarum, 10g of Citrus grandis peel, 12g of Zedoariae rhizome, 15g of Codonopsis pilosula, and 12g of roasted liquorice.

[0053] Test Example 1: Diuretic effect of the Chinese medicine composition of the present invention on rats with chronic heart failure

[0054] 1 Test method

[0055] 1.1 Model preparation

[0056] SD rats, SPF grade, male, weighing (270±20) g were selected. Rats were fixed on the operating table in the supine position under general anesthesia with intraperitoneal injection of 3% sodium pentobarbital 60 mg / kg. The hair of the anterolateral surgical field of the chest was removed and routinely disinfected. The skin and muscle layer were incised, the muscle layer was purse-string sutured, the thoracotomy was performed in the fourth intercostal space on the left side, and the heart was pulled out with a circular hook. At the position of the anterior descending coronary artery 3 to 4 mm below the left atrial appendage, the anterior descending coronary artery was ligated with 6 / 0 non-damaging silk thread. The heart was returned to the chest cavity, the air in the chest cavity was emptied, the chest cavity was closed (the animals in the sham operation group only had the threading at the corresponding coronary artery position, and no ligation was performed. The other surgical procedures were the same as those of the ligated animals), and the muscle layer and skin were sutured.

[0057] Four weeks after coronary artery ligation, Doppler ultrasound was used to measure cardiac function and compared with that before surgery. A decrease of more than 30% in the ejection fraction (LVEF) of M-mode echocardiography was used as the standard for successful model preparation.

[0058] 1.2 Grouping and Dosing

[0059] After 4 weeks of coronary artery ligation to form chronic heart failure, the mice were randomly divided into 4 groups according to the degree of LVEF, with 10 mice in each group, namely model control group, Chinese medicine control group, low-dose group, and high-dose group. In addition, 10 normal mice were set as blank control group. The administration method and dosage of each group are shown in Table 1. All groups were administered by gavage, once a day, for 30 consecutive days.

[0060] Table 1 Administration method and dosage of each group

[0061]

[0062] 1.3 Urine volume measurement

[0063] After 25 days of administration, rats in each group were given 2 ml / 100 g body weight of NS subcutaneously for water loading, and the rats were assisted to empty their urine. The rats were placed in metabolic cages and the urine volume was accurately measured for 0-2 hours and 2-24 hours. The ratio of urine volume (mL) to body weight 100 BW (100 g) (mL / 100 g BW) was used to express the degree of urine excretion.

[0064] 1.5 Statistical analysis

[0065] The experimental data were analyzed by one-way ANOVA using GraphPad Prism 8.0 software. The results were expressed as mean ± standard deviation, and (P < 0.05) indicated a significant difference.

[0066] 2 Results

[0067] 2.1 Effect of the Chinese medicine composition of the present invention on urine volume in rats with chronic heart failure

[0068] As shown in Table 2, compared with the blank control group, the urine volume in the model group decreased, indicating that water and sodium retention occurred in the chronic heart failure rat model. After administration, there was no significant difference in the 0-2h urine volume / 100BM ratio among the Chinese medicine control group, low-dose and high-dose groups (P>0.05); compared with the model control group, the 2-24h urine volume / 100BM ratio of the Chinese medicine control group, low-dose and high-dose groups increased significantly (P<0.05); compared with the blank control group, there was no significant difference in the 2-24h urine volume / 100BM ratio of the Chinese medicine control group (P>0.05), and the 2-24h urine volume / 100BM ratio of the low-dose group and the high-dose group was significantly higher than that of the blank control group, among which the low-dose group The 0-24h urine volume / 100BM ratios of the low-dose group and the high-dose group were significantly higher than those of the Chinese medicine control group (P<0.05). Compared with the model control group, the 0-24h urine volume / 100BM ratios of the Chinese medicine control group, the low-dose group and the high-dose group were significantly higher than those of the Chinese medicine control group (P<0.05). Compared with the blank control group, there was no significant difference in the 0-24h urine volume / 100BM ratio of the Chinese medicine control group (P>0.05), and the 0-24h urine volume / 100BM ratios of the low-dose group and the high-dose group were significantly higher than those of the blank control group, among which the low-dose group and the high-dose group were significantly higher than those of the Chinese medicine control group (P<0.05).

[0069] The above results show that the Chinese medicine combination of the present invention has a significant diuretic effect, can significantly increase the urine excretion of chronic heart failure rat models, and reduce water and sodium retention. Compared with Wuling Powder, it has a greater advantage in the therapeutic effect of diuresis.

[0070] Table 2 Effect of the Chinese medicine composition of the present invention on urine volume in rats with chronic heart failure

[0071]

[0072] Note: In the same column of data, the same lowercase letters or no letters indicate P>0.05, and different lowercase letters indicate P<0.05.

[0073] Test Example 2

[0074] 1. Case source

[0075] From January 2016 to December 2017, 60 patients with diuretic-resistant heart failure were admitted to Guangwai Hospital, Xicheng District, Beijing.

[0076] 2. Inclusion and exclusion standards

[0077] Inclusion criteria: patients who meet the Framingham diagnostic criteria for heart failure, are clearly diagnosed with heart failure, and have a heart function classification (NYHA) of III to IV, who have used 80 mg of furosemide intravenously daily, or the equivalent daily dose of furosemide, and whose heart failure symptoms have not improved after 3 days, and whose body weight loss cannot reach 0.5-1 kg / day. TCM syndrome differentiation is Yang deficiency and water flooding syndrome (refer to the relevant standards in the "Guidelines for Clinical Research of New Chinese Medicines").

[0078] Exclusion criteria: Those who do not meet the inclusion criteria or whose data are incomplete and affect the judgment; patients with heart failure caused by failure of important organs such as kidney and liver; pregnant or lactating women; patients with severe primary diseases such as liver, kidney, endocrine system, and hematopoietic system; patients with mental disorders or unwillingness to cooperate; patients with diseases that may increase mortality, such as cardiogenic shock, pericardial tamponade, and pulmonary embolism.

[0079] Case dropout criteria: those who cannot continue to participate in the clinical trial due to lack of efficacy; those who withdraw voluntarily or are lost to follow-up due to fear, adverse events or no reason.

[0080] Case termination criteria: The patient's condition continues to deteriorate during the trial, and a dangerous event may occur; severe adverse reactions or severe allergic reactions occur; the patient himself or his legal guardian requests the termination of the trial; the researcher has to terminate due to unpredictable factors

[0081] 3. Treatment methods

[0082] Control group: routine bed rest, strict control of fluid intake, on the basis of primary disease treatment, routine use of nitrates, spironolactone, diuretics, cardiotonic agents, beta-blockers, angiotensin converting enzyme inhibitors (ACEI), infection control, correction of water and electrolyte disorders and symptomatic supportive treatment.

[0083] Treatment group: on the basis of the control group treatment, the Chinese medicine composition of the present invention was added (processed aconite (pre-decocted) 9g, astragalus 20g, white imperata root 20g, wax gourd peel 30g, atractylodes 12g, Poria 24g, tangerine peel 15g, rehmannia glutinosa 20g, ophiopogon 10g, wolfberry fruit 20g, tangerine peel 10g, zedoaria 12g, codonopsis pilosula 15g, and glycyrrhiza uralensis 12g), 1 dose per day, decocted in water, taken in the morning and evening, 150ml / time.

[0084] 4. Observation indicators

[0085] (1) TCM syndrome efficacy:

[0086] Markedly effective: Symptoms basically or completely disappeared, and the symptom score after treatment was 0 or decreased by ≥70%.

[0087] Effective: The symptom score decreases by ≥30%. Ineffective: The symptom score decreases by less than 30%.

[0088] Aggravation: The symptom score exceeds the score before treatment.

[0089] The scoring of TCM syndromes refers to the relevant methods in the "Guidelines for Clinical Research of New Chinese Medicines": main symptoms such as palpitations, shortness of breath, fatigue, puffy face and limb swelling, chills and cold limbs, oliguria, chest tightness, etc. are scored as 0, 2, 4, and 6 points respectively according to their absence, mild, moderate, and severe levels; secondary symptoms such as night sweats, spontaneous sweating, dry mouth, cough, sputum, irritability, and abdominal distension are scored as 0, 1, 2, and 3 points respectively according to their absence, mild, moderate, and severe levels.

[0090] (2) Cardiac function efficacy:

[0091] The NYHA cardiac function classification method was used to determine the cardiac function efficacy.

[0092] Markedly effective: symptoms or signs disappear, and NYHA heart function improves by more than 2 levels.

[0093] Effective: Symptoms or signs are alleviated, and NYHA heart function improves by 1 level but less than 2 levels.

[0094] Ineffective: Symptoms or signs and NYHA heart function remain unchanged. Aggravated: Symptoms or signs worsen, and NYHA heart function deteriorates by 1 grade or more.

[0095] (3) Detect the patient’s urine volume and body weight before and after treatment.

[0096] (4) B-type natriuretic peptide (BNP): 1 ml of venous blood was drawn before and after treatment and placed in a plastic test tube containing 10% EDTA anticoagulant, and B-type natriuretic peptide (BNP) was detected using a tester.

[0097] (5) Left ventricular ejection fraction (LVEF) Left ventricular ejection fraction (LVEF) was measured by echocardiography before and after treatment.

[0098] (6) Safety: Blood routine, urine routine, stool routine, liver function, kidney function, and blood electrolytes were tested before and after treatment; any adverse reactions that occurred were observed and recorded in a timely manner during the trial.

[0099] 5. Statistical analysis

[0100] The collected clinical cases were quality controlled. Data were collated and analyzed for cases that met the research criteria. All count data were statistically analyzed using SPSS18.0 software and expressed as mean ± standard deviation. The rank sum test was used for graded data, and the independent sample t test was used for measurement data. P < 0.05 was considered statistically significant.

[0101] 6 Results

[0102] A total of 60 patients were enrolled, 10 of whom dropped out, including 26 in the control group and 24 in the treatment group. There was no significant difference in baseline data such as age and height between the two groups (P>0.05), and they were comparable.

[0103] 6.1 Comparison of TCM symptom efficacy between the two groups

[0104] Before treatment, there was no statistically significant difference in the TCM symptom scores between the control group and the treatment group (P>0.05); compared with before treatment, the TCM symptom scores of both the control group and the treatment group were significantly reduced after treatment (P<0.05); after treatment, the TCM symptom scores of the treatment group were lower than those of the control group, with a significant difference (P<0.05).

[0105] Table 3 Comparison of TCM symptom efficacy between the two groups (points)

[0106] Group n Before treatment After treatment Control group 26 45.54±7.38 <![CDATA[24.92±11.62 * <!-- 7 -->]]> Treatment Group 24 44.83±6.89 <![CDATA[16.42±10.35 *△ ]]>

[0107] Note: Compared with the group before treatment, *P<0.05, **P<0.01; compared with the control group after treatment, △ P<0.05, △△ P<0.01.

[0108] 6.2 Comparison of cardiac function classification between the two groups

[0109] The total effective rate of cardiac function treatment in the treatment group was 91%, significantly higher than 76% in the control group.

[0110] Table 4 Comparison of cardiac function classification between the two groups [n(%)]

[0111] Group n Significant effect efficient invalid Total effective rate (%) Control group 26 6(23) 14(54) 6(23) 76 Treatment Group 24 14(28) 8(33) 2(8) 91

[0112] 6.3 Comparison of urine volume between the two groups

[0113] Before treatment, there was no significant difference in urine volume between the control group and the treatment group (P>0.05); compared with before treatment, the urine volume of both the control group and the treatment group increased significantly after treatment (P<0.05); after treatment, the urine volume of the treatment group was significantly higher than that of the control group, with a significant difference (P<0.05).

[0114] Table 5 Comparison of urine volume between the two groups (mL)

[0115] Group n Before treatment After treatment Control group 26 659.23±151.71 <![CDATA[1207.38±140.56 * ]]> Treatment Group 24 663.75±212.19 <![CDATA[1662.5±288.25 *△ ]]>

[0116] Note: Compared with the group before treatment, *P<0.05, **P<0.01; compared with the control group after treatment, △ P<0.05, △△ P<0.01.

[0117] 6.4 Comparison of body weight between the two groups

[0118] Before treatment, there was no significant difference in body weight between the control group and the treatment group (P>0.05); compared with before treatment, the body weight of the control group and the treatment group decreased significantly after treatment (P<0.05); After treatment, the weight difference of the treatment group was significantly greater than that of the control group, and the difference was significant (P<0.05).

[0119] Table 6 Comparison of body weight between the two groups (Kg)

[0120] Group n Before treatment After treatment weight difference Control group 26 64.59±13.72 <![CDATA[62.95±13.66 * ]]> 1.64±0.21 Treatment Group 24 67.28±14.06 <![CDATA[64.23±13.75 * ]]> <![CDATA[3.05±0.44 △ ]]>

[0121] Note: Compared with the group before treatment, *P<0.05, **P<0.01; compared with the control group after treatment, △ P<0.05, △△ P<0.01.

[0122] 6.5 Comparison of B-type natriuretic peptide (BNP) between the two groups

[0123] Before treatment, the BNP levels of both groups were >400ng / mL. After treatment, the BNP levels of 10 patients in the control group recovered to the normal range of 0-400ng / mL, and the BNP levels of 16 patients in the treatment group recovered to the normal range of 0-400ng / mL. The proportion of patients in the control group whose BNP levels recovered to the normal range of 0-400ng / mL was 38.46%, and the proportion of patients in the treatment group whose BNP levels recovered to the normal range of 0-400ng / mL was 66.67%.

[0124] Table 7 B-type natriuretic peptide (BNP) [n (%)] in two groups

[0125]

[0126] 6.7 Comparison of left ventricular ejection fraction (LVEF) between the two groups

[0127] Before treatment, there were 17 cases with EF≤35% in the control group, 9 cases with 36≤EF≤49%, and 0 cases with EF≥50%; there were 13 cases with EF≤35%, 11 cases with 36≤EF≤49%, and 0 cases with EF≥50% in the treatment group. After treatment, the control group had EF≤35% reduced to 9 cases, 36≤EF≤49% to 8 cases, and EF≥50% increased to 9 cases; the treatment group had EF≤35% reduced to 2 cases, 36≤EF≤49% to 5 cases, and EF≥50% increased to 17 cases.

[0128] Table 8 Comparison of left ventricular ejection fraction between the two groups [n(%)]

[0129]

[0130] 7 Conclusion

[0131] The above results show that the Chinese medicine combination of the present invention has significant efficacy in patients with heart failure and diuretic resistance, can significantly improve the symptoms of patients, and has the effects of significantly increasing urine volume, reducing body weight, lowering BNP, and improving LVEF for patients, providing a new treatment method for patients with heart failure and diuretic resistance.

[0132] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A Chinese medicine composition for diuretic resistance in heart failure, characterized in that: The Chinese medicine composition is composed of the following raw materials by weight: 1-20g of processed aconite, 10-30g of astragalus, 10-30g of Imperata root, 20-40g of wax gourd peel, 5-25g of Atractylodes macrocephala, 15-35g of Poria, 5-25g of dried tangerine peel, 10-30g of Rehmannia root, 1-20g of Ophiopogon japonicus, 10-30g of Lycium barbarum, 1-20g of Citrus grandis peel, 5-20g of Zedoariae rhizome, 5-25g of Codonopsis pilosula, and 5-25g of roasted liquorice.

2. A Chinese medicine composition for treating diuretic resistance in heart failure according to claim 1, characterized in that: The Chinese medicine composition is composed of the following raw materials by weight: 5-15g of processed aconite, 15-25g of astragalus, 15-25g of Imperata root, 25-35g of wax gourd peel, 10-20g of atractylodes, 20-30g of Poria, 10-20g of tangerine peel, 15-25g of rehmannia root, 5-15g of ophiopogon, 15-25g of wolfberry, 5-15g of tangerine peel, 10-20g of zedoaria, 10-20g of codonopsis pilosula, and 10-20g of roasted liquorice.

3. A Chinese medicine composition for treating diuretic resistance in heart failure according to claim 1, characterized in that: The Chinese medicine composition is composed of the following raw materials by weight: 9g of processed aconite, 20g of astragalus, 20g of Imperata root, 30g of wax gourd peel, 12g of Atractylodes macrocephala, 24g of Poria, 15g of tangerine peel, 20g of Rehmannia root, 10g of Ophiopogon japonicus, 20g of Lycium barbarum, 10g of Citrus grandis peel, 12g of Zedoariae rhizome, 15g of Codonopsis pilosula, and 12g of roasted liquorice.

4. Use of the Chinese medicine composition according to any one of claims 1 to 3 in the preparation of a drug for diuretic resistance in heart failure, characterized in that: The Chinese medicine composition is prepared into a medically acceptable oral dosage form.

5. Use of the Chinese medicine composition according to claim 4 in preparing a drug for treating diuretic resistance in heart failure, characterized in that: The dosage forms include granules, oral liquids, decoctions and powders.

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