A Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating the weakness thereof, and its preparation method and application

Abstract

The present invention belongs to the field of medical science, relates to a Chinese medicine, and specifically relates to a Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating its weak state, and its preparation method and application. The formula of the composition is 20-30g of Astragalus, 10-15g of Ginseng, 15-30g of Atractylodes macrocephala, 10-15g of Aconite (pre-decocted), 15-30g of Amomum villosum, 3-12g of Tortoise Shell, 20-30g of Phellodendron, 6-12g of Angelica sinensis, 6-12g of Tangerine Peel, 6-12g of Cimicifuga heracleifolia, 6-12g of Bupleurum, and 10-30g of Radix Glycyrrhizae Preparata. The composition provided by the present invention replenishes the vital energy of the heart and kidney and subdues Yin fire. Chronic coronary syndrome and chronic heart failure can be treated, and their weak state can be prevented and treated, their clinical symptoms can be improved, the patient's resistance can be improved, the patient's quality of life can be improved, the weak state can be prevented and treated, and the disease can be prevented from being prolonged and recurring. Reduce the current use of Western medicine, the efficacy is significant, and there are few safety issues.

Description

Technical Field

[0001] The present invention belongs to the field of medical science and relates to a traditional Chinese medicine, and specifically relates to a traditional Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating the weakness thereof, as well as a preparation method and application thereof. Background Art

[0002] With the improvement and popularization of coronary intervention, bypass surgery, and the treatment of acute myocardial infarction, the mortality rate of acute coronary syndrome and acute heart failure has been greatly reduced, and the number of patients with chronic coronary syndrome and chronic heart failure (CHF) has greatly increased, becoming a problem that needs to be urgently addressed in the cardiovascular field.

[0003] Chronic coronary syndrome is common, and multiple inducing factors lead to repeated myocardial ischemia, causing the occurrence and development of chronic heart failure. At the same time, chronic heart failure (CHF) is a group of complex clinical syndromes caused by abnormal changes in cardiac structure and / or function due to multiple reasons, resulting in disorders of ventricular systolic and / or diastolic function. As the terminal stage of the evolution of various heart diseases, CHF is one of the diseases with the highest hospitalization rate and mortality rate in the world. How to block or delay the progression of CHF, reduce the occurrence of endpoint events, and improve the quality of life of patients are major challenges facing the cardiovascular field.

[0004] Frailty is a common clinical phenomenon in chronic coronary syndrome and chronic heart failure cardiovascular diseases. It refers to a non-specific state in which the patient's physiological reserve decreases, leading to increased vulnerability of the body and reduced tolerance to stressors such as cold and high temperature. It is an independent risk factor that promotes the progression of chronic heart failure or induces acute heart failure.

[0005] With the accelerated aging of the population, the incidence of frailty caused by other factors of heart disease such as chronic coronary syndrome and chronic heart failure has increased. Chronic heart failure is not only the main manifestation of frailty, but also an important factor leading to the progression of frailty. In 2019, the European Society of Cardiology (ESC) emphasized the importance of frailty assessment in CHF patients, and believed that frailty for CHF patients should be defined as "a state that is unrelated to age, changes dynamically, and is caused by the combined effects of multiple factors, which ultimately increases the vulnerability of CHF patients under stress."

[0006] Patients with chronic coronary syndrome and chronic heart failure, after conventional treatment of modern medicine and traditional Chinese medicine treatments such as invigorating qi and promoting blood circulation, warming yang and promoting diuresis, have their symptoms alleviated, but the body is still in a state of deficiency of vital energy and spleen and lung qi, or elderly heart patients, who have symptoms of upper heat and lower cold such as chest tightness and shortness of breath, weakness, fear of cold, sweating, irritability and dry mouth, poor appetite and weight loss, insomnia and dizziness. These patients are in a weak state, which is more likely to cause angina pectoris, progression of heart failure and decompensation of heart failure, leading to the occurrence of adverse cardiovascular events.

[0007] For such patients, the inventors believe that the pathological mechanism is that the patient's coronary artery stenosis and myocardial damage lead to insufficient vital energy of the heart, or long-term illness, old age, etc. lead to insufficient vital energy and rising Yin fire. Therefore, it is necessary to replenish the vital energy of the heart and kidney and subdue Yin fire. The prescription of the present invention is used to improve the patient's resistance, improve the patient's quality of life, prevent and treat the weak state, and prevent the disease from protracted recurrence. However, in the current preparations of Chinese patent medicines for the treatment of chronic coronary syndrome and chronic heart failure, most of them are based on the treatment of invigorating qi and promoting blood circulation, warming yang and promoting diuresis, which is different from the prescription of this party.

[0008] At present, the treatment of patients with chronic coronary syndrome and chronic heart failure is mostly based on various clinical guidelines, and long-term medication, including antiplatelet drugs, lipid-lowering drugs, ARNI drugs, beta-blockers, diuretics, etc. However, there are currently no good treatment plans and drugs for the stability of chronic coronary syndrome and chronic heart failure, as well as the prevention of decompensation. When encountering inducing factors, the disease progresses or acute decompensation occurs. Patients suffer from the disease for a long time, and long-term use of Western medicine has great side effects on the body. Summary of the invention

[0009] In view of the shortcomings of the above-mentioned prior art, the present invention provides a Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating asthenia, which has a definite curative effect and prevents and treats the progression of the disease according to the characteristics of the patients with chronic coronary syndrome and chronic heart failure. The Chinese medicine composition of the present invention can treat chronic coronary syndrome and heart failure, improve the prognosis of patients, prevent and treat asthenia, and is particularly suitable for elderly patients with cardiovascular disease.

[0010] The present invention also provides a method for preparing a Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating asthenic state.

[0011] Another object of the present invention is to provide the use of the above-mentioned Chinese medicine composition in the preparation of medicines for treating chronic coronary syndrome, chronic heart failure, and preventing and treating asthenic state.

[0012] The technical solution adopted by the present invention to achieve the above-mentioned purpose is:

[0013] The invention provides a Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating asthenic state, comprising the following raw materials by weight: 20-30g of astragalus, 10-15g of ginseng, 15-30g of atractylodes, 15-30g of amomum, 3-12g of tortoise shell, 20-30g of phellodendron, 6-12g of angelica, 6-12g of tangerine peel, 6-12g of cimicifuga, 6-12g of bupleurum, and 10-30g of roasted liquorice.

[0014] Preferably, the above important composition may also include 10-15g of aconite (pre-decocted).

[0015] The most preferred raw materials include the following components by weight: 24g Astragalus, 12g Ginseng, 15g Atractylodes, 12g Aconitum (pre-decocted), 15g Amomum, 6g Tortoise Shell, 21g Phellodendron, 9g Angelica, 9g Tangerine Peel, 9g Cimicifuga, 9g Bupleurum, and 15g Radix Glycyrrhizae.

[0016] Furthermore, in the formula provided by the present invention, the raw material medicine may also include 6 to 15 g of cassia twig by weight.

[0017] Furthermore, in the formula provided by the present invention, the raw material medicine may also include 1 to 5 g of asarum by weight.

[0018] Furthermore, in the formula provided by the present invention, the raw material medicine may also include 6 to 18 g of Cornus officinalis and 6 to 15 g of Cuscuta australis by weight.

[0019] The present invention also provides a method for preparing the above-mentioned traditional Chinese medicine composition, comprising the following steps: weighing the raw medicine for each dose of medicine by weight, soaking it in warm water for 180-360 minutes, adding water to cover the raw medicine by about 1-2 cm, decocting the aconite root for 40 minutes, and then decocting it twice with other raw medicines, the first decoction is 60-90 minutes after boiling, and the second decoction is 60 minutes after boiling, the two decoctions are combined to a total of 400 mL, and the medicine is taken warm 2 hours after breakfast and dinner, 200 mL each time, and one dose per day.

[0020] Compared with the prior art, the present invention has significant advantages:

[0021] After conventional treatment of modern medicine and traditional Chinese medicine treatment of invigorating qi and promoting blood circulation, warming yang and promoting diuresis, although the symptoms of patients with chronic coronary syndrome and chronic heart failure have been alleviated, the body is still in a state of deficiency of vital energy and spleen and lung qi, manifested by chest tightness, shortness of breath, weakness, fear of cold, sweating, irritability, dry mouth, poor appetite, weight loss, insomnia, dizziness and other symptoms of upper heat and lower cold. Such patients are in a weak state, which is more likely to cause angina pectoris or heart failure decompensation, and accelerate the progression of heart failure.

[0022] For such patients, the pathological mechanism is: insufficient vital energy and rising Yin fire. Therefore, in the remission period, it is necessary to replenish the vital energy of the heart and kidney, replenish qi and strengthen the spleen, and subdue Yin fire. It is used to prevent and treat asthenia, improve the patient's resistance, improve the patient's quality of life, prevent and treat weakness, and prevent the disease from recurring. At present, Chinese patent medicines for the treatment of coronary heart disease and heart failure mostly use the treatment method of replenishing qi and activating blood circulation, warming yang and promoting diuresis, which is different from the intention and composition of this prescription.

[0023] 1. Formula analysis:

[0024] Main herbs: Astragalus, Ginseng, Atractylodes macrocephala, Aconite

[0025] The pathological mechanism of such patients is insufficient vital energy, weak and vulnerable body, which is more likely to cause angina pectoris and heart failure decompensation, further aggravating the condition. Therefore, the Chinese medicine composition of the present invention adds astragalus, ginseng, and white atractylodes to invigorate qi and strengthen the spleen, raise yang and benefit the defense, and aconite warms and nourishes the heart and kidney yang. Ginseng tastes sweet, slightly bitter, slightly warm in nature, and enters the spleen and lung meridians. "Compendium of Materia Medica" says: "Sweet, warm, slightly bitter, greatly replenishes the vital energy in the lungs, purges fire and relieves restlessness, promotes the production of body fluids and quenches thirst, opens the heart and improves intelligence, improves hearing and eyesight, calms the spirit, stabilizes the soul, stops panic, and dredges the blood vessels." "Famous Doctors' Records" says: "Slightly warm, non-toxic. It is mainly used to treat coldness in the stomach and intestines, heart and abdomen pain, chest and flank fullness, cholera vomiting, regulates the middle, stops thirst, dredges the blood vessels, breaks up hard masses, and is unforgettable." Astragalus tastes sweet, slightly warm in nature, and enters the spleen and lung meridians. "Compendium of Materia Medica" states: "It is a medicine that nourishes the lungs and spleen, strengthens the defense system, restrains sweat, and drives away wind and poison." "Medical Records of Chinese and Western Medicine" states: "It can nourish qi and raise qi, and is good at treating the sinking of qi in the chest." Cinnamon is pungent and sweet, and warm in nature. "Compendium of Materia Medica" states: "It is pungent, warm, and non-toxic. It is mainly used to treat cough, qi stagnation, throat paralysis, vomiting and breathing, heartache, flank wind, flank pain, warms the tendons and unblocks the meridians, stops sweating, benefits the joints, and replenishes the middle and replenishes qi." Atractylodes macrocephala tastes bitter and sweet, and is warm in nature. It has the effects of strengthening the spleen and replenishing qi, drying dampness and promoting diuresis, stopping sweating and stabilizing pregnancy. "The Origin of Medicine": "It removes dampness and replenishes dryness, harmonizes the middle and replenishes Qi. It has nine uses: one is to warm the middle; two is to remove dampness from the spleen and stomach; three is to remove stomach heat; four is to strengthen the spleen and stomach and promote appetite; five is to harmonize the stomach and produce body fluids; six is ​​to control muscle heat; seven is to treat sleepiness of the limbs, unwillingness to open the eyes, laziness and love of lying down, and loss of appetite; eight is to quench thirst; nine is to calm the fetus." Aconite tastes pungent and sweet, and is very hot in nature. It has the effects of restoring yang, replenishing fire and assisting yang, dispersing cold and relieving pain. "Leigong's Explanation of the Properties of Medicinal Materials" states: "It can be used in all meridians. It can treat deep cold in the six internal organs, three yang meridians, accumulation of hard symptoms, and cold and dampness cramps. Aconite is the yang among the yang, its nature is floating but not sinking, and its function is to move without stopping. Therefore, it can enter the meridians and collaterals everywhere, and is suitable for causing abortion and removing symptoms. It is pungent, sweet and hot, and can replenish the fire of the gate of life to nourish the spleen and earth." The Chinese medicine composition of the present invention uses ginseng, astragalus, white atractylodes, and aconite as the main medicine, which can not only replenish the qi of the spleen and lungs, but also warm and replenish the yang qi of the heart and kidneys, so that the body's vital energy is sufficient, the defensive qi is abundant, and the evil is strong; when the qi is full, the blood flows, and the qi and blood flow smoothly, circulate throughout the body, and nourish the five internal organs, six internal organs, and the limbs. Astragalus can also raise yang, benefit the defensive qi and consolidate the exterior, and can raise the qi that sinks in the chest and benefit the defensive qi to stop sweating.

[0026] Assistant drugs: tortoise shell, phellodendron, amomum villosum

[0027] In addition to insufficient vital energy, such patients also have an important pathological mechanism of Yin fire rising, so patients will have dry mouth, irritability, insomnia, dizziness and other manifestations of heat. In view of this pathological mechanism, the present invention adds tortoise shell, phellodendron, and amomum to suppress Yin fire. Turtle shell tastes salty and sweet, is slightly cold in nature, and enters the liver, kidney, and heart meridians. It has the effects of nourishing Yin and suppressing Yang, benefiting the kidney and strengthening bones, and nourishing blood and nourishing the heart. "Ben Cao Meng Quan" says: "Specially replenishing Yin deficiency, good at nourishing kidney damage." Zheng Qinan: "What's more, tortoise shell is a thing, hard, born from the essence of water, and has the power to clear Yin and help Yang." Phellodendron is bitter in taste and cold in nature. It has the effects of clearing heat and dampness, purging fire and detoxifying, and relieving deficiency heat. "Zhenzhu Nang": "It treats kidney water. Bladder deficiency, various paralysis, weakness of waist and knees." Zheng Qinan: "Huangbai tastes bitter and enters the heart. It inherits the cold water of Tiandong and enters the kidney. It is yellow and enters the spleen. The spleen is the pivot of harmonizing water and fire. This taste alone has the meaning of the three talents." Amomum villosum tastes pungent and warm in nature. It enters the spleen and stomach meridians and has the effects of removing dampness and promoting qi, warming the middle and calming the fetus. Zheng Qinan: "Xisha is pungent and warm, and can dispel all yin evils in the middle palace, and can also absorb qi and return to the kidney." "Yi Lin Zuan Yao": "It nourishes the kidney, nourishes the liver, nourishes the gate of life, harmonizes the spleen and stomach, and relieves depression." The Chinese medicine composition of the present invention uses tortoise shell, Huangbai and Amomum villosum as ministers. Tortoise shell submerges yang and enters yin to suppress virtual fire; Huangbai drains the hidden fire in the yin, strengthens yin qi, and harmonizes water and fire; Amomum villosum absorbs the qi of the five internal organs and returns to the kidney.

[0028] Auxiliary drugs: Angelica sinensis, dried orange peel, Cimicifuga heracleifolia, Bupleurum

[0029] The composition provided by the present invention is added with Chinese angelica, dried orange peel, cimicifuga and bupleurum as adjuvants. Chinese angelica is sweet and pungent in taste, warm in nature, enters the liver, heart and spleen meridians, and has the effects of nourishing blood, activating blood circulation, relieving pain and moistening intestines. "Bie Lu" says: "Warming the middle and relieving pain, removing the internal blockage of foreign blood, stroke spasm, sweating, dampness and arthralgia, evil foreign qi, coldness, nourishing the five internal organs, and growing muscles." "Rihuazi Bencao" says: "Cure all wind, all blood, nourish all fatigue, break bad blood, nourish new blood and treat main symptoms and obsessions." Dried orange peel is pungent and bitter in taste, warm in nature, enters the spleen and lung meridians, and has the effects of regulating qi, regulating the middle, drying dampness and resolving phlegm. "Medical Origin" says: "It removes cold evil in the chest, breaks stagnant qi, and benefits the spleen and stomach." "Bielu" says: "It can reduce qi, stop vomiting and coughing, remove heat in the bladder, water retention, and five stranguria, and promote urination. It can treat the spleen's inability to digest food, qi rushing to the chest, vomiting and cholera, stop diarrhea, and remove inch white." Cimicifuga tastes pungent and sweet, is slightly cold in nature, and enters the lung, spleen, large intestine, and stomach meridians. It has the effects of raising yang and lifting the sunken, clearing away heat and detoxifying, and releasing rashes. "Compendium of Materia Medica" says: "It can eliminate macules and rashes, promote blood theft, treat yang sunken dizziness, chest and flank pain, heaviness after long-term diarrhea and dysentery, turbidity, leucorrhea, metrorrhagia, hematuria, bleeding, impotence and cold feet." Chaihu tastes bitter and pungent, is slightly cold in nature, and enters the pericardium, liver, triple energizer, and gallbladder meridians. It has the effects of raising yang, reconciling and reducing fever, and relieving liver and depression. "Bencao Gangmu" says: "It can replenish the five kinds of fatigue and seven kinds of injuries, eliminate restlessness and stop convulsions, increase energy, eliminate phlegm and stop coughing, moisten the heart and lungs, replenish essence and replenish marrow, and treat fever, fever, fatigue, chest and flank qi fullness, and forgetfulness." Tangerine peel is added to the present invention to regulate qi and balance the middle, so that it can be replenished without stagnation; Angelica sinensis nourishes blood and harmonizes the body, qi is the leader of blood, and blood is the mother of qi. Adding angelica sinensis can replenish both qi and blood, and at the same time, angelica sinensis has the effect of activating blood circulation; at the same time, a small amount of bupleurum and cimicifuga are added to the present invention to assist the main medicine in replenishing vital energy and promoting the clear yang.

[0030] Adjuvant drug: Roasted Licorice

[0031] Roasted licorice root: sweet and mild in taste, it enters the heart, lung, spleen and stomach meridians. It can nourish the heart qi, replenish qi and restore the pulse. At the same time, it is good at entering the middle burner, replenishing the spleen and replenishing qi. "Bencao Zheng" says: "It helps ginseng and Astragalus to achieve the effect of qi deficiency."

[0032] The whole prescription uses Astragalus, Ginseng, Atractylodes macrocephala, and Aconitum as the main ingredients, which greatly replenish the vital energy of the heart and kidney, strengthen the spleen and warm the kidney; Tortoise shell, Phellodendron chinense, and Amomum villosum as the subordinate ingredients, which submerge yang into yin and suppress virtual fire; Angelica sinensis and dried orange peel as the auxiliary ingredients, which nourish blood and coordinate the operation, regulate qi and relieve stagnation; Cimicifuga heracleifolia and Bupleurum chinense as the auxiliary ingredients, which raise yang and lift the sunken; Licorice is used as the messenger to harmonize the various medicines. The whole prescription focuses on replenishing vital energy, submerging yin fire, preventing and treating asthenia and depletion, improving the resistance of patients, improving the quality of life of patients, preventing and treating the weak state, and preventing the disease from prolonging and recurring. The innovative points of the present invention also include focusing on the rise and fall of the body's vital energy, replenishing the vital energy of the heart, kidney and spleen, and submerging yang into yin and suppressing virtual fire. It is different from the conventional prescription and medicine compatibility.

[0033] Since chronic coronary syndrome and chronic heart failure belong to the categories of "chest pain", "heart damage" and "deficiency fatigue" in traditional Chinese medicine, they are a kind of disease with deficiency in the root and excess in the superficial. According to the treatment principle of "tonifying the vital energy of the heart and kidney, and subduing the Yin fire", a Chinese medicine composition is formulated to prevent and treat the onset of chronic coronary syndrome and chronic heart failure patients, prevent and treat weakness, and achieve good therapeutic effects. The pathogenesis of this disease is complex. In the past, it was mostly based on qi deficiency, qi and yin deficiency, and yang deficiency, and blood stasis, water dampness, and phlegm and fluid were the symptoms. The Chinese medicine composition of the present invention is used to tonify the vital energy of the heart and kidney, and subduing the Yin fire. It is based on tonifying deficiency, and subduing the Yin fire, and regulating qi, blood, yin and yang. It prevents and treats the occurrence and development of blood stasis, water dampness, and phlegm and fluid, so as to treat both the root and the superficial, and finally achieves the purpose of improving the clinical symptoms of patients, improving the resistance of patients, and preventing the onset of decompensation.

[0034] 2. Modern pharmacological research

[0035] (1) Astragalus

[0036] Modern pharmacological studies have shown that astragalus can increase myocardial contractility, increase coronary blood flow, slow down heart rate, and thus resist myocardial ischemia. Astragaloside (AS) inhibits platelet aggregation and prolongs the time of arterial thrombosis, thereby playing an anti-thrombotic role. Astragalus can inhibit the increase in myocardial mitochondrial malondialdehyde, aspartate aminotransferase, and serum creatine phosphokinase activity caused by adriamycin and reduce superoxide dismutase activity, thereby protecting the heart. Astragalus can also resist arrhythmia, dilate coronary arteries and peripheral blood vessels, and lower blood pressure. It promotes metabolism, resists fatigue, has a significant diuretic effect, can regulate blood sugar, excite breathing, enhance and regulate the body's immune function, lower blood lipids, and resist aging.

[0037] (2) Ginseng

[0038] Modern pharmacological studies have shown that ginsenosides have the effect of resisting myocardial ischemia-reperfusion injury and can significantly reduce myocardial infarction area and myocardial enzymes. Ginsenoside Rg1 can inhibit apoptosis, inflammatory response, and regulate energy metabolism through multiple pathways such as inhibiting excessive mitochondrial autophagy, downregulating the nuclear transcription factor-κB pathway, and the Rho A signaling pathway. Ginsenoside Rb1 can restore the function of the heart or mitochondria through multiple signaling pathways, thereby inhibiting myocardial fibrosis. Ginsenoside Re can promote the release of nitric oxide in vascular endothelial cells, reduce atrial contractility, and prolong the effective refractory period of the left atrium, thereby exerting an anti-arrhythmic effect. Ginseng polysaccharides can lower cholesterol and triglycerides, restore myocardial mitochondrial activity, and have anti-myocardial hypertrophy effects.

[0039] (3) Atractylodes macrocephala

[0040] Modern pharmacological studies have shown that Atractylodes macrocephala has anti-inflammatory and antioxidant effects, can significantly increase serum total superoxide dismutase activity and the gene expression level of myocardial angiotensin II receptors, improve hemodynamics, inhibit the activation of the RAAS system, and reduce myocardial hypertrophy, myocardial fibrosis and ventricular remodeling. Atractylodes macrocephala lactone III can inhibit inflammatory response and myocardial cell apoptosis, correct excessive autophagy, improve the cardiac function of mice with myocardial infarction, and play a cardioprotective role.

[0041] (4) Aconite

[0042] Modern pharmacological studies have found that the alkaloid sassolinol in Aconite can downregulate mitochondrial Ca 2+ It absorbs membrane protein activity, thereby blocking mitochondrial dysfunction and protecting myocardial cells. The natural benzylisoquinoline alkaloids extracted from aconite can promote myocardial energy metabolism, promote mitochondrial energy metabolism, and prevent congestive heart failure. Aconite has a bidirectional effect on myocardial contractility and blood pressure, first inhibiting or reducing, and then enhancing or increasing; at the same time, it is the first time to prove that the non-alkaloid water-soluble components in aconite can selectively counteract alkaloid-induced arrhythmias, with a rapid and lasting effect.

[0043] (5) Tortoise shell

[0044] Modern pharmacological research has found that tortoise shell can restore the growth of an atrophied thymus, increase the lymphocyte transformation rate, increase the IgG content in serum, and enhance cellular and humoral immune functions.

[0045] (6) Phellodendron chinense

[0046] Modern pharmacological research has found that the extract of Phellodendron can promote the synthesis of liver glycogen, regulate the sugar content in the blood, and achieve the purpose of lowering blood sugar. The active ingredients in Phellodendron, mainly berberine, have a significant antihypertensive effect after being applied to experimental animals, dogs, and the effect lasts for a long time, up to about 2 hours, fully demonstrating that its antihypertensive effect is significant and has a good therapeutic effect. In addition, other studies have found that Phellodendron has the effects of inhibiting immune response, anti-oxidation, and reducing inflammatory damage.

[0047] (7) Amomum villosum

[0048] Modern pharmacological studies have found that Amomum villosum extract has significant analgesic and anti-inflammatory effects, and the main active ingredient is the volatile oil component in Amomum villosum. Amomum villosum water extract can effectively inhibit the production of ROS and other substances, further inhibiting the NF-κB pathway and thus reducing the inflammatory response; at the same time, it can also effectively inhibit the activation of MPO, making it impossible for caspase-3 to be expressed smoothly. In addition, studies have found that Amomum villosum also has certain antioxidant, hypoglycemic and anti-obesity effects.

[0049] (8) Angelica

[0050] Modern pharmacological studies have found that angelica volatile oil can inhibit the pathological intimal thickening of atherosclerotic spontaneously hypertensive rats, and can lower blood pressure and blood lipids. Angelica volatile oil has a protective effect on the myocardium of rats with myocardial injury caused by ischemia-reperfusion, can reduce myocardial injury and myocardial infarction area in rats, reduce inflammatory response, and reduce the expression levels of P-NF-κBP65 and P-IκBα proteins. Angelica volatile oil can also reduce the content of total cholesterol, triglycerides, free fatty acids, and free cholesterol in the liver, and reduce the content of blood lipids in serum and cholesterol in the liver; the expression of lipid metabolism proteins in the liver is increased.

[0051] (9) Tangerine peel

[0052] Modern pharmacological studies have found that tangerine peel and its extracts have the effect of regulating blood vessels. Nobiletin can inhibit PE-induced endothelial stripping rat aorta contraction by activating cGC and opening KATP channels through cGMP-independent pathways to increase intracellular cGMP content. Tangerine peel extracts and monomers hesperidin, naringenin, hesperidin and their derivatives can regulate blood vessels through platelet aggregation, anticoagulation and other pathways. Among them, hesperidin can inhibit arachidonic acid-induced serotonin secretion to achieve anti-platelet aggregation. Tangerine peel active ingredients hesperidin, nobiletin, baicalin, scutellariae tetramethyl ether, and sweet orange have anti-angiogenic effects.

[0053] (10) Cimicifuga

[0054] Modern pharmacological research has found that Cimicifuga can increase the activity of superoxide dismutase and reduce the content of NO to inhibit the effects of inflammatory factors. Cimicifuga inhibits pathological changes caused by inflammatory cells by regulating the expression of some genes in local tissues, thereby showing anti-inflammatory and anti-allergic effects.

[0055] (11) Bupleurum

[0056] The active ingredients of Bupleurum can protect the heart by regulating apoptosis signaling pathways and oxidative stress responses. Isorhamnetin can reduce the apoptosis rate of rat cardiomyocytes, improve cell viability, regulate the expression of cardiomyocyte autophagy and apoptosis pathways, and thus reduce myocardial damage. Isorhamnetin can also reduce reactive oxygen species, prevent myocardial hypertrophy and myocardial fibrosis. Quercetin has a protective effect on myocardial toxicity, and its mechanism of action may be related to inhibiting mitochondrial autophagy, reducing mitochondrial ROS production, and promoting ATP synthesis. Bupleurum saponin a can prevent and treat thrombus formation by inhibiting thrombin activity and inhibiting α1 adrenergic receptors, thereby reducing the generation of insoluble fibrin and vasodilation. It can also improve endothelial viability, inhibit endothelial cell oxidative stress and ferroptosis, and thus prevent and treat the occurrence and development of atherosclerosis.

[0057] The beneficial effects of a Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating weakness and disease attacks provided by the present invention are:

[0058] 1) It can replenish the vital energy of the heart and kidneys, suppress Yin fire, and prevent and treat exhaustion and debilitation. It is especially suitable for patients with chronic coronary syndrome and chronic heart failure who have insufficient vital energy and rising Yin fire.

[0059] 2) Prevent and treat frailty, improve quality of life, stabilize the condition, prevent and treat decompensation attacks, and delay disease progression. DETAILED DESCRIPTION

[0060] The beneficial effects of the Chinese medicine composition of the present invention are further illustrated below through clinical trial data and specific examples.

[0061] Example 1 Chronic Coronary Syndrome

[0062] 1. Diagnostic criteria

[0063] 1. TCM diagnostic criteria:

[0064] Formulated based on the relevant contents of the "Guidelines for Clinical Research of New Chinese Medicines".

[0065] Main symptoms: chest tightness or chest pain, aggravated by exertion;

[0066] Secondary symptoms: fatigue, shortness of breath, weakness, fear of cold, dry mouth, irritability, insomnia, dizziness, poor appetite and weight loss;

[0067] Tongue and pulse: pale tongue or red tongue with yellow coating, weak pulse, or thin and rapid pulse, or deep and thin pulse;

[0068] If the patient has one main symptom and any three or more secondary symptoms, and also refers to the tongue and pulse, he can be diagnosed as having insufficient vital energy and rising Yin fire.

[0069] (II) Western medicine diagnostic criteria:

[0070] It was formulated with reference to the "Guidelines for the Diagnosis and Management of Chronic Coronary Syndromes" issued by the European Society of Cardiology in 2019.

[0071] (1) Patients with suspected CAD and “stable” angina and / or dyspnea;

[0072] (2) Patients with new-onset heart failure (HF) or left ventricular (LV) dysfunction and suspected CAD;

[0073] (3) patients who were stable and asymptomatic or had symptoms within 1 year after ACS, or patients who had recent revascularization;

[0074] (4) Asymptomatic and symptomatic patients more than one year after initial diagnosis or revascularization;

[0075] (5) Patients with angina pectoris and suspected vasospasm or microvascular lesions;

[0076] (6) Asymptomatic patients with CAD detected during screening.

[0077] 2. Case selection criteria.

[0078] 1. Case inclusion criteria:

[0079] (1) Meet the above-mentioned Western medical diagnostic criteria;

[0080] (2) The TCM syndrome differentiation meets the diagnostic criteria of insufficient vital energy and rising Yin fire;

[0081] (3) Aged 40-80 years old, regardless of gender;

[0082] (4) Comorbidities (such as hypertension, diabetes, etc.) are controlled within the ideal range and remain stable;

[0083] (5) Patients who volunteer to participate in the study and give their informed consent.

[0084] (II) Case exclusion criteria:

[0085] (1) Those who do not meet the above inclusion criteria or have incomplete information;

[0086] (2) Patients with acute coronary syndrome or severe heart disease (acute heart failure, chronic heart failure, severe arrhythmia, aortic dissection or requiring emergency PCI, etc.);

[0087] (3) Pregnant or lactating women, people with allergies, and those who are allergic to multiple drugs;

[0088] (4) Patients with severe primary diseases of the liver, kidney, endocrine system, hematopoietic system, etc.;

[0089] (5) Those with mental disorders and unwilling to cooperate;

[0090] (6) Patients with factors that may increase mortality, such as cardiogenic shock, severe ventricular arrhythmias, complete atrioventricular block, obstructive cardiomyopathy, unrepaired valvular disease, constrictive pericarditis, cardiac tamponade, pulmonary embolism, obvious infection, and uncontrolled hypertension, should not be included.

[0091] (III) Case criteria for dropout, exclusion and termination of observation:

[0092] (1) Patients who experience severe adverse reactions or serious complications during the trial;

[0093] (2) Patients who voluntarily request to withdraw from the trial or fail to take medication as required;

[0094] (3) Patients who are unable to follow the study protocol and have poor compliance.

[0095] 3. Research content and methods.

[0096] 1. Grouping method:

[0097] Patients who met the inclusion criteria were randomly divided into a control group and an experimental group.

[0098] (II) Treatment methods:

[0099] 1. Control group:

[0100] (1) General treatment:

[0101] 1) Eliminate the predisposing factors, such as infection, severe arrhythmia, electrolyte imbalance, pulmonary infarction and improper use of drugs; 2) Actively control underlying cardiovascular diseases; 3) Eat a low-salt, low-fat diet, quit smoking and limit alcohol consumption, etc.; 4) Keep a good mood and reduce various mental stimulations.

[0102] (2) Drug treatment:

[0103] 1) Antiplatelet drugs: Enteric-coated aspirin tablets (National Medicine Standard HJ20160685, Bayer HealthCareManufacturing Srl), 100 mg, once a day. 2) Lipid-lowering drugs: Rosuvastatin calcium tablets (National Medicine Standard HJ20160545, IPR Pharmaceuticals, INCORPORATED), 10 mg, once a day. 3) Beta-blockers: Metoprolol succinate sustained-release tablets (National Medicine Standard J20150044, AstraZeneca AB), 47.5 mg, once a day. 4) Coronary dilation drugs: Isosorbide mononitrate sustained-release tablets (National Medicine Standard H20030417, National Medicine Standard H20030417), 30 mg, once a day.

[0104] 2 Treatment groups:

[0105] The composition of the present invention was additionally used on the basis of the treatment of the control group.

[0106] The Chinese medicine composition of the present invention comprises: 24g of astragalus, 12g of ginseng, 15g of atractylodes, 12g of aconite (pre-decocted), 21g of phellodendron, 15g of amomum, 6g of tortoise shell, 9g of angelica, 9g of tangerine peel, 9g of cimicifuga, 9g of bupleurum and 15g of roasted liquorice.

[0107] The above Chinese medicines are all from the Chinese medicine pharmacy of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine.

[0108] Decoction method: For each dose of medicine, weigh the raw materials by weight, soak in warm water for 180-360 minutes, add water to cover the medicine by about 1-2 cm, decoct the aconite for 40 minutes first, and then decoct it twice with other raw materials, about 60 minutes after the first decoction and about 60 minutes after the second decoction, combine the two decoctions to a total of 400mL, take warm 2 hours after breakfast and dinner, 200mL each time, one dose per day.

[0109] Treatment course: Both groups were treated with medication for 4 weeks.

[0110] 3. Efficacy evaluation indicators:

[0111] (1) Angina symptom score:

[0112] The angina symptom score is formulated according to the "Angina Symptom Score Quantification Standard" and is divided into four items: number of attacks, duration, pain intensity and nitroglycerin dosage. Each item is scored as 0, 2, 4 and 6. Finally, the score of each item is added together to obtain the patient's angina symptom score. The higher the score, the more obvious the patient's angina symptoms, the greater the impact of angina on daily life, and the lower the quality of life.

[0113] (2) Electrocardiogram indicators:

[0114] The evaluation standard of electrocardiogram efficacy is based on the "Coronary Heart Disease Angina and Electrocardiogram Efficacy Standards", and the reference standards are as follows:

[0115] ① Significantly effective: After treatment, the electrocardiogram returns to “roughly normal” or reaches “normal range”;

[0116] ② Effective: After treatment, the ST segment depression of the electrocardiogram rebounds by more than 0.05mV, the inverted T wave becomes shallower by more than 25% or the flat T wave becomes upright, and the atrioventricular conduction block improves;

[0117] ③ Ineffective: no significant changes in the electrocardiogram after treatment;

[0118] ④ Worsening: After treatment, the ST segment drops by more than 0.05mV, the inverted T wave deepens by more than 25%, or the originally upright T wave becomes flat, or the originally flat T wave becomes inverted, or arrhythmia or atrioventricular block occurs.

[0119] (3) TCM syndrome score:

[0120] The TCM syndrome scoring refers to the "Guidelines for Clinical Research of New Chinese Medicines". The main symptoms are scored as severe (6 points), moderate (4 points), mild (2 points), and none (0 points). The secondary symptoms are scored as severe (3 points), moderate (2 points), mild (1 point), and none (0 points). The higher the score, the more severe the symptom.

[0121] (4) Criteria for determining the efficacy of TCM symptoms:

[0122] Refer to the heart failure scoring method in the "Guidelines for Clinical Research of New Chinese Medicines" to determine the efficacy of TCM symptoms: efficacy index (N) = (pre-treatment score - post-treatment score) / pre-treatment score * 100%.

[0123] Markedly effective: clinical symptoms and signs disappeared or improved significantly, N ≥ 70%;

[0124] Effective: clinical symptoms and signs have improved, 30%≤N<70%;

[0125] Ineffective: clinical symptoms and signs have no significant improvement, or even worsen, N < 30%;

[0126] Aggravation: The original symptoms worsen after treatment, and the total score increases by more than 10% compared with before treatment.

[0127] (5) Seattle Angina Scale evaluation:

[0128] The Seattle Angina Scale has a total of 19 questions, including five dimensions: degree of limitation of physical activity, stable state of angina, angina attack, satisfaction with treatment, and degree of disease awareness. For the five major items and 19 small questions, score each item starting from 1 (indicating the score corresponding to the lowest level of function), and each score is positively processed, and then the score is converted into a standard score. The standard score is calculated by subtracting the lowest score of each major item from the actual score of the major item, then divided by the difference between the possible highest score and the lowest score of the major item, and finally multiplied by 100. Since the five major items represent five different dimensions of the disease, there is no comparability and need for summation between each major item, so each major item has a standard score, but there is no total score for the entire table.

[0129] (6) Edmonton Frailty Scale evaluation:

[0130] The Edmonton Frailty Scale was used to assess the frailty status of patients with chronic coronary syndrome, with a score of 0-18, 0-5 for no frailty; 6-7 for frailty; 8-9 for mild frailty; 10-11 for moderate frailty; and 12-18 for severe frailty.

[0131] 4. Statistical methods:

[0132] SPSS 25.0 statistical software was used for analysis and processing, and the measurement data were expressed as mean ± standard deviation. If the data conform to normal distribution and the variance is equal, the t test is used. If the data are not normally distributed, the rank sum test is used. The rank sum test is used for rank data and the x test is used for count data. 2 P < 0.05 was considered to be significantly different, and P < 0.01 was considered to be very significantly different.

[0133] 4. Efficacy analysis.

[0134] 1. General information:

[0135] After the trial, a total of 80 cases had complete data, including 40 cases in the experimental group and 40 cases in the control group. There was no significant difference in gender and age distribution between the two groups (see Table 1 and Table 2).

[0136] Table 1 Gender distribution of patients in the two groups

[0137]

[0138] As shown in Table 1, there was no statistically significant difference in gender distribution between the control group and the experimental group (P>0.05), and the baselines were comparable.

[0139] Table 2 Age distribution of patients in the two groups

[0140]

[0141] As shown in Table 2, there was no statistically significant difference in age distribution between the control group and the experimental group (P>0.05), and the baselines were comparable.

[0142] 2. Efficacy analysis

[0143] 1. Comparison of efficacy of angina pectoris:

[0144] As shown in Table 3, there was no significant difference in the angina pectoris symptom scores between the experimental group and the control group before treatment (P>0.05), which showed comparability; there was a significant difference in the angina pectoris symptom scores between the experimental group and the control group before and after treatment (P<0.01); there was a significant difference in the angina pectoris symptom scores between the experimental group and the control group after treatment (P<0.01).

[0145] This shows that the therapeutic effect of angina pectoris in the experimental group is better than that in the control group.

[0146] Table 3 Comparison of angina pectoris symptom scores between the two groups before and after treatment

[0147]

[0148] Comparison between the two groups before treatment: # P>0.05; Comparison between the two groups after treatment: △ P<0.05, △△ P<0.01; Comparison of each group before and after treatment: * P<0.05, ** P<0.01.

[0149] 2. Comparison of the efficacy of electrocardiogram between the two groups:

[0150] The ECG efficacy of the two groups is shown in Table 4. It can be seen that the total effective rate of the control group and the experimental group was 20% and 42.5% respectively. 2 Inspection, X 2 =4.71, P=0.03. The difference in electrocardiogram efficacy between the two groups was statistically significant (P<0.05).

[0151] This shows that the electrocardiogram efficacy of the experimental group is better than that of the control group.

[0152] Table 4 Comparison of the efficacy of electrocardiogram between the two groups of patients before and after treatment (%)

[0153]

[0154] 3. Comparison of TCM symptom efficacy between the two groups:

[0155] The TCM symptom scores of the two groups are shown in Table 5. It can be seen that there was no significant difference in the TCM symptom scores between the control group and the experimental group before treatment (P>0.05), and they were comparable; there were significant differences in the TCM symptom scores before and after treatment in the experimental group (P<0.01). Except for insomnia, dizziness, poor appetite and weight loss in the control group, there were significant differences in the TCM symptom scores before and after treatment (P<0.01); there were significant differences in the TCM symptom scores between the experimental group and the control group after treatment (P<0.05).

[0156] Table 5 Comparison of TCM symptom scores between the two groups of patients before and after treatment

[0157]

[0158] Comparison between the two groups before treatment: # P>0.05; Comparison between the two groups after treatment: △ P<0.05, △△ P<0.01; Comparison of each group before and after treatment: * P<0.05, ** P<0.01.

[0159] The efficacy of TCM symptoms in the two groups is shown in Table 6. It can be seen that the total effective rates of the control group and the experimental group were 65% and 92.5% respectively. 2 Test, P < 0.01, the difference in the efficacy of TCM symptom score between the two groups was statistically significant.

[0160] This shows that the efficacy of TCM in the experimental group is better than that in the control group.

[0161] Table 6 Comparison of the efficacy of TCM symptom scores between the two groups of patients before and after treatment (%)

[0162]

[0163] 4. Comparison of the efficacy of the Seattle Angina Scale between the two groups:

[0164] The Seattle Angina Scale scores of the two groups are shown in Table 7. It can be seen that there was no statistically significant difference in the Seattle Angina Scale scores of the two groups before treatment (P>0.05). The Seattle Angina Scale scores of the experimental group and the control group before and after treatment were compared, and the differences in all dimensions were statistically significant (P<0.05). The Seattle Angina Scale scores of the experimental group and the control group after treatment showed statistically significant differences in the degree of limitation of physical activity PL, stable state of angina AS, angina attack AF, and treatment satisfaction T (P<0.05), but there was no statistically significant difference in the degree of disease awareness DP (P>0.05).

[0165] This indicates that the Seattle Angina Scale efficacy of the experimental group is better than that of the control group.

[0166] Table 7 Comparison of Seattle Angina Scale scores between the two groups before and after treatment

[0167]

[0168] Comparison between the two groups before treatment: # P>0.05; Comparison between the two groups after treatment: △ P<0.05, △△ P<0.01; Comparison of each group before and after treatment: * P<0.05, ** P<0.01.

[0169] 5. Comparison of the efficacy of the two groups in terms of asthenia:

[0170] The frailty scale scores of the two groups are shown in Table 8. It can be seen that there was no statistically significant difference in the frailty scale scores between the two groups before treatment (P>0.05). There was a statistically significant difference in the frailty scale scores between the experimental group and the control group before and after treatment, and the difference in the experimental group was more obvious. There was a statistically significant difference in the frailty scores between the two groups after treatment (P<0.01).

[0171] This shows that the therapeutic effect of the experimental group on asthenia is better than that of the control group.

[0172] Table 8 Comparison of Edmonton Frailty Scale scores between the two groups before and after treatment

[0173]

[0174] Comparison between the two groups before treatment: # P>0.05; Comparison between the two groups after treatment: △ P<0.05, △△ P<0.01; Comparison of each group before and after treatment:* P<0.05, ** P<0.01.

[0175] From the above data, it can be seen that the Chinese medicine composition of the present invention can effectively relieve the patient's angina symptoms, improve the patient's traditional Chinese medicine symptoms, improve the electrocardiogram indicators, and reduce the Seattle Angina Scale score. At the same time, it can also improve the patient's frail state, reduce the frailty scale score, improve the patient's quality of life, and reduce the occurrence of adverse cardiovascular events.

[0176] Example 2 Chronic heart failure

[0177] Patients with chronic heart failure were selected and divided into an experimental group and a control group. On the basis of conventional western medicine treatment, the experimental group was treated with the Chinese medicine composition of the present invention, and the control group was treated with Qili Qiangxin Capsule. The treatment effect was followed up clinically and the results were compared. After the trial, a total of 60 patients were included in the trial, including 30 in the control group and 30 in the experimental group.

[0178] 1. Diagnostic criteria

[0179] 1. TCM diagnostic criteria:

[0180] Based on the "Guidelines for Clinical Research of New Chinese Medicines for the Treatment of Heart Failure - Traditional Chinese Medicine Symptom Diagnostic Standards" in the "Guidelines for Clinical Technical Research of New Chinese Medicines".

[0181] Taking the "National Standard of TCM Clinical Diagnosis and Treatment Terminology - Syndrome Part" as the main dialectical outline, referring to the "Chinese Medicine Diagnosis" textbook (edited by Zhu Wenfeng), and taking into account the clinical incidence of chronic heart failure, the TCM diagnostic standards for the syndromes of deficiency of vital energy and rising of yin fire were formulated.

[0182] Main symptoms: chest tightness, shortness of breath, weakness, fear of cold, sweating;

[0183] Secondary symptoms: irritability, dry mouth, poor appetite, weight loss, insomnia and dizziness;

[0184] Tongue and pulse: pale tongue with white coating or red tongue with yellow coating, weak pulse, or thin and rapid pulse, or deep and thin pulse.

[0185] If the patient has three main symptoms and any two or more secondary symptoms, and also refers to the tongue and pulse, the patient can be diagnosed as having the Ying-Wei imbalance type.

[0186] (II) Western medicine diagnostic criteria:

[0187] Table 9 refers to Framingham's diagnostic criteria for heart failure, as follows:

[0188]

[0189] The diagnosis can be confirmed by the presence of two major criteria, or one major criterion and two minor criteria.

[0190] (III) Cardiac function classification standards:

[0191] The NYHA classification of cardiac function refers to the 1928 standard of the New York Heart Association (NYHA) of the United States.

[0192] Table 10 New York Heart Association cardiac function classification standards (NYHA classification)

[0193]

[0194] 2. Case selection criteria.

[0195] 1. Case inclusion criteria:

[0196] (1) Patients with mild to moderate heart failure who meet the diagnostic criteria for chronic heart failure and whose heart function is graded as II or III (NYHA classification);

[0197] (2) Age 45 to 75 years old;

[0198] (3) Comorbidities (such as hypertension, coronary heart disease, cardiomyopathy, diabetes, etc.) are controlled within the ideal range and maintained stable;

[0199] (4) The TCM syndrome differentiation meets the diagnostic criteria of insufficient vital energy and rising Yin fire;

[0200] (5) Patients who volunteer to participate in the study and give their informed consent.

[0201] (II) Case exclusion criteria:

[0202] (1) Those who do not meet the above inclusion criteria or have incomplete information;

[0203] (2) Patients aged <45 years or >75 years;

[0204] (3) Patients with severe heart failure and heart function level IV;

[0205] (4) Patients with heart failure due to failure of important organs such as liver and kidney;

[0206] (5) Pregnant or lactating women, people with allergies, and those who are allergic to multiple drugs;

[0207] (6) Patients with severe primary diseases of the liver, kidney, endocrine system, hematopoietic system, etc.;

[0208] (7) Those with mental disorders and unwilling to cooperate;

[0209] (8) Patients with factors that may increase mortality, such as cardiogenic shock, severe ventricular arrhythmias, complete atrioventricular block, obstructive cardiomyopathy, unrepaired valvular disease, constrictive pericarditis, cardiac tamponade, pulmonary embolism, obvious infection, and uncontrolled hypertension, should not be included.

[0210] (III) Case criteria for dropout, exclusion and termination of observation:

[0211] (1) Patients who experience severe adverse reactions or serious complications during the trial;

[0212] (2) Patients who voluntarily request to withdraw from the trial or fail to take medication as required;

[0213] (3) Patients who are unable to follow the study protocol and have poor compliance.

[0214] 3. Research content and methods.

[0215] 1. Grouping method:

[0216] Chronic heart failure patients who met the inclusion criteria were randomly divided into a control group and an experimental group. After the trial, a total of 60 cases were enrolled, with 30 cases in each group.

[0217] (II) Treatment methods:

[0218] Refer to the methods and principles recommended in my country's 2018 "Guidelines for the Diagnosis and Treatment of Heart Failure in China".

[0219] (1) General treatment:

[0220] 1) Eliminate predisposing factors, such as infection, severe arrhythmia, electrolyte imbalance, pulmonary infarction and improper use of drugs; 2) Actively control underlying cardiovascular diseases; 3) Limit sodium intake (<3g / d). For patients with acute heart failure accompanied by volume overload, limit sodium intake to <2g / d, limit fluid intake, eat a low-fat diet, quit smoking, etc.; 4) Keep a good mood and reduce various mental stimulations;

[0221] (2) Drug treatment:

[0222] 1) ARNI drug: Sacubitril-valsartan sodium tablets (registration standard for imported drugs JX20160017, NovartisSingapore Pharmaceutical Manufacturing Private Ltd), 100 mg, twice a day. If the patient tolerates it, the dose will be gradually increased to the target dose.

[0223] 2) β-blockers: Metoprolol succinate tablets (National Medicine Standard H32025391, AstraZeneca Limited), 6.25-12.5 mg, once a day, starting with a low dose. If the patient tolerates it, the dose can be doubled in 2-4 weeks and gradually increased to the target dose;

[0224] 3) Diuretics: Hydrochlorothiazide tablets (National Medicine Standard H37020788, Shandong Renhetang Pharmaceutical Co., Ltd.), 25 mg, once a day. Adjust the dose according to the fluid retention. Once the condition is under control, the minimum effective dose can be used for a long time. If the edema symptoms cannot be improved or worsen, furosemide 20 mg, once a day, can be used instead, and the dose can be adjusted at any time according to the condition;

[0225] 4) ARB drugs: Valsartan (National Medicine Approval No. H20010217, Beijing Novartis Pharmaceuticals Co., Ltd.), 80 mg, once / day.

[0226] When the above four drugs are used in combination, attention should be paid to changes in blood pressure and heart rate. If symptoms of systolic heart failure persist, digoxin tablets (digitalis preparation, national medicine standard number: H3102067, produced by Shanghai Xinyi Pharmaceutical Factory Co., Ltd.) can be added, 0.125-0.25 mg, once a day, and the dose can be adjusted according to the condition.

[0227] Control group: In addition to conventional western medicine treatment, patients were treated with Qili Qiangxin Capsule (National Medicine Standard No. Z20040141, Shijiazhuang Yiling Pharmaceutical Co., Ltd.), 1.2 g, 3 times / day.

[0228] Experimental group: On the basis of conventional western medicine treatment, the Chinese medicine composition of the present invention was taken.

[0229] The Chinese medicine composition of the present invention comprises: 24g of astragalus, 12g of ginseng, 15g of atractylodes, 9g of angelica, 9g of tangerine peel, 9g of cimicifuga, 9g of bupleurum, 15g of amomum, 12g of aconite (pre-decocted), 6g of tortoise shell, 21g of phellodendron and 15g of roasted liquorice.

[0230] The above Chinese medicines are all from the Chinese medicine pharmacy of the Affiliated Hospital of Shandong University of Traditional Chinese Medicine.

[0231] Decoction method: For each dose of medicine, weigh the raw materials by weight, soak in warm water for 180-360 minutes, add water to cover the medicine by about 1-2 cm, decoct the aconite for 40 minutes first, and then decoct it twice with other raw materials, about 60 minutes after the first decoction and about 60 minutes after the second decoction, combine the two decoctions to a total of 400mL, take warm 2 hours after breakfast and dinner, 200mL each time, one dose per day.

[0232] Treatment course: Both groups were treated with medication for 4 weeks.

[0233] 3. Observation indicators:

[0234] (1) Echocardiography: to detect changes in left ventricular ejection fraction (LVEF) before and after treatment;

[0235] (2) Detect the changes in serum amino-terminal pro-brain natriuretic peptide (NT-proBNP) before and after treatment to evaluate the condition of heart failure;

[0236] (3) TCM syndrome score: TCM syndrome score refers to the Guiding Principles for Clinical Research of New Chinese Medicines. The main symptoms are scored as severe (6 points), moderate (4 points), mild (2 points), and none (0 points). The secondary symptoms are scored as severe (3 points), moderate (2 points), mild (1 point), and none (0 points). The higher the score, the more serious the symptom.

[0237] (4) Criteria for determining the efficacy of TCM symptoms:

[0238] Refer to the heart failure scoring method in the "Guidelines for Clinical Research of New Chinese Medicines" to determine the efficacy of TCM symptoms: efficacy index (N) = (pre-treatment score - post-treatment score) / pre-treatment score * 100%.

[0239] Markedly effective: clinical symptoms and signs disappeared or improved significantly, N ≥ 70%;

[0240] Effective: clinical symptoms and signs have improved, 30%≤N<70%;

[0241] Ineffective: clinical symptoms and signs have no significant improvement, or even worsen, N < 30%;

[0242] Aggravation: The original symptoms worsen after treatment, and the total score increases by more than 10% compared with before treatment.

[0243] (5) Lee's heart failure score:

[0244] The scoring system developed by Lee (N. Engl. J. Med 1982; 306, 699) in 1982 based on clinical and X-ray changes was used.

[0245] Heart failure symptom classification standard:

[0246] Mild: heart failure symptom score <6 points;

[0247] Moderate: heart failure symptom score 6 to 12 points;

[0248] Severe: Heart failure symptom score ≥ 12 points.

[0249] (6) CFS score: The CFS scale is used to assess the patient's frailty status. The score ranges from 1 to 9, with 1 representing the best status and 9 representing the terminal status. The higher the score, the more severe the patient's frailty.

[0250] 4. Statistical methods:

[0251] SPSS 25.0 statistical software was used for analysis and processing, and the measurement data were expressed as mean ± standard deviation. If the data conform to normal distribution and the variance is equal, the t test is used. If the data are not normally distributed, the rank sum test is used. The rank sum test is used for rank data and the x test is used for count data. 2 P < 0.05 was considered to be significantly different, and P < 0.01 was considered to be very significantly different.

[0252] 4. Efficacy analysis.

[0253] 1. General information:

[0254] After the trial, there were 60 cases with complete data, including 30 cases in the experimental group and 30 cases in the control group; the specific distribution is shown in Table 11-12.

[0255] Table 11 Gender distribution of patients in the two groups

[0256]

[0257] As shown in Table 11, there was no statistically significant difference in gender distribution between the control group and the experimental group (P>0.05), and the baselines were comparable.

[0258] Table 12 Age distribution of patients in the two groups

[0259]

[0260] As shown in Table 12, there was no statistically significant difference in age distribution between the control group and the experimental group (P>0.05), and the baselines were comparable.

[0261] 2. Efficacy evaluation:

[0262] 1. Comparison of ejection fraction between the two groups:

[0263] As can be seen from Table 13, there was no significant difference in ejection fraction between the experimental group and the control group before treatment (P>0.05), which showed comparability; there was a significant difference in ejection fraction between the experimental group and the control group before and after treatment (P<0.01); there was a significant difference in ejection fraction between the experimental group and the control group after treatment (P<0.05).

[0264] This indicates that the improvement of ejection fraction in the experimental group is better than that in the control group.

[0265] Table 13 Comparison of left ventricular ejection fraction (LVEF) between the two groups before and after treatment

[0266]

[0267] Table 13 Comparison between the two groups before treatment: # P>0.05; Comparison of each group before and after treatment: ** P<0.01; Comparison between the two groups after treatment: △ P<0.05.

[0268] 2. Comparison of NT-proBNP between the two groups:

[0269] As can be seen from Table 14, there was no significant difference in NT-proBNP between the experimental group and the control group before treatment (P>0.05), which showed comparability; there was a significant difference in NT-proBNP between the experimental group and the control group before and after treatment (P<0.01); there was a significant difference in NT-proBNP between the experimental group and the control group after treatment (P<0.01).

[0270] This indicates that the decrease in NT-proBNP in the experimental group was greater than that in the control group.

[0271] Table 14 Comparison of NT-proBNP between the two groups of patients before and after treatment

[0272]

[0273] Table 14 Comparison between the two groups before treatment: # P>0.05; Comparison of each group before and after treatment: ** P<0.01; Comparison between the two groups after treatment: △△ P<0.01.

[0274] 3. Comparison of TCM symptom efficacy between the two groups:

[0275] As shown in Table 15, there was no significant difference in the scores of the main TCM symptoms between the two groups before treatment (P>0.05), which was comparable. There were significant differences in the scores of the main TCM symptoms between the two groups before and after treatment (P<0.01); there were significant differences in the scores of the main TCM symptoms between the two groups after treatment (P<0.05), among which the differences in chest tightness, shortness of breath, weakness, and fear of cold were more significant (P<0.01).

[0276] Table 15 Comparison of the main TCM symptom scores of the two groups of patients before and after treatment

[0277]

[0278] Table 15 Comparison between the two groups before treatment: # P>0.05; Comparison of each group before and after treatment: ** P<0.01; Comparison between the two groups after treatment: △△ P<0.01.

[0279] As shown in Table 16, there was no significant difference in the scores of minor TCM symptoms between the two groups before treatment (P>0.05), which was comparable. There were significant differences in the scores of major TCM symptoms before and after treatment in the experimental group (P<0.01); there were significant differences in the scores of major TCM symptoms before and after treatment in the control group (P<0.05), but no significant differences in insomnia and dizziness (P>0.05); there were significant differences in the scores of minor TCM symptoms between the two groups after treatment (P<0.05), among which the difference in the scores of major TCM symptoms before and after treatment was more obvious (P<0.01).

[0280] Table 16 Comparison of minor TCM symptom scores between the two groups of patients before and after treatment

[0281]

[0282] Table 16 Comparison between the two groups before treatment: # P>0.05; Comparison of each group before and after treatment: * P<0.05, ** P<0.01; Comparison between the two groups after treatment: △ P<0.05, △△ P<0.01.

[0283] As shown in Table 17, the total effective rates of the control group and the experimental group were 66.7% and 90% respectively. 2 Inspection, X 2 =4.81, P=0.028. The difference in the efficacy of TCM symptom scores between the two groups was statistically significant (P<0.05).

[0284] This shows that the TCM symptom efficacy of the experimental group is better than that of the control group.

[0285] Table 17 Comparison of the efficacy of TCM symptom scores between the two groups of patients before and after treatment (%)

[0286]

[0287] 4. Comparison of Lee's heart failure scores between the two groups:

[0288] As can be seen from Table 18, there was no significant difference in Lee's heart failure scores between the experimental group and the control group before treatment (P>0.05), which showed comparability; there was a significant difference in Lee's heart failure scores between the experimental group and the control group before and after treatment (P<0.01); there was a significant difference in Lee's heart failure scores between the experimental group and the control group after treatment (P<0.01).

[0289] This indicates that the Lee's heart failure score in the experimental group decreased more than that in the control group.

[0290] Table 18 Comparison of Lee's heart failure scores between the two groups of patients before and after treatment

[0291]

[0292] Table 18 Comparison between the two groups before treatment: # P>0.05; Comparison of each group before and after treatment: * P<0.05, ** P<0.01; Comparison between the two groups after treatment: △ P<0.05, △△ P<0.01.

[0293] 5. Comparison of weakness status between the two groups:

[0294] As shown in Table 19, there was no significant difference in the frailty scale scores between the two groups before treatment (P>0.05). There was a significant difference in the frailty scale scores between the experimental group and the control group before and after treatment (P<0.01). There was a significant difference in the frailty scores between the two groups after treatment (P<0.05).

[0295] This indicates that the improvement of frailty in the experimental group was better than that in the control group.

[0296] Table 19 Comparison of frailty scale scores between the two groups of patients before and after treatment

[0297]

[0298] Comparison between the two groups before treatment: # P>0.05; Comparison between the two groups after treatment: △ P<0.05, △△ P<0.01; Comparison of each group before and after treatment: * P<0.05, ** P<0.01.

[0299] It can be seen from the above statistical data that the Chinese medicine composition of the present invention can alleviate the patient's clinical symptoms, reduce Lee's heart failure score, reduce the NT-proBNP value, increase the ejection fraction, improve cardiac function, improve the patient's weak state, improve the quality of life, and reduce the occurrence of adverse cardiovascular events.

[0300] The following is a typical case and a preferred formula to specifically illustrate the Chinese medicine composition of the present invention.

[0301] Typical Case 1

[0302] Mr. Liu, male, 76 years old.

[0303] First visit on April 8, 2023: The patient had paroxysmal chest tightness and chest pain for more than 8 years, which worsened for one month. The patient had chest tightness and chest pain without obvious cause 8 years ago, and it occurred occasionally, and no systematic diagnosis and treatment was given. In January 2022, chest tightness and chest pain occurred more frequently than before. Coronary CT showed moderate stenosis of the left anterior descending branch and circumflex branch. He was diagnosed with coronary atherosclerotic heart disease and treated with aspirin, rosuvastatin, isosorbide mononitrate, and metoprolol sustained-release tablets, and the symptoms were relieved compared with before. One month ago, the symptoms were suspected to be aggravated by fatigue. Now I come to see a doctor for traditional Chinese medicine treatment. Current symptoms: paroxysmal chest tightness and chest pain, easy to occur after fatigue, dull pain in the front chest, palpitations, fatigue and shortness of breath, fear of cold, sweating, dry mouth and bitter mouth, appetite, poor sleep, and regular bowel movements. The tongue is pale with thin white fur and a deep and fine pulse. Electrocardiogram shows: 1. Sinus rhythm; 2. ST-T changes. Angina symptom score: 14 points, limitation of body movement in Seattle Angina Scale: 44 points, stable angina: 25 points, angina attack: 30 points, treatment satisfaction: 38 points, disease awareness: 42 points. Edmonton Frailty Scale score: 10 points. TCM diagnosis: chest pain (lack of vital energy, Yin fire rising); Western medicine diagnosis: 1. Coronary atherosclerotic heart disease.

[0304] The treatment is based on the principle of replenishing vital energy and subduing yin fire. The Chinese medicine complex of the present invention is added or subtracted, and its proportion by weight is: 24g of Astragalus, 12g of Ginseng, 15g of Atractylodes, 9g of Angelica, 9g of Tangerine Peel, 9g of Cimicifuga, 9g of Bupleurum, 15g of Amomum, 12g of Aconite (pre-decocted), 6g of Tortoise Shell, 21g of Phellodendron, and 15g of Radix Glycyrrhizae Preparata.

[0305] Decoction, one dose per day, taken twice a day, warm in the morning and evening, for 14 days.

[0306] Second visit on April 23, 2023: The patient's chest tightness and chest pain were alleviated compared to before, physical strength was improved compared to before, palpitations were alleviated, shortness of breath was alleviated, fear of cold was slightly alleviated, dry mouth and bitter taste were alleviated, appetite was good, sleep was good, and bowel movements were regular.

[0307] In treatment, add 12g of cinnamon twig and 3g of asarum to the above formula, and take 14 doses.

[0308] Third visit on May 9, 2023: The patient occasionally had chest tightness and chest pain, his physical strength improved significantly, his shortness of breath was reduced, his palpitations improved, his fear of cold improved, his mouth was slightly dry and bitter, his appetite was good, his sleep improved, and his bowel movements were normal. The angina symptom score was 6 points, the degree of limitation of physical activity in the Seattle Angina Scale was 64 points, the stable state of angina was 100 points, the attack of angina was 80 points, the satisfaction with treatment was 63 points, and the degree of awareness of the disease was 67 points. The Edmonton Frailty Scale score was 6 points.

[0309] Remove cinnamon twig and asarum from the above prescription and add 9g of Morinda officinalis and 12g of Cuscuta australis. Continue to take 14 doses.

[0310] Typical Case 2

[0311] Mr. Liu, male, 49 years old.

[0312] First visit on August 24, 2023: The patient had chest tightness and shortness of breath for more than one month. The patient had sudden chest tightness and chest pain without obvious cause one month ago, and went to a local hospital for treatment. The electrocardiogram showed: ST segment arch-like elevation in leads II, III, and avF, and frequent premature atrial contractions. Diagnosed with acute coronary syndrome, no coronary angiography. Cardiac ultrasound showed: segmental ventricular wall dyskinesis, mild mitral regurgitation, mild tricuspid regurgitation, decreased left ventricular systolic function, EF: 44%. NT-proBNP: 2889ng / L. Current symptoms: chest tightness and shortness of breath, aggravated by fatigue, awakening at night, chest pain, no palpitations, fatigue and shortness of breath, fear of cold, dry and bitter mouth, good appetite, poor sleep, difficulty falling asleep, shallow sleep and easy awakening, and regular bowel movements. The tongue is pale red, the fur is thin and white, and the pulse is deep and thin. Lee's heart failure score is 13 points, and the frailty scale score is 6 points. Traditional Chinese medicine diagnosis: heart failure (insufficient vital energy, rising of Yin fire); Western medicine diagnosis: 1. Heart failure, 2. Acute coronary syndrome.

[0313] The treatment is based on the principle of replenishing vital energy and subduing yin fire. The Chinese medicine complex of the present invention is added or subtracted, and its proportion by weight is: 24g of Astragalus, 12g of Ginseng, 15g of Atractylodes, 9g of Angelica, 9g of Tangerine Peel, 9g of Cimicifuga, 9g of Bupleurum, 15g of Amomum, 12g of Aconite (pre-decocted), 6g of Tortoise Shell, 21g of Phellodendron, and 15g of Radix Glycyrrhizae Preparata.

[0314] Decoction, one dose per day, taken twice a day, warm in the morning and evening, for 14 days.

[0315] Second visit on September 8, 2023: The patient's chest tightness and wheezing were alleviated compared to before, the number of night awakenings decreased, fatigue improved slightly, fear of cold, dry and bitter mouth, good appetite, poor sleep, and regular bowel movements.

[0316] Add 9g of Morinda officinalis and 12g of Cuscuta australis to the above formula and take 14 doses.

[0317] Third visit on September 23, 2023: The patient's chest tightness and wheezing have improved significantly compared with before, and the nighttime waking has basically disappeared, physical strength has improved, fear of cold has eased, dry mouth and bitter taste have eased, appetite is good, sleep is normal, and bowel movements are normal. Cardiac ultrasound showed: segmental ventricular wall dyskinesis, mild mitral regurgitation, mild tricuspid regurgitation, EF: 52%. NT-proBNP: 985ng / L. Lee's heart failure score is 8 points, and the frailty scale score is 2 points.

[0318] Add 12g of Cornus officinalis in wine to the above formula and take 14 doses.

[0319] Typical Case 3

[0320] Chen, male, 60 years old.

[0321] First visit on September 7, 2023: The patient had chest tightness and shortness of breath for more than 3 years, which worsened for 1 week, and had a history of myocardial infarction. The patient had chest tightness and shortness of breath without obvious cause 3 months ago. He went to the local hospital and was diagnosed with heart failure. After receiving relevant treatment, he improved and was discharged from the hospital. Later, the patient was prone to repeated attacks of chest tightness after fatigue. In the past week, the chest tightness and shortness of breath were aggravated by fatigue, so he came to our clinic for treatment. Current symptoms: chest tightness, shortness of breath, aggravated after fatigue, waking up at night, palpitations, fatigue and shortness of breath, sweating, fear of cold, cold lower limbs, dry and bitter mouth, poor appetite, no appetite, poor sleep, difficulty falling asleep, shallow sleep and easy to wake up, and regular bowel movements. The tongue is pale red, the fur is thin and white, and the pulse is deep and thin. Lee's heart failure score is 12 points, and the frailty scale score is 5 points. Cardiac ultrasound shows: segmental ventricular wall dyskinesis, mild tricuspid valve regurgitation, decreased left ventricular systolic function, EF: 37%. NT-proBNP: 2507ng / L. TCM diagnosis: heart failure (lack of vital energy, rising of Yin fire); Western medicine diagnosis: 1. Decompensated chronic heart failure.

[0322] The treatment is based on the principle of replenishing vital energy and subduing yin fire. The Chinese medicine complex of the present invention is added or subtracted, and its proportion by weight is: 24g of Astragalus, 12g of Ginseng, 15g of Atractylodes, 9g of Angelica, 9g of Tangerine Peel, 9g of Cimicifuga, 9g of Bupleurum, 15g of Amomum, 12g of Aconite (pre-decocted), 6g of Tortoise Shell, 21g of Phellodendron, and 15g of Radix Glycyrrhizae Preparata.

[0323] Decoction, one dose per day, taken twice a day, warm in the morning and evening, for 14 days.

[0324] Second visit on September 21, 2023: The patient's chest tightness and wheezing were alleviated compared with before, the nighttime waking was improved, palpitations were alleviated, shortness of breath was alleviated, fatigue was slightly improved, fear of cold, sweating was reduced compared with before, coldness of both lower limbs was improved, dry and bitter mouth, poor appetite, poor sleep, and normal bowel movements.

[0325] Add 12g of cinnamon twig and 3g of asarum to the above formula and take 14 doses.

[0326] Third visit on October 12, 2023: The patient’s chest tightness and wheezing were significantly relieved, the number of night awakenings decreased, fatigue improved, fear of cold improved, dry and bitter mouth, good appetite, poor sleep, and regular bowel movements.

[0327] Use the Chinese medicine of the present invention (24g of Astragalus, 12g of Ginseng, 15g of Atractylodes, 9g of Angelica, 9g of Tangerine Peel, 9g of Cimicifuga, 9g of Bupleurum, 15g of Amomum, 12g of Aconite (pre-decocted), 6g of Tortoise Shell, 21g of Phellodendron, 15g of Radix Glycyrrhizae Preparata), plus 9g of Cornus Fruit and 12g of Cuscuta Seed, to nourish kidney yin and kidney yang, and continue to take 14 doses.

[0328] Fourth visit on October 26, 2023: The patient's chest tightness and shortness of breath have improved significantly and have basically disappeared, palpitations have improved, physical strength has improved, fear of cold has eased, sweating has been normal, dry mouth and bitter taste have been reduced, appetite has been good, sleep is normal, and bowel movements are normal. Cardiac ultrasound showed: normal segmental ventricular wall motion, mild tricuspid regurgitation, EF: 53%. NT-proBNP: 872ng / L. Lee's heart failure score is 8 points, and the frailty scale score is 2 points.

[0329] The above three typical cases show that the Chinese medicine composition of the present invention can significantly improve the clinical symptoms of patients, improve the quality of life of patients, reduce the heart failure index, enhance the physical fitness of patients, improve the weak state of patients, and reduce the occurrence of adverse cardiovascular events.

Claims

1. A Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating the weakness thereof, characterized in that: It is composed of the following raw materials by weight: 20-30g of Astragalus, 10-15g of Ginseng, 15-30g of Atractylodes, 15-30g of Amomum, 3-12g of Tortoise Shell, 20-30g of Phellodendron, 6-12g of Angelica, 6-12g of Tangerine Peel, 6-12g of Cimicifuga, 6-12g of Bupleurum, 10-30g of Roasted Licorice, and 10-15g of Aconite Decoction.

2. The Chinese medicine composition according to claim 1, characterized in that: It is composed of the following raw materials by weight: 24g of Astragalus, 12g of Ginseng, 15g of Atractylodes, 12g of Aconite decocted first, 15g of Amomum villosum, 6g of Tortoise Shell, 21g of Phellodendron, 9g of Angelica sinensis, 9g of Tangerine Peel, 9g of Cimicifuga heracleifolia, 9g of Bupleurum, and 15g of Radix Glycyrrhizae Preparata.

3. A Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating the weakness thereof, characterized in that: It is composed of the following raw materials by weight: 20-30g of Astragalus, 10-15g of Ginseng, 15-30g of Atractylodes, 15-30g of Amomum, 3-12g of Tortoise Shell, 20-30g of Phellodendron, 6-12g of Angelica, 6-12g of Tangerine Peel, 6-12g of Cimicifuga, 6-12g of Bupleurum, 10-30g of Roasted Licorice, 10-15g of Aconite Decoction, and 6-15g of Cinnamon Twig.

4. A Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating the weakness thereof, characterized in that: It is composed of the following raw materials by weight: 20-30g of Astragalus, 10-15g of Ginseng, 15-30g of Atractylodes, 15-30g of Amomum, 3-12g of Tortoise Shell, 20-30g of Phellodendron, 6-12g of Angelica, 6-12g of Tangerine Peel, 6-12g of Cimicifuga, 6-12g of Bupleurum, 10-30g of Roasted Licorice, 10-15g of Pre-decocted Aconite, 6-15g of Cinnamon Twig, and 1-5g of Asarum.

5. A Chinese medicine composition for treating chronic coronary syndrome, chronic heart failure, and preventing and treating the weakness thereof, characterized in that: It is composed of the following raw materials by weight: 20-30g of Astragalus, 10-15g of Ginseng, 15-30g of Atractylodes, 15-30g of Amomum, 3-12g of Tortoise Shell, 20-30g of Phellodendron, 6-12g of Angelica, 6-12g of Tangerine Peel, 6-12g of Cimicifuga, 6-12g of Bupleurum, 10-30g of Roasted Licorice, 10-15g of Aconite Decoction, 6-18g of Cornus Fruit, and 6-15g of Cuscuta Seed.

6. A method for preparing the Chinese medicine composition according to any one of claims 1 to 5, characterized in that: The following steps are involved: For each dose of medicine, weigh the raw materials by weight, soak them in warm water for 180-360 minutes, add water to cover the raw materials by about 1-2 cm, boil the aconite for 40 minutes, and then boil it twice with other raw materials, 60-90 minutes after the first decoction and 60 minutes after the second decoction, and combine the two medicinal solutions.

7. Use of the Chinese medicine composition according to any one of claims 1 to 5 in the preparation of medicines for treating chronic coronary syndrome, chronic heart failure, and preventing and treating the asthenic state thereof.

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