Application of Danshu Fuyuan Prescription in the Preparation of Drugs for Treating Vascular Dementia

Abstract

The present invention belongs to the field of medicine, and particularly relates to the application of Danshu Fuyuan Formula in the preparation of a medicament for treating vascular dementia (VD). Research has shown that the basic formula of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat and dissipating stasis" (Danshu Fuyuan Formula) of the present invention can reduce the TCM syndrome scores of VD patients, significantly improve the related TCM syndromes of VD patients; and can effectively increase the MMSE and MoCA scores of VD patients, significantly improve the cognitive function of the patients; at the same time, it can effectively reduce the ADL score of VD patients and improve the daily living ability of VD patients.

Description

Technical Field

[0001] The present invention belongs to the field of drugs, and particularly relates to the application of Danshu Fuyuan Formula in the preparation of drugs for treating vascular dementia (VD). Background Art

[0002] Vascular dementia (VD) refers to a severe cognitive impairment syndrome caused by ischemic stroke, hemorrhagic stroke, and cerebrovascular diseases that result in hypoperfusion in brain regions such as memory, cognition, and behavior.

[0003] Generally, vascular dementia is often treated by controlling hypertension, diabetes, controlling high cholesterol levels, and using anticoagulant drugs, or by using drugs that improve brain tissue metabolism such as piracetam, nefiracetam, aniracetam, etc.

[0004] When the above-mentioned Western medicine intervention is stopped, vascular dementia may still relapse. Therefore, it is necessary to comprehensively treat with the idea of overall conditioning in traditional Chinese medicine, changing from point treatment to surface treatment.

[0005] Based on this, the technical solution of the present invention is proposed. Summary of the Invention

[0006] In order to solve the problems existing in the prior art, the present invention provides the application of Danshu Fuyuan Formula in the preparation of drugs for treating vascular dementia. The raw materials of the Danshu Fuyuan Formula include: Salvia miltiorrhiza, Atractylodes macrocephala, Astragalus membranaceus, Lonicera japonica, Polygonum cuspidatum, Curcuma aromatica, Poria cocos, Coix lacryma-jobi, and Notopterygium incisum.

[0007] Combined with the pathogenesis characteristics of vascular dementia, the present invention proposes an innovative theory on the etiology, pathogenesis, diagnosis, and treatment of phlegm-stasis intermingling in vascular dementia with the core of "deficiency of primordial qi, intermingling of phlegm and stasis, and malnourishment of the original spirit". The location of vascular dementia is in the brain. Insufficiency of the spleen and kidney in the elderly leads to gradual deficiency of primordial qi, affecting the operation of blood and body fluids, resulting in the production of pathological products such as phlegm and stasis. The heat transformation of phlegm and stasis further consumes primordial qi, causing mutual causation and influence. Phlegm coagulates and qi stagnates, phlegm blocks the collaterals, stasis blocks the channels, and then phlegm and turbidity combine with stasis, forming a syndrome of phlegm-stasis intermingling. The long-term accumulation damages the brain collaterals, jointly leading to the occurrence of dementia. This formula of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat, and dissipating nodules" has good curative effects.

[0008] In the formula, Salvia miltiorrhiza is bitter and slightly cold in nature, enters the pericardium and liver meridians, and has the same effect as the four substances for promoting blood circulation, playing the role of cooling blood and promoting blood circulation, and is the monarch drug of this formula; Atractylodes macrocephala and Astragalus membranaceus are used as ministers to supplement primordial qi, Lonicera japonica and Polygonum cuspidatum are used to clear the heat in the blood vessels and disperse the formed nodules; Poria cocos and Coix lacryma-jobi are used as assistants to strengthen the spleen and resolve phlegm, and also make Astragalus membranaceus and Atractylodes macrocephala tonify without causing stagnation; Curcuma aromatica combined with Lonicera japonica and Polygonum cuspidatum helps Salvia miltiorrhiza clear heat, cool blood, and dissipate nodules; Notopterygium incisum is used as an assistant envoy. On the one hand, due to its pungent and warm nature, the whole formula is not overly cold, and on the other hand, with the ascending and clearing power of the wind drug, it can promote the ascending of yang qi, and combined with Astragalus membranaceus and Atractylodes macrocephala, it restores the ascending and descending of the qi movement in the spleen and stomach.

[0009] Preferably, the Danshu Fuyuan Formula can also be modified according to the emphasis on pathogenesis, specifically as follows:

[0010] 1) For those with obvious phlegm-heat, add Acorus tatarinowii and Bamboo Shavings;

[0011] 2) For those with obvious phlegm-dampness, add Tsaoko Fruit and Amomum villosum;

[0012] 3) For those with obvious blood stasis, add Notoginseng and Chuanxiong Rhizome;

[0013] 4) For those with obvious heat-toxin, add Prunella vulgaris and Bombyx batryticatus;

[0014] 5) For those with concurrent kidney deficiency, add Rehmannia glutinosa and Alpinia oxyphylla;

[0015] 6) For those with concurrent abdominal excess, add Coptis chinensis and Rheum palmatum;

[0016] 7) For those with concurrent qi and blood deficiency, add Codonopsis pilosula and Angelica sinensis;

[0017] 8) For those with concurrent hyperactivity of liver yang, add Achyranthes bidentata and Gastrodia elata.

[0018] Preferably, the Danshu Fuyuan Formula comprises the following raw materials in parts by weight: 25 - 35 parts of Salvia miltiorrhiza, 10 - 15 parts of Atractylodes macrocephala, 25 - 35 parts of Astragalus membranaceus, 10 - 20 parts of Lonicera japonica, 10 - 20 parts of Polygonum cuspidatum, 10 - 20 parts of Curcuma aromatica, 10 - 15 parts of Poria cocos, 25 - 35 parts of Coix lacryma-jobi, and 10 - 15 parts of Notopterygium incisum.

[0019] Preferably, the Danshu Fuyuan Formula comprises the following raw materials in parts by weight: 30 parts of Salvia miltiorrhiza, 12 parts of Atractylodes macrocephala, 30 parts of Astragalus membranaceus, 15 parts of Lonicera japonica, 15 parts of Polygonum cuspidatum, 15 parts of Curcuma aromatica, 12 parts of Poria cocos, 30 parts of Coix lacryma-jobi, and 12 parts of Notopterygium incisum.

[0020] Preferably, the preparation method of the Danshu Fuyuan Formula is as follows:

[0021] Crush the raw materials of the Danshu Fuyuan Formula and then mix them to obtain a composition;

[0022] Or, mix the raw materials of the Danshu Fuyuan Formula and then crush them to obtain a composition;

[0023] Or, extract and refine the raw materials of the Danshu Fuyuan Formula according to conventional processes to obtain one of tablets, capsules, granules, pills, powders or oral liquids.

[0024] Preferably, the drug is a drug for reducing the TCM syndrome score of patients with vascular dementia.

[0025] Preferably, the drug is a drug for increasing the MMSE score of patients with vascular dementia.

[0026] Preferably, the drug is a drug for increasing the MoCA score of patients with vascular dementia.

[0027] Preferably, the drug is a drug for reducing the ADL score of patients with vascular dementia.

[0028] The beneficial effects of the present invention are as follows:

[0029] Studies have shown that the basic formula of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat and dissipating stasis" (Danshu Fuyuan Formula) of the present invention can reduce the TCM syndrome scores of VD patients, significantly improve the related TCM syndromes of VD patients; and can effectively improve the MMSE and MoCA scores of VD patients, significantly improving the cognitive function of the patients; at the same time, it can effectively reduce the ADL score of VD patients and improve the daily living ability of VD patients.

[0030] Moreover, the new prescription medication plan of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat and dissipating stasis" (Danshu Fuyuan Jiawei Formula) of the present invention can also effectively improve the related TCM syndromes of VD patients, improve the cognitive function of VD patients, and improve their daily living ability. During the entire research process, the patients did not experience serious adverse reactions and had good safety. Detailed implementation manners

[0031] To make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be described in detail below. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other implementation manners obtained by those of ordinary skill in the art without creative efforts shall fall within the scope protected by the present invention.

[0032] Example 1

[0033] This example provides a preparation method of Danshu Fuyuan Formula, specifically: 25 g of Salvia miltiorrhiza, 10 g of Atractylodes macrocephala, 25 g of Astragalus membranaceus, 10 g of Lonicera japonica, 10 g of Polygonum cuspidatum, 10 g of Curcuma aromatica, 10 g of Poria cocos, 25 g of Coix lacryma-jobi and 10 g of Notopterygium incisum are pulverized and then mixed to obtain a composition, and then the composition is conventionally processed into tablets.

[0034] Example 2

[0035] This example provides a preparation method of Danshu Fuyuan Formula, specifically: 35 g of Salvia miltiorrhiza, 15 g of Atractylodes macrocephala, 35 g of Astragalus membranaceus, 20 g of Lonicera japonica, 20 g of Polygonum cuspidatum, 20 g of Curcuma aromatica, 15 g of Poria cocos, 35 g of Coix lacryma-jobi and 15 g of Notopterygium incisum are mixed and then pulverized to obtain a composition, and then the composition is conventionally processed into capsules.

[0036] Example 3

[0037] This embodiment provides a preparation method of Danshu Fuyuan Formula, specifically as follows: Mix 30 g of Salvia miltiorrhiza, 12 g of Atractylodes macrocephala, 30 g of Astragalus membranaceus, 15 g of Lonicera japonica, 15 g of Polygonum cuspidatum, 15 g of Curcuma aromatica, 12 g of Poria cocos, 30 g of Coix lacryma-jobi, and 12 g of Notopterygium incisum, and perform extraction and refining according to conventional processes to obtain a granule.

[0038] Example 4

[0039] The difference between Example 4 and Example 3 is that the Danshu Fuyuan Formula is made into pills.

[0040] Example 5

[0041] The difference between Example 5 and Example 3 is that the Danshu Fuyuan Formula is made into powder.

[0042] Example 6

[0043] The difference between Example 6 and Example 3 is that the Danshu Fuyuan Formula is made into oral liquid.

[0044] Verification example (using the granule obtained in Example 3 as the verification object)

[0045] (I) Efficacy verification of Danshu Fuyuan Formula (Bayesian basket trial)

[0046] 1. Research object

[0047] Adopt the research design of Bayesian basket trial, and a total of 52 patients who meet the diagnostic criteria and inclusion criteria of VD syndrome of phlegm stasis intermingling are collected.

[0048] 2. Test plan

[0049] On the basis of conventional western medicine treatment, the subjects are given Danshu Fuyuan Formula granules (the formulated granules are uniformly prepared and provided by China Resources Sanjiu Medical & Pharmaceutical Co., Ltd.), taken with warm boiled water, once in the morning and once in the evening, 1 bag each time.

[0050] If the patient has other underlying diseases, continue to take the relevant symptomatic western medicines (such as antihypertensive, lipid-lowering, hypoglycemic, antiplatelet aggregation drugs, etc.), but other traditional Chinese medicines or western medicines that have an impact on cognitive function are not allowed to be used.

[0051] The test period of this study is 24 weeks, and all enrolled patients collect efficacy indicators before intervention, at 12 weeks of intervention, and at 24 weeks of intervention (within ±7 days).

[0052] 3. Diagnostic criteria

[0053] 3.1. Western medicine diagnostic criteria

[0054] Diagnosis is made with reference to the diagnostic criteria for VD or vascular cognitive impairment published by Vas-Cog in 2014 and the "2018 Chinese Guidelines for the Diagnosis and Treatment of Dementia and Cognitive Impairment (I): Diagnostic Criteria for Dementia and Its Classification":

[0055] 1) Meeting the diagnostic criteria for dementia: For patients who were previously intellectually normal but later developed cognitive decline (including impairment of memory, executive function, language, or visuospatial function) or abnormal mental behavior, which affects the patient's work or daily life and cannot be explained by delirium or other mental disorders, a tentative diagnosis of dementia can be made. Cognitive decline or mental behavior impairment can be objectively confirmed through history-taking and neuropsychological assessment, and at least 2 of the following 5 items must be present: a. Decreased memory and learning ability compared to before; b. Impaired executive function such as reasoning, judgment, and handling complex affairs; c. Impaired visuospatial function; d. Impaired language function (including listening, speaking, reading, and writing); e. Abnormal changes in the patient's behavior, personality, or demeanor. These functional impairments significantly affect the patient's daily living ability, occupation, or social interaction, and these impairments are not simply due to the decline in daily living ability caused by physical disorders resulting from stroke.

[0056] 2) Evidence of cerebrovascular lesions: including relevant risk factors for vascular lesions, a history of stroke, focal neurological signs, and cerebrovascular lesions shown by imaging examinations. It is not necessary to have all of the above evidence simultaneously.

[0057] 3) There must be a causal relationship between dementia and cerebrovascular lesions: Clinically, by asking the patient's medical history, performing physical examinations, and conducting relevant laboratory and imaging examinations to determine whether there is a causal relationship between dementia and vascular factors, and the onset of dementia must be related to at least 1 cerebrovascular event in terms of time (with repeated similar cerebrovascular events, dementia shows a stepwise progression or fluctuations, and dementia still persists 3 months after the cerebrovascular event). Other types of dementia (such as Alzheimer's disease (AD), frontotemporal dementia (FTD), dementia with Lewy bodies (DLB), Parkinson's disease dementia (PDD), etc.) are excluded.

[0058] 3.2、Traditional Chinese Medicine Diagnostic Criteria

[0059] 1) Main symptoms: Intellectual decline, abnormal behavior, slow reaction, dull expression, apathy, few words, mental confusion.

[0060] 2) Secondary symptom 1: Dizziness or heaviness, heaviness and fatigue of the limbs, fullness and oppression in the chest, obesity and bloatedness, expectoration of phlegm.

[0061] 3) Secondary symptom 2: Headache like a stabbing pain, dark complexion and purple lips, purple and dull nails, hemiplegia of the limbs, speech impairment.

[0062] 4) Tongue manifestation: The tongue body is enlarged with tooth marks, the tongue coating is greasy, the tongue texture is purplish dark with ecchymosis, and the sublingual collaterals are congested, cyanotic, and varicose.

[0063] 5) Pulse condition: The pulse is slippery or soft, deep or unsmooth or taut.

[0064] If at least 2 of the above main symptoms are present (intellectual decline is essential), 1 item each from the secondary symptoms 1 and 2, and 1 item each from the tongue and pulse conditions, the diagnosis can be made.

[0065] 4. Test observation indicators

[0066] 4.1 General information

[0067] Demographic data: including name, age, gender, ethnicity, height, weight, marital status, education level, occupation, medical history, and smoking and drinking history, etc.

[0068] Routine physical examination: such as body temperature, heart rate, respiration, pulse, blood pressure, etc.

[0069] Safety indicators: blood and urine routine, liver and kidney function, and electrocardiogram.

[0070] 4.2 Efficacy indicators

[0071] Main indicators: The Traditional Chinese Medicine Syndrome Score Scale (as shown in Table 1) is used to evaluate the improvement of the Traditional Chinese Medicine clinical symptoms and signs of the patients before and after treatment.

[0072] Table 1

[0073]

[0074]

[0075] Secondary indicators:

[0076] 1) Cognitive function: The MMSE and MoCA scales are used to evaluate the patients before and after treatment, including changes in memory, orientation, calculation ability, etc.

[0077] 2) Activities of daily living: The ADL scale is used to evaluate the changes in the activities of daily living of the patients before and after treatment.

[0078] 5. Research results

[0079] 5.1 General information

[0080] From September 2020 to December 2021, a total of 52 subjects who met the inclusion criteria were screened, and a total of 2 cases were lost to follow-up, 1 case each for the first and second times.

[0081] 1) Distribution of patient gender, age, and disease course

[0082] Among the 52 patients, 25 were male and 27 were female; the age of the patients ranged from 41 to 85 years old, with an average age of 67.83 ± 9.44 years; the course of the disease of the patients was 6 to 37 months, with an average of 18.25 ± 9.62 months.

[0083] 2) Distribution of the degree of the patients' condition, educational level, and co - morbidities

[0084] Degree of the patients' condition (CDR classification): 35 cases were mild and 17 cases were moderate; educational level of the patients: 4 cases were illiterate, 15 cases were primary school educated, and 33 cases were junior high school educated or above; co - morbidities of the patients: 27 cases had hypertension, 8 cases had coronary heart disease, 13 cases had diabetes, 20 cases had hyperlipidemia, and 15 cases had hyperhomocysteinemia.

[0085] 5.2 Efficacy indicators

[0086] 1) Changes in the traditional Chinese medicine syndrome scores of the patients

[0087] After treatment, the traditional Chinese medicine syndrome scores of the patients were all lower compared with those before treatment, and the difference was statistically significant (P < 0.01), as shown in Table 2 specifically.

[0088] Table 2 Comparison of traditional Chinese medicine syndrome scores (points) of patients before and after treatment in the Bayesian trial (x ± s)

[0089]

[0090] Note: Comparison after treatment with before treatment: *P < 0.01.

[0091] 2) Changes in the MMSE scores of the patients

[0092] After treatment, the MMSE scores of the patients were all higher compared with those before treatment, and the difference was statistically significant (P < 0.01), as shown in Table 3 specifically.

[0093] Table 3 Comparison of MMSE scores (points) of patients before and after treatment in the Bayesian trial (x ± s)

[0094]

[0095] Note: Comparison after treatment with before treatment: *P < 0.01.

[0096] 3) Changes in the MoCA scores of the patients

[0097] After treatment, the MoCA scores of the patients were all higher compared with those before treatment, and the difference was statistically significant (P < 0.01), as shown in Table 4 specifically.

[0098] Table 4 Comparison of MoCA scores (points) of patients before and after treatment in the Bayesian trial (x ± s)

[0099]

[0100] Note: Comparison after treatment with that before treatment: *P < 0.01.

[0101] 4) Changes in the ADL scores of the patients

[0102] After treatment, the ADL scores of the patients were all lower compared with those before treatment, and the difference was statistically significant (P < 0.01), as shown in Table 5 specifically.

[0103] Table 5 Comparison of ADL scores (points) of patients in the Bayesian trial before and after treatment (x±s)

[0104]

[0105] Note: Comparison after treatment with that before treatment: *P < 0.01.

[0106] 5) Safety indicators

[0107] During the whole trial process, 2 cases were lost to follow-up, 1 case each in March and June, and both were lost to follow-up.

[0108] All the patients in this study underwent blood, urine routine, liver and kidney function, and electrocardiogram examinations before and after treatment. No abnormal changes in the above indicators were found in both groups of patients. Among the 50 patients who completed the trial, 2 patients (incidence rate 4%) complained of gastrointestinal reactions (nausea, discomfort in the epigastric region) after taking the medicine. The patients were instructed to take the medicine more than half an hour after meals, and no special drug treatment was given. The symptoms of the patients disappeared by themselves.

[0109] 6. Discussion

[0110] The inventors have long-term research and found that the location of vascular dementia is in the brain, which is closely related to the kidneys, heart, spleen, and liver, and is also related to qi, blood, and body fluids. Qi and blood are the material basis for the mental activities of the brain. Therefore, the deficiency of primordial qi and essence and blood, resulting in the reduction of marrow and the atrophy of the brain, is the root cause of the disease; phlegm turbidity and stasis blood are not only the pathological products produced by the deficiency of various zang-organs, but also the pathogenic factors leading to the loss of the function of the mental mechanism. The two often exist simultaneously, forming the syndrome of mutual binding of phlegm and stasis. Clinically, the method of treating both phlegm and stasis is often used to treat this disease. The present invention believes that the "mutual binding of phlegm and stasis" is the key pathogenesis causing the cognitive function impairment in patients with vascular dementia. Therefore, taking the "mutual binding of phlegm and stasis" as the breakthrough point, the treatment principle of "tonifying qi, resolving phlegm, promoting blood circulation, clearing heat, and dissipating nodules" (i.e., Danshu Fuyuan Prescription) is proposed, and the patients are treated based on syndrome differentiation, and the curative effect is proved to be significant through the above results.

[0111] 7. Conclusion

[0112] The results of this study showed that the basic formula of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat and dissipating stasis" (Danshu Fuyuan Formula) could effectively reduce the TCM syndrome scores of VD patients and improve their TCM syndromes (the average score before treatment was 30.27, 19.00 after 3 months of treatment, and 14.96 after 6 months of treatment); comparing the MMSE scores of patients before and after treatment, it was found that it had a therapeutic effect on improving the cognitive function of patients (the average score before treatment was 17.24, 21.02 after 3 months of treatment, and 22.86 after 6 months of treatment); comparing the MoCA scores of patients before and after treatment, it was found that it had a therapeutic effect on improving the cognitive function of patients (the average score before treatment was 16.58, 19.53 after 3 months of treatment, and 21.48 after 6 months of treatment); comparing the ADL scores of patients before and after treatment, it was found that it had a therapeutic effect on improving the daily living ability of patients (the average score before treatment was 38.96, 32.31 after 3 months of treatment, and 28.30 after 6 months of treatment); the incidence of adverse reactions (gastrointestinal reactions, which disappeared without special treatment) was 4%, indicating that Danshu Fuyuan Formula had good safety.

[0113] (II)Efficacy verification of modified Danshu Fuyuan Formula

[0114] 1. Research subjects

[0115] A total of 303 patients who met the diagnostic criteria and inclusion criteria for phlegm-stasis intermingling syndrome of VD were selected and collected.

[0116] 2. Trial plan

[0117] On the basis of routine Western medicine treatment, all subjects were given the prescription medication plan of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat and dissipating stasis method". This prescription medication plan was modified according to the emphasis of pathogenesis on the basis of the "prescription for tonifying qi, resolving phlegm, activating blood circulation, clearing heat and dissipating stasis" (Danshu Fuyuan Formula): for those with obvious phlegm-heat, Acorus tatarinowii and Bambusa textilis were added; for those with obvious phlegm-dampness, Amomum tsaoko and Amomum villosum were added; for those with obvious blood stasis, Panax notoginseng and Ligusticum chuanxiong were added; for those with obvious heat-toxin, Prunella vulgaris and Bombyx batryticatus were added; for those with concurrent kidney deficiency, Rehmannia glutinosa and Alpinia oxyphylla were added; for those with concurrent solid abdominal syndrome, Coptis chinensis and Rheum palmatum were added; for those with concurrent qi and blood deficiency, Codonopsis pilosula and Angelica sinensis were added; for those with concurrent hyperactivity of liver-yang, Achyranthes bidentata and Gastrodia elata were added.

[0118] If the patient had other underlying diseases, they continued to take the relevant symptomatic Western medicine (such as antihypertensive, lipid-lowering, hypoglycemic, antiplatelet aggregation drugs, etc.), but other traditional Chinese medicines or Western medicines that had an impact on cognitive function could not be used.

[0119] The trial period of this study was 24 weeks. All enrolled patients collected the efficacy indicators before the intervention and at 12 weeks and 24 weeks (within ±7 days) after the intervention.

[0120] 3. Diagnostic criteria

[0121] Same as the corresponding part of "(I) Efficacy Verification of Danshu Fuyuan Prescription (Bayesian Basket Trial)".

[0122] 4. Observation Indicators of the Trial

[0123] Same as the corresponding part of "(I) Efficacy Verification of Danshu Fuyuan Prescription (Bayesian Basket Trial)".

[0124] 5. Research Results

[0125] 5.1 General Information

[0126] From September 2020 to December 2021, a total of 303 subjects meeting the inclusion criteria were screened, and 19 cases were lost to follow-up.

[0127] 1) Distribution of patient gender, age, and disease course

[0128] Among the 303 patients, 188 were male and 115 were female; the age of the patients ranged from 38 to 85 years old, with an average age of 71.81 ± 9.32 years; the disease course of the patients was 2 to 95 months, with an average of 29.53 ± 12.20 months.

[0129] 2) Distribution of patient disease severity, educational level, and comorbid diseases

[0130] Patient disease severity (CDR classification): 169 cases were mild and 134 cases were moderate; patient educational level: 16 were illiterate, 127 were primary school educated, and 160 had junior high school education or above; patient comorbid diseases: 217 had hypertension, 50 had coronary heart disease, 72 had diabetes, 21 had hyperlipidemia, and 4 had hyperhomocysteinemia.

[0131] 5.2 TCM Syndrome Types

[0132] A total of 303 VD patients were included in this study, with a total of 871 consultations. Statistical analysis of their TCM syndrome types found that the frequency of the single phlegm-stasis mutual binding syndrome type was 1 time (0.11%), and the phlegm-stasis mutual binding syndrome with obvious blood stasis was the most common, reaching 206 times (23.65%). Followed by the phlegm-stasis mutual binding syndrome with obvious phlegm dampness, reaching 133 times (15.27%), and the phlegm-stasis mutual binding syndrome combined with qi and blood deficiency, reaching 130 times (14.93%). The specific details are shown in Table 6.

[0133] Table 6 Statistical Table of Syndrome Type Frequencies of VD Patients in Clinical Research

[0134]

[0135] 5.3 Frequency of Traditional Chinese Medicines

[0136] A total of 303 patients and 871 prescriptions were included in this study, involving 25 Chinese herbal medicines. The cumulative medication frequency was 8,488 times. The frequencies ranked from high to low were Salvia miltiorrhiza, stir-fried Atractylodes macrocephala, Poria cocos, Curcuma aromatica, Lonicera japonica, Astragalus membranaceus, Polygonum cuspidatum, Coix lacryma-jobi, Notopterygium incisum, Bamboo Shavings, Acorus tatarinowii, Panax notoginseng, Ligusticum chuanxiong, Amomum villosum, Tsaoko fruit, Bombyx batryticatus, Codonopsis pilosula, Prunella vulgaris, Angelica sinensis, Alpinia oxyphylla, Rehmannia glutinosa, Gastrodia elata, Achyranthes bidentata, Rheum palmatum, Coptis chinensis, reaching 871 times, 765 times, 765 times, 765 times, 765 times, 764 times, 763 times, 645 times, 638 times, 202 times, 198 times, 166 times, 166 times, 135 times, 135 times, 102 times, 102 times, 102 times, 102 times, 75 times, 74 times, 64 times, 64 times, 30 times, 30 times, 30 times, 30 times respectively.

[0137] 5.4. Chinese Medicine Properties

[0138] 1) The four natures of the drugs were statistically analyzed to obtain the results of the four natures of the drugs with higher usage frequencies. Among them, the ones with higher frequencies were slightly cold (1,836), cold (1,692), and warm (1,615). The overall ranking from high to low was slightly cold, cold, warm, neutral, slightly warm, and cool. There were no drugs with extremely cold, extremely hot, or hot properties. The specific details are shown in Table 7.

[0139] Table 7 Statistical Table of the Four Natures of Chinese Medicines Used by VD Patients in Clinical Research

[0140]

[0141] 2) The five flavors of the drugs were statistically analyzed to obtain the results of the five flavors of the drugs with higher usage frequencies. Among them, the ones with higher frequencies were sweet (3,575), bitter (2,634), and pungent (2,418). The overall ranking from high to low was sweet, bitter, pungent, bland, slightly bitter, and salty. There were no drugs with sour, astringent, slightly pungent, slightly sweet, or sour flavors. The specific details are shown in Table 8.

[0142] Table 8 Statistical Table of the Five Flavors of Chinese Medicines Used by VD Patients in Clinical Research

[0143]

[0144] 3) The effects of the drugs were statistically analyzed. The top 10 in terms of frequency were clearing heat and detoxifying, dredging meridians and relieving pain, clearing the heart and removing vexation, promoting blood circulation and removing stasis, cooling blood and dissipating carbuncles, promoting diuresis and removing jaundice, clearing the heart and cooling blood, promoting bile secretion and removing jaundice, regulating qi and relieving depression, and promoting diuresis and percolating dampness. The specific details are shown in Table 9.

[0145] Table 9 Statistical Table of the Effects of Chinese Medicines Used by VD Patients in Clinical Research

[0146]

[0147] 5.5. Efficacy Indicators

[0148] 1) Changes in the TCM syndrome scores of the patients

[0149] After treatment, the TCM syndrome scores of the patients were all lower than those before treatment, and the difference was highly statistically significant (P < 0.01), as shown in Table 10 specifically.

[0150] Table 10 Comparison of the TCM syndrome scores (points) of the patients in the clinical study before and after treatment (x±s)

[0151]

[0152] Note: Compared with before treatment, *P < 0.01.

[0153] 2) Changes in the MMSE scores of the patients

[0154] After treatment, the MMSE scores of the patients were all higher than those before treatment, and the difference was statistically significant (P < 0.01), as shown in Table 11 specifically.

[0155] Table 11 Comparison of the MMSE scores (points) of the patients in the clinical study before and after treatment (x±s)

[0156]

[0157] Note: Compared with before treatment, *P < 0.01.

[0158] 3) Changes in the MoCA scores of the patients

[0159] After treatment, the MoCA scores of the patients were all higher than those before treatment, and the difference was statistically significant (P < 0.01), as shown in Table 12 specifically.

[0160] Table 12 Comparison of the MoCA scores (points) of the patients in the clinical study before and after treatment (x±s)

[0161]

[0162] Note: Compared with before treatment, *P < 0.01.

[0163] 4) Changes in the ADL scores of the patients

[0164] After treatment, the ADL scores of the patients were all lower than those before treatment, and the difference was statistically significant (P < 0.01), as shown in Table 13 specifically.

[0165] Table 13 Comparison of the ADL scores (points) of the patients in the clinical study before and after treatment (x±s)

[0166]

[0167] Note: Compared with before treatment, *P < 0.01.

[0168] 5.6. Safety indicators

[0169] A total of 19 cases dropped out during the entire trial process, all due to loss to follow-up.

[0170] Among the 284 patients who completed the trial, 11 patients (incidence rate 3.9%) reported gastrointestinal reactions (nausea, discomfort in the epigastric region) after taking the medicine. The patients were instructed to take the medicine more than half an hour after meals, and no special drug treatment was given. The symptoms of the patients disappeared on their own.

[0171] 5.7. Discussion

[0172] 1) Analysis of traditional Chinese medicine syndrome types

[0173] Among all the syndrome types included in this study, the syndrome of phlegm stasis intermingling with obvious stasis is the most common, followed by the syndrome of phlegm stasis intermingling with obvious phlegm-dampness, the syndrome of phlegm stasis intermingling with qi and blood deficiency, and the syndrome of phlegm stasis intermingling with obvious phlegm-heat. It can be seen that the basic pathogenesis of VD is the reduction of marrow and the withering of the brain, the malfunction of the mental mechanism, the location of the disease is in the brain, and it is closely related to the dysfunction of the zang-fu organs of the heart, liver, spleen and kidney. The general pathogenesis belongs to deficiency in origin and excess in superficiality. Deficiency of the zang-fu organs and qi and blood is the root, while phlegm, stasis and heat-toxin are the superficiality. Phlegm and stasis often combine to cause diseases, forming the syndrome of phlegm stasis intermingling. Over time, heat-toxin is generated, which runs through the entire process of the occurrence and development of VD. "Classified Treatises of Syndromes" says: "The brain is the residence of the original spirit... The forgetfulness of the elderly is due to the gradual emptiness of the marrow sea", indicating that the normal function of the brain's memory depends on the nourishment and transformation of the brain marrow. "Spiritual Pivot - Pathogenic Factors and Zang-Fu Organs Patterns" points out: "All the twelve meridians and three hundred and sixty-five collaterals, their qi and blood all ascend to the face and flow into the empty orifices", and Wang Qingren in "Corrections of Medical Errors - Brain Marrow" said: "The spiritual mechanism and memory are in the brain... The clear essence juice is transformed into marrow, which ascends along the spinal cord into the brain and is called the marrow sea". It shows that the qi and blood of the whole body are all infused into the brain, and the cognitive function can be normally exerted. Therefore, deficiency of the zang-fu organs and qi and blood is an important pathogenesis basis for the occurrence of VD.

[0174] The occurrence of VD is not only related to deficiency of the zang-fu organs and qi and blood, but also related to phlegm, stasis, heat-toxin generated by deficiency of the zang-fu organs. Phlegm turbidity is infused into the blood vessels, congesting the blood vessels, obstructing blood flow, and the collaterals losing smoothness. Coupled with deficiency of the zang-fu organs and deficiency of vital qi, the power to promote blood circulation is insufficient, and stasis is thus generated. Phlegm and stasis intersect and accumulate, and over time, heat-toxin is generated, blocking the clear orifices, the brain collaterals losing harmony, and blocking the spirit and mind, thus causing VD. It can be seen that VD occurs on the basis of deficiency of the zang-fu organs and qi and blood, brewing phlegm and stasis, phlegm and stasis intermingling, and over time, heat-toxin is generated, damaging the brain collaterals and brain marrow, resulting in the malfunction of the spirit and mind and the onset of the disease.

[0175] 2) Analysis of the properties of traditional Chinese medicine

[0176] Among the drugs used, the four natures with the highest frequencies are slightly cold, cold, warm, and neutral. Slightly cold and cold drugs such as Salvia miltiorrhiza, Curcuma aromatica, Polygonum cuspidatum, and Coix lacryma-jobi have the effects of clearing heat and promoting blood circulation. Warm drugs such as Acorus tatarinowii and Alpinia oxyphylla have the effects of resuscitating the mind and resolving phlegm, and improving intelligence. Ligusticum chuanxiong and Amomum villosum have the effects of promoting qi circulation and activating blood circulation. Neutral drugs such as Codonopsis pilosula, Achyranthes bidentata, and Poria cocos have the effects of tonifying qi and strengthening the spleen, tonifying the liver and kidney, promoting diuresis and excreting dampness, etc., which conform to the pathogenesis of deficiency in origin and excess in superficiality of VD. The five flavors with the highest frequencies are sweet, bitter, and pungent. Sweet "can tonify, can harmonize, and can soothe", and has the functions of tonifying and regulating the middle energizer, such as drugs like Astragalus membranaceus, Codonopsis pilosula, Angelica sinensis, Poria cocos, Atractylodes macrocephala, and Rehmannia glutinosa can tonify qi and strengthen the spleen, tonify the kidney and replenish essence, which fits the pathogenesis of deficiency in origin of VD; Bitter "can purge, can dry, and can strengthen", and has the functions of clearing heat and purging fire, drying dampness, purging fire and preserving yin, etc., such as Polygonum cuspidatum, Prunella vulgaris, Rheum palmatum, and Coptis chinensis, which have the effects of clearing heat and dissipating nodules, and drying dampness; Pungent "can disperse and can move", and has the functions of dispersing and promoting qi circulation and activating blood circulation, such as Curcuma aromatica, Ligusticum chuanxiong, Amomum villosum, Amomum kravanh, and Alpinia oxyphylla, which can promote qi circulation and activate blood circulation, resuscitate the mind and resolve phlegm, and fit the pathogenesis of excess in superficiality of VD. Among the drug effects, clearing heat and detoxifying, dredging channels and relieving pain, clearing the heart and relieving vexation, and promoting blood circulation to remove stasis are the most common, which conform to the pathogenesis of VD with the combination of phlegm and stasis and the long-term accumulation and transformation of heat toxin.

[0177] 5.8. Conclusions

[0178] Among all the syndrome types included in the research institute, the syndrome of phlegm-stasis intermingling with obvious stasis is the most common, followed by the syndrome of phlegm-stasis intermingling with obvious phlegm-dampness, the syndrome of phlegm-stasis intermingling combined with qi and blood deficiency, and the syndrome of phlegm-stasis intermingling with obvious phlegm-heat. Among the drugs used, the four natures with the highest frequencies are slightly cold, cold, and warm; the five flavors with the highest frequencies are sweet, bitter, and pungent; the most common drug effects are clearing heat and detoxifying, dredging channels and relieving pain, clearing the heart and removing vexation, and activating blood circulation and removing stasis, which conform to the pathogenesis of VD with deficiency in origin and excess in superficiality, with deficiency of zang-fu organs and qi and blood as the root, and phlegm, stasis, and heat-toxin as the superficiality, and the long-term accumulation and transformation of phlegm-stasis into heat-toxin. The formula of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat, and dissipating nodules" can effectively reduce the TCM syndrome scores of VD patients and improve the TCM syndromes of patients (the average score before treatment was 31.94, 20.57 after 3 months of treatment, and 16.34 after 6 months of treatment); from the comparison of the MMSE scores of patients before and after treatment, it was found that it has a therapeutic effect on improving the cognitive function of patients (the average score before treatment was 17.22, 20.73 after 3 months of treatment, and 22.52 after 6 months of treatment); from the comparison of the MoCA scores of patients before and after treatment, it was found that it has a therapeutic effect on improving the cognitive function of patients (the average score before treatment was 16.84, 19.61 after 3 months of treatment, and 21.43 after 6 months of treatment); from the comparison of the ADL scores of patients before and after treatment, it was found that it has a therapeutic effect on improving the daily living ability of patients (the average score before treatment was 39.80, 33.67 after 3 months of treatment, and 29.61 after 6 months of treatment); the incidence of adverse reactions was 3.9%, mainly digestive tract symptoms (nausea, discomfort in the epigastric region), and no special drug treatment was given, and the symptoms of the patients disappeared by themselves, indicating that the formula of "tonifying qi, resolving phlegm, activating blood circulation, clearing heat, and dissipating nodules" has good safety.

[0179] As described above, it is only the specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention can easily think of changes or substitutions, which should all be covered within the protection scope of the present invention. Therefore, the protection scope of the present invention should be subject to the protection scope of the claimed rights.

Claims

1. Use of a Danshu Fuyuan formula in the preparation of a medicament for treating vascular dementia, characterized in that, The raw materials of the Danshu Fuyuan Prescription are in parts by weight as follows: 25-35 parts of Salvia miltiorrhiza, 10-15 parts of Atractylodes macrocephala, 25-35 parts of Astragalus membranaceus, 10-20 parts of Lonicera japonica, 10-20 parts of Polygonum cuspidatum, 10-20 parts of Curcuma aromatica, 10-15 parts of Poria cocos, 25-35 parts of Coix lacryma-jobi, and 10-15 parts of Notopterygium incisum.

2. The use according to claim 1, characterized in that, The raw materials of the Danshu Fuyuan Prescription are in parts by weight as follows: 30 parts of Salvia miltiorrhiza, 12 parts of Atractylodes macrocephala, 30 parts of Astragalus membranaceus, 15 parts of Lonicera japonica, 15 parts of Polygonum cuspidatum, 15 parts of Curcuma aromatica, 12 parts of Poria cocos, 30 parts of Coix lacryma-jobi, and 12 parts of Notopterygium incisum.

3. The use according to claim 1 or 2, characterized in that, The preparation method of the Danshu Fuyuan Prescription is as follows: Crush the raw materials of the Danshu Fuyuan Prescription and then mix them to obtain a composition; Or, mix the raw materials of the Danshu Fuyuan Prescription and then crush them to obtain a composition; Or, extract and refine the raw materials of the Danshu Fuyuan Prescription according to the conventional process to obtain one of tablets, capsules, granules, pills, powders or oral liquids.

4. The use according to claim 1 or 2, characterized in that, The drug is a drug for reducing the TCM syndrome score of patients with vascular dementia.

5. The use according to claim 1 or 2, characterized in that, The drug is a drug for increasing the MMSE score of patients with vascular dementia.

6. The use according to claim 1 or 2, characterized in that, The drug is a drug for increasing the MoCA score of patients with vascular dementia.

7. The use according to claim 1 or 2, characterized in that, The drug is a drug for reducing the ADL score of patients with vascular dementia.

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