LIU Xiang, WANG Chao, AN Ying, TANG Zhuo-ran, QI Xin, ZHAO Hai-bin?

1. Beijing University of Chinese Medicine, Beijing 100029, China

2. Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100071, China

Keywords:Cardiac neurosis Traditional Chinese medicine Traditional Chinese Medicine Inheritance Assistant Platform Medication rule

ABSTRACT Objective: To analyze the prescription and medication rule of traditional Chinese medicine(TCM) in treating cardiac neurosis by using the software of "Traditional Chinese Medicine Inheritance Assistant Platform (V2.5)". Methods: China Journal Full-Text Database,Wanfang database, Weipu Chinese Periodical Service Platform and Chinese biomedical literature database were retrieved according to the inclusion and exclusion criteria. Literatures on the treatment of cardiac neurosis with TCM prescriptions were screened out and data mining was carried out using the TCM inheritance assistant platform. Use frequency,commonly used dose, the frequency of properties, flavors and meridian distribution were counted. Association rules and entropy clustering analysis for complex system were used to extract core drug combinations and unsupervised entropy hierarchical clustering was used to predict potential new prescriptions. Results: Through literature retrieval and screening, 210 types of prescriptions were finally selected, and 181 types of Chinese herbs were extracted,with cumulative frequency of 2 410 times. Among them, there were 46 traditional Chinese medicines that were used more than 15 times. According to the efficacy and indication, they were classified into qi - regulating drugs, tranquilizers, qi - tonifying drugs, heat - clearing drugs, blood - tonifying drugs, etc. According to properties, flavors, and meridian distribution,warm and sweet drugs were the most commonly used, mostly distributing to the heart meridian,followed by liver and spleen meridians. Association rules showed that combination of radix paeoniae and paeonia-bupleurum was the most used; faructus aurantii and bupleurum had the strongest correlation, up to 90%. The network diagram indicated that bupleurum, angelica sinensis, radix paeoniae radix, and poria cocos were the core of the association network.Based on complex system entropy clustering, 24 core drug combinations were obtained.The unsupervised entropy hierarchical clustering algorithm was used to extract 12 core drug combinations, and 6 potential new formulae were obtained by further clustering. Conclusion:Regulating qi and blood, addressing both symptoms and causes,and using purgation and tonification at the same time is the principle of the treatment of cardiac neuropathy with TCM.The treatment mainly starts from the heart, liver and spleen, and therapies include soothing the liver and regulating qi, clearing heat and resolving phlegm, tranquilizing and calming the nerves,and prompting blood circulation and diuresis.

1. Introduction

Cardiac neurosis is the result of the dysfunction of the nervous regulation of cardiovascular system symptoms as the main performance of the clinical syndrome. Clinically, precardiac pain,chest tightness and palpitation are the main manifestations, all of symptoms will worsen after activity or emotional agitation.And it may be accompanied by difficulties in sleeping, dizziness, headache,upset, tinnitus, deafness and other co-symptoms, but there is no evidence of organic heart disease [1]. At present, western medicine mostly uses β-blockers, sedative drugs, glutamate and other symptomatic treatment, the effect is not good and side effects are obvious.However, traditional Chinese medicine has ideal efficacy and high safety in the treatment of cardiomyopathy, which not only significantly improves palpitation, shortness of breath, emotional depression and other symptoms, but also has better improvement than western medicine in the main symptom score, anxiety scale score and depression scale score [2]. However, due to the flexible and changeable characteristics of TCM prescriptions, it is more difficult to further explore the rules of prescription medication in the treatment of cardiac neurosis by TCM [3]. On the basis of TCM inheritance assistance platform, this paper summarized relevant literatures from CNKI, Wanfang and Weiping, conducted data mining on 210 included prescriptions,analyzed and explored the rule of prescription and characteristics in treating neurosis in order to provide guidance for clinical development and drug research of cardiac neurosis.

2. Materials and methods

2.1 Prescription sources

In CNKI, Wanfang Database, Weipuand China Biomedical Literature Database, the "title or subject" was set as "cardiac neurosis", and the full text qualifier was "Chinese medcine ","Chinese herb" or "Traditional Chinese medicine" for secondary retrieval. The term of validity was established from the construction of the database to February 21, 2021.EndNotex8.2 was used to de-duplicate the retrieved documents.

2.2 Inclusion criteria

The prescription is derived from typical cases in case control studies or therapeutic effect analysis, theoretical discussion and expert experience summary of cardiac neurosis treated by traditional Chinese medicine or integrated traditional Chinese and western medicine.The criteria for diagnosis, inclusion and exclusion of medical records are clear and correct;The prescription of traditional Chinese medicine is taken orally.The prescription of traditional Chinese medicine is clearly recorded and complete in literature, and the composition, dosage and usage of traditional Chinese medicine are accurate.Only if all the above conditions are met can they be included.

2.3 Exclusion criteria

Literature on complications in cases;Repeated publications and papers with different names of the same name;Lack of clear drug composition and specific dose of literature;The therapeutic drugs were single Chinese medicine, injection or capsule, etc.Satisfy one of above can be removed.

2.4 Specifications for names of traditional Chinese medicines

In order to ensure the degree of data aggregation, the 2020 edition of Pharmacopoeia of the People's Republic of China [4]and Dictionary of Traditional Chinese Medicine [5] are taken as references to further standardize and unify the names of traditional Chinese medicines. For example, Yunling is defined as Poria, Xian Lingpi is defined as Herba Epimedii, and Danpii is defined as Cortex Moutan. For traditional Chinese medicines without clear processing methods,Such as keel and raw keel unified entry for keel,raw licorice and licorice unified entry for licorice, raw atractylodes and atractylodes unified entry for atractylodes and so on.The traditional Chinese medicine with clear processing method should be recorded in standard, such as calcined keel, Chinese pinellia,Fried atractylodes and so on.In addition, after the processing of drug properties and efficacy have significant changes need to be accurately recorded, such as Dried ginger, Ginger, Simmered ginger,Raw jujube kernel and Fried jujube kernel.

2.5 Data selection

A total of 599 literatures related to the treatment of cardiac neurosis by traditional Chinese medicine were retrieved.According to the above inclusion and exclusion criteria, 174 literatures meeting the criteria were screened out, and a total of 210 prescriptions were recorded after double collation and verification.

2.6 Data entry and analysis

2.6.1 Data entry and verificationData entry shall be jointly reviewed and recorded by two people,and then the selected TCM prescriptions shall be recorded into the TCM Inheritance Assistance Platform (V2.50) by specialized personnel, so as to ensure the accuracy of data mining results.

2.6.2 Establishment of databaseThe 210 selected TCM prescriptions were accurately input into the"prescription management" module under the column of "platform management" in the "TCM Inheritance Assistant System (V2.50)"(provided by Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences), and the prescription database was established.

3. Results

3.1 Analysis of medication frequency

A total of 210 prescriptions and 181 TCM flavors were selected,with a total frequency of 2410 times.Among them, 46 traditional Chinese medicines were used more than 15 times. The top 10 traditional Chinese medicines were Radix bupleurum, Angelica sinensis, Radix Paeoniae alba, Poria cocos, Fried licorice, Spina date seed, Polygala tenuifolia, licorice root,Salvia miltiorrhiza and Chuanxiong.According to the induction of drug efficacy, the treatment of cardiac neurosis by TCM is mainly composed of Qi regulating drug, Tranquilizer, Qi tonifying drug, Heat-clearing drug and hematinic.The statistics of frequency and efficacy of TCM are shown in Tabe 1.

3.2 Four gas frequency analysis of the drug

According to the Pharmacopoeia of the People's Republic of China [4], the statistical analysis of the four qi of traditional Chinese medicine shows that the highest frequency is warm (36%), followed by cold (31%) and peaceful (29%). The specific results are shown in Figure 1.

Figure 1 Frequency distribution of properties

3.3 Frequency analysis of five flavors of drugs

According to the frequency statistics of the five flavors of drugs, the highest frequency was sweet (35%), followed by bitter (28%) and spicy (25%), as shown in Figure 2.

Figure 2 Frequency distribution of flavors

3.4 Frequency analysis of drug circulation

The statistical results of the frequency of TCM meridians returning showed that the highest frequency of TCM meridians returning was the heart meridian (19%), followed by the liver meridian (18%) and the spleen meridian (17%), as shown in Figure 3.

Figure 3 Frequency of meridian distribution

3.5 Dosage analysis of commonly used traditional Chinese medicine

Enter the "data analysis" module, select "prescription analysis- dosage of medicine" to count the dose frequency of commonly used traditional Chinese medicine, in order to provide reference and guidance for clinical medication.According to the above analysis, Bupleurum was used the most frequently, so the clinical dosage of Bupleurum was mainly analyzed.As shown in Figure 4, the use frequency of Bupleurum was the highest when the dosage of Bupleurum was 10 g and 15 g, and the use frequency was higher when the dosage of Bupleurum was 12 g.Similarly,it can be concluded that the dosage of traditional Chinese medicines with high frequency of use, such as Angelica sinensis,Radix paeoniae alba, Poria cocos, Prepared liquorice, Jujube kernel and Polygala tenuifolia, was the highest at 15 g, 15 g, 15 g, 6 g, 15 g and 10 g, respectively.

Figure 4 Analysis of clinical dosage of radix bupleuri

3.6 Analysis of group square rule based on association rules

The "number of support degrees" (the frequency of occurrence in all TCM prescriptions) was set to 35, and the "confidence degree"was set to 0.8. A total of 24 records were analyzed, that is, there were 24 drug combinations, including 15 TCM flavors.Appeared on the basis of drug combination frequency of sorting, the top five combination of traditional Chinese medicines, in turn, is Radix paeoniae alba-Radix bupleuri, Radix angelicae sinensis-Radix bupleuri, Angelica sinensis-Radix paeoniae alba, Radix bupleuri-Poria cocos, Angelica-Radix paeoniae alba-Radix bupleuri.Among them, drug combinations with use frequency ≥35 are shown in Table 2 and shown on the network in Figure 5.Analyze the correlation law of the above-mentioned TCM combinations, Fructus Aurantii and Bupleurum have the highest correlation degree, up to 90%. The results are shown in Table 3.As can be seen from the above, among the core drug pairs of traditional Chinese medicine in the treatment of Angelica sinensis,Radix bupleuri, Radix paeoniae and Poria cocos appear more frequently and are the core of the associated network.

Table 2 Herbs with frequency higher than 35 times in prescriptions

Figure 5 Network display of association rules

Table 3 Association rules of herb combinations in prescriptions

3[6.]7 Entropy clustering combination based on complex system

By referring to the above analysis results, parameters were adjusted for several times, and finally the "correlation coefficient" was set as 5, the "penalty coefficient" was set as 2, and the "Result" value was set as 3 (that is, the extracted drug combination consisted of 3 Chinese herbs). A total of 24 core combinations were derived, as shown in Table 4.

Table 4 Core combinations based on complex system entropy clustering

3.8 New square analysis based on unsupervised hierarchical clustering [7]

Based on the above drug core combination results, the unsupervised entropy hierarchical clustering algorithm was applied to select"cluster-extraction combination", and a total of 12 groups of core combinations were extracted, as shown in Table 5 and shown in Figure 6 for network display.Further clustering extracted 6 potential new prescriptions, as shown in Table 6.The network presentation of the new side is shown in Figure 7.

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Table 5 Core combinations based on hierarchical clustering analysis

Figure 6 Network display of herb core combinations

Table 6 New prescription based on entropy hierarchical clustering

Figure 7 Network display of potential new prescriptions

4. Discussion

Cardiac neurosis is the name of Western medicine, and the relevant TCM discourse is scattered in chapters such as "palpitation", "zang mania", "depression syndrome" and "chest pain". Among them,the symptoms of autonomic nervous dysfunction are more similar to "depression syndrome" and "zang mania" [8].Jiang Jian believed that emotional dysfunction was the core pathogenesis of palpitation,so it was also called "depressive palpitation" [9].At the same time,he believed that anxiety, depression, anger and other emotions can cause the disease, but panic is the most common cause [10].Cheng Shanting believed that the pathogenesis of the disease was deficiency of heart blood, as well as deficiency of spleen, depression of liver and deficiency of kidney, with liver depression as the core [11]. As said in "Danxi Heart Fa · Six Yu", "Harmonious qi and blood lead to non-existent diseases, but only to crabbed depression, resulting in various diseases". If we usually think more, Liver Qi is easy to stasis, leading to Qi and blood stasis in the chest, this is chest pain." On the blood syndrome, on the pathogenesis of viscera"also said: "If Liver qi is normally discharge, blood vessels will be unobstructed". Therefore, the stagnation of liver qi can be regarded as the initial pathogenesis of cardiac neurosis [12]. Synopsis of the Golden Chamber said: "See the liver disease, know the liver spread the spleen, the first to strengthen the spleen". Liver qi is not discharged, anti-cross invasion of the spleen, spleen deficiency, loss of heart qi and blood maintenance, causing palpitation. The spleen is not healthy for a long time, the water does not become wet, and the fluid accumulates into sputum, which disturbs the liver, gallbladder and mind, causing palpitation in another way[13].Therefore, Cheng Wei [14] believed that the disease could be divided into deficiency syndrome and positive syndrome, and deficiency syndrome was mainly caused by deficiency of Qi, blood and Yin. The positive evidence is mainly caused by qi stagnation, phlegm turbidities and blood stasis. Ye Xiaohan also emphasized the theory of "wet block"in the treatment of cardiac neurosis, and proposed that although wet block originated from the spleen, it should be specifically treated to ease the liver, invigorate the spleen and clearing damp [11].

Based on the analysis results of TCM inheritance assistance platform, 210 prescriptions for the treatment of cardiac neurosis contained 181 Chinese herbs, and 46 of them were used with frequency ≥15. According to the classification standard of efficacy,the above-mentioned drugs can be classified into the following categories: Qi regulating drugs, tranquilizing drugs, Qi tonifying drugs, heat-clearing drugs, blood tonifying drugs and waterenhancing drugs with reference to the textbook of the 4th edition of Chinese Medicine [15].The results of four qi and five flavors of drugs and their meridian return indicated that sweet and warm drugs were the most frequently used, followed by bitter and cold drugs.The highest frequency of drug channeling was heart meridian,followed by liver meridian and spleen meridian. Close examination showed that cardiac neurosis was located in the heart, but involved the liver, spleen, lung and kidney, and was closely related to the liver and spleen. TCM treatment of cardiac neuropathy stresses coordination and balance, one tonic and one diarrhea, one cold and one temperature, and contains theories such as "both tonic and diarrhea", "Qi, blood and water co-regulation [16]", and " present and foundation".

Based on association rules, Fructus Aurantii and Bupleurum had the strongest correlation, and the correlation between the two was as high as 90%.In addition, the correlation degree between Radix Bupleuri and Yujin, Paeonia lactiflora, Ligusticum chuanxiong,Atractylodes atractylodes and Danggui is relatively high, which reflects the treatment method of "Qi and blood harmonize with each other" and is in line with the theory of "Qi is the leader of blood"and "Blood is the mother of Qi". In Treatise on Febrile Diseases,keel and oyster are common medicine pairs, which can calm the mind and cure symptoms. As Kechin said, "keel weight can calm the panic and level the wood; Oysters are unbreakable, and their nature is not moved. They can be quiet and calm, and cold can remove irritability and heat [17].Second, it can calm the liver and cure the root causes of phlegm. It is said in the Book of Benzajing that"phlegm and water are born with fire, and the keel can attract the fire and flooding water and return to its house. If it is used with oysters,it is the magic product for curing phlegm. "It not only shows that the combination of keel and oyster can dispel phlegm, but also reflects the treatment principle of "taking both specimens into account".Combined with the analysis results of the frequency of drug use,poria cocos, atractylostomy and other drugs have the function of invigorating the spleen and reducing dampness, which shows that phlegm dampnedampness is an important cause of cardiac neurosis.Therefore, the treatment of cardiac neurosis should follow the principle of "treating both qi and blood" and "taking both samples into account", which can be specifically treated by regulating qi and blood, removing phlegm and improving water, and calming the nerves.

Based on unsupervised entropy hierarchical clustering algorithm,12 core combinations were extracted, and 6 potential new methods were further extracted by clustering. They are :(1) Bamboo shavings-Pinellia-Coptis-Gentiana;(2) Fragrant wood-Longan meat-Fried atractylodes-Angelica-Rehmannia glutinosa-Atractylodes;(3) Radix paeoniae alba-Radix bupleuri-Radix curcumae-Fructus Aurantii-Peach kernel-Red flower;(4) Codonopsis pilosula-Gardenia-Astragalus membranaceus-Moutan bark;(5) Chinese yam-Dogwood-Rhizoma alismatis-Dried ginger-Epimedium;(6) Buddha hands-Oyster-keel-Rhubarb.Among them, the new formula 1 has the main effect of clearing heat and reducing phlegm. Pinellia can dryness and dampness dissipate phlegm, Bamboo shavings and rhizoma coptidis can clear heat and clean phlegm. It has the meaning of Huanglian Wendan Decoction, and it is combined with Gentian to clear heat and reduce liver and gallant fire. The prescription of Pinellia chinensis has anti-inflammatory, anti-arrhythmia, increasing coronary flow, inhibiting heart ischemia reperfusion injury and other pharmacological effects [18]. The combination of the new formula 2 and 3 follows the principle of "co-treatment of Qi and blood",one complements the other line. Formula 2 mainly uses Qi and blood nourishing drugs, together with products to promote blood circulation and qi circulation, so that the Qi and blood circulation can be replenished without stagnation. At the same time, not forget to treat from the spleen, give consideration to the benefit of water,reflecting the close relationship between gas, blood and water. Tang Rongchuan's Treatise on Blood Evidence once said, "Water disease causes blood fatigue, and blood disease causes blood fatigue", and"blood and water are not separated from each other. Patients with sick blood have not tasted sick water, and patients with sick water have not tasted sick blood", which happened to agree with the argument of Zhang Zhongjing in Synopses of the Golden Chamber that " Blood and water can influence each other " [19]. Formula 3 mainly uses qi-promoting and blood-activating drugs, together with the drugs of tonifying Yin blood, so that it can produce blood without hurting blood, reflecting the principle that "blood is the mother of qi".In addition, it was found that most of the drugs were used to soothe the liver and relieve depression. Combined with the analysis of the frequency of drugs returning to the meridian, the author believed that the stagnation of liver qi could be the initial pathogenesis of the disease, and further lead to blood stasis, phlegm and dampness and other lesions. The new prescription 4 and 5 reflect the principle of both reinforcing and reducing energy. In prescription 4, Gardenia and Moutan bark are added to replenish energy and reduce deficiency and heat, so as to avoid the disadvantage of overheating. Formula 5 starts with liver and kidney, pays attention to Yin and Yang, and adds rhizoma alismatis to facilitate water infiltration and dampness.It has the meaning of Shenqi Pill and Liuwei Dihuang Pill. While calming the mind and treating the symptoms with the Oysters and Keels, prescription 6 does not forget to carry out the qi and the fuorgans, the two drugs of Buddha hands and Rhubarb, open the bitter health, and regulate the qi machine, again emphasizing the importance of "taking both present and foundation into account".In conclusion, the potential new prescriptions obtained in this study further reflect the therapeutic principles and methods of "regulating Qi and blood together", "promoting blood circulation and benefiting water", "reinforcing and reducing both" and "taking both present and foundation into account". At the same time, the heart, liver and spleen for the treatment of cardiac neurosis in Chinese medicine is an important focus.

In conclusion, the author believes that qi depression is often the initial pathogenesis of cardiac neurosis, which further leads to the pathological evolution of blood stasis, phlegm and dampness.Based on the database sources of CNKI, Wanfang, Weipu and China Biomedical Literature Network, this paper conducted a statistical analysis based on the traditional Chinese medicine inheritance assistance platform, analyzed the prescription medication rules of traditional Chinese medicine in the treatment of cardiac neuropathy from multiple perspectives, and dug out its potential new prescriptions. Finally, the following conclusions are drawn: the treatment of cardiac neuropathy by traditional Chinese medicine follows the principles of "regulating qi and blood together","reinforcing and reducing qi simultaneously", "taking present and foundation into account" and other treatment principles, and pays attention to the initial use of qi stagnation. It mainly starts from the heart, liver and spleen, and takes dredging the liver and relieving depression, calming the nerves, clearing heat and resolving phlegm,promoting blood circulation and benefiting water, and enriching blood and nourishing the heart as specific treatment methods.However, this paper did not exclude the types of articles such as theoretical discussion and experience of famous doctors when screening the literatures, so there may be drawbacks of inclusion in the prescriptions. Therefore, the practicability of the analyzed drug combinations and potential new prescriptions need to be verified in clinical practice.

Author Contribution:

Zhao Haibin and Liu Xiang designed this study, Wang Chao and An Ying screened and sorted out the literatures, Qi Xin and Wang Chao were responsible for data entry and proofreading, Liu Xiang was responsible for summary analysis and writing, and Tang Zhuoran was responsible for proofreading.