“Disease-symptom-herb” Supernetwork Analysis And Core Formula Discovery Of Postmarketing Chinese Patent Medicines For Treatment Of Kidney-yang Deficiency

Abstract: Objective To analyze the postmarketing Chinese patent drugs with the main kidney-yang deficiency by using the supernetwork method, in order to explore its clinical application, core herbs and core formula, and explore the application law of traditional Chinese medicine formula. Methods 

From the Chinese patent medicine database and the network of medicine intelligence network, we collected the postmarketing Chinese patent medicines for the treatment of kidney-yang deficiency syndrome, searched their clinical studies in the literature database, and observed their applications. The diseases and symptoms involved in Chinese patent medicines and traditional Chinese medicines were used as the nodes of the supernetwork, and the Apriori algorithm was used to analyze the association rules among the nodes, and the association combinations with the corresponding support and confidence were used as the edges of the supernetwork to construct the "disease-symptom-herb" supernetwork for kidney-yang deficiency. Network visualization and topological analysis were performed using the Cytoscpe3.9.1 software, and the importance of nodes in the network was measured by hyper degree of herbs, from which the main diseases, core prescriptions and drug compounding patterns of kidney yang deficiency syndrome were mined. Results A total of 191 formulas were selected, involving 293 kinds of medicine, 43 diseases and 19 symptoms; Among them, 64 formulas were reported for clinical application; The core formulas of kidney-yang deficiency were Lurong (Cervi Cornu Pantotrichum), Roucongrong (Cistanches Herba), Yinyanghuo (Epimedii Folium), Dihuang (Rehmanniae Radix), Gouqizi (Lycii Fructus), Renshen (Ginseng Radix et Rhizoma), Tusizi (Cuscutae Semen), Buguzhi (Psoraleae Fructus), Duzhong (Eucommiae Cortex), and Fuzi (Aconiti Lateralis Radix Praeparata). The main diseases were insomnia and impotence. 

Conclusion Based on the core formula of the treatment of kidney-yang deficiency, it reflects the thinking of TCM different diseases from multiple dimensions and provides a certain reference for clinical diagnosis and treatment and new herb research and development.

Key words: kidney-yang deficiency; Chinese patent medicines; supernetwork; core formula; Cervi Cornu Pantotrichum; Cistanches Herba; Epimedii Folium; Rehmanniae Radix; Lycii Fructus; Ginseng Radix et Rhizoma; Cuscutae Semen; Psoraleae Fructus; Eucommiae Cortex; Aconiti Lateralis Radix Praeparata; insomnia; impotence

 KIDNEY-YANG DEFICIENCY TREATMENT HERBAL CISTANCHE

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Kidney yang deficiency syndrome refers to a type of deficiency and cold syndrome caused by excessive deficiency of yang qi in the body and imbalance of warmth function [1]. This syndrome can occur in the development process of many diseases, such as impotence, insomnia, and late-stage diabetes [2] , functional constipation in the elderly [3-4], primary osteoporosis [5] and perimenopausal syndrome [6], etc. Under the guidance of the idea of treating different diseases with the same treatment, even though the diseases are different, the same treatment method is usually used when the kidney yang deficiency syndrome is manifested, and the prescriptions are also the same or similar. Currently, there are many

A large number of commercially available Chinese patent medicines can treat diseases characterized by kidney-yang deficiency syndrome. However, the diseases, symptoms and drug compatibility rules for the treatment of kidney-yang deficiency syndrome by Chinese patent medicines after they are released are still unclear.

There are currently studies using the Internet to explore the "disease-prescription-drug" pattern of marketed Chinese patent medicines [7], and have reached conclusions with important clinical significance. However, only constructing a single-layer network analysis of diseases, symptoms, and drugs is not enough to reveal The mechanism by which traditional Chinese medicine compounds effectively treat diseases cannot reflect the relationship between "disease-symptoms-drugs". Hypernetwork [8] is a multi-layer network with large data scale, complex connections and nested networks. The meaning of its nodes and edges is different from that of a single-layer network. It is no longer separately described as a node or an edge. The super network in the hypernetwork Edges are used to represent combinatorial preferences and combinatorial moves within a given set, while nodes represent the network of a given set.

Supernetworks have been widely used in the medical field in recent years. For example, Hu Ruixue et al. [9] analyzed the impact of different diagnosis and treatment elements on the differences in the process of cerebral infarction by constructing a supernetwork for the diagnosis and treatment of acute cerebral infarction using traditional Chinese and Western medicine. Li Chanxiu et al. [10] based on Alzheimer's disease data constructs a brain functional hypernetwork to analyze the association between brain imaging features and genes. In addition, research on evolutionary hypernetworks based on genetic algorithms classifies data sets such as acute leukemia and lung cancer, and the classification accuracy and readability of the results are more significant [11]. This study uses the hypernetwork method to construct a "disease-symptom-drug" network for kidney yang deficiency syndrome. Through the analysis of hyperedges, node hyperdegrees, etc. in the network, the inter-layer relationships are described, key drugs, common diseases and symptoms are discovered, and core prescriptions are mined. This article explores the medication rules for treating different diseases with this syndrome, and attempts to provide new ideas for clinical diagnosis and treatment and the development of new Chinese patent medicines.

 KIDNEY-YANG DEFICIENCY TREATMENT HERBAL CISTANCHE

1 Materials and methods

1.1 Data collection

1.1.1 Post-marketing proprietary Chinese medicine database and prescription screening standards 

The Chinese patent medicine value evaluation information database (http://crd.releae.daodikeji.com) is proprietary Chinese medicine information established by integrating the national Chinese medicine drug registration database, the national drug review database, etc. The database extensively collects information on Chinese patent medicines that were launched before 2020, such as the efficacy, category, adverse reactions, etc. of the medicines. This study retrieved and sorted the data from the establishment of the database to October 1, 2021, and combined it with "kidney yang deficiency, kidney yang deficiency, kidney yang deficiency, kidney deficiency and cold, kidney yang deficiency, kidney yang deficiency, kidney yang" The information on Chinese patent medicines for the treatment of kidney yang deficiency syndrome was searched on Yaozhi.com (January 2020 - December 2022) using the keywords "fatigue, kidney yang deficiency, Mingmen fire failure, kidney yin and yang deficiency", and a standardized database was established. Search by efficacy, indications, and common names of traditional Chinese medicines to obtain prescription sources.

The searched prescriptions are standardized and sorted, and prescriptions with repeated names, the same composition of Chinese medicine and the same composition of Chinese medicine are excluded. Prescriptions with incomplete composition of Chinese medicine are searched and completed through Pubiao.com (https://db.ouryao.com/); and removed Chemical ingredients and preparation methods contained in Chinese patent medicines.

1.1.2 Clinical research on post-marketing proprietary Chinese medicines

Computer search of CNKI, Wanfang, VIP, PubMed, Embase, Cochrane

The search time limit for clinical research literature on post-market Chinese patent medicines for the treatment of kidney-yang deficiency syndrome in databases such as Library and Web of Science is from the establishment of the database to June 15, 2023. The Chinese search terms are mainly "name of listed Chinese patent medicines", kidney yang deficiency, kidney yang deficiency syndrome, clinical research, clinical observation, randomized controlled trials, systematic reviews and meta-analysis, etc.; the English search terms are mainly "names of listed Chinese patent medicines", Shen YangXu, kidney-yang deficiency, kidney yang deficiency, kidney deficiency, observational study, clinical trial,

Randomized controlled trial, RCT, systematic review, Meta analysis, etc. The search strategy adopts a combination of subject words and free words. English abstracts from Chinese journals are counted as Chinese journals and are not included in the English literature.

Inclusion criteria: (1) Published journal articles; (2) Routine treatment with single drug or combination of chemical drugs; (3) Full-text published literature. Exclusion criteria: (1) Combined external therapy (acupuncture, massage and other physical therapy); (2) Dissertations; (3) Conference papers; (4) Review.

1.2 Data standardization

1.2.1 Standardization of information on proprietary Chinese medicines

The prescriptions obtained after removing duplicates will be divided into word-by-word terms according to the "functions and indications" and "composition of traditional Chinese medicine" in the instructions, and the three parts of disease, symptoms, and traditional Chinese medicine will be standardized in terminology. In order to ensure the rigor and accuracy of the research, the researchers discussed and decided with more than 3 people during the screening of Chinese patent medicine compounds and clinical literature, data extraction, and classification of doubtful Chinese patent medicines and their data, and sorted out the drug names, functions and indications of Chinese patent medicines. , efficacy, prescription composition and other information.

(1) Standardization of disease information: according to the International Classification of Diseases

(International classification of diseases, ICD10/11) coding [12] standardizes the diseases involved in the instructions of Chinese patent medicines. The disease keywords segmented word by word are searched in ICD10/11, and the search results are retained as nodes of the disease network. , because ICD11 includes traditional medical disease names, there is a possibility that TCM disease names and Western medicine disease names coexist during disease standardization.

 KIDNEY-YANG DEFICIENCY TREATMENT HERBAL CISTANCHE

(2) Symptom information standardization: Symptom relationship segmented word by word

The keywords are searched and compared in the "Terminology Standards for Common Clinical Symptoms of Traditional Chinese Medicine" and the search results are retained. The names of symptoms that are not included are kept unified and serve as nodes in the disease network. Keywords whose meanings are not exactly the same as those in the "Terms" were decided to be deleted or retained after discussion. For example, fatigue is classified as fatigue and weakness; frailty in the elderly is classified as physical weakness; oliguria and spotting of urine are classified as difficulty in urination, etc.

(3) Standardization of traditional Chinese medicine information: According to the "Chinese Pharmacopoeia" [13] and "Traditional Chinese

 Materia Medica" [14], the names of traditional Chinese medicines in the instructions are standardized, and chemical ingredients, excipients, and processing methods are removed. For example, velvet antler (hairless)/antler slices are unified as velvet antler, Polygonum multiflorum made from beans (soybean roasted in wine) is unified as Polygonum multiflorum, golden cherry fruit (meat/extract) is unified as golden cherry fruit, dogwood (wine prepared) is unified as dogwood, etc. The standardized results are used as traditional Chinese medicine network nodes.

1.2.2 Standardization of literature information

Use EndNoteX9.0 to organize and summarize the clinical research literature obtained in item "1.1.2", and use Excel2019 software to sort and summarize.

1.3 Data Mining

1.3.1 Descriptive analysis uses Excel 2019 for frequency statistics, and calculates and counts the diseases, symptoms and frequency of single drug use of Chinese patent medicines for kidney yang deficiency syndrome [16], the proportion of single drug use times to the total number of drug use, and Distribution of marketed Chinese patent medicine dosage forms and concurrent syndromes for the treatment of kidney-yang deficiency syndrome.

1.3.2 Analysis of clinical applications of commonly used Chinese patent medicines

The composition of the retrieved Chinese and English literature was described, and prescription literature with a number of documents ≥ 10 was extracted, including prescriptions, authors, corresponding diseases, interventions, courses of treatment, effects and outcome indicators, etc.

1.3.3 Analysis of "disease-symptom-drug" association rules for kidney-yang deficiency syndrome

The Apriori algorithm plug-in in IBM SPSS Modeler 18.0 software was used to analyze the three categories of terms of diseases, symptoms, and drugs for the treatment of kidney yang deficiency syndrome of Chinese patent medicines on the market [16], to explore the compatibility rules of compound drugs and the internal relationships between symptoms and diseases, and to set the minimum support The degree is 10%, the confidence is 80%, the maximum number of antecedents is 1, with diseases, symptoms, and drugs as nodes, the association combinations that meet the support degree ≥ 10% and the confidence ≥ 80% are the edges of the super network.

1.3.4 Construction of a single-layer network of drugs, symptoms and diseases related to kidney-yang deficiency syndrome and identification of core nodes of a single-layer network

Node associations of the same type of data constitute a single-layer network. In each layer of the network, comprehensive consideration is given to the

Number centrality (betweenness centrality, BC), closeness centrality (closeness centrality, CC) and degree centrality (degree centrality, DC) [17] are used to screen the core nodes of each layer of the network.

 KIDNEY-YANG DEFICIENCY TREATMENT HERBAL CISTANCHE

1.3.5 Construction of "disease-symptom-drug" super network for kidney yang deficiency syndrome

  Based on a single-layer network, there is a correlation between any two or three of diseases, symptoms, and drugs. At this time, the edge between two or three heterogeneous nodes can be regarded as a hyperedge, and the multi-layered network of proprietary Chinese medicines for the treatment of kidney-yang deficiency syndrome (hereinafter referred to as the super-network of kidney-yang deficiency syndrome) has been launched.

The core nodes of the entire super network are identified by calculating the node hyperdegree value in the kidney yang deficiency syndrome hypernetwork. The node hyperdegree value [18] is also called hyperdegree centrality, which includes the number of hyperedges of the node. Point importance is positively related to the number of hyperedges it is on. The obtained results were imported into Cytocape 3.9.1 for network visualization.

1.3.6 Super network core node identification and core prescription discovery

Calculate and sort the node excess values of traditional Chinese medicine across the 3-layer network in the entire "disease-symptoms-drug" super network, take the top 10 drugs, and analyze the drugs with frequencies greater than 30 to obtain the core drugs of the kidney yang deficiency syndrome super network , and then screen out the core prescriptions for treating kidney yang deficiency syndrome.

In the same way, calculate the node excess values across the 3-layer network for the drugs that treat the main diseases of kidney-yang deficiency syndrome and sort them, and take the top 10 drugs to discover the core prescriptions for the main diseases.

 KIDNEY-YANG DEFICIENCY TREATMENT HERBAL CISTANCHE

1.3.7 Comparative analysis of prescription similarity and drug compatibility scores for major diseases

Analyze and compare the similarities between the selected core prescriptions for the treatment of kidney yang deficiency syndrome and the high-frequency drugs selected in this study, as well as the similarity between the core prescriptions for the kidney yang deficiency syndrome and the core prescriptions related to core diseases; and analyze the similarities of the marketed Chinese patent medicines for the treatment of kidney yang Medication compatibility rules for major diseases with deficiency syndrome.