Analysis on medication rule of traditional Chinese medicine treating chemotherapy-induced diarrhea based on traditional Chinese medicine(TCM) inheritance computing platform system

Yu Gao, Shao-Bo Hu, Chao Deng, Fei Su, Li-Qun Jia?

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

2. Department of Oncology of Integrated Chinese and Western Medicine, China-Japan Friendship Hospital, Beijing 100029, China

ABSTRACT Objective: To dig deeper into the traditional Chinese medicine treatment rules of chemotherapy?induced diarrhea with traditional Chinese medicine (TCM) inheritance computing platform system. Methods: Taking “traditional Chinese medicine”, “chemotherapy”and “diarrhea” as the theme words, comprehensive search of the database of CNKI, Wanfang and VIP from its inception to November 2020 was conduct?ed. The formulas of external treatment of traditional Chinese medicine for chemotherapy?induced diarrhea were included and the association rule, clustering and factor analysis were carried out. Results: A total of 145 papers, 57 prescriptions meeting the inclusion criteria were collected, among which high?frequency drugs including Baizhu (Atractylodis macrocephalae rhizoma), Fuling (Poria),Dangshen (Codonopsisradix), Huanglian (Coptidis rhizoma), Zhigancao (Glycyrrhizae radix et rhizoma praeparata cum melle) were the most commonly used. The confidence level was set as 0.7 and the support level was set as 10, 12 core compatibility groups were obtained,and 6 categories were cluster analyzed. Conclusion: The principle of external treatment of chemotherapy?induced diarrhea is mainly “restore deficiency and benefiting qi”, “benefiting water infiltration and dampness”, “clearing heat” and “inducing astringency”. Prescription combination and new prescription combination based on traditional Chinese medicine (TCM)inheritance computing platform system can be used as reference for clinicians and applied in primary hospitals.

Keywords:Chemotherapy induced diarrhea Traditional Chinese medicine Medication regulation Data mining Traditional Chinese medicine(TCM)inheritance computing platform system?Corresponding author: JIA Li?qun, M.D., Chief Physician.E?mail: liqun?jia@hotmail.com.

1. Introduction

Chemotherapy?related diarrhea (CID) refers to diarrhea in patients with cancer during or after chemotherapy. It is caused by cytotoxic chemotherapy drugs and is a common gastrointestinal toxicity. The chemotherapeutic drugs that cause CID are mainly fluorouracil(5?FU) and irinotecan (CPT?11). Delayed diarrhea caused by irinotecan sometimes occurs 24 hours after chemotherapy.Hydroxycamptothecin, capecitabine, gibberellin Fetinib, etc. can also cause CID [1,2]. Chemotherapy?related diarrhea can affect the efficacy of chemotherapy, leading to changes or termination of chemotherapy plans, and even life?threatening dehydration and electrolyte disturbances. At present, the expert consensus and recommended guidelines apply the basic treatment of western medicine to loperamide, octreotide and other drugs, and patients with severe diarrhea with dehydration and electrolyte disorders should be given fluid supplement support [3]. At present, there are many clinical studies on TCM chemotherapy?related diarrhea,which can effectively improve the diarrhea of chemotherapy patients, relieve the pain of tumor patients, and improve their quality of life. At present, there is no standard, norms and consensus on the treatment of Chinese medicine. The clinical treatment ideas are blooming. This study aims to analyze Chinese medicine by collecting and sorting out the Chinese medicine treatment CID prescriptions in the literature database, using the traditional Chinese medicine inheritance computing platform, using association rules and cluster analysis the prescriptions and medication rules for the treatment of CID, analysis of syndrome differentiation and treatment ideas, provide guidance and reference for the clinical selection of prescriptions and medications.

2. Materials and methods

2.1 Data source

Search databases such as CNKI, Wanfang, and VIP. The search time is from the self?built database until November 2020, using “Chinese medicine”, “Chinese medicine”, “chemotherapy” and “diarrhea” as keywords, and manually screened and retrieved relevant literature.

2.2 Inclusion criteria and exclusion criteria

Choose to use traditional Chinese medicines or proprietary Chinese medicines orally to take chemotherapy?related clinical studies. The literature reports that the therapeutic effect is effective. The research types are randomized controlled studies, case reports, clinical observations, etc., and basic experimental studies such as animal experiments, reviews, conference papers, and no specific drugs are excluded Composition, use of external application of Chinese medicine, acupuncture and other documents. Finally, from the 145 preliminary screenings, 57 papers that meet the criteria were further screened.

2.3 Data processing

Refer to the “Chinese Pharmacopoeia” [4] 2015 edition to standardize the names of traditional Chinese medicines included in the prescriptions, and treat the origin, processing methods, and aliases of the drugs in a unified manner.

2.4 Data Entry

The 57 collected prescriptions were entered into the traditional Chinese medicine inheritance calculation platform software (V3.0)using the double entry method, and the two persons were responsible for data review to prevent duplication, wrong entry, and omission,and to ensure the authenticity and accuracy of the data.

2.5 Data analysis

We use the traditional Chinese medicine inheritance computing platform (V3.0) system to divide the prescription information,describe the four qi, five flavours, meridians, and effects of traditional Chinese medicine and generate a radar chart to display the distribution of the medicine in a visual display. And use the data to conduct association rule analysis, cluster analysis (a combination of k?means algorithm and regression model), and summarize the group.

3. Results

3.1 Occurring frequency of drugs

After a comprehensive search, 57 prescriptions that meet the criteria were finally included, involving 79 Chinese medicines,and the cumulative frequency of occurrence was 471. Among them, there are 11 traditional Chinese medicines with frequency of use ≥15 times, with a total of 223 occurrences. They are Baizhu(Atractylodis macrocephalae rhizoma) (34 times), Fuling (Poria)(33 times), Dangshen (Codonopsisradix) (21 times), Huanglian(Coptidis rhizoma) (19 times),Zhigancao (Glycyrrhizae radix et rhizoma praeparata cum melle) (18 times), Baishao (Paeoniae radix alba) (17 times), Huangqin (Scutellariae radix) (17 times), and Shanyao (Dioscoreae rhizoma) (16 times) ), Gancao (Glycyrrhizae radix et rhizoma) (16 times), Yiyiren (Coicis semen) (16 times),Chenpi (Citri reticulatae pericarpium) (16 times), Ganjiang(Zingiberis rhizoma) (13 times), Sharen (Amomi fructus)(12 times), Roudoukou (Myristicae semen) (10 times), Wuzhuyu(Euodiae fructus) (10 times), Huangqi (Astragali radix) (10 times).See Table 1 for 20 traditional Chinese medicines used more than 10 times.

Table1 Usage of Drugs(Number of times≥10 )

3.2 Distribution of Four nature of drugs, Five Flavours and channel tropisms

Medications are classified according to the four nature of drugs,including cold, hot, warm and cool. Different characteristics of the same drug were included in the analysis. The most frequent is the warm natured drugs, followed by the calm natured drugs.The warm natured drugs and the calm natured drugs account for 72.82%, accounting for the main part. After that, cold natured drugs accounted for 15%. The statistical results are shown in Table 2.According to the analysis of the five flavours, the drugs are mostly sweet, followed by bitter drugs, and salty drugs were not included.The statistical results are shown in Table 3. The four?nature radar chart is shown in Figure 1, and the five?flavours radar chart is shown in Figure 2. The numbers in the figure indicate the frequency of use of the drugs, and the difference can be clearly seen. Analysis of the distribution of the channel tropisms shows that most of the drugs belong to the spleen meridian, lung meridian and stomach meridian,accounting for 27.27%, 17.57%, and 15.7% respectively. The rest of the drugs are distributed in the heart meridian, kidney meridian,large intestine, bladder meridian, etc., not involving the pericardium meridian. The statistical results are shown in Table 4. Figure 3 is a radar chart of channel tropisms analysis. The numbers in the figure indicate the frequency of use of drugs.

Table 2 Analysis of Four Nature of Drugs

Figure 1 The Four?Nature Radar Chart

Table 3 Analysis of Five Flavours of Drugs

Figure 2 The five?flavours radar chart

Table 4 Analysis of Channel Tropisms of Drugs

Figure 3 The channel tropisms analysis radar chart

3.3 Efficacy of Drugs

We ranked the efficacy of the drugs contained in the 57 prescriptions in descending order of frequency. The most important one is tonic drugs, accounting for 36.94%. Secondly, there are eliminating dampness and diuresis type, heat?clearing type,astringent collection type, and superficies?relieving type. Warming interior, regulating qi?flowing and dissipating dampness also account for a certain proportion. See Table 5 and Figure 4 for details. Figure 4 is a histogram of the top 10 power distributions, and the numbers in the figure are the frequency of occurrence.

Table 5 Efficacy of Drugs

Figure 4 Histogram of Efficacy Statistics

Through correlation analysis, the relationship between drug and drug in the prescription is obtained, and the correlation analysis is carried out on the medication. The support degree indicates the frequency of the two drugs at the same time; the confidence degree indicates the probability of the second drug when the first drug appears in the medicine pair. Through the above methods, 12 pairs of combinations with a higher frequency were obtained, mainly Baizhu? Fuling, Baizhu? Dangshen and other drugs which have the effect of tonifying spleen and qi combinations, as well as Huanglian and Yiyiren which have the effect of clearing heat and dampness,strengthening spleen and dampness. We set the confidence level to 1, and get 24 association rules. Baibiandou (Lablab semen album)and Fuling have the effect of invigorating the spleen, promoting dampness and relieve diarrhea, often appear with Dangshen, Baizhu,and Shanyao, Sharen to relieve dampness and appetite, warm the spleen and relieve diarrhea. The support degree was set as 10, and the confidence degree was set as 1. The relationship diagram of core drugs was shown in Figure 5. The main drugs were Baizhu, Fuling,Dangshen, Shanyao, Yiyiren.

Table 6 Core couplet medicines

Table 7 Association rule statistics table

Figure 5 The Relationship Diagram of Core Drugs

3.4 Cluster analysis

Based on clinical experience, 57 prescriptions were divided into 6 categories.

The first category includes Shengjiang (ZINGIBERIS RHIZOMA RECENS); Zhigancao; Dangshen; Ganjiang; Huangqin; Jiangbanxia(PINELLIAE RHIZOMA PRAEPARATUM CUM ZINGIBERE ET ALUMINE); Huanglian; Dazao (JUJUBAE FRUCTUS); Huangqi;Baibiandou (LABLAB SEMEN ALBUM); Baizhu; Fuling. The second category includes Fuzi (ACONITI LATERALIS RADIX PRAEPARATA), Renshen (GINSENG RADIX ET RHIZOMA);Ganjiang, Gancao. The third category includes Chaihu (BUPLEURI RADIX); Huangqin; Banxia (PINELLIAE RHIZOMA); Baizhu;Zexie (ALISMATIS RHIZOMA); Zhuling (POLYPORUS); Guizhi(CINNAMOMI RAMULUS); Dangshen; Fuling; Gancao; Shengjiang;Dazao. The fourth category includes Buguzhi (PSORALEAE FRUCTUS); Wuzhuyu; Roudoukou; Shengma (CIMICIFUGAE RHIZOMA); Wuweizi (SCHISANDRAE CHINENSIS FRUCTUS);Huangqi; Ganjiang.The fifth category includes Dangshen; Fuling;Baizhu; Shanyao; Yiyiren; Baibiandou; Lianzi (NELUMBINIS SEMEN); Chenpi; Sharen; Jiegeng (PLATYCODONIS RADIX);Zhigancao;Cangzhu (ATRACTYLODIS RHIZOMA); Hezi(CHEBULAE FRUCTUS); Dazao. The sixth category includes Baizh u;Chenpi;Baishao;Fuling;Dangshen; Fangfeng (SAPOSHNIKOVIAE RADIX); Zhigancao.

4. Discussion

Chemotherapy induced diarrhea is caused by the damage of intestinal mucosa caused by chemotherapy drugs, which is known as “diarrhea” in Chinese medicine. According to traditional Chinese medicine, tumor is caused by the hybrid of “deficiency”,“pathogenic”, “stasis” and “toxin”. Cancer patients are generally weak. Metabolism of drugs to gastrointestinal tract leads to dysfunction of spleen and stomach in transportation, and diarrhea occurs. Although there are many western medicine drugs for the prevention and treatment of chemotherapy?induced diarrhea, there is still no clear and effective standard treatment. In addition to internal administration, there are other methods of traditional Chinese medicine, such as acupuncture and moxibustion [5] and umbilical application [6]. Monomer active ingredients, such as curcumin [7]and Auckabea sinica [8], have been proved by scientific studies to be able to improve chemotherapy?associated diarrhea, but it is often difficult to obtain definite efficacy with single acting drugs.Modern pharmacology has confirmed that TCM compound has the characteristics of multi?target and multi?channel action, and can be treated according to different individual syndrome differentiation,and often has a good effect in the treatment of chemotherapy?associated diarrhea.

Based on the analysis of 57 treatments for chemotherapy?induced diarrhea, this study found that tonic drugs, eliminating dampness and diuresis drugs accounted for the main part, and high?frequency drugs Baizhu, Fuling, Dangshen, Shanyao, and Yiyiren were represented by clinicians. The method of “supporting the healthy energy and replenishing deficiency, dissipating dampness and stopping diarrhea”is consistent. From the statistics of drug properties, it can be seen that the properties of commonly used drugs are mainly warm,calm, and cold. According to the analysis of the five flavours, the drugs are mostly sweet and bitter; most drugs belong to the spleen and stomach meridians, as well as the Lung meridians and Heart meridians, Kidney Channel, Large Intestine, Bladder Channel, etc. In“Suwen·Jutong Theory”, there is a saying: Cold pathogen penetrates into the small intestine, preventing food from accumulating, so abdominal pain and diarrhea. The clinical diarrhea is mostly considered as the cold pathogen guest in the small intestine. There are also physicians who believe that the pathogenesis of diarrhea is a mixture of cold and heat [9], Huanglian and Huangqin should be added, which is consistent with the results of the drug analysis in this article.

Through correlation analysis, it can be concluded that the commonly used drugs are combined by Baizhu, Fuling, Dangshen, Shanyao,Huangqi, Huanglian and other drugs. The core combination has the functions of invigorating the middle and nourishing qi, invigorating the spleen and stomach, diminishing water and dampening. From the perspective of cluster analysis, drugs can be divided into 6 categories, the first category: Shengjiang; Zhigancao; Dangshen;Ganjiang; Huangqin; Jiangbanxia; Huanglian; Dazao; Huangqi;Baibiandou; Baizhu; Fuling. Most of these drugs are derived from the prescription Shengjiang Xiexin Decoction. Shengjiang Xiexin Decoction and Gancao Xiexin Decoction are commonly used clinical prescriptions. Xiexin Decoctions are derived from “Shanghan Lun”.The therapeutic method is pungent open and bitter down bearing and combined therapy of cooling with warming. The effect of the prescription is to stop diarrhea and invigorate deficiency, treat both symptoms and root causes. The power is suitable for diarrhea with stagnation of spleen and stomach qi, stomach heat and cold spleen,and mixed cold and heat.

The second category: Fuzi; Renshen; Ganjiang; Gancao; Baizhu.These drugs are mainly warming yang and invigorating the spleen,similar to Fuzi Ganjiang Decoction. The effect of Shengjiang is warming interior for dispersing cold, and the effect of Fuzi is invigorating yang.Both of Shengjiang and Fuzi can warm the spleen and help the spleen to transport and transform, warm the yang to dispel cold, and warm the middle of the dampness. The third category: Chaihu; Huangqin; Banxia; Baizhu; Zexie; Zhuling;Guizhi; Dangshen; Fuling; Gancao; Shengjiang; Dazao. Xiao Chaihu Decoction is a method of “relieving shaoyang disorder”.The effect of Xiao Chaihu Decoction is resolving exterior and interior, harmonizing liver and spleen, soothing liver and stomach,transmitting membrane, dividing up and down. Xiao Chaihu Decoction has a significant effect on the complicated diarrhea caused by chemotherapy in cancer patients. And it is suitable for diarrhea caused by other reasons such as irritable bowel syndrome, ulcerative colitis [10]. The fourth category: Buguzhi; Wuzhuyu; Roudoukou;Shengma; Wuweizi; Huangqi; Ganjiang. These drugs conform to the composition of Sishen Pills, which are the key prescriptions for tonifying kidney and warming spleen and strengthening astringency and stopping diarrhea. The fifth category: Dangshen; Fuling; Baizhu;Shanyao; Yiyiren; Baibiandou; Lianzi; Chenpi; Sharen; Jiegeng;Zhigancao; Cangzhu; Hezi; Dazao. Shenling Baizhu Powder is a representative prescription for the treatment of spleen deficiency and dampness syndrome and embodies the treatment of “supplementing spleen to nourish lung”. It has the effects of tonifying spleen and lung, infiltrating dampness and stopping diarrhea, and promoting qi and protecting lung. Shenling Baizhu powder is mild, warm and not dry.The sixth category: Baizhu; Chenpi; Baishao; Fuli;Dangshen; Fangfeng; Zhigancao. Tongxie Yaofang is mainly used for diarrhea of disharmony between liver and spleen. It has the effect of harmonizing liver and spleen, tonifying spleen and softening liver,dispelling dampness and stopping diarrhea. Cancer patients are often emotionally unhappy. In the treatment of diarrhea in cancer patients,attention should be paid to soothing liver and invigorating spleen and regulating qi stagnation.

Based on the frequency statistics of prescription drugs, analysis of natures, flavours, and the channel tropisms of drugs, it can summarize commonly used Chinese medicines and their drug characteristics, analyze and summarize clinical medication rules, and help organize new clinical prescriptions to guide clinical medication.Chemotherapy?related diarrhea is a common clinical symptom, and there is still room for exploration in the research of TCM treatment.At present, clinicians do not yet fully understand the pathogenesis of diarrhea caused by different tumors and different types of chemotherapeutic drugs, and their understanding of the etiology and pathogenesis is too single. In addition to replenishing qi deficiency,diuresis and moisturizing, the traditional Chinese medicines we use should also be more accurate in diagnosis and treatment analysis. In treatment, it can be combined with genetic results, such as increasing or decreasing the dose of drugs for patients with differential expression of UGT1A1 gene [11]. As far as the mechanism of action is concerned, it can be combined with changes in the intestinal flora for analysis [12,13]. The literature included in this study is limited,and further clinical studies are still needed to provide a higher level of evidence?based medicine to treat chemotherapy?related diarrhea.

Author's contribution explanation: Gao Yu and Jia Liqun carried out the design of this study, Gao Yu and Su Fei carried out the screening and extraction of the literature, Hu Shaobo and Deng Chao carried out processing operations on the collected data, Gao Yu made a summary analysis and wrote the pen, Jia Liqun reviewed .