Yu-Qiang Lu,Hui Ding,Zhao-Lin Shi,Ru-Ying Li,Guo-Cheng Zhang＊

1Shaanxi University of Chinese Medicine,Xi Xian New Area,Shaanxi 712046,China;2The Second Affiliated Hospital of Shaanxi University of Chinese Medicine,Xianyang 712046,China.

Background:To analyze the medication rule of Chinese patent medicine compound for constipation by data mining,and to provide reference for the treatment of constipation.Methods:The Chinese patent medicines for constipation in thePharmacopoeia of the People’s Republic of China (2020) and Chinese patent medicine prescription database of yaozhi.com (https://db.yaozh.com/chufang) were collected and sorted.The prescriptions and drug composition were input into Excel2010.ategories,nature,flavour and channel tropism of drugs were analyzed by using ancient and modern medical case cloud platform (V2.3.5).The cluster analysis of high-frequency drugs was carried out by SPSS 22.0,and rules of high-frequency drugs were analyzed by Apriori algorithm provided by SPSS modeler 18.0.Results:Two hundred and thirty-six Chinese patent medicine prescriptions that met the requirements were collected,containing 349 Chinese medicines in total,with a total frequency of 2,277.The drugs with frequency ≥ 25 times were high-frequency drugs,with a total of 24 flavours,and the top 5 were Dahuang (Rhei radix et rhizoma),Huangqin(Scutellariae radix),Gancao (Glycyrrhizae radix et rhizoma),Huanglian (Coptidis rhizoma) and Bohe (Menthae haplocalycis herba).The top 3 frequency of efficacy of high-frequency drugs were “Heat-Clearing (remove heat from the body surface and inside)” drugs,“Purgating (to promote excretion of stools)” drugs and “Reinforcing” (to supplement the body’s lack of “Qi,Blood,Yin and Yang” ) drugs.The nature of high-frequency drugs were cold,warm and flat.The top 3 flavour of the high frequency drugs were bitter,spicy and sweet.The top 4 channel tropism of high-frequency drugs were “Spleen”,“Stomach”,“Lung”,“Large intestine”.According to the association rule,11 drug pairs were obtained,and the core drug pairs were Zhizi (Gardeniae fructus)-Rhei radix et rhizoma,Huangbo(Phellodendri chinensis cortex)-Rhei radix et rhizoma. Four new methods were obtained based on cluster analysis.Conclusion:Chinese patent medicine has a certain regularity in the treatment of constipation.This paper can provide some references for the clinical treatment of constipation with Chinese medicine.

Key words: Chinese patent medicine,Constipation,Medication rule,Data mining

Background

Constipation is a common gastrointestinal disease,but there is no ideal definition in the world at present.In China,it is generally believed that constipation refers to defecation less than 3 times per week,exertion of defecation,dry stool,difficulty in defecation,lack of feeling of defecation,and assisted defecation with deficiency in severe cases [1].With the rapid development of society and economy,people’s pace of life is getting faster and faster,and there are more and more irregular and bad habits.The incidence of constipation is also on the rise,especially in the elderly,constipation is as high as 15%–20% [2].For functional constipation,western medicine mainly used combined with health education,and suppositories or clean enemas are used in severe cases.Western medicine laxatives include salt laxatives such as sulfate,osmotic laxatives such as lactulose,expansive laxatives such as polyethylene glycol,irritant laxatives such as senna,pro-motility drugs such as etopril,and intestinal flora regulating drugs such as caseobacterium tablets.However,long-term use of western medicine is prone to side effects such as drug resistance,recurrent illness,and even colonic blackening,which not only affects the physical and mental health of patients,but also aggravates the economic burden of the family [3–5].Traditional Chinese medicine (TCM) has unique advantages in the treatment of functional constipation.Under the guidance of the basic theory of TCM,drugs with single or multiple TCM flavors properly processed are called Chinese patent medicines,which have the advantages of being easy to take,having good efficacy,and being convenient to store and carry [6].In this paper,we collected and sorted out Chinese patent medicines for the treatment of functional constipation and analyzed their medication rules,in order to provide TCM reference for the treatment of functional constipation.

Materials and methods

Sources of prescription

The prescription of Chinese patent medicine for the treatment of functional constipation comes from Chinese patent medicine prescription database of yaozhicom,and also refers to the 2020 edition of thePharmacopoeia of the People’s Republic of China[7](Chinese Pharmacopoeia).

Inclusion criteria

The subjects of “functional constipation” and “dry stool” were used to search the above 2 databases,and the included Chinese patent medicines should meet the following criteria:(1) constipation diagnosis requirements [2];(2) clinical class,there are specific prescriptions;(3) in the case of the same constituent drugs,the prescription type is different,only one type is selected,and the selection cannot be repeated;(4) a clear curative effect of Chinese patent medicine.

Exclusion criteria

(1) Constipation is not mentioned in the treatment or function;(2) incomplete composition of Chinese patent medicine;(3) only single Chinese medicine;(4) the composition of Chinese patent medicine contains western medicine.

Data standardization

Chinese patent medicine prescription and specific composition of drugs were recorded in Excel 2010,and the names of collected Chinese medicines were standardized according to the standards of theChinese Pharmacopoeia(2020 edition).For example,some drugs need to be specially processed in some prescriptions according to the need for treatment,and these drugs need to be standardized,such as Shenghuangqi (Astragali radix) was unified as Huangqi(Astragali radix),Dangguiwei (Angelica tail) was changed to Danggui (Angelicae sinensis radix).The main efficacy,four qi and five flavors of the drugs and their channel tropism were recorded into Excel 2010 respectively.For example,Huanglian (Coptidis rhizoma) is a heat-clearing drug with cold and bitter taste,and its channel tropism belongs to the heart,spleen,stomach,liver,gallbladder and large intestine.

Statistic analysis

According to the requirements and norms,the data of medicinal effect,nature,flavour and channel tropism of TCM compounds were sorted out.The assignment of each TCM was based on “NO=0,Have=1”,input Excel 2010 software,and made system cluster analysis in IBM SPSS 22.0 software and got a new formula.The allocation of each TCM was based on “N=None,Y=Yes”,which was input into Excel 2010 software,and association rule analysis was carried out in SPSS Modeler18.0 software,and association drug pairs were obtained through modeling.

Results

Drug use frequency

The 236 Chinese patent medicine prescriptions that met the exclusion and inclusion criteria and their drugs were introduced into the ancient and modern medical case cloud platform.A total of 349 Chinese medicines were counted,with a total frequency of 2,277 occurrences.The frequency of efficacy and medicine was 2,277 times,the frequency of medicine taste was 3,418 times,and the frequency of meridian return was 5,545 times.

High frequency drug distribution

There were 24 TCM ≥ 25 times,960 times in total,accounting for 42.16% of the total frequency.Table 1 showed that Dahuang (Rhei radix et rhizoma),Huangqin (Scutellariae radix),Gancao (Glycyrrhizae radix et rhizoma),Coptidis rhizomaand Bohe (Menthae haplocalycis herba) were the five drugs with the highest frequency,and the frequency percentages were 6.11%,3.21%,3.21%,1.98% and 1.76%,respectively (2,277 times,Table 1).

Efficacy distribution of high frequency drugs

As can be seen from Table 2,there are 8 kinds of effects of high-frequency drugs,and the drugs with frequency≥ 100 times are “Heat-Clearing” drugs,“Purging” drugs,“Reinforcing” drugs and “Qi-regulating” drugs(to Promote the movement of human “Qi” ).

Distribution of nature of high-frequency drugs

The results showed that the high frequency drugs had four properties,which were cold,warm,flat and cool.The first three drugs were used 920 times,accounting for 41.57% of the total times (2,277 times,Table 3).

Distribution of high frequency drug flavor

The results showed that there were 4 kinds of high frequency drugs,namely bitter,acrid,sweet and sour.The top 3 flavors were used for 1,342 times,accounting for 39.26% of the total times (3,418 times,Table 4).

The channel tropism of high frequency drugs

As can be seen from Table 5,the channelization of highfrequency drugs includes 11 types,such as spleen,stomach and large intestine.The total frequency of high-frequency drug passage was 3,100 times,accounting for 55.91% of all drug passage (5,545 times,Table 5).

High frequency drug association rules

In SPSS Modeler18.0 software,the minimum support is set as 10%,the minimum confidence is set as 80%,and the maximum preceding item number is set as 1.As can be seen from Table 6,there are 11 drug pairs in the highfrequency drug association rules.The upper limit of weak link is set to 15,and the lower limit of strong link is set to 35.The networked display diagram of association rules is obtained (Figure 1).The thicker the line segment is,the stronger the correlation is.

Table 1 Top 24 Chinese medicines for the treatment of constipation

Table 2 High frequency drug efficacy

Table 3 Nature of high-frequency drugs in the treatment of constipation

Table 4 The flavour of high frequency drugs

Table 5 The Meridian tropism of high frequency drugs

Table 6 Association rule of high frequency drugs

Clustering analysis of high frequency drugs

High-frequency drug data was imported into SPSS 22.0 software,intergroup links were selected by clustering method,Pearson correlation was selected by interval,and 4 new prescriptions were analyzed (Figure 2).

Figure 1 Association network diagram of high-frequency TCM in the treatment of constipation

Figure 2 Cluster analysis of high frequency TCMin the treatment of constipation

Discuss

The analysis of high frequency drug

The top 3 high-frequency drugs wereRhei radix et rhizoma,Scutellariae radixandGlycyrrhizae radix etrhizoma.Rhei radix et rhizomahas been used as atreatment for constipation for a long time,and the first documented use of it can be found in theShennong Chinese Herbal Scriptures(written by Shennong about 2,000 years ago).Wang Xin et al.believed thatRhei radix et rhizomabelongs to anthraquinone drugs,which can induce and promote defecation by changing the movement pattern and increasing the amount of colon fluid [8].Experimental results proved the synergistic effect of various components inRhei radix et rhizoma,suggesting that aloe-emodin andRhei radix et rhizomaplay a laxative role by directly acting on smooth muscle,while emodin plays an indirect laxative role by affectingthe nervous system [9].Constipation is located in the large intestine,which is related to the dysfunction of the spleen,stomach,liver,kidney,lung and other viscera.Its basic pathogenesis is “Heat Accumulation in the Large Intestine”,or “Qi Stagnation”,or “Cold Coagulation”,or “Deficiency of Yin and Yang,Qi and Blood” (these factors can lead to stool excretion difficulties).Zhou Cong [10] believed that pain,diarrhea,constipation of stools or acute symptoms caused by dampness and heat in the epigastric area needed medicines such asScutellariae radixto clear the organs and relieve heat.The weakness of spleen function and disorder of the large intestine peristalsis could cause the defecation difficulty,the shortness of breath after defecation,and reduction of the meal quantity.Glycyrrhizae radix et rhizomais a “Qi Reinforcing” drug.Professor Liu Yuedong usedGlycyrrhizae radix et rhizomaand other “Qi Reinforcing” medicines to “Invigorate the Spleen,Replenish Qi” (to enhance the function of the spleen to aid digestion) and relieve constipation [11].Shen Deli[12] through the experiment found that constipation model group myosin light-chain kinase content in intestinal tissues and myosin phosphorylation were significantly lower than normal control group.Addition of glycyrrhizic acid can significantly recover myosin light-chain kinase content and myosin phosphorylation levels.It reveals that the glycyrrhizic acid can stimulate smooth muscle contraction by enhancing protein phosphorylation.

Efficacy analysis of high frequency drugs

TCM believes that constipation is due to feelings of external evil (viruses or bacteria in the air can cause intestinal dysfunction and make it difficult to defecate),unhealthy diet,emotional disorders or old age.Feces stay in the intestines for too long,stool texture becomes hard,defecation time increases [13].Zhang Zhongjing,a famous doctor of the Han Dynasty,believed that “Excessive Heat in the Stomach and Insufficient Spleen Yin” (heat to reduce the body fluid in the stomach and intestines,stool becomes dry) would lead to dry stools.Therefore,“Heat-Clearing” drugs (325 times),“Purgating” drugs (200 times) and “Reinforcing” drugs(170 times) accounted for 30.57%.

Analysis of high frequency drug nature and drug flavour

The highest frequency drugs for the treatment of constipationare cold drugs (583 times) followed by warm drugs 196 times and flat drugs 141 times.Gastrointestinal heat andconsumption of body fluid can result in dry stool and difficult excretion,so the use of cold drugs can “Clear Heat and Defecation”.Some doctors believe that most elderly patients with chronic constipation belong to deficiency syndrome,which is mainly caused by overeating raw and cold food,fatigue,or being attacked by cold and dampness (these are thefactors that make the spleen function decline,resulting in difficult defecation),[14].Accordingly,the clinical need ofAucklandiae radix,Paeoniae radix albaisothermal medicine will invigorate spleen and defecate.Disease is a state of imbalance between “Yin” and “Yang” in the human body.TCM pays attention to peace,but for some mild constipation,violent drugs can not be used,so flat drugs such asCannabis fructusare widely used.High frequency drugs for the treatment of constipation include bitter (719 times),acrid (364 times),sweet (259 times),sour (59 times),bitter flavour can promote stool excretion;the combination of pungent and sweet flavour can transform into “Yang” and promote defecation with warm spleen and stomach(combination of these 2 types of drugs can “Replenish Yang” ).The combination of sour and sweet flavour can be transformed into “Yin” to moisten the intestines and defecate (combination of these 2 types of drugs can “Replenish Yin” ).

The analysis of channel tropism with high frequency drugs

Among the high-frequency drugs used to treat constipation,the top 5 were spleen (721 times),stomach(463 times),lung (417 times),large intestine (411 times)and liver (372 times),accounting for 42.99%.The spleen and stomach are essential organs for survival after birth.The spleen plays a leading role in transporting water and grain,while the stomach plays a leading role in receiving and digesting water and grain.The drugs of the spleen and stomach meridian can promote the absorption of food and fecal transmission.The large intestine dominates the transmission of dross such as feces.Excessive water absorption of the large intestine will lead to dry stool.The drugs of the large intestine meridian can relieve the symptoms of constipation.Lung and air are closely connected,large intestine in the body,“Lung Qi” disorder will lead to large intestine conduction disorder,so the treatment of constipation can use lung medicine.Liver is closely related to emotion,and symptoms such as dry stools,difficult defecation,dry mouth and bitter mouth appear in mood depression,so it is appropriate to use liver meridian medicine to regulate qi and relieve constipation [15].

Association rule analysis of high-frequency drugs

In order of confidence percentage,Gardeniae fructuswithRhei radix et rhizoma,Phellodendri chinensiscortexwithRhei radix et rhizoma,Gardeniae fructuswithScutellariae radix,andPlatycodonis radixwithRhei radix et rhizomawere the most important combination for the treatment of constipation,and the confidence percentages were 97.06%,92.00%,88.24%,88.24%,respectively.The lung is closely related to the large intestine,with healthy lung function,normal breathing,unobstructed air in the large intestine and unobstructed stool [16].

Clustering results and new method analysis

The abscissa “20” is selected as the dividing line,and a total of 4 groups of squares are obtained.Group 1 consists ofMenthae haplocalycis herba,Forsythiae fructus,Platycodonis radix,Glycyrrhizae radix et rhizoma,Gypsum fibrosum,Scutellariae radix,Gardeniae fructus,Phellodendri chinensis cortex,Coptidis rhizoma,Borneolum syntheticum,Rhei radix et rhizoma,Trichosanthis radix,Paeoniae radix rubra.The main effect is to clear heat and purge fire,detoxify and defecate (anti-inflammatory and reduce fever,reduce toxins and promote defecation).Group 2 is composed of a singleCannabis fructus,and the experimental study found thatCannabis fructusoil with different concentrations significantly improved the defecation function,mental state and stool texture of constipated mice [17].Group 3 is composed ofAngelicae sinensis radix,Atractylodis macrocephalae rhizomaandPaeoniae radix alba.The 3 medicines are all reinforcing drugs,which can regulate intestinal function,promote stool excretion,for the treatment of “Qi” and blood deficiency constipation.Group 4 is composed ofCitri reticulatae pericarpium,Rehmanniae radix,Saposhnikoviae radix,Arecae semen,Pharbitidis semen,Aurantii fructus immaturus,Aucklandiae radix.Most of these drugs are “Qi” regulating drugs.Some researchers believe that qi regulating drugs should be used to relieve constipation with abnormal “Qi” transmission function [18].

Defect and improvement

Constipation is a common symptom or disease,and TCM can play a unique role in treating it.However,the application of TCM in the clinical treatment of constipation also has some shortcomings,such as classical prescriptions and experimental studies of traditional Chinese medicine still need to be further explored.The dosage of TCM also needs to be collected further.With the aggravation of ecological environmental pollution,the efficacy of Chinese medicinal materials decreases or changes,and its clinical efficacy in the treatment of constipation also needs further study.