| BackgroundTherapeutic method is a product of the combination of the unique thinking method of traditional Chinese medicine and clinical experience.It has the function of connecting the theories and unifying the prescriptions and medicines in the system of theories,principles,prescriptions,and medicines,highly summarizing the basic laws and principles of traditional Chinese medicine treatment.Currently,traditional Chinese medicine theory and clinical research mostly focus on diseases,while therapeutic methods,as an important link in clinical diagnosis and treatment of traditional Chinese medicine,is often ignored.There are problems such as vague concepts,non-standard application,and low ease of use,which hinder its guiding role in prescription medication and the establishment of a standardized theoretical system of traditional Chinese medicine.The method of softening hardness and dissipating bind(SHADBM)is one of the important methods commonly used in clinical treatment of solid nodules under the guidance of syndrome differentiation and treatment in traditional Chinese medicine.With the increasing detection rate of hard knot diseases characterized by nodules,tumors,polyps,and sclerosis in today’s society,the application and research of SHADBM has increasingly become a hot spot in clinical and research.However,as an abstract concept,SHADBM has the problem of "not being able to use" for most clinical doctors,which seriously restricts the realization of its clinical value,and there is a great risk of obscurity.How to make the SHADBM used in ancient times for today and applied in clinical practice is an urgent problem to be solved.The study of ancient books is the foundation.The inheritance and promotion of SHADBM requires a systematic review,summary,and sublimation of the literature of previous dynasties from a clinical practical perspective.However,currently,with SHADBM as the theme,there are few studies that have sorted out and summarized its origin,the understanding of clinicians of previous dynasties,and the laws of prescription and medication.Supplementing the relevant research gaps can provide important reference value for the inheritance,innovation,and clinical application of the theory of SHADBM.Modern research is the key point.Although there are many studies on the modern clinical application and experimental mechanism of the SHADBM,there is a lack of understanding of the development trends and research hotspots of the modern research of the SHADBM.Analyzing the development context of the modern research of the SHADBM from a time dimension is conducive to a comprehensive view of the evolution and focus of its modern clinical application and basic research for future researchers to focus on.Combining with evidence-based medicine is the only way to answer modern clinical questions with the SHADBM.Under the guidance of the theory of "treating different diseases with same method",the application,clinical efficacy,and safety of the SHADBM in the treatment of its dominant diseases still lack comprehensive and systematic evidence integration and evaluation,The overall description of clinical evidence such as specific intervention measures and efficacy outcome indicators for the SHADBM can provide a reference basis for its clinical practice and evidence-based decision-making.In addition,there is currently no specific application regimen for the SHADBM to guide clinical practice.Formulating a clear medication regimen for the application of the SHADBM is conducive to its clinical application and promotion.Therefore,this study focused on the development of ancient and modern Chinese medicine theories of SHADBM,taking nodular diseases as an example to carry out modern evidence-based evaluation research,and put forward specific suggestions for the clinical application of SHADBM.This not only can make the theoretical and pharmaceutical system of SHADBM more complete,but also can provide evidence-based basis for its clinical practice,providing reference for improving the ease of use and standardization of SHADBM.ObjectiveThis study aimed to address the following four issues.Firstly,this study was to comb the theoretical development of the SHADBM in ancient books from three aspects.To begin with,to explore the understanding of ancient clinicians on SHADBM based on ancient medical books and clarify its theoretical origin.Next,to explore the scope of main symptoms and signs of the ancient method of SHADBM based on the SHADB formula as well as the rules of prescription and medication.Moreover,to explore the characteristics of traditional Chinese medicine with the effect of SHADB.Secondly,it was to explore the development trends,research hotspots,and trends of modern research on SHADBM,explore its advantages of disease,and provide clues for evidence-based research on SHADBM.Thirdly,taking nodular diseases as an example,an evidence-based evaluation of the SHADBM was conducted using scoping review.It was.to explore the application,the distribution of efficacy outcome indicators,and the distribution of efficacy and safety evidence of the SHADBM in the same category of diseases.Thereby it can present the current evidence status and limitations of the SHADBM in this research field.Fourthly,based on the previous three parts of the study,and further using the literature review analysis method,this paper proposed clinical application suggestions for the clinical application of the SHADBM from the aspects of scope of application,category,representative prescription,stage and divisional medication,clinical application of nodular diseases,treatment differentiation,and attention to use.Through the above four parts of research,this article clarified the development of TCM theory of SHADBM,described the current status of clinical evidence for the treatment of nodular diseases with SHADBM,and proposed specific recommendations for the application of SHADBM.MethodsUsing literature research methods,data mining,and induction methods,this study combed the development of TCM theory of SHADBM in ancient books.Using the method of literature research,to clarify the origin and development and the understanding of clinicians in previous dynasties of the SHADBM.This included comprehensive collection,excavation,and collation of information related to the SHADBM in historical literature,selection of representative works,and comprehensive research on the concept,theoretical origin,and development of the SHADBM.Using data mining methods and induction method,to summarize the rules of prescription and medication of ancient SHADBM,respectively from prescription and medicine.In terms of formula research,the ancient SHADB formulas were thoroughly searched in the "Chinese Medical Classics"(5th edition),and a SHADB formula research database was established.The formula name,source,dynasty,main treatment disease,main treatment syndrome,main treatment basis,main treatment symptoms,formula composition,dosage ’form,administration method,special decoction method,special administration method,medication time and other information were extracted.Data cleaning was performed on disease names,syndrome,syndrome basis,symptoms,Chinese medicine names,and Chinese medicine classifications.Frequency analysis was used to statistically analyze the SHADB formulas from various dynasties,the main diseases and syndromes,the medicine,the dosage form,and usage.Association rule analysis was used to mine the core drug pairs,disease-syndrome basis,and disease/syndrome/symptom-Chinese medicine correspondence in the formulas.Cluster analysis was used to mine the core drug combinations of the formulas.In terms of medicine research,a comprehensive search was conducted in the materia medica literature of the "Chinese Medical Classics"(5th Edition)to identify Chinese herbal medicines with the efficacy of SHADB.A research database of SHADB Chinese herbal medicines was established,and the relevant information,such as the name,source,and indications of the included herbs,was extracted.The information on the four properties,five flavors,meridians,and toxicity of the included herbs was also extracted,based on the "Chinese Pharmacopoeia"(2020)and the"Chinese Materia Medica".After data cleaning of the herbal names and properties,a frequency analysis method was used to statistically analyze the properties of the included herbs.Based on the induction method of the Chinese Pharmacology" textbook and the therapeutic approaches of SHADBM,the included herbs were classified using an inductive method.Then,based on the description of the herbal indications,the therapeutic herbs for SHADB were qualitatively classified according to the differentiation of diseases,patterns,and affected body parts.Using bibliometric analysis method,this study analyzed the knowledge evolution,research hotspots,and research trends of the modern research on the SHADBM.The study comprehensively searched the databases of CNKI,VIP,Wanfang,and SinoMed,from the establishment of the database to August 28th,2022.All research literature with the SHADBM as the main topic was included,and NoteExpress V3.7 software was used to preprocess data such as the names of publishing institutions,authors,and keywords.Excel spreadsheets were used to extract information such as titles,publication years,regions,journals,and degree-granting institutions.Descriptive statistics were used to analyze the annual number of publications,distribution of publishing regions,distribution of publishing journals,and distribution of degree-granting institutions.VOSviewer software was used to conduct co-occurrence cluster analysis on institutions and authors,and to conduct co-occurrence cluster analysis and time overlay view analysis on keywords.CiteSpace6.1.R3 software was used to conduct keyword burst analysis.Using the method of scoping review,this study described and presented the application status,efficacy evidence,and safety evidence of the SHADBM in the treatment of nodular diseases.The study conducted a comprehensive search of Chinese databases,including CNKI,Wanfang,VIP,and SinoMed,as well as international databases,including PubMed,EMbase,Web of Science,and Cochrane Library.The search period was from the establishment of the database to October 15th,2022.The study included clinical studies(including randomized controlled trials,quasi-randomized controlled trials,non-randomized controlled trials,cohort studies,case-control studies,and case series studies),systematic reviews,meta-analyses,clinical practice guidelines,and expert consensus on the use of SHADBM in the treatment of thyroid nodules,breast hyperplasia,and pulmonary nodules.Basic information such as the first author,publication year,article title,publication area,study type,and disease were extracted from all studies.Information such as TCM syndrome type,sample size,intervention measures in the experimental group,type of TCM formula(decoction,Chinese patent medicine,or hospital-made preparation),TCM formula name and composition,intervention measures in the control group,treatment duration,outcome indicators,and study results were extracted from clinical original studies.Information such as the number of original studies included,total sample size,intervention measures,control measures,outcome indicators,funding support,and conflicts of interest were extracted from systematic reviews/meta-analyses.The methodological quality of the included systematic reviews/meta-analyses was evaluated using the AMSTAR 2 tool.All research data was analyzed and presented using a combination of charts and qualitative descriptions.Based on the research in the above three parts,suggestions for the clinical application of SHADBM are proposed using the method of literature review and analysis.These included the scope,categories and representative drugs of SHADBM,drug use for different stages and body parts,clinical application of nodular diseases,treatment discrimination,and precautions for use.Results1 The Theoretical Development of the SHADBM in Ancient Books1.1 The SHADBM originated in the Qin and Han dynasties.The Huangdi Neijing first proposed the therapeutic principle of "hardness and bind",with"softening the hardness" and "dissipating the bind" becoming the earliest theoretical basis of the method.In the Shanghan Zabing Lun,the complexity of the pathological mechanism of "hardness and bind’ was recognized,which expanded the application principle in the Huangdi Neijing and formed the idea of considering both pathogenic qi and vital qi and using multiple methods.Many classic formulas were created,providing important references for the formulation of SHADB formulas in later generations.During the Tang,Song,Jin,and Ming dynasties,theories of schools of TCM emerged,and various medical practitioners interpreted and expounded on the SHADBM from different perspectives,such as warming yang,strengthening vital qi,dissipating phlegm and eliminating blood stasis.This enriched the specific application of the method and enriched the treatment techniques of the SHADBM.In addition to formulas,techniques such as moxibustion and plaster were added,making the theoretical framework of the SHADBM increasingly comprehensive and refined.The proposal of "softening method","resolving method","dispersing method",and"eliminating method" in the Shishi Milu and the Yixue Xinwu in the Qing Dynasty marked the maturity of the development of the SHADBM.1.2 The study of SHADB formula included 368 oral prescriptions,which exhibit certain patterns in their treatment of diseases,selection of medicines,dosage forms,and administration methods.In terms of the range of diseases treated,the main diseases treated by the SHADBM include lymphadenopathy,thyroid disease,lumps and masses,accumulation of pathogenic factors,and tumor-related diseases.Commonly treated clinical symptoms include qi stagnation,phlegm,heat,blood stasis,toxins,and liver-related disorders,with symptoms such as swelling,pain,and hardness being the main indications of the SHADBM.Furthermore,there is a good convergence between the diseases,patterns,and symptoms treated by the SHADBM.The medication strategy of the SHADBM primarily involved using drugs that promote qi circulation and dissipate phlegm,activate blood circulation and dissipate blood stasis,and clear heat and dispel nodules.Additionally,reinforcing deficiency with tonifying yin,invigorating qi,strengthening the spleen,and warming yang herbs are also incorporated.Through statistical analysis,a total of 53 high-frequency Chinese herbs,21 core drug pairs,29 high-frequency auxiliary herbs,and 5 core drug groups were identified.Different diseases,syndromes,and symptoms corresponded to specific therapeutic main drugs.In terms of dosage forms and usage,the main forms of SHADB formulas are pills,decoctions,and powders.The decoction methods mainly use water or wine,and administration methods included oral,with wine,with warm water,or with rice soup.The most frequent administration times are on an empty stomach and after meals.Statistical analysis of the main diseases treated,syndrome types,and Chinese herbs used in historical SHADB formulas showed a similar trend of expansion in disease types,syndrome types,and number of Chinese herbs used over time,reaching their peak during the Ming and Qing Dynasties.1.3 The study of SHADB herb included a total of 228 Chinese herbs,with their properties,flavors,and meridians having biases and particularities.The properties and flavors of the Chinese herbs are mostly pungent,bitter,and salty,while the meridians are mainly the liver meridian,lung meridian,stomach meridian,and spleen meridian.Different drugs can gradually dissolve and dissipate the adhesions through multiple pathways and links,such as regulating Qi,promoting blood circulation,resolving phlegm,clearing heat,dispersing cold,and tonifying deficiency.The efficacy characteristics of the SHADB Chinese herbs have individual differences,and there are specific drugs for the treatment of different clinical signs and symptoms,pathogenesis,and sites of bind.Through qualitative analysis,a total of 43 specific drugs for disease diagnosis and 50 essential drugs for syndrome differentiation and site selection were summarized."2 Bibliometric Analysis of Modern Research on the SHADBMThe study for modern research on the SHADBM yielded a total of 56,042 articles,of which 9,425 were ultimately included.The annual output of articles on the SHADBM showed an overall increasing trend,with most articles being published in the eastern coastal and central regions of China.The distribution of journals and institutions where the articles were published generally followed Bradford’s Law.A total of 5,245 institutions participated in research on SHADBM,and a co-occurrence cluster analysis of 85 institutions with a publication output of 12 or more articles resulted in an institutional collaboration network,with most institutions being affiliated with traditional Chinese medicine universities and their affiliated hospitals.The included articles had 17,348 authors,and a co-occurrence cluster analysis of 176 authors with a publication output of 8 or more articles resulted in the identification of 10 core teams.The total number of keywords was 14,663,and after grouping the 227 high-frequency keywords that appeared 15 or more times.They were classified into nine categories,including research type and method,diseases studied,TCM syndrome,clinical symptoms and signs,TCM therapeutic methods,TCM prescriptions,clinical outcome measures,experimental research methods and content,and others.Through co-occurrence clustering analysis of high-frequency keywords and literature review,the advantages of disease of the SHADBM have been identified in five major disease categories,including nodular diseases,stasis-related diseases,accumulation and tumor-related diseases,stone-related diseases,and micro-nodular stasis-related diseases.By analyzing the co-occurrence timeline and burst of keywords,the research hotspots and trends of the SHADBM are mainly as follows.(1)The research scope has expanded from macroscopic nodules,accumulations,nodules,and tumors to microscopic micro-nodules and accumulations,constantly expanding the spectrum of diseases.(2)In terms of clinical medication,scholars in this field are more concerned with the application of ancient formulas with new uses and traditional Chinese medicine,and the transformation of empirical formula achievements into clinical applications may be a new research trend.(3)In terms of mechanism research,the treatment of malignant tumors through the SHADBM by inhibiting cell proliferation,promoting cell apoptosis,inhibiting tumor angiogenesis,and anti-inflammatory effects is currently a research hotspot.3 The Evidence-Based Evaluation of the SHADBM in nodular diseases:a Scoping Review.A total of 12,157 literature searches were retrieved for the treatment of nodular diseases using the SHADBM,and 263 Chinese and English literature were finally included.Among them,there were 243 clinical original studies(189 randomized controlled trials,17 quasi/non-randomized controlled trials,and 37 case series studies),16 systematic reviews/Meta-analyses,and 4 clinical practice guidelines/expert consensuses.The studies included 131 cases of thyroid nodules,125 cases of breast hyperplasia,and 7 cases of lung nodules.Among the clinical original studies,there were 21 types of syndrome differentiation,and the top three were phlegm-blood stasis interlocking syndrome,qi stagnation phlegm congealing syndrome,and liver depression phlegm congealing syndrome.The sample size of the studies mainly focused on 60-100 cases(n=88,36.21%).The intervention measures of the SHADBM were diverse,with 85 literature mentioning Chinese patent medicine,15 kinds of SHADB Chinese patent medicine were involved;22 literature mentioning medical institution preparations,16 kinds of medical institution preparations were involved;140 literature mentioning decoction,and 136 prescriptions were involved.A total of 232 original studies clearly mentioned the treatment course,which was mainly concentrated in 60-90 days(n=119,51.29%).This study focused on the analysis of outcome indicators and efficacy evidence of 206 controlled studies,including 112 studies on thyroid nodules,88 studies on breast hyperplasia,and 6 studies on lung nodules.A total of 26 efficacy outcome indicators were involved in the study.The existing clinical research evidence mostly indicates that the SHADBM is beneficial for improving the clinical outcomes of nodular diseases,including clinical effective rate,TCM syndrome/symptom efficacy,nodule/tumor diameter or shrinkage rate,and incidence of adverse events.Seven systematic reviews/meta-analyses were included for thyroid nodules,and nine for breast hyperplasia.The conclusions of most systematic reviews and meta-analyses affirmed to some extent the efficacy and safety of the SHADBM in treating thyroid nodules and breast hyperplasia.However,four of them were rated as "lowt" in terms of methodological quality,and 12 were rated as " very low".4 Clinical Application Suggestion for the SHADBMBased on the above research results,the following recommendations are proposed for the clinical application of the SHADBM.(1)Clarify the concept and scope of application of the SHADBM.The method has a wide range of applications,including not only macroscopic "hardness and bind" such as nodules,polyps,and tumors,but also microscopic stasis such as atherosclerosis detected by modern medical instruments,microvascular eomplications caused by diabetic nephropathy,etc.(2)Understanding the pathogenesis is crucial for the application of the SHADBM."Hardness and bind" is the composite result of the attachment,agglomeration,and adhesion of invisible pathogenic factor and visible objects due to deficiency of vital qi.The formation of "hardness and bind" can further damage vital qi.Due to the complexity of the pathogenesis of "hardness and bind," the SHADBM can be combined with seven types of eliminating pathogenic factor and SHADBM,including promoting blood circulation and removing blood stasis,resolving phlegm,regulating qi,clearing heat,dispersing cold,promoting bowel movement,and dissolving stones,or combined with four types of tonifying vital qi and SHADBM,including benefiting qi,nourishing blood,nourishing yin,and warming yang.Comprehensive effects are exerted from multiple angles and levels to achieve the goal of SHADB.(3)Different SHADBM should be applied according to the disease stage and location.The application of SHADBM often runs through the entire treatment of "hardness and bind".In the early stage,it focuses on "eliminating pathogenic factor".In the middle stage,it requires both eliminating pathogenic factor and strengthening vital qi.In the late stage,it tends to focus on "strengthening vital qi".The method can also be flexibly used based on different pathological mechanisms,physiological stages,and locations of the disease.(4)Pay attention to the dosage and nature of the drugs used in the SHADBM.For long-term "hardness and bind," a small amount of a variety of flavors is appropriate,while for stubborn "hardness and bind," a larger amount of drugs is needed.For patients with critical or unstable conditions,decoctions are often used to seek rapid effects,while pills are used more for chronic and weak patients to achieve a gradual effect.When choosing drugs with pungent and salty flavors,it is also important not to overuse them.In addition,taking nodular diseases as an example,the drug treatment plan of the SHADBM is proposed for the application of thyroid nodules,breast hyperplasia,and pulmonary nodules,as a specific reference for the application of the SHADBM.Conclusion1.The SHADBM originated in the Qin and Han dynasties.Its theoretical development gradually improved with medical practice,and the range of diseases it treats and the spectrum of drugs used continued to expand.It matured during the Qing dynasty,and a basic understanding of the rules for prescribing drugs,the pharmacological properties,and efficacy characteristics of the drugs used in the SHADBM was formed.In modern times,it has developed into five types of advantages of disease,and the application of the SHADBM in micro-accumulation diseases has become a research hotspot in recent years.2.The SHADBM has accumulated some clinical evidence in the treatment of nodular diseases,mainly focused on thyroid nodules and breast hyperplasia,with relatively less research on lung nodules.The intervention measures of the SHADBM has diverse characteristics,and the existing clinical research evidence mostly indicates that it is beneficial to improve the clinical effectiveness,TCM syndrome/symptom efficacy,nodule/tumor diameter or diameter reduction rate,and other clinical outcomes of nodular diseases.This suggests that the SHADBM is a useful strategy for treating nodular diseases.However,due to the need for improvement in the methodological quality of the studies included,and because overview evaluations aim to provide a summary of the evidence,this study can only provide a reference for clinical practice and decision-making in this field.Researchers should take an objective and cautious attitude towards the conclusions.3.Clinical application recommendations for the SHADBM have been proposed.The scope of application of this method not only includes macroscopic "hardness and knots" manifested as nodules,polyps,and tumors,but also includes micro lesions detected by modern medical instruments,such as microvascular complications caused by arteriosclerosis or diabetic nephropathy.Due to the complex pathogenesis of"hardness and knots," the SHADBM can be combined with other methods of eliminating pathogen and strengthening vital qi.When applying the SHADBM,flexible selection of drugs should be made according to different stages of the disease and the body part,and attention should be paid to the gentleness or harshness of the medication and the nature of the drug. |
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