Benefit-risk Assessment And Clinical Practice Of Pungent And Hot Toxic Chinese Medicines In The Treatment Of Arthralgi

This study was the in-depth and continuing work of the project from Center for National Drug Evaluation,which was Research on Pharmacovigilance of Aconitum Herbal Based on the Data-mining of TCM Classics Works.Background and Significance of the ResearchChinese herbs with acrid,hot and toxic properties(XRT herbs),one of the kinds of commonly used herbs from ancient to now and still in the front line in the treatment,have obviously advantages in the treatment of joint diseases with obstinate and chronic characteristics,which could be classified as Bi syndrome.However,XRT herbs were unacceptable due to their toxic,or abused in spite of toxicity,which has been hot topic controversy in clinic.Therefore,this study cut into the practical issue of the decision of medication benefit-risk regarding toxic herbs in clinic,learn from the benefit-risk assessment(BRA)methods from international,a new BRA model was established and conducted localization example application research,which in accordance with the complex clinical application and evaluation characteristics of Traditional Chinese Medicine(TCM).The results would not only provide objective basis and risk prevention measures for XRT herbs’ application from multi-dimension,but also change the status that none BRA model and example of TCM medication.In this study,XRT herbs in the treatment of Bi syndromes was the BRA research carrier,by introducing BRA method from international,then exploring to establish a new BRA model combing traditional and modern records,and the literature and clinical practice,which to fit the complex characteristics of TCM clinical application.And based on the clinic case report,to validate the model,and apply in the local.This study was tried its best to demonstrate the benefit-risk relationship of XRT herbs in the treatment of Bi syndromes as a visually quantifiable form,which not only provides objective basis,forms risk prevention measures for XRT herbs’application from multi-dimension,but also provides reference to other herbs which need the medication evaluation.The assessment result answer clinic if XRT herbs can be used or not,how to use,and so on,in order to increase the level of rational use of drugs,and use scientific and objective language to have a conversation to international.Objectives1.Combining the traditional and modern data,literature assessment and clinical practice,a new BRA model of XRT herbs for assessing the benefit and risk in the treatment of Bi syndromes with the characteristics of TCM medications would be conducted,which can provide reference for developing BRA for TCM.2.Base on the BRA model,quantitatively assessment of benefits and risks of XRT herbs would be presentation,so as to provide objective evidence for using toxicity herbs in the treatment of Bi syndromes.3.Data-mining the traditional pharmacovigilance records about XRT herbs,exploring the key measures to prevent their medication risks in the treatment of Bi syndromes,in order to promote the rational use of drugs in clinical.Content and MethodsCentering on the benefit-risk relationship of XRT herbs in the treatment of Bi syndromes,the study conducted three parts,which is relying on the examples,such as Aconiti Radix(Chuanwu),Aconiti Kusnezoffii Radix(Caowu),Aconiti Lateralis Radix Praeparata(Fuzi),Curculiginis Rhizoma(Xianmao)and Tripterygium hypoglaucum(Kunmingshanhaitang).Firstly,data-mining the traditional records of XRT herbs’ efficacy-toxicity.BRA indicators from traditional were extracted by data-mining from the 120 ancient classical works that from Qin to Qing Dynasty,which including TCM works,prescription works,and comprehensive works.By using the methods of frequency statistics,percentile,and Association Rules Apriori Algorithm,the records development of toxic cognition,medication law of example XRT herbs,toxic precautions and poisoning rescue measures were combed.And then the pharmacovigilance process of example herbs "recognizing-using-preventingrescuing toxicity" was established,in order to provide the basis for the risk assessment and prevention.Secondly,the construction and quantification of BRA model of XRT herbs in the treatment of Bi syndromes.In order to constructed a new model of XRT herbs in the treatment of Bi syndromes,comprehensive application of bibliographic analysis,Delphi method,percent weight,single attribute utility function transformation was used to choose BRA indicators and assign corresponding weights,which constituted the main Multi-criteria decision analysis(MCDA)model of XRT herbs in the treatment of Bi syndromes.And applying Monte Carlo simulation,entropy method,and so on to optimize the model,which reflected the complex TCM medication characteristics,and explain the influence degree of BRA multi-dimensional factors.Combined random clinical trials(RCTs)reports,the example herbs’benefit-risk value can be calculated.Visually quantifiable BRA results were presented,in order to illuminate the benefit-risk relationship of XRT herbs in the treatment of Bi syndrome,and provide basis for the Bi syndrome use of XRT herbs.Thirdly,clinical practice of XRT herbs BRA in the treatment of Bi syndromes.In order to verify the model and examine the applicability,clinical retrospective case observation study was conducted to collect Bi syndromes inpatients who had been treated by XRT herbs from 8 hospitals that including secondary and tertiary hospitals,and comprehensive and TCM hospitals in Beijing.Based on the clinical BRA results,the comparison of the clinical results and literature results was conducted,if they were in accordance,the BRA model of XRT herbs in the treatment of Bi syndromes were verified.ResultsBased on the above content,the research path of "document data-mining-model construction-example assessment-clinical practice" was established.In the study,BRA-MCDA model of XRT herbs in the treatment of Bi syndromes was established,and model validation and practice were carried out through clinical actual cases.The existing research indicated that the medication benefit of XRT herbs was higher than risk when treating Bi syndromes,in which Chuanwu and Caowu had the highest benefit-risk value.When they were using for cold patterns,with processed products,and controlling doses,the risk of XRT herbs could be reduced more,more details were as follows:1.BRA-MCDA model of XRT herbs in the treatment of Bi syndromesBased on the current decision-making environment,the assessment model included benefit and risk indicators.When they were as the first-level assessment indicators,accounting for 49%and 51%respectively.The second-level assessment indicators of benefit including joint tenderness,number of swellings,morning stiffness,and so on.The incidence of ADR/ADE and the incidence of different system damage were as the second-level indicators of risk.2.Quantitative assessment of benefit-risk relationship of XRT herbs in the treatment of Bi syndromesA total of 166 RCTs regarding Chuanwu,Caowu,Fuzi,Xianmao,and Kunmingshanhaitang were included,involving 12 575 participants.The assessment results indicated that the benefit of XRT herbs was superior to risk when using to treat Bi syndromes:(1)The benefit-risk value of Chuanwu and Caowu was 38.3±9.9(6-55).When only using Chuanwu for Bi syndromes with cold pattern,proceed ones,3～9g,2～3 month course in the decoction,clinic could achieve higher benefit and lower risk.Bi syndromes involved in different diseases had no effect on the benefit-risk value of Chuanwu and Caowu.(2)The benefit-risk value of Fuzi was 35.53±9.89(11～51).When only using Fuzi for Bi syndromes with cold-heat complicated pattern,proceed ones,3～15g,within 2 month course in the Chinese patent drug for treating Axial spondyloarthritis,clinic could achieve higher benefit and lower risk.(3)The benefit-risk value of Xiaomao was 37[95%CI(34.47,39.53)].(4)The benefit-risk value of Kunmingshanhaitang was 29.5±3.5(26～33),in which the Chinese patent drug had the most high benefit-risk.3.Clinical practice of BRA-MCDA modelA retrospective observation of 226 cases of inpatients with Bi syndromes,of which 181 cases were treated with decoction or patent drugs containing Chuanwu,Caowu or Fuzi,and 45 cases with western medicines were in control groups.Based on the clinical cases,compared with the control group,the actual drug herbs’ benefit was almost same,but the risk was lower,the benefit-risk value was 21[95%CI(19.56,22.44)],which fell within the scope of the theoretical assessment results,which verified the feasibility of BRA model,and the model can be practiced in clinic.4.Influence degree of BRA multi-dimensional factorsBased on the assessment result,the influence degree of the single factors and multi-dimensional comprehensive effect were quantitatively interpret,in order to focus on the targeted risk prevention and pharmacovigilance.5.Risk pharmacovigilance of XRT herbsCombined with the XRT herbs pharmacovigilance information and assessment results,excluding Fuzi could be used in the Bi syndromes with cold-heat complicated patterns,the other XRT herbs only for cold pattern.And the proceed ones should be used.In clinical,the dosage of Chuanwu and Caowu should be minimized,and Fuzi kept the usual,which could reduce the medication risk at a certain extent.Conclusions1.The benefit of XRT herbs in the treatment of Bi syndromes is higher than risk,in which Chuanwu could achieve the highest benefit,which provide direct evidence for using XRT herbs in the treatment of Bi syndromes.2.The BRA-MCDA model of XRT herbs in the treatment of Bi syndromes,which was constructed in this study,was fully in accordance with TCM characteristics and had clinical applicability.The model not only provided the basis for XRT herbs application,but also provided reference for clinical evaluation for other toxic Chinese medicines.3.Under the characteristics of TCM therapy,multi-dimension guidance for using XRT herbs was formed.Exclude Fuzi could be used in with cold-heat complicated pattern,other example herbs only should be used in cold pattern.And also,through the application with processed products,and controlling dose,the medication risk of XRT herbs can be further decreased,which was to provide rational basis for clinical use.Innovation1.Exploring BRA methods localization research in the field of toxic Chinese medicineBRA has no precedent application in the field of toxic herbs before.This study introduced a quantitative BRA method,and applied in the XRT herbs in the treatment of Bi syndromes.It present traditional empirical and vague effect-toxic knowledge in an intuitive,quantifiable and objective manner.The BRA localization research,and provide research model of risk assessment for other toxic herbs.2.Multi-method optimization the BRA model which meeting the TCM complex characteristicsBased on the BRA-MCDA model,multi-methods of Delphi survey,Monte Carlo simulation,entropy method were integrated application to optimize the model,in order to fit the complex features of TCM clinical application and evaluation.Integrating the data-mining in traditional classic works and clinical retrospective case observation study,a new assessment mode of"document data-mining-model construction-example assessment-clinical practice" was established,which further improved the TCM BRA model.3.Provide multi-dimensional and objective medication basis of XRT herbs to clinicThe exist evidence indicated that the benefit-risk of XRT herbs in the treatment of Bi syndromes can be quantitative.At the same time,combining with their complex characteristics of medication,the basis of multi-dimension,and object was provided to clinic,further,more targeted risk prevention and control suggestions such as syndromes,concocting,and dosages will be formed.