[Clinical comprehensive evaluation of Diemailing~® Kudiezi Injection in treatment of cerebral infarction].

Clinical comprehensive evaluation was conducted in "6+1" dimensions(safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine) to reflect the advantages and characteristics of Diemai-ling~® Kudiezi Injection in the treatment of cerebral infarction. This study adopted a combination of qualitative and quantitative evaluation methods. Based on the methodologies of evidence-based medicine, epidemiology, clinical medicine, evidence-based pharmacy, pharmacoeconomics, mathematical statistics, and health technology assessment(HTA), experts gave weight to the criterion layer and index layer, and multi-criteria decision analysis(MCDA) model and CSC v2.0 were used for calculations to evaluate the clinical value of Diemailing~® Kudiezi Injection. The existing evidence showed that active monitoring and a number of randomized controlled trials(RCTs) have been carried out after the listing of Diemailing~® Kudiezi Injection. Since the total incidence of adverse reactions is 0.099% and the incidence of adverse drug reactions(ADR) is rare, the safety evaluation is grade A. The evidence value of effectiveness demonstrated that Diemailing~® Kudiezi Injection combined with conventional western medicine improves the total effective rate of neurological deficit score and quality of daily life in the acute stage of cerebral infarction, which is superior to that in the conventional western medicine treatment group, and the level of evidence is high. Therefore, its efficacy is assessed as grade A. According to the results of economic research, when Diemailing~® Kudiezi Injection combined with conventional western medicine treatment is compared with conventional western medicine treatment, the Diemailing~® Kudiezi Injection group has a greater incremental effect, but the cost is affordable. Given the overall quality evaluation results of economic report is clear, it is evaluated as grade B. The innovation is grade A. The drug is favorable for clinical operation by medical staff and can be accepted by patients due to easy usage without special technical and management requirements. Since the drug exhibits good suitability for clinicians, nurses, pharmacists, and patients, it is evaluated as grade B. Considering its moderate price among similar drugs and good affordability and availability, it is evaluated as grade B. Diemailing~® Kudiezi Injection can evidently improve the clinical symptoms and neurological deficits of fire toxin syndrome of acute cerebral infarction, and this medicine belongs to ethnic medicine. Large-sample active monitoring research has been conducted with rich experience in human use. Therefore, the characteristics of traditional Chinese medicine are evaluated as grade A. The comprehensive clinical evaluation of Diemailing~® Kudiezi Injection is class A. We suggest that it can be directly transformed into relevant policy results of basic clinical medication management by procedure.

Clinical comprehensive evaluation of Diemailing~® Kudiezi Injection in treatment of cerebral infarction / 中国中药杂志

Clinical comprehensive evaluation was conducted in "6+1" dimensions(safety, effectiveness, economy, innovation, suitability, accessibility, and characteristics of traditional Chinese medicine) to reflect the advantages and characteristics of Diemai-ling~® Kudiezi Injection in the treatment of cerebral infarction. This study adopted a combination of qualitative and quantitative evaluation methods. Based on the methodologies of evidence-based medicine, epidemiology, clinical medicine, evidence-based pharmacy, pharmacoeconomics, mathematical statistics, and health technology assessment(HTA), experts gave weight to the criterion layer and index layer, and multi-criteria decision analysis(MCDA) model and CSC v2.0 were used for calculations to evaluate the clinical value of Diemailing~® Kudiezi Injection. The existing evidence showed that active monitoring and a number of randomized controlled trials(RCTs) have been carried out after the listing of Diemailing~® Kudiezi Injection. Since the total incidence of adverse reactions is 0.099% and the incidence of adverse drug reactions(ADR) is rare, the safety evaluation is grade A. The evidence value of effectiveness demonstrated that Diemailing~® Kudiezi Injection combined with conventional western medicine improves the total effective rate of neurological deficit score and quality of daily life in the acute stage of cerebral infarction, which is superior to that in the conventional western medicine treatment group, and the level of evidence is high. Therefore, its efficacy is assessed as grade A. According to the results of economic research, when Diemailing~® Kudiezi Injection combined with conventional western medicine treatment is compared with conventional western medicine treatment, the Diemailing~® Kudiezi Injection group has a greater incremental effect, but the cost is affordable. Given the overall quality evaluation results of economic report is clear, it is evaluated as grade B. The innovation is grade A. The drug is favorable for clinical operation by medical staff and can be accepted by patients due to easy usage without special technical and management requirements. Since the drug exhibits good suitability for clinicians, nurses, pharmacists, and patients, it is evaluated as grade B. Considering its moderate price among similar drugs and good affordability and availability, it is evaluated as grade B. Diemailing~® Kudiezi Injection can evidently improve the clinical symptoms and neurological deficits of fire toxin syndrome of acute cerebral infarction, and this medicine belongs to ethnic medicine. Large-sample active monitoring research has been conducted with rich experience in human use. Therefore, the characteristics of traditional Chinese medicine are evaluated as grade A. The comprehensive clinical evaluation of Diemailing~® Kudiezi Injection is class A. We suggest that it can be directly transformed into relevant policy results of basic clinical medication management by procedure.

[Expert consensus statement on Diemailing~® Kudiezi Injection in clinical practice].

Diemailing~® Kudiezi Injection( DKI) is widely used in the treatment of cerebral infarction,coronary heart disease and angina pectoris. Long-term clinical application and related research evidence showed that DKI has a good effect in improving the clinical symptoms of cardiovascular and cerebrovascular diseases. However,this injection has not been included in any clinical practice guideline. It has been found that the use of DKI is in wrong way in clinical practice in recent years. Therefore,clinical experts from the field of cardiovascular and cerebrovascular diseases nationwide are invited to compile this expert consensus in order to guide clinicians.GRADE system is used to grade the quality of evidence according to different outcomes according to degrading factors. Then it forms the recommendation or consensus suggestion through the nominal group method. The formation of expert consensus mainly considers six factors: quality of evidence,economy,efficacy,adverse reactions,patient acceptability and others. Based on these six aspects,if the evidence is sufficient,a " recommendation" supported by evidence is formed,and GRADE grid voting rule is adopted. If the evidence is insufficient,a " consensus suggestions" will be formed,using the majority voting rule. In this consensus,the clinical indications,efficacy,safety evidences and related preliminary data of DKI were systematically and comprehensively summarized in a concise and clear format,which could provide valuable reference for the clinical use of DKI. This consensus has been approved by China association of Chinese medicine which is numbered GS/CACM 202-2019.

[Editorial explanation for Expert consensus statement on Diemailing Kudiezi Injection in clinical practice].

Expert consensus statement on Diemailing Kudiezi Injection in clinical practice was approved on April 17,2019 by the Standardadization Office of the Chinese Association of Chinese Medicine. This project,which started in November 2017,has been developed and completed in accordance with the standard developing procedure. This paper will give a detailed introduction to the compilation process about the consensus. The aim is to enable readers to understand the background,purpose and basis of this consensus in a timely manner. Readers can learn about diffferent stages of develping process,including project management system,drafting,consulting,expert consensus,as well as current problems and shortcomings. Such an editorial explanation is just a dynamic follow-up of the whole consensus-making process. It also plays a good supervisory role in the whole consensus-making. It could be a guarantee for the quality of the consensus. There is no doubts that the editorial explanation is an important auxiliary document in the process of consensus-making. It is the extension and supplement of consensus content and a basis for fully understanding the technical content of this consensus. Therefore it is an indispensable document in the process of consensus-making.

[Systematic review and Meta-analysis on randomized controlled trials on effectiveness and safety of Kudiezi Injection in treatment of acute cerebral infarction].

To systematically review the effectiveness and safety of Kudiezi Injection in treating patients with acute cerebral infarction( ACI). Four Chinese databases( CNKI,VIP,Wan Fang,Sino Med),three English databases( Cochrane Library,EMbase,Medline)and Clinical Trail.gov were systematically and comprehensively retrieved. The retrieval time was from the establishment of each database to November 2017. Randomized controlled trials( RCTs) for the treatment of acute cerebral infarction with Kudiezi Injection were screened out according to pre-established inclusion criteria and exclusion criteria. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool,and the included studies were put into descriptive analysis or Meta-analysis using the Rev Man 5. 3 software. A total of 932 articles were retrieved,and finally 14 studies were included. Except for 2 multi-arm trials,the total sample size was 1 244 in the experimental group and 638 in the control group. The overall quality of the included studies was not high. The results of Meta-analysis showed that Kudiezi + conventional therapy for acute cerebral infarction was superior to conventional therapy in total effective rate( RR = 0. 86,95% CI[0. 77,0. 96],P = 0. 006); Kudiezi + conventional therapy for acute cerebral infarction was superior to conventional therapy in serum inflammatory factors( MDhs-CRP=-3. 77,95% CI[-4. 17,-3. 37],P < 0. 000 01; MDIL-18=-16. 18,95% CI[-19. 26,-13. 11],P<0. 000 01); Kudiezi + conventional therapy was superior to conventional therapy in Barthel index( MD = 12. 52,95%CI[8. 93,16. 10],P<0. 000 01). Adverse reactions included in the study reports showed mild adverse reactions. Based on the results of this study,Kudiezi Injection combined with conventional therapy or other Western medicine had a certain curative effect on acute cerebral infarction,with no serious adverse reactions. However,due to the low quality of the included research methodology,the conclusions of this study were not recommended. In addition,in order to produce high-quality evidence for the clinical application of Kudiezi Injections,more randomized controlled trials with a large sample size,scientific design and strict implementation were required to study the effectiveness and safety of Kudiezi Injection in the treatment of cerebral infarction.

Systematic review and Meta-analysis on randomized controlled trials on effectiveness and safety of Kudiezi Injection in treatment of acute cerebral infarction / 中国中药杂志

To systematically review the effectiveness and safety of Kudiezi Injection in treating patients with acute cerebral infarction( ACI). Four Chinese databases( CNKI,VIP,Wan Fang,Sino Med),three English databases( Cochrane Library,EMbase,Medline)and Clinical Trail.gov were systematically and comprehensively retrieved. The retrieval time was from the establishment of each database to November 2017. Randomized controlled trials( RCTs) for the treatment of acute cerebral infarction with Kudiezi Injection were screened out according to pre-established inclusion criteria and exclusion criteria. The quality of the included studies was assessed using the Cochrane Risk Assessment Tool,and the included studies were put into descriptive analysis or Meta-analysis using the Rev Man 5. 3 software. A total of 932 articles were retrieved,and finally 14 studies were included. Except for 2 multi-arm trials,the total sample size was 1 244 in the experimental group and 638 in the control group. The overall quality of the included studies was not high. The results of Meta-analysis showed that Kudiezi + conventional therapy for acute cerebral infarction was superior to conventional therapy in total effective rate( RR = 0. 86,95% CI[0. 77,0. 96],P = 0. 006); Kudiezi + conventional therapy for acute cerebral infarction was superior to conventional therapy in serum inflammatory factors( MDhs-CRP=-3. 77,95% CI[-4. 17,-3. 37],P < 0. 000 01; MDIL-18=-16. 18,95% CI[-19. 26,-13. 11],P<0. 000 01); Kudiezi + conventional therapy was superior to conventional therapy in Barthel index( MD = 12. 52,95%CI[8. 93,16. 10],P<0. 000 01). Adverse reactions included in the study reports showed mild adverse reactions. Based on the results of this study,Kudiezi Injection combined with conventional therapy or other Western medicine had a certain curative effect on acute cerebral infarction,with no serious adverse reactions. However,due to the low quality of the included research methodology,the conclusions of this study were not recommended. In addition,in order to produce high-quality evidence for the clinical application of Kudiezi Injections,more randomized controlled trials with a large sample size,scientific design and strict implementation were required to study the effectiveness and safety of Kudiezi Injection in the treatment of cerebral infarction.

Expert consensus statement on Diemailing~® Kudiezi Injection in clinical practice / 中国中药杂志

Diemailing~® Kudiezi Injection( DKI) is widely used in the treatment of cerebral infarction,coronary heart disease and angina pectoris. Long-term clinical application and related research evidence showed that DKI has a good effect in improving the clinical symptoms of cardiovascular and cerebrovascular diseases. However,this injection has not been included in any clinical practice guideline. It has been found that the use of DKI is in wrong way in clinical practice in recent years. Therefore,clinical experts from the field of cardiovascular and cerebrovascular diseases nationwide are invited to compile this expert consensus in order to guide clinicians.GRADE system is used to grade the quality of evidence according to different outcomes according to degrading factors. Then it forms the recommendation or consensus suggestion through the nominal group method. The formation of expert consensus mainly considers six factors: quality of evidence,economy,efficacy,adverse reactions,patient acceptability and others. Based on these six aspects,if the evidence is sufficient,a " recommendation" supported by evidence is formed,and GRADE grid voting rule is adopted. If the evidence is insufficient,a " consensus suggestions" will be formed,using the majority voting rule. In this consensus,the clinical indications,efficacy,safety evidences and related preliminary data of DKI were systematically and comprehensively summarized in a concise and clear format,which could provide valuable reference for the clinical use of DKI. This consensus has been approved by China association of Chinese medicine which is numbered GS/CACM 202-2019.

Editorial explanation for Expert consensus statement on Diemailing Kudiezi Injection in clinical practice / 中国中药杂志

Expert consensus statement on Diemailing Kudiezi Injection in clinical practice was approved on April 17,2019 by the Standardadization Office of the Chinese Association of Chinese Medicine. This project,which started in November 2017,has been developed and completed in accordance with the standard developing procedure. This paper will give a detailed introduction to the compilation process about the consensus. The aim is to enable readers to understand the background,purpose and basis of this consensus in a timely manner. Readers can learn about diffferent stages of develping process,including project management system,drafting,consulting,expert consensus,as well as current problems and shortcomings. Such an editorial explanation is just a dynamic follow-up of the whole consensus-making process. It also plays a good supervisory role in the whole consensus-making. It could be a guarantee for the quality of the consensus. There is no doubts that the editorial explanation is an important auxiliary document in the process of consensus-making. It is the extension and supplement of consensus content and a basis for fully understanding the technical content of this consensus. Therefore it is an indispensable document in the process of consensus-making.

Simultaneous Determination of Five Phenolic Acids and Four Flavonoid Glycosides in Rat Plasma Using HPLC-MS/MS and Its Application to a Pharmacokinetic Study after a Single Intravenous Administration of Kudiezi Injection.

This study has developed a reliable and precise high performance liquid chromatography-tandem mass spectrometry method for the simultaneous determination of five phenolic acids and four flavonoid glycosides in rat plasma after a single intravenous administration of Kudiezi injection (KI). Chromatographic separation was carried out on an Ultimate®XB-C18 column (4.6 × 100 mm, 3.5 µm) using a gradient elution program with a mobile phase consisting of water containing 0.5% acetic acid and acetonitrile at a flow rate of 0.6 mL/min. Detection was performed on a triple-quadrupole tandem mass spectrometry using multiple reaction monitoring in negative electrospray ionization mode. The calibration curves of all analytes showed good linearity (R² > 0.990). The results of selectivity, intra-day and inter-day precisions, extraction recoveries, matrix effects and stability were satisfactory. Pharmacokinetic parameters showed that luteolin-7-O-ß-d-gentiobioside, luteolin-7-O-ß-d-glucuronide, luteolin-7-O-ß-d-glucoside and apigenin-7-O-ß-d-glucuronide were eliminated quickly (0.07 h < t1/2 < 0.66 h), whereas 5-caffeoylquinic acid, caftaric acid, chlorogenic acid, 4-caffeoylquinic acid and caffeic acid were eliminated relatively slowly (2.22 h < t1/2 < 6.09 h) in rat blood. The pharmacokinetic results would be valuable to identify bioactive constituents, elucidate mechanisms of pharmacological actions or adverse drug reactions and guide the rational clinical use of KI.

[Effectiveness and safety of Kudiezi injection in treating coronary angina pectoris: systematic review and Meta-analysis of randomized controlled trials].

To evaluate the effectiveness and safety of Kudiezi injection in the treatment of angina pectoris of coronary heart disease. Four Chinese databases (CNKI, VIP, WanFang, and SinoMed) and three English databases (Cochrane Library, Medline, and ClinicalTrail.gov) were systematically and comprehensively searched from the establishment of each database to March 2018. Randomized controlled trials (RCTs) on the treatment of angina pectoris of coronary heart disease with Kudiezi injection (KDZ) were screened according to the pre-established inclusion criteria and exclusion criteria. The quality of the included studies was evaluated by using the ROB tool developed by the Cochrane Collaboration, and RevMan 5.3 software was used for Meta-analysis. A total of 712 articles were retrieved and finally 38 studies were included. The total sample size was 3 812 cases, 1 945 in the experimental group and 1 867 in the control group. The overall quality of the included studies was generally low. The results of Meta-analysis showed that: KDZ combined with conventional or western medicine was superior to conventional or western medicine alone in the effectiveness and electrocardiogram efficacy of angina pectoris and unstable angina. The descriptive analysis showed that KDZ combined with conventional treatment group was superior to conventional treatment group in agina pectoris associated indicators of angina pectoris and unstable angina. Other outcome measures were easily affected by various factors (such as too large heterogeneity of outcome indicators) and could not be concluded. Adverse reactions included in the study report were all mild adverse reactions and did not affect treatment. Based on the results of this study, it can be seen that Kudiezi injection had a certain effect on the treatment of angina pectoris of coronary heart disease, especially with significant positive effect on the improvement of the curative effect for angina pectoris and the effect of electrocardiogram. No serious adverse reactions occurred. However, due to the limited number of studies included, the generally low quality of the included studies, and the existence of published biases, the quality of the evidence in this study was low, so that caution should be taken to apply this conclusion. The effectiveness and safety of Kudiezi injection in the treatment of angina pectoris of coronary heart disease remained to be confirmed in the future with a well-designed and rigorous multi-center randomized controlled trials with standardized report, large sample, and enough follow-up time.

A high expression Mas-related G protein coupled receptor X2 cell membrane chromatography coupled with liquid chromatography and mass spectrometry method for screening potential anaphylactoid components in kudiezi injection.

Kudiezi injection is a traditional Chinese medicine injection used widely in China to alleviate blood stasis and to stimulate blood circulation. Its use has been associated with a high rate of adverse effects including anaphylactoid reactions. In the present study, a two-dimensional system comprised of high expression Mas-related G protein-coupled receptor X2 cell membrane chromatography coupled online with HPLC-ESI-IT-TOF-MS was established, and used to screen and identify anaphylactoid components in kudiezi injection. Luteolin-7-O-glucuronide, apigenin-7-O-glucronide, luteoloside and luteolin were identified as the potential anaphylactoid components. The release of ß-hexosaminidase and histamine from Laboratory of Allergic Disease 2 cells enabled evaluation of the anaphylactoid activities of these compounds in vitro. Both ß-hexosaminidase and histamine release were enhanced markedly with increasing concentrations of the anaphylactoid components. The molecular docking assay showed excellent interactions between the potential anaphylactoid constituents and MRGPRX2. In general, the two-dimensional system developed in this study is effective in screening for the anaphylactoid components in Kudiezi injection.

UPLC-HRMS-Based Plasma Metabolomic Profiling of Novel Biomarkers by Treatment with KDZI in Cerebral Ischemia Reperfusion Rats.

Kudiezi injection (KDZI), also known as Diemailing injection, is a traditional Chinese medicine injection of the composite plant Ixeris sonchifolia Hance (also known as Kudiezi), and has been widely used to treat coronary heart disease, angina pectoris, and cerebral infarction, but its pharmacological mechanisms remain unclear. This study is designed to explore the effects of KDZI on middle cerebral artery occlusion and reperfusion (MCAO/R) rats, and to identify metabolic features of cerebral ischemia reperfusion by using a nontargeted metabolic profiling method based on ultra-performance liquid chromatography-high resolution mass spectrometry (UPLC-HRMS). In this process, 32 potential biomarkers were found in plasma. KDZI significantly upregulated the levels of taurochenodesoxycholic acid, leucine, l-phenylalanine, l-tryptophan, arachidonic acid (ARA), and phosphatidyl ethanolamines (PE), phosphatidyl cholines (PC) and downregulated the levels of l-valine and 5-hydroxyindole-3-acetic acid (5-HIAA) in plasma. The results indicated that the mechanisms of KDZI on MCAO/R were related to the mechanisms of amino acid and lipid metabolism.

Rapid screening and identification of sesquiterpene lactones in Kudiezi injection based on high-performance liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry.

Sesquiterpene lactones are considered as the major active compounds in Kudiezi injection in virtue of their special structures and activities. Herein, an analytical method was developed for rapid screening and identification of sesquiterpene lactones in Kudiezi injection using high-performance liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) in negative ion mode. First, two sesquiterpene lactone reference standards were analyzed to obtain their characteristic ESI-MS/MS fragmentation patterns. Second, based on extracted ion chromatography (EIC) data-mining method and characteristic fragmentation pathways analysis, sesquiterpene lactones in Kudiezi injection were rapidly screened and identified. Finally, an important parameter Clog P was adopted to discriminate the isomers of sesquiterpene lactones. As a result, 50 sesquiterpene lactones were characterized, including 9 sesquiterpene lactone aglycones, 39 sesquiterpene lactone glycosides, and 2 amino acid-sesquiterpene lactone conjugates. Among them, 13 compounds were tentatively identified as new compounds. The results demonstrated that the established method would be a rapid, effective analytical tool for screening and identification of sesquiterpene lactones in the complex system of natural medicines.

Metabolic profile of Kudiezi injection in rats by UHPLC coupled with Fourier transform ion cyclotron resonance mass spectrometry.

In this study, a reliable and sensitive ultra-high performance liquid chromatography coupled with fourier transform ion cyclotron resonance mass spectrometry method was developed for the systematic study of the metabolic profile of Kudiezi injection in rat plasma, bile, urine, and feces after intravenous administration of a single dose. The chromatographic separation was performed on an Agilent Eclipse Plus C18 column (4.6 mm × 50 mm, 1.8 µm) and the identification of prototype components and metabolites was achieved on a Bruker Solarix 7.0 T ultra-high resolution spectrometer in negative ion mode. Results indicated that a total of 76 constituents including 29 prototype compounds and 47 metabolites (10 phase I metabolites and 37 phase II metabolites) were tentatively identified. And the metabolic pathways of these prototype compounds including hydroxylation, dehydrogenation, glucuronidation, and sulfate conjugation. In conclusion, the developed method with high resolution and sensitivity was effective for screening and identification of prototypes and metabolites of Kudiezi injection in vivo. Moreover, these results would provide significant information for further pharmacokinetic and pharmacological research of Kudiezi injection in vivo.

Rapid screening and identification of sesquiterpene lactones in Kudiezi injection based on high-performance liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry / 中国天然药物

Sesquiterpene lactones are considered as the major active compounds in Kudiezi injection in virtue of their special structures and activities. Herein, an analytical method was developed for rapid screening and identification of sesquiterpene lactones in Kudiezi injection using high-performance liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) in negative ion mode. First, two sesquiterpene lactone reference standards were analyzed to obtain their characteristic ESI-MS/MS fragmentation patterns. Second, based on extracted ion chromatography (EIC) data-mining method and characteristic fragmentation pathways analysis, sesquiterpene lactones in Kudiezi injection were rapidly screened and identified. Finally, an important parameter Clog P was adopted to discriminate the isomers of sesquiterpene lactones. As a result, 50 sesquiterpene lactones were characterized, including 9 sesquiterpene lactone aglycones, 39 sesquiterpene lactone glycosides, and 2 amino acid-sesquiterpene lactone conjugates. Among them, 13 compounds were tentatively identified as new compounds. The results demonstrated that the established method would be a rapid, effective analytical tool for screening and identification of sesquiterpene lactones in the complex system of natural medicines.

Effectiveness and safety of Kudiezi injection in treating coronary angina pectoris: systematic review and Meta-analysis of randomized controlled trials / 中国中药杂志

To evaluate the effectiveness and safety of Kudiezi injection in the treatment of angina pectoris of coronary heart disease. Four Chinese databases (CNKI, VIP, WanFang, and SinoMed) and three English databases (Cochrane Library, Medline, and ClinicalTrail.gov) were systematically and comprehensively searched from the establishment of each database to March 2018. Randomized controlled trials (RCTs) on the treatment of angina pectoris of coronary heart disease with Kudiezi injection (KDZ) were screened according to the pre-established inclusion criteria and exclusion criteria. The quality of the included studies was evaluated by using the ROB tool developed by the Cochrane Collaboration, and RevMan 5.3 software was used for Meta-analysis. A total of 712 articles were retrieved and finally 38 studies were included. The total sample size was 3 812 cases, 1 945 in the experimental group and 1 867 in the control group. The overall quality of the included studies was generally low. The results of Meta-analysis showed that: KDZ combined with conventional or western medicine was superior to conventional or western medicine alone in the effectiveness and electrocardiogram efficacy of angina pectoris and unstable angina. The descriptive analysis showed that KDZ combined with conventional treatment group was superior to conventional treatment group in agina pectoris associated indicators of angina pectoris and unstable angina. Other outcome measures were easily affected by various factors (such as too large heterogeneity of outcome indicators) and could not be concluded. Adverse reactions included in the study report were all mild adverse reactions and did not affect treatment. Based on the results of this study, it can be seen that Kudiezi injection had a certain effect on the treatment of angina pectoris of coronary heart disease, especially with significant positive effect on the improvement of the curative effect for angina pectoris and the effect of electrocardiogram. No serious adverse reactions occurred. However, due to the limited number of studies included, the generally low quality of the included studies, and the existence of published biases, the quality of the evidence in this study was low, so that caution should be taken to apply this conclusion. The effectiveness and safety of Kudiezi injection in the treatment of angina pectoris of coronary heart disease remained to be confirmed in the future with a well-designed and rigorous multi-center randomized controlled trials with standardized report, large sample, and enough follow-up time.

Rapid screening and identification of sesquiterpene lactones in Kudiezi injection based on high-performance liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry / 中国天然药物

Sesquiterpene lactones are considered as the major active compounds in Kudiezi injection in virtue of their special structures and activities. Herein, an analytical method was developed for rapid screening and identification of sesquiterpene lactones in Kudiezi injection using high-performance liquid chromatography coupled with linear ion trap-orbitrap mass spectrometry (HPLC-LTQ-Orbitrap) in negative ion mode. First, two sesquiterpene lactone reference standards were analyzed to obtain their characteristic ESI-MS/MS fragmentation patterns. Second, based on extracted ion chromatography (EIC) data-mining method and characteristic fragmentation pathways analysis, sesquiterpene lactones in Kudiezi injection were rapidly screened and identified. Finally, an important parameter Clog P was adopted to discriminate the isomers of sesquiterpene lactones. As a result, 50 sesquiterpene lactones were characterized, including 9 sesquiterpene lactone aglycones, 39 sesquiterpene lactone glycosides, and 2 amino acid-sesquiterpene lactone conjugates. Among them, 13 compounds were tentatively identified as new compounds. The results demonstrated that the established method would be a rapid, effective analytical tool for screening and identification of sesquiterpene lactones in the complex system of natural medicines.

[HUVECs extraction and UHPLC LTQ Orbitrap analysis for screening vascular endothelium protective components in Kudiezi injection].

An effective method has been employed as a tool for screening active components in Kudiezi injection by using cell chromatography and sensitive UHPLC-HR-MSn method. The potential bioactive components in Kudiezi injection could be selectively bound to the HUVECs target cells first. After cell target desensitization and inactivation, the chemical constituents with cell target affinity were identified by LC-MS, so as to screen the possible active components in Kudiezi injection. Based on the accurate mass measurements and the retention time, in total, 9 compounds were tentatively identified and characterized, including 4 sesquiterpene lactones, 3 phenolic acids and 2 flavonoids. HUVECs biospecific extraction coupled with UHPLC-LTQ-Orbitrap analysis could provide a rapid and efficient method for the identification of potential bioactive components in Kudiezi injection, and provide the reference for further research on its effective materials basis.

[Post-marketing safety surveillance of Diemailing Kudiezi injection: real world study in 30 233 cases].

This study was aimed to obtain the incidence of adverse drug reaction (ADR) of Diemailing Kudiezi injection, explore its characteristics, related risk factors and application in real world. A prospective single cohort study was conducted from 25 hospitals (including Chinese medicine hospitals and Western medicine hospitals) for 4 years. 30 233 consecutive inpatients using Diemailing Kudiezi injection were observed. Their general information was analyzed by using statistic frequency description. Association rules were used to analyze the correlation between comorbidities or drug combinations; the influential factors for ADRs were initially screened by using cross contingency method and Chi-square test, and then Group LASSAO method was used for further analysis. 54 patients with adverse drug events and 30 patients with ADRs were reported among 30 233 patients, with a total ADR incidence of 0.099%[95%CI (0.06%, 0.13%)]. There were 27 patients identified as the "general" ADR, one patients with "severe" ADR (anaphylactic shock) and two patients with new ADRs. ADR occurred most in 30 min after using Diemailing Kudiezi injection, in a total of 16 patients. The most ADRs were palpitation, vomiting, chills, pruritus and rash, 6 times for each symptom. Diemailing Kudiezi injection was well tolerated in the general population. The overall incidence of adverse reactions was rare, with high safety. However, the real incidence of ADRs may be underestimated in this study, and the blood samples were not obtained for the patients, so further mechanism studies shall be conducted.

[Systematic review of Kudiezi injection drug safety].

To systematically evaluate the safety of Kudiezi injection. Databases such as Cochrane library, Medline, EMbase, Web of Science, Clinical Trials, CBM, CNKI, VIP, Wanfang and Chinese Clinical Trial Register were searched to collect the literature on all the study types of Kudiezi injection. Two researchers screened literature, assessed quality and extracted data according to inclusion and exclusion criteria. All studies were assessed by using internationally recognized methodological quality assessment tools or reporting quality evaluation criteria; Meta-analysis of adverse drug reaction/adverse events (ADR/AE) of Kudiezi injection was performed by using Stata 12.0 software. There were 411 clinical studies included, out of which 315 studies were analyzed finally. 18 072 patients in total used kudiezi injection, and there were 330 cases with ADRs and 13 cases with AEs. The most common ADR related system was the central and peripheral nervous system, with a weighted incidence of 2.9% [95%CI(0.022, 0.036)]. From the current evidence, the overall safety of Kudiezi injection was acceptable. Although data could be collected from all kinds of published reports, there are lack of mechanism experiments or observational studies with large samples of Kudiezi injection. Therefore, it is necessary to carry out further research on the safety of Kudiezi injection. Meanwhile, off label use of Kudiezi injection is common, so it is urgent for relevant governmental departments to formulate drug use specifications and provide better guidance for clinical drug use.