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.

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.

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.

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.

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.

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.

Clinical effect of alprostadil combined with Kudiezi injection in the treatment of posterior circulation ischemic vertigo and its effect on levels of Iysophosphatidic acid, acidic phospholipid / 中国基层医药

Objective To explore the clinical effect of alprostadil combined with Kudiezi injection in the treatment of posterior circulation ischemic vertigo,and its effect on levels of lysophosphatidic acid (LPA),acidic phospholipid (AP).Methods From October 2015 to October 2017,92 cases of posterior circulation ischemia in the Affiliated Hospital of Medical College were selected and randomly divided into observation group(n =46) and control group(n =46) according to the digital table.The control group was treated with Kudiezi injection,while the observation group was treated with alprostadil combined with Kudianzi injection.The clinical efficacy and LPA,AP levels before and after treatment were compared between the two groups.Results After treatment,the total effective rate in the observation group was 95.65％,which in the control group was 82.61％,there was statistically significant difference between the two groups(x2 =8.622,P ＜0.05).After treatment,Vm and Vs of bilateral vertebrobasilar artery in both two groups were increased more rapidly than those before treatment(observation group:t =14.041,11.124,11.207,10.057,10.925,11.920;control group:t =7.204,7.057,8.145,6.572,6.581,5.481,all P ＜ 0.05).Compared with the control group,the Vm [(34.24 ± 3.04) cm/s,(30.54 ± 3.33) cm/s,(35.42 ± 3.46) cm/s] and Vs[(40.09 ± 5.14) cm/s,(40.24 ± 5.02) cm/s,(43.14 ± 4.97) cm/s] of bilateral vertebrobasilar artery in the observation group were significantly higher (t =7.825,4.581,8.610,7.256,7.017,5.824,all P ＜ 0.05).After treatment,the levels of LPA and AP in the two groups were significantly lower than those before treatment(observation group:t =18.054,17.259;control group:t =17.651,14.254,all P ＜ 0.05).The levels of LPA and AP in the control group [(1.75 ± 0.52) μmol/L,(2.42 ± 0.51) μmol/L] were significantly higher than those in the observation group [[(1.05 ± 0.28) μmol/L,(1.84 ± 0.48) μmol/L] (t =8.571,7.224,all P ＜ 0.05).Before treatment,the number of white blood cells in two groups were (6.23 ±0.54) × 109/L,(6.68 ±0.57) × 109/L,respectively,which after treatment were (6.57 ±0.61) × 109/L,(6.42 ±0.64) × 109/L,respectively,there was no statistically significant difference in leukocyte count between the two groups before and after treatment(all P ＜ 0.05).During the treatment,there was no obvious adverse reaction in the two groups.Conclusion Alprostadil combined with Kudiezi injection in the treatment of circulatory ischemic vertigo has excellent clinical effect,there are no adverse reactions such as leukopenia occurred and the safety is good.

Effect ofKudiezi injection combined with rosuvastatin on patients with acute cerebral infarction / 国际中医中药杂志

Objective To investigate the clinical effect ofKudiezi injection combined with rosuvastatin on patients with acute cerebral infarction(ACI).Methods A total of 90 patients with ACI patients of Department of Neurology of our hospital, from March 2015 to June 2016, were randomly divided into treatment group Ⅰ, treatment group Ⅱ and the control group, 30 in each group. The control group was given atorvastatin, the treatment group Ⅰ received rosuvastatin, and the treatment group Ⅱ was adopted Kudiezi injection combined with rosuvastatin. The curative effect was observed, and blood lipid and coagulation function were compared, and daily life ability and nerve function were recorded.Results The curative ratein treatment group Ⅱ (96.7%)was significantly better than that in treatment group Ⅰ (76.7%) and the control group (73.3%) (χ2=6.537,P<0.05). Total cholesterol,three acyl glycerin,low density lipoprotein in treatment group Ⅱ (4.03 ± 0.83 mmol/L, 1.68 ± 0.46 mmol/L, 2.37 ± 0.48 mmol/Lvs. 4.61 ± 0.89 mmol/L, 2.02 ± 0.81 mmol/L, 2.74 ± 0.68 mmol/L and 5.42 ± 0.75 mmol/L, 2.38 ± 0.67 mmol/L, 3.11 ± 0.81 mmol/L) were significantly lower than those in treatment group Ⅰ and the control group (F=21.538, 8.585, 9.092,P<0.05), and those in treatment group Ⅰ was significantly lower than those in the control group (P<0.05).The fibrinogen (2.48 ± 0.37 g/Lvs.2.81 ± 0.46 g/L, 2.95 ± 0.51 g/L), platelet counts[(125.27 ± 11.88)×109vs.(132.13 ± 13.55)×109 and (133.83 ± 13.91)×109] and prothrombin time (17.52 ± 1.94 svs.(16.14 ± 1.62 s, 15.34 ± 1.18 s) in treatment group Ⅱ were significantly lower and higher than those in treatment group Ⅰ and control group (F=8.592, 3.571, 14.139,P<0.05). The scores of Barthel index (85.63 ± 4.10 vs.81.83 ± 3.92, 79.23 ± 4.81) and NIHSS (3.57 ± 1.17 vs. 4.63 ± 1.22, 5.57 ± 1.33) intreatment group Ⅱ were significantly higher and lower than those in treatment group Ⅰand the control group (F=16.873, 19.550,P<0.05), those in treatment group Ⅰ was significantly higher and lower than those in the control group (P<0.05).ConclusionsKudiezi injection combined with rosuvastatin could improve curative effect ,reduce blood lipid, improve coagulation function, improve quality of life and promote recovery of nerve function in patients with acute cerebral infarction.

Clinical evaluation of Kudiezi injection in acute cerebral infarction and its effects on serum VEGF, S-100βand MMP-9 levels / 中国生化药物杂志

Objective To investigate clinical evaluation of Kudiezi injection in treatment of acute cerebral infarction and its effects on serum vascular endothelial growth factor(VEGF), S-100β, matrix metalloproteinases(MMP)-9 levels.Methods 98 patients of acute cerebral infarction who received therapy from October 2014 to October 2016 in our hospital were selected.Those patients were randomly divided into the observation group and the control group with 48 cases in each group.The control group was treated with routine treatment, while the observation group was treated with Kudiezi injection.After treatment of 14 days, the clinical curative effect, serum VEGF, S-100β, MMP-9, National institutes of health stroke scale (NIHSS) and Barthel index were compared.Results After treatment, the total effective rate in the observation group 87.75%(43/49) was significantly higher than that of the control group 65.31%( 32/49 ) , the difference was statistically significant ( P<0.05 ) , the level of VEGF in the observation group was significantly higher than that of the control group, and the S-100βand MMP-9 were significantly lower than that of the control group, the difference was statistically significant (P<0.05), the NIHSS score in the observation group was significantly lower than that of the control group, the difference was statistically significant (P<0.05), the Barthel index in the observation group was significantly higher than that of the control group, the difference was statistically significant (P<0.05).Conclusion Kudiezi injection is well for acute cerebral infarction, which can effectively improve the serum levels of VEGF, S-100β, MMP-9, and can improve the therapeutic effect, promote the recovery of neurological function and improve the quality of life.

Effect of Kudiezi Injection on inflammation and TLR-4/NF-κB signal in cerebral ischemia reperfusion rats / 药物评价研究

Objective To investigate the protective effects of Kudiezi (KDZ) Injection on cerebral ischemia reperfusion injury in rats and to explore its protective mechanism.Methods The rat model of middle cerebral artery occlusion (MCAO) was established by modified suture method,and cerebral blood flow was monitored using laser Doppler flowmetry (LDF).Male SD rats were randomly divided into control group,model group,Kudiezi Injection high and low dose groups.After ischemia-reperfusion for 24 h,the neurological scores were evaluated.After anesthesia,the blood samples and brain tissues were collected,and the expression of inflammatory was detected by Elisa.Western blotting was used to detect the expression of TLR-4 and NF-κB protein.Results Behavioral scores showed that neural function defect was serious in model group compared with control group (P ＜ 0.01).In model group,cerebral index and cerebral infarction area were significantly higher than those of the control group;After KDZ intervention,the symptoms of neurological deficit was alleviated (P ＜ 0.01),the cerebral index and cerebral infarction area of mode were decreased,and the neuronal necrosis was reduced.Kudiezi Injection could significantly reduce the cerebral homogenate and serum levels of TNF-α (P ＜ 0.05) and increase IL-10 level (P ＜ 0.05).Westem blotting showed that Kudiezi Injection could reduce the expression of TLR-4 and NF-κB protein (P＜0.05).Conclusion Kudiezi Injection has protective effect on cerebral ischemia reperfusion rats.After ischemia-reperfusion,Kudiezi Injection could reduce the levels of TNF-α and raise IL-10.Its mechanism may be associated to the down-regulation of TLR-4/NF-κB signaling pathway.

Effect of Kudiezi Injection on inflammation and TLR-4/NF-κB signal in cerebral ischemia reperfusion rats / 药物评价研究

Objective To investigate the protective effects of Kudiezi (KDZ) Injection on cerebral ischemia reperfusion injury in rats and to explore its protective mechanism.Methods The rat model of middle cerebral artery occlusion (MCAO) was established by modified suture method,and cerebral blood flow was monitored using laser Doppler flowmetry (LDF).Male SD rats were randomly divided into control group,model group,Kudiezi Injection high and low dose groups.After ischemia-reperfusion for 24 h,the neurological scores were evaluated.After anesthesia,the blood samples and brain tissues were collected,and the expression of inflammatory was detected by Elisa.Western blotting was used to detect the expression of TLR-4 and NF-κB protein.Results Behavioral scores showed that neural function defect was serious in model group compared with control group (P ＜ 0.01).In model group,cerebral index and cerebral infarction area were significantly higher than those of the control group;After KDZ intervention,the symptoms of neurological deficit was alleviated (P ＜ 0.01),the cerebral index and cerebral infarction area of mode were decreased,and the neuronal necrosis was reduced.Kudiezi Injection could significantly reduce the cerebral homogenate and serum levels of TNF-α (P ＜ 0.05) and increase IL-10 level (P ＜ 0.05).Westem blotting showed that Kudiezi Injection could reduce the expression of TLR-4 and NF-κB protein (P＜0.05).Conclusion Kudiezi Injection has protective effect on cerebral ischemia reperfusion rats.After ischemia-reperfusion,Kudiezi Injection could reduce the levels of TNF-α and raise IL-10.Its mechanism may be associated to the down-regulation of TLR-4/NF-κB signaling pathway.

To establish a body of evidence on safety for postmarketing Chinese medicine: A new research paradigm / 中国结合医学杂志

The issue of safety evaluation on postmarketing Chinese medicines has become a hot topic in mainland China recently. Researchers and decision-makers can obtain a variety of evidence resources about safety in order to evaluate the safety profile for postmarketing Chinese medicines. A registry study on ten Chinese medicine injections for postmarketing surveillance has come to the end. From such a study observing more than 300,000 patients for more than 4 years, a theoretical research question emerges, that is, how to identify and evaluate safety evidence systematically. We put forward a brand new research paradigm on the theory level, which is to establish a body of evidence on safety evaluation for postmarketing Chinese medicine. Therefore, multiple information sources were explored and extracted from preclinical experiments for toxicity, postmarketing clinical trials for effificacy and safety evaluation, registry study for surveillance, retrospective data analysis from hospital information system and spontaneous response system, and case reports and systematic review from literature. Greater efforts for this idea and cooperation with experts in this fifield both in China and abroad are urgently needed.

Systematic review of Kudiezi injection drug safety / 中国中药杂志

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.

HUVECs extraction and UHPLC LTQ Orbitrap analysis for screening vascular endothelium protective components in Kudiezi injection / 中国中药杂志

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 / 中国中药杂志

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.

UHPLC-LTQ-Orbitrap-based metabolomics coupled with metabolomics pathway analysis method for exploring the protection mechanism of Kudiezi injection in a rat anti-ischemic cerebral reperfusion damage model / 中国天然药物

Kudiezi injection has been used extensively in the treatment of cerebrovascular and cardiovascular diseases. However, its therapeutic effects and underlying mechanism of action are not fully understood. The aim of the present study was to clarify the protective mechanisms of Kudiezi injection on cerebral ischemic injury, using metabolomics methods. Middle cerebral artery occlusion (MCAO) was introduced in rats to build the cerebral ischemic damage. UHPLC-LTQ-Orbitrap-based analytical method was established for analysis of the metabolites. The raw mass data of all samples were normalized with Sieve 2.2 software and then introduced to orthogonal partial least squares discriminant analysis (OPLS-DA) model. Finally, 23 metabolites in plasma (15 were tentatively identified) were chosen as potential biomarkers, according to accurate mass measurements (< 5 ppm), MS/MS fragmentation patterns, and diagnostic product ions. Furthermore, on the basis of metabolic pathway analysis via metabolomics pathway analysis (MetPA), we first discovered that the protection mechanism in anti-ischemic cerebral reperfusion damage of Kudiezi injection was possibly related to the biosynthesis of phenylalanine, tyrosine, and tryptophan. The present study provided a useful approach for exploring the mechanism of ischemic stroke and evaluating the efficacy of Kudiezi injection or other traditional medicines.

Analysis of Diemailing Kudiezi injection use in real world in 7 189 patients with cerebral infarction / 中国中药杂志

This is a study based on hospital intensive monitoring to explore medication use of Diemailing Kudiezi injection(one Chinese herbal medicine injection) in real word in the patients with cerebral infarction. The active monitoring model was adopted and hospital intensive monitoring on safety of 7 189 cases of patients with cerebral infarction was conducted to obtain the drug use information of Diemailing injection. The results were analyzed by using statistical description and association rule method. The statistical description and association rule analysis were conducted based on patients' basic demographic characteristics, use of Diemailing injection and combined use of drugs. Sixty-two percent(4 437/7 189) of the patients were from traditional Chinese medicine hospitals as compared with 39%(2 752/7 189) from western medicine hospitals; 84%(6 003/7 189) of the patients were from tertiary hospitals as compared with 16%(1 186/7 189) from second-class hospitals. The hospitals were mostly located in north China. Drug related indicators such as a single dripping speed, stash time after allocating transfusion, duration of injection, and injecting room temperature were not noted in instruction manual. It was also found that there were off label use in the practice, for instance, non-intravenous infusion, >14 d treatment course, use of non-designated solvent, and a single dose>40 mL or<10 mL. Analysis of association rules showed that only Edaravone among the most frequent combined drugs was listed in the current guideline in China, and the other three most frequent combined drugs deproteinized calf blood extractive injection, Cinepazide Maleate injection and Alprostadil injection were used with little evidence. Diemailing＋Aspirin＋Alprostadil was the most common combined use in our study, but the recommended clopidogrel＋Aspirin was not found in this study. The drug use situation of Diemailing injection in the real world was obtained by data analysis on large size samples, providing basic reference information for clinicians and researchers. However, efficacy was not concerned in this study, so efficacy-related information could not be explained.

Rapid characterization of chemical constituents and rats metabolites of Kudiezi injection by UHPLC-LTQ-Orbitrap / 中国中药杂志

A rapid and sensitive UHPLC-HR-MSn method was used for the identification of Kudiezi injection and its main metabolites in rat plasma. After the tail intravenous injection of Kudiezi, ACQUITY UHPLC BEH C₁₈ (2.1 mm×100 mm, 1.7 μm) was used, with 0.1% formic acid-acetonitrile solution as the mobile phase for gradient elution. Kudiezi injection and plasma were detected by ESI-LTQ-Orbitrap equipped with an ESI ion source in a negative mode. Based on the accurate mass measurements, the retention time and the mass fragmentation patterns, a total of 53 compounds were tentatively identified and characterized. Furthermore, metabolites in rat plasma after the intravenous administration of Kudiezi injection were also analyzed. A total of 38 compounds were identified, including 27 prototypes and 11 metabolites through metabolic pathways of methylation, glucuronide conjugation, sulfate conjugation and hydrolysis. As a result, UHPLC-LTQ-Orbitrap technique was applied to comprehensively expound Kudiezi injection's chemical components and constituents migrating to rat plasma, and provide scientific basis for further studies on Kudiezi injection's in vivo metabolic process and effective material base.

Clinical Observation of Kudiezi Injection Combined with Alprostadil in the Treatment of Posterior Circula-tion Ischemic Vertigo / 中国药房

OBJECTIVE:To observe the clinical efficacy and safety of Kudiezi injection combined with alprostadil in the treat-ment of posterior circulation ischemic vertigo. METHODS:Totally 180 patients with posterior circulation ischemia were randomly divided into group A,group B and group C. All patients were given aspirin,atorvastatin,nutrition nerve,antihypertensive,hypo-glycemic and other conventional treatment. On this basis,group A was given Alprostadil injection 10 μg,adding into 0.9% Sodium chloride injection 100 ml,iv,once a day;Kudiezi injection 30 ml,adding into 0.9% Sodium chloride injection 250 ml,iv,once a day. Group B was given Alprostadil injection(the same usage as group A);group C was given Kudiezi injection(the same usage as group A). The course was 14 d. The clinic data was observed,including clinical efficacy;blood flow velocity in left vertebral ar-tery(LVA),blood flow velocity in right vertebral artery(RVA),blood flow velocity of basilar artery(BA),changes of peak laten-cy(PL)and incubation period latency(IPL)before and after treatment;and the incidence of adverse reactions. RESULTS:The to-tal effective rate in group A was significantly higher than group B and C,with significant difference(P0.05). There were no obvious adverse reactions during treatment. CONCLUSIONS:Kudiezi injection combined with alprostadil has better effica-cy than only Kudiezi injection or alprostadil in the treatment of posterior circulation ischemic vertigo,with good safety.