A Retrospective Analysis on 1330Adverse Event Reports of Qingkailing in China:Further Perception of Its Risks and Rational Use

Qingkailing (QKL)is a modern preparation exploited according to the traditional Chinese medicine theory.It becomes the second leading cause of adverse drug events (ADEs)in all traditional Chinese medicine injections.The safety evaluation and rational use of QKL are of special importance.This retrospective study used data from Adverse Drug Reaction Monitoring Center of Hubei Province in China from January 2012 to December 2014.ADE cases induced by QKL were collected and analyzed according to patients'demographics,characteristics of drugs involved,characteristics of ADEs,causality,and outcomes.A total of 1330 qualified ADEs were included.Most ADEs occurred within 30 min after administration and the 0-10 years old age group had the highest number of ADEs.The common ADEs included anaphylactic reaction,dyspnea and nausea.Serious reactions accounted for 5.19%.Combination with cephalosporin (74/146,50.69%) caused more ADEs than other drugs did.Serious attention should be paid when QKL is used for children,and combination with cephalosporin should be avoided.

Therapeutic window of Qingkailing injection for focal cerebral ischemia/reperfusion injury

The time window in which a drug is effective varies between drugs. The present study investigated the therapeutic window of Qingkailing injection for focal cerebral ischemia/reperfusion in mice. Animals underwent middle cerebral artery occlusion and were injected with Qingkailing （1.5, 3, 6 mL/kg）. Infarct volume and neurological function were assessed after 24 hours of ischemia. In addition, to establish the therapeutic time window, mice were injected with 3 mL/kg Qingkailing at 0, 1, 3, 4, 6, 9 and 12 hours after occlusion. Results revealed that Qingkailing injection significantly reduced infarct volume and improved neurological function in model mice after cerebral infarction for up to 9 hours, demonstrating that the therapeutic window of Qingkailing injection can extend to 9 hours for cerebral ischemia/reperfusion in mice.

Qingkailing injection for the treatment of acute upper respiratory infection in children: a systematic review and meta-analysis

Objective:To systematically evaluate the clinical efficacy and safety of Qingkailing (QKL) injection for pediatric acute upper respiratory infection (AURI).Methods:We searched for randomized controlled trials (RCTs) of pediatric AURI treated by QKL and western medicine (WM) in the China National Knowledge Infrastructure Database,China Science and Technology Journal Database,Wanfang,Chinese Biomedical Literature Database,PubMed and Cochrane Library from inception to August,2016.Two reviewers independently retrieved the RCTs and extracted information.The Cochrane Collaboration Risk of Bias Assessment Tool was used to evaluate the methodological quality of RCTs.The data were meta-analyzed by RevMan 5.3 software.Results:Ultimately,21 RCTs that involved 2364 participants were included,and the quality of RCTs was generally poor.According to the meta-analysis,the combined use of QKL and WM for treating AURI can be effective,with a higher total effective rate,less defervescence time and less recovery time of tonsil and throat inflammation.Twenty-five adverse drug reactions (ADRs) were reported in three RCTs,but there were no serious ADRs.Conclusion:The combination of QKL and WM for treating pediatric AURI can result in better effects,but no definitive conclusions can be made regarding its safety.More rigorous RCTs are needed to support the clinical application of QKL.

Qingkailing injection for the treatment of acute stroke: a systematic review and Meta-analysis

OBJECTIVE： To evaluate systematically the clinical efficacy and safety of Qingkailing （QKL） injection in the treatment of acute stroke. METHODS： Searches for randomized controlled trials into acute stroke treated with QKL injection were performed in the China National Knowledge Infrastructure Database, China Science and Technology Journal Database, Wan fang Database, Chinese Biomedical Literature Database, PubMed and Cochrane Library, from January 1979 to March 2013. Two reviewers independently retrieved the RCTs and extracted the information. The Cochrane risk of bias method was used to assess the quality of the included studies, and a Meta-analysis was conducted with Review Manager 5.2 software. RESULTS： A total of 13 studies with 1110 participants were included. The quality of the studies was generally low. The Meta-analysis indicated that the combined use of QKL and Western Medicine was significantly superior to control group therapy in terms of the total effective rate. The relative risk （RR） in the acute cerebral hemorrhage （ACH） sub-group was 1.17 [95% confidence interval （CI） （1.08, 1.26）, P=0.0001]. In the acute cerebral infarction （ACI） sub-group, RR was 1.27 [9.5% CI （1.14, 1.42）, P〈0.0001], and in the ACH and ACI mixed sub-group, RR was 1.34 [95% CI （1.20,1.50）,P〈0.00001]. Additionally, QKL promoted the absorption of hematoma [mean difference （MD）= - 3.73, 95%0 （ - 4.48, - 2.98）, P〈0.000 01], decreased neurological damage in ACI [MD= - 5.60, 95% CI （ - 8.50, - 2.70）, P=0.0002] and ACH [MD= 4.08, 95% CI （ - 8.00, 0.16）, P=0.04], promoted the recovery of awareness [RR=1.56, 95% CI （1.09, 2.21）, P=0.01] and reduced the whole blood viscosity coefficient [MD=- 0.75, 95% CI （ - 1.47, - 0.03）, P=0.04]. There were no adverse drug reactions reported in the included studies. CONCLUSION＂ Based on this systematic review, QKL combined with conventional therapy was effective compared with control treatment. However, because the articles used in the study were not of high quality, further studies should be conducted into the efficacy and safety of QKL in treating acute stroke.

Qingkailing Injection(清开灵注射液)for Treatment of Children Pneumonia Induced by Respiratory Syncytial Virus:A Meta-Analysis of Rando mized Controlled Trials

Objective： To evaluate the efficacy and safety of Qingkailing Injection（清开灵注射液, QKL） for treatment of children pneumonia caused by respiratory syncytial virus（RSV）. Methods： Randomized clinical trials（RCTs） comparing QKL with ribavirin injection in the treatment of children pneumonia induced by RSV were searched in Pub Med, Science Direct, Cochrane Library, Chinese VIP database, CNKI and Wanfang databases from their inception to March 2014. Meta-analyses were performed using RevMan 5.2 software. The methodological quality of the selected RCTs was evaluated by the Modified Jadad Score. The primary outcome measures were effective rate and the secondary outcomes were relief time of fever and cough. Results： Seven RCTs with 992 cases published from 2008 to 2013 were identified. The meta-analysis results indicated that QKL was more effective in cure rate [risk ratios（RR）=1.32, 95% CI（1.17, 1.50）, P〈0.01], total effective rate [RR=1.07, 95% CI（1.02, 1.13）, P=0.009] and less fever clearance time [mean difference=–0.73, 95% CI（–1.22, –0.23）, P=0.004], compared with ribavirin injection in the treatment of RSV-induced children pneumonia. No dead case was reported in all trials. There were 3 trials mentioned adverse events, 2 reported no obvious adverse event occurred while 1 reported adverse events described as skin hypersensitivity, elevation of ALT, a mild abnormal of hepatic and renal function in both QKL and ribavirin group. Conclusions： QKL was an effective and relatively safe option for the treatment of RSV-induced children pneumonia. These therapeutic effects were promising but need to be interpreted with caution due to variations in the treatment and methodological weakness in the studies.

Experimental study on anaphylaxis of Qingkailing injection and its components on Beagle dogs

OBJECTIVE:To study the anaphylaxis of Qingkailing injection(QI) and its components.METHODS:Experimental anaphylactoid and allergic reactions were used.Changes in the behaviors of Beagles and serum levels of histamine,immunoglobulin(Ig)E,IgG,IgM,eosinophil cationic protein(ECP),and interleukin(IL)-4,as well as blood pressure,after injecting QI and its components on the forelimb veins of Beagles were observed.RESULTS:According to comprehensive determination of abnormal behavior scores and changes in serum levels of histamine,IgE,IgG,IgM,ECP,and IL-4,as well as in blood pressure,radix isatidis and hyodeoxycholic acid caused anaphylactoid reactions,and honeysuckle,radix isatidis,hydrolysate,cholic acid and Gardenia jasminoides caused allergic reactions.The anaphylaxis of QI involved anaphylactoid and allergic reactions.CONCLUSION:QI and its components need to be refined further to improve the safety,efficacy,and quality of its use in clinical settings.

Network pharmacology assessment of Qingkailing injection(清开灵注射液)treatment of cholestatic hepatitis

OBJECTIVE:To investigate the targets and mechanisms of action of Qingkailing injection(清开灵注射液,QKL)in the treatment of cholestatic hepatitis.METHODS:A network pharmacology method was implemented using drug and disease databases to target QKL and cholestasis hepatitis,respectively.The functional protein association network STRING database was used to construct a protein-protein interaction network using R language and the Bioconductor toolkit.The org.Hs.eg.db and cluster Profiler packages were used for gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis,which explored biological functions and pathways of potential targets.Targets were then visualized using Cytoscape 3.6.0 software.RESULTS:We screened 121 compounds in QKL and identified 112 targets for the treatment of cholestatic hepatitis.QKL played a role in the treatment of cholestatic hepatitis through 305 biology process terms,15 cellular component and 29 molecular function terms.The mechanism of QKL action was mainly related to tumor necrosis factor,mitogen-activated protein kinase,and PI3 K-Akt signaling pathways.CONCLUSION:The treatment of cholestatic hepatitis by QKL involved multiple targets,biological functions,and signaling pathways that are closely associated with the disease.

Comparative pharmacokinetics of baicalin and geniposide in juvenile and adult rats after oral administration of Qingkailing Granules

Objective:To explore the effect of age on Qingkailing Granules disposition by comparing the pharmacoknetics of geniposide and baicalin in juvenile and adult rats.Methods:A simple and rapid LC-MS/MS method was developed and validated to simultaneously determine geniposide and baicalin in rat plasma after a simple protein precipitation.The analytes were separated on an Agilent ZORBAX Extend-C18 column.The mobile phase consisted of acetonitrile and water with 0.1%(volume percent)formic acid at a flow rate of 0.6 mL/min.The ionization was conducted using an ESI source in negative ion mode.Multiple reaction monitoring was used for quantification at transitions of m/z 445.0→m/z 268.9 for baicalin,m/z 433.2→m/z 225.0 for geniposide,m/z 431.0→m/z341.0 for vitexin(IS).Juvenile and adult rats were administrated Qingkailing Granules(3 g/kg)orally.Plasma concentrations of baicalin and geniposide were determined by LC-MS/MS.Results:The linear ranges of the analytes were 1-1000 ng/mL for baicalin and 2-2000 ng/mL for geniposide.The method was successfully applied to compare the pharmacokinetics of the analytes between juvenile and adult rats after oral administration of Qingkailing Granules.AUC was bigger in adult rats,while t1/2 was longer in juvenile rats.Conclusion:These results suggested that the absorption and elimination of baicalin and geniposide in juvenile rats was lower than that in adult rats.Additional attention should be paid to the pharmacokinetic difference when Qingkailing Granules were used in children.

Application of near-infrared spectroscopy for the rapid analysis of Lonicerae Japonicae Flos solution extracted by water

A rapid quantitative analytical method for three components of Lonicerae Japornicae Flos solution(Lonicera Japonica Thumb.)extracted by water was developed using near-infrared(NIR)spectroscopy and the partial least-squares(PLS)method.The NIR spectra of 81 samples collected from a production line were obtained.The concentrations of secologanic acid,chlorogenicacid and galuteolin were detemmined by using high-performance liquid chromatography-diodearray detection as the reference method.Several pretreatment methods for the NIR spectra wereusedi during PLS calibration.The most appropriate latent variable number of the PLS factor wasselected based on the standard error of cross-validation(SECV).The performance of the finalPLS models was evaluated according to SECV,standard error of predliction(SEP)and deter-mination coeficient(R^(2)).The compounds secologanic acid,chlorogenic acid and galuteolin hadSEP values of 0.030,0.061 and 1.668μg/mL,respectively and R^(2) values over 0.85.This workshows that NIR spectroscopy is a rapid and convenient method for the analysis of LoniceraeJaponicae Flos solution extracted by water.The proposed method can help in the application ofprocs analytical technology in the pha maceutical industry,particularly in tra ditional Chinesemedicine injections.