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(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.

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.

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.

基于UPLC-QTOF/MS的清开灵注射液过敏反应豚鼠血清代谢组学研究

目的:利用代谢组学方法研究清开灵注射液过敏反应豚鼠血清样本,探索其可能存在的特征性生物标志物。方法:利用超高效液相色谱-四级杆飞行时间串联质谱(UPLC-QTOF/MS)技术对清开灵注射液组豚鼠和空白对照组豚鼠血清代谢指纹图谱展开分析,根据主成分分析(PCA)和正交信号校正偏最小二乘判别分析(OSC-PLS-DA)结果筛选出差异性代谢物。结果:清开灵注射液组与空白对照组分别呈现聚类分布,确认出5个生物标志物,包括硬脂酰溶血磷脂酰胆碱、肉豆蔻酰溶血磷脂酰胆碱、二氢神经鞘氨醇、蟾二烯羟酸内酯和3α,12β-二羟基-5β-胆烷酸。结论:建立了利用液相色谱-质谱技术进行清开灵注射液过敏反应豚鼠血清代谢组学研究的方法,为进一步认识清开灵注射液的过敏反应及中药注射剂安全性评价研究提供了新的思路。

清开灵注射液联合阿托伐他汀钙片治疗急性脑梗死患者的效果及安全性

目的 观察清开灵注射液联合阿托伐他汀钙片治疗急性脑梗死(ACI)患者的效果及安全性。方法 选取2021年1月—2023年1月上饶市广信区人民医院收治的68例ACI患者,采用随机抽签法分为A组34例(采用阿托伐他汀钙片治疗)和B组34例(在A组基础上联合清开灵注射液治疗),2组患者均持续治疗7 d。比较2组临床疗效,治疗前后美国国立卫生研究院卒中量表(NIHSS)评分、凝血功能指标、血液流变学指标及不良反应。结果 B组治疗总有效率高于A组(94.12%vs.76.47%,χ^(2)=4.221,P=0.040)。治疗7 d后,2组NIHSS评分、血浆纤维原蛋白水平降低,凝血酶原时间、活化部分凝血活酶时间延长,且B组变化幅度大于A组(P<0.01);2组全血黏度、血小板聚集率、血浆黏度降低,且B组低于A组(P<0.01)。B组药物不良反应总发生率低于A组(5.88%vs.26.47%,χ^(2)=5.314,P=0.021)。结论 采用清开灵注射液与阿托伐他汀钙片联合治疗ACI患者不仅可改善凝血功能和血液流变学,促进神经功能恢复,还能减少不良反应,提高用药安全性。

清开灵对人冠状病毒肺炎寒湿疫毒袭肺证小鼠病证结合模型的治疗作用

目的:构建寒湿疫毒袭肺病证动物模型,考察清开灵注射液缓解寒湿症作用的功效。方法:从小鼠证型外观表现,血清中胃动素(Motilin,MTL)、胃泌素(Gastrin,GAS)含量,肺指数及抑制率,肺组织中病毒核酸表达量、炎症因子表达量等方面进行药效学评价。结果:小鼠感染后,肺指数较模型组明显增大(p <0.01);与寒湿感染组相比,低、高剂量给药组肺指数均显著降低(p <0.01),肺指数抑制率分别为82.20%、69.12%。清开灵注射液可明显改善感染小鼠一般状态,显著降低小鼠肺部炎症,降低小鼠肺组织中病毒核酸表达、白细胞介素-6(Interleukin-6,IL-6)等炎症因子含量以及血清中MTL、GAS含量,增大淋巴细胞百分比。结论:清开灵注射液对人冠状病毒肺炎寒湿疫毒袭肺证有明显的治疗作用。

清开灵注射液辅助治疗小儿脓毒症毒热证的效果及对炎症因子、心肌受损程度的影响

目的探讨清开灵注射液辅助治疗小儿脓毒症毒热证的效果及对炎症因子、心肌受损程度的影响。方法选取沭阳县中医院2020年5月至2023年7月收治的60例脓毒症毒热证患儿作回顾性分析,根据不同治疗方案分为对照组(n=30)与观察组(n=30)。对照组采用常规综合治疗,观察组在对照组基础上联合清开灵注射液治疗。比较两组病情程度、炎症因子水平、心肌损伤标志物水平及凝血功能。结果治疗后,观察组小儿危重症评分高于对照组,快速序贯器官衰竭评分、急性生理与慢性健康评分低于对照组(P<0.05)。治疗后,观察组肿瘤坏死因子-α、超敏C反应蛋白、白细胞介素-6水平较对照组低,白细胞介素-10水平较对照组高(P<0.05)。治疗后,观察组N端脑钠肽前体、超敏肌钙蛋白T、肌酸激酶同工酶水平均低于对照组(P<0.05)。治疗后,观察组纤维蛋白原、D-二聚体水平较对照组低,抗凝血酶Ⅲ水平较对照组高(P<0.05)。结论小儿脓毒症毒热证采取清开灵注射液治疗可有效改善患儿病情,降低炎症因子水平及心肌损伤程度,改善凝血功能,可在临床中借鉴使用。

清开灵注射液治疗急性上呼吸道感染的临床研究

目的：探讨清开灵注射液（简称清开灵）对急性发热的疗效。方法：每日采用清开灵１２０、１６０、２００ｍｌ３个剂量，并以洁霉素注射液（简称洁霉素）１８ｇ做对照，观察急性上呼吸道感染患者４００例的疗效。结果：清开灵愈显率８４１４％，洁霉素愈显率７５８３％，前者疗效优于后者（Ｐ＜００１）。清开灵（一次性常规剂量）降低体温平均起效时间（１２６ｈ）较洁霉素（１７６ｈ）短，清开灵对病程１天以内的患者，疗效优于病程３天者。但３个剂量之间，疗效无显著性差异（Ｐ＞００５）。清开灵各剂量组及总体降低白细胞总数的效果，均与洁霉素相仿。清开灵对咽拭子培养有致病菌生长者，体内抗菌作用很好。结论：清开灵是治疗急性上呼吸道感染的高效。

4种中药注射剂皮肤过敏试验方法与意义的探讨

黄芪多糖粉针剂皮下法皮肤过敏试验阳性率12．3％，清开灵粉针剂3．0％，清开灵注射液7．6％，双黄连注射液6．3％。青霉素过敏反应率为0．7％～10％。不同剂型（粉针与液剂），不同浓度等均可能会影响皮试阳性率。皮试阳性不用药。皮试阴性用药，用药后仍有过敏反应发生。黄芪多糖粉针剂皮试阴性，用药后过敏反应发生率为2．1％。清开灵为0．4％（1／224），双黄连注射液为0．9％～2．6％。双黄连注射液在人群中的致敏率为8．6％（31／360包括皮试阳性数加过敏反应数）。清开灵粉针剂组致敏率为4．5％（6／132），清开灵注射液组致敏率9．1％（12／132）。黄芪多糖粉针剂组致敏率15．4％（62／402）。合计致敏率10．8％（111／1026）。青霉素皮下法试验阳性主要表现以皮丘为主，伴有周围红晕，而中药注射液皮肤以红晕为主，皮丘多不明显。皮试对减少黄芪多糖粉针剂、清开灵粉针剂、双黄连注射液用药后过敏反应有一定意义。可作为临床减少不良反应的措施之一。

清开灵和生脉注射液联合用药对油酸型急性肺损伤家兔的治疗作用

目的:观察静脉注射清开灵、生脉注射液(生脉)及其联合用药对油酸型急性肺损伤(ALI)家兔的影响。方法:家兔随机分为11组:对照组,油酸组,治疗组分别包括清开灵和生脉以及清开灵+生脉小、中、大剂量组。iv油酸(0.05mL·kg-1)复制家兔ALI模型后,立即iv上述药液,观察给予油酸前及以后30,60,120min时的呼吸频率和幅度,于各时间点测定动脉血气含量;实验后处死家兔取肺组织,测定肺组织LDH,CAT,MDA的含量及观察病理变化。结果:与油酸组比较,清开灵、生脉及清开灵+生脉的小、大剂量组的呼吸幅度均显著升高;清开灵+生脉小剂量组PaO2显著升高(P<0.05),清开灵、生脉及清开灵+生脉小剂量组的PaCO2均显著降低(P<0.05);清开灵、生脉各剂量组的MDA均显著降低,清开灵+生脉小剂量组的MDA显著降低、CAT显著增加;清开灵、生脉及清开灵+生脉小剂量组可以减轻油酸引起的病理改变。结论:清开灵+生脉小剂量对油酸型肺损伤家兔的疗效优于同剂量下的单独用药。

清开灵注射液对急性脑梗死患者血小板CD62P与细胞因子的影响

目的:观察清开灵注射液对急性脑梗死(ACI)患者的临床疗效及血小板 CD62P阳性表达率与细胞因子含量动态变化的影响。方法:65例发病在 3天以内的 ACI患者随机分为两组,治疗组用清开灵注射液和低分子右旋糖研治疗,对照组用低分子右旋糖研治疗。采用流式细胞仪(FCM)、电化学发光(EC)等技术测定两组 ACI患者治疗前后血小板 CD62P的阳性表达率与肿瘤坏死因子a(TNF-α)、白细胞介素-2受体(IL-2R),白细胞介素一6(IL.6)等指标的水平,并以3O例健康人作正常对照及相关分析。结果:ACI患者治疗前后CD62P、TNF-a、I丁ZR、IL-6水平均显著高于健康人组(P<0.05或P<0.01),ACI患者CD62P表达与 TNF-a、IL-ZR二L-6水平升高呈正相关;治疗组治疗后 CD62P、TNF.a、IL.ZR、IL-6水平的降低较对照组显著(P<0.05),临床治愈率、显效率亦明显高于对照组(P<0.05)。结论:清开灵注射液治疗ACI的作用机制与其抑制血小板活化增强、减轻细胞因子介导的中枢神经系统免疫应答及炎症损伤等有关。

清开灵注射液对大鼠CYP1A2和2D6的影响

目的:通过清开灵注射液的大鼠体内、外实验,观察清开灵注射液对大鼠CYP1A2亚型,CYP2D6亚型的影响。方法:通过HPLC法测定全血中咖啡因的代谢率,观测清开灵注射液对大鼠CYP1A2活性的影响;通过HPLC法测定大鼠肝微粒体重组系统非那西丁的代谢比率,确定清开灵注射液对大鼠肝微粒体CYP1A2亚型的作用;测定大鼠肝微粒体重组系统右美沙芬的代谢比率,确定清开灵注射液对大鼠肝微粒体CYP2D6亚型的作用。结果:实验组中给予大鼠不同浓度的清开灵注射液(0.15,0.3,0.6 mL.kg-1),其咖啡因代谢率为(15.9±3.8)%,(14.5±1.8)%,(12.3±1.2)%,对照组为(16.8±5.9)%,各剂量组及对照组间均无显著性差异;肝微粒体体外重组系统中,实验组各浓度清开灵注射液对CYP2D6没有影响;高剂量组清开灵注射液对CYP1A2有抑制作用。结论:清开灵注射液对CYP1A2和CYP2D6的活性没有影响。

清开灵注射液中三种胆酸含量测定方法比较

目的 :建立同时测定清开灵注射液中 3种胆酸 (牛胆酸 ,猪去氧胆酸和去氧胆酸 )含量的 2种高效液相色谱法(HPLC UV和HPLC ELSD) ,并与原有的测定总胆酸含量的紫外分光光度法进行比较。方法 :高效液相色谱法测定 ,采取紫外与蒸发光散射 2种检测方式 ;结果 :同时测定了清开灵注射液中的 3种胆酸物质 ,方法回收率HPLC/ELSD为1 0 0 % ,HPLC/UV为 97% ,均高于原有的紫外方法 (95 %～ 96 % ) ;结论 :HPLC/ELSD测定清开灵中胆酸成分 ,方法简便准确 。

清开灵注射液中黄芩苷在大鼠体内代谢动力学的研究

目的:研究清开灵注射液中黄芩苷在大鼠体内的代谢动力学,为探索清开灵注射液的体内效应物质基础提供依据。方法:大鼠尾静脉注射清开灵粉针剂后,于不同时间点取血、肝、肺组织,采用高效液相质谱联用法测定样品中黄芩苷含量,并用3P87拟合求算药代动力学参数。结果:静脉给药后,黄芩苷在大鼠体内符合二室模型。45 min时肝组织中分布达峰值,接着肝中浓度急剧下降,120 min后开始缓慢回升,呈现双峰现象。肺组织中黄芩苷浓度远高于肝组织中浓度,且消除较肝脏慢,但达峰时间同肝脏。结论:静注清开灵后,黄芩苷迅速分布至效应器官肺、肝中,黄芩苷为清开灵注射液的肝肺效应物质基础之一。黄芩苷在大鼠体内可能存在一定程度的肝肠循环。

三种神经功能评分在鼠类局灶性脑缺血模型评价中的比较

目的:比较Garcia JH、Clark和Bederson3种神经功能评分对鼠类局灶性脑缺血模型的评价意义。方法:采用线栓法阻塞大鼠和小鼠大脑中动脉,造成局灶脑缺血模型,并采用脑缺血治疗药物清开灵注射液进行干预。24h后,分别采用3种神经功能评分方法进行评价,测定脑梗死体积比例;分析神经功能评分与脑梗死体积比例的相关性及不同评分间的相关性,并进行比较。结果:大脑中动脉阻塞模型(MCAO)术后,动物均出现了脑梗死病灶及神经功能的损伤,清开灵注射液治疗可显著减小脑梗死体积并改善神经功能。采用相关性分析发现,大鼠实验中GarciaJH评分和Bederson评分与梗死体积显著相关,且两种神经评分之间显著相关;小鼠实验Clark局灶性功能损伤评分与梗死体积显著相关,Bederson评分和Clark一般功能损伤评分未显示与脑梗死体积相关,但局灶性功能损伤评分与一般功能损伤评分和Bederson评分均显著相关。结论:同Bederson评分相比,Garcia JH评分和Clark局灶性功能损伤评分与脑梗死体积具有更好的相关性,更适合作为脑缺血治疗药物疗效评价的指标。

RP-HPLC法测定血浆中栀子苷浓度及药动学研究

目的:建立反相高效液相色谱法测定血浆中栀子苷的浓度,研究比较栀子药材及其制剂加味逍遥丸和清开灵注射液中栀子苷在小鼠体内的药动学行为。方法:血浆样品用甲醇沉淀蛋白后,采用Kromasil C18色谱柱(250 mm×4.6 mm,5μm),柱温:室温;流动相:乙腈-水(10:90);流速:1.0 mL·min-1;检测波长238 nm,进样量20μL。结果:线性范围1.02-51.0μg·mL-1(r=0.9992);最低检测浓度0.255μg·mL-1;回收率分别为93.14%,91.90%,108.2%;日内和日间精密度RSD均小于10%。小鼠灌胃栀子提取液和加味逍遥丸提取液后栀子苷的药动学行为均符合一室模型,而小鼠静脉注射栀子提取液和清开灵注射液后栀子苷的药动学行为均符合二室模型。结论:2种不同的提取液以相同途径给予栀子苷后,药材和制剂中栀子苷的房室模型没有改变,但灌胃加味逍遥丸比栀子药材的分布及消除半衰期长,达峰时间长,达峰浓度低;静注清开灵注射液比栀子药材的分布及消除半衰期短、消除速率快。