荆花胃康胶丸及其拆方抗耐药幽门螺杆菌作用和机制研究
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摘要
系统性评价荆花胃康胶丸联合PPI三联疗法治疗幽门螺杆菌感染的荟萃分析研究
目的：系统评价荆花胃康胶丸联合PPI三联疗法治疗幽门螺杆菌感染与单纯三联疗法的疗效和不良反应的差异,为深入研究荆花胃康胶丸的抗幽门螺杆菌作用寻找事实依据
方法：计算机检索PubMed、Cochrane图书馆、EMbase、Web of Science、CNKI、VIP和中华医学会数字化期刊库,收集荆花胃康胶丸联合三联疗法与单纯三联疗法随机对照试验,检索时间均从建库至2013年2月,并追查已获文献的参考文献。按照纳入标准由2名研究者独立筛选文献并提取资料,参照Jadad评分标准对纳入文献的方法学质量进行评估,而后采用RevMan5.0软件进行Meta分析。
结果：共纳入14项研究,1619例患者。Meta分析结果显示：荆花胃康胶丸联合PPI三联疗法对幽门螺杆菌的根除率优于单纯PPI三联疗法[OR=3.29,95%CI(2.44,4.44),P<0.00001]；8项研究报道了不良反应发生情况,两组不良反应发生率比较差异无统计学意义,各研究报道的不良反应轻微,未发现严重不良反应,临床应用安全。
结论：目前研究表明荆花胃康胶丸与PPI三联疗法联合治疗幽门螺杆菌感染根除率优于单纯PPI三联,且安全性好。
买验一荆花胃康胶丸原料药及其主要成分在体外对耐药幽门螺杆菌的杀菌作用
目的：通过杀菌实验的方式证实荆花胃康胶丸原料药及其主要成分在体外对耐药幽门螺杆菌的作用,及其与抗生素联用是否具有协同作用
方法：以E-test方法对临床采集的Hp菌株进行耐药性筛选,使用琼脂稀释法分别测定荆花胃康胶丸及其主要成分土荆芥及水团花原料药对临床耐药Hp的平均最低抑菌浓度(MIC)。通过体外杀菌实验的方式,分别测定不同浓度的荆花胃康胶丸原料药及其主要成分土荆芥及水团花单药在不同浓度下对耐药Hp的时间-杀菌曲线,测定甲硝唑或克拉霉素与荆花胃康胶丸、土荆芥及水团花原料药联用与单用时对耐药Hp的时间-杀菌曲线,判断其协同作用的有无。
结果：荆花胃康胶丸原料药和土荆芥原料药在1/2倍MIC即对临床耐药Hp具有较为明显的体外杀菌作用,其杀菌效果随剂量和时间增加而增强。荆花胃康胶丸和土荆芥在和抗生素联用后,对临床耐药Hp的体外杀菌作用得到了加强。荆花胃康胶丸另一成分水团花在体外对耐药Hp的杀菌作用不明显。
结论：荆花胃康胶丸和土荆芥原料药在体外对耐药Hp具有杀灭作用,其杀菌效果随剂量和时间增加而增强,与抗生素联合应用时可加强抗生素的杀菌效果。
实验二土荆芥提取物对耐药幽门螺杆菌主动外排泵hefABC基因表达的作用
目的：研究荆花胃康胶丸的主要成分土荆芥对幽门螺杆菌主动外排泵hefABC基因表达的影响,探索土荆芥抗耐药Hp的分子机制。
方法：实验菌株北京大学第一医院消化科实验室保存的幽门螺杆菌标准菌株NCTC11637,临床耐药菌株9株,均经E-test (AB Biodisk, Solna, Sweden)药敏试验检测对常用抗生素的耐药情况。通过琼脂稀释法测定土荆芥挥发油对幽门螺杆菌的最低抑菌浓度(MIC),收取培养48-72h的新鲜幽门螺杆菌于含10%胎牛血清的布氏肉汤中,于37℃微需氧环境中进行振荡培养,将菌液分为6份,其中5份分别加入土荆芥,使所含土荆芥浓度分别1/8、1/4、1/2、1、2倍MIC。继续于上述环境中培养3h后,收集菌液。RNA的提取RNA提取按Trizol提取试剂盒操作说明书进行。提取的RNA质量由A260/A280比值和1.5%琼脂糖凝胶电泳鉴定。以Oligo dT为引物进行RT反转录。通过荧光定量PCR反应测定各样本中hefA、hefB、hefC的基因表达量,以2-△△Ct表示。
结果：与对照组相比,耐药Hp菌株在加入土荆芥原料药后其主动外排泵基因hefA、hefB、 hefC基因表达均呈不同程度的下调,且在土荆芥原料药的亚抑菌浓度时对细菌外排泵基因的抑制最为明显。
结论：土荆芥原料药可下调耐药幽门螺杆菌外排泵hefABC基因的表达,可能是其对耐药幽门螺杆菌产生抑制杀灭作用的分子机制。
Systematic Review:Meta-analysis of Jinghua Weikang capsules combined PPI triple therapy on Helicobacter pylori infection
Objective:Systematic review of the difference of efficacy and adverse reactionsbetween Jing Hua Wei Kang capsule combined PPI triple therapy and triple therapy alone on Helicobacter pylori infection.
Methods:We searched PubMed, Cochrane Library, EMBASE, Web of Science, CNKI, VIP and the Chinese Medical Association digital journal library for randomized controlled trial comparing Jinghua Weikang Capsules combined triple therapy vs. triple therapy alone, with retrieval time from the built of the library till February2013, and traced the literature references. According to the inclusion criteria literatures were selected independently by two researchers and data was extracted. The methodological quality of the included studies were evaluated according to the Jadad scoring criteria. Meta-analysis was conducted with RevMan5.0software.
Results:A total of14studies and1619patients were included. Meta-analysis showed:H. pylori eradication rate of Jinghua Weikang capsules combined PPI triple therapy vs. PPI triple therapy alone [OR=3.29,95%CI (2.44,4.44), P<0.00001];8studies reported incidence of adverse reactions, incidence of adverse reactions of the two groups was no significant difference; adverse reactions reported were mild.
Conclusion:The present studies showed that the Helicobacter pylori infection eradication rate of Jinghua Weikang capsules with PPI triple therapy was better than PPI triple with mild adverse reactions.
Experiment1:The bactericidal action of pharmaceutical raw materials of Jinghua Weikang Capsule and its main components on resistant Helicobacter pylori in vitro
Objective:To confirm the bactericidal action of pharmaceutical raw materials of Jing Weikang Capsule and its main components on resistant Helicobacter pylori, and their synergistic effect when combining with antibiotics.
Methods:E-test method was used for screening of resistance of clinical isolates.The minimum inhibitory concentration (MIC) of Jing WeikangCapsule and its main ingredients drug Chenopodium ambrosioides L. and pilular adinawere determined with the agar dilution method.By the way of in vitro bactericidal experiments, time-killing curveof Jinghua Weikangand its main ingredients Chenopodium ambrosioides L. and pilular adina alone on resistant Hp were measured at different concentrations.The synergy effect of metronidazoleor clarithromycin combined with Jinghua Weikang Capsule, Chenopodium ambrosioides L. or pilular adina were also analyzed with time-killing curve.
Results:Jinghua Weikang Capsuleand Chenopodium ambrosioides L. had an obvious bactericidal effecton clinical drug resistant Hp in vitro at1/2times of the MIC concentration.The bactericidal effect increasedin dose and time dependent manner. In combination withJinghua Weikangor Chenopodium ambrosioides L., the in vitro bactericidal effect of metronidazole or clarithromycin on clinical resistantHp has been strengthened. The bactericidal effect of Jinghua Weikang's another ingredient pilular adina is not obvious.
Conclusion:Jinghua Weikang Capsule and Chenopodium ambrosioides L. APIs had a bactericidal effect on resistant Hp, and its bactericidal effect increased with dose and time, andthe strengthen the bactericidal effect was enhanced in combination with the antibiotic.
Experiment2:Role ofChenopodium ambrosioides L. extract on efflux pump hefABCgene expression of drug-resistant Helicobacter pylori strains
Objective:To study Jinghua Weikang capsule's main component Chenopodium ambrosioides L.on efflux pump hefABC gene expression of drug-resistant Helicobacter pylori strains, explore molecular mechanisms of Chenopodium ambrosioides L. anti-drug-resistant H pylori.
METHODS:The experiment strains H. pylori NCTC11637and three clinical strains were selected from the department of gastroenterology laboratory of Peking University First Hospital saved strains, the clinical drug-resistant strains were confirmed by E-test (AB Biodisk Solna, Sweden) susceptibility test for detection of resistance to commonly used antibiotics. The minimum inhibitory concentration (MIC) of the Chenopodium ambrosioides L. volatile oil on H. pylori were determined byagar dilution method.Put fresh H. pylori strains cultured about48-72h intobrucella broth containing10%fetal bovine serum for shaking culturing, at37°C, in micro-aerobic environment. The broth was divided into6parts. Chenopodium ambrosioides L. were added into5parts, andthe concentration of the drug were as follows respectively,1/8,1/4,1/2,1and2times of the MIC. Collected the strains at3h after culturing. RNA extraction RNA was extracted by Trizol extraction kit Operating Instructions. The quality of the extracted RNA was identified by the A260/A280ratio and1.5%agarose gel electrophoresis. Oligo dT primers were used in RT reverse transcription. The amount of gene expression of each sample's hefA, hefB and hefC were determinated by quantitative PCR reaction, which were expressed by2-△△Ct.
Results:Compared with the control group, when added of Chenopodium ambrosioides L.,the amount of genes expression of hefA, hefB and hefC decreased in each group. The genes expression were inhibited obviouslyat1/2MIC concentration of Chenopodium ambrosioides L.
Conclusion:Chenopodium ambrosioides L. can downgradegene expression of resistant Helicobacter pylori efflux pump hefABC, which may be the molecular mechanism of the drug anti resistant Helicobacter pylori strains.
目的：系统评价荆花胃康胶丸联合PPI三联疗法治疗幽门螺杆菌感染与单纯三联疗法的疗效和不良反应的差异,为深入研究荆花胃康胶丸的抗幽门螺杆菌作用寻找事实依据
方法：计算机检索PubMed、Cochrane图书馆、EMbase、Web of Science、CNKI、VIP和中华医学会数字化期刊库,收集荆花胃康胶丸联合三联疗法与单纯三联疗法随机对照试验,检索时间均从建库至2013年2月,并追查已获文献的参考文献。按照纳入标准由2名研究者独立筛选文献并提取资料,参照Jadad评分标准对纳入文献的方法学质量进行评估,而后采用RevMan5.0软件进行Meta分析。
结果：共纳入14项研究,1619例患者。Meta分析结果显示：荆花胃康胶丸联合PPI三联疗法对幽门螺杆菌的根除率优于单纯PPI三联疗法[OR=3.29,95%CI(2.44,4.44),P<0.00001]；8项研究报道了不良反应发生情况,两组不良反应发生率比较差异无统计学意义,各研究报道的不良反应轻微,未发现严重不良反应,临床应用安全。
结论：目前研究表明荆花胃康胶丸与PPI三联疗法联合治疗幽门螺杆菌感染根除率优于单纯PPI三联,且安全性好。
买验一荆花胃康胶丸原料药及其主要成分在体外对耐药幽门螺杆菌的杀菌作用
目的：通过杀菌实验的方式证实荆花胃康胶丸原料药及其主要成分在体外对耐药幽门螺杆菌的作用,及其与抗生素联用是否具有协同作用
方法：以E-test方法对临床采集的Hp菌株进行耐药性筛选,使用琼脂稀释法分别测定荆花胃康胶丸及其主要成分土荆芥及水团花原料药对临床耐药Hp的平均最低抑菌浓度(MIC)。通过体外杀菌实验的方式,分别测定不同浓度的荆花胃康胶丸原料药及其主要成分土荆芥及水团花单药在不同浓度下对耐药Hp的时间-杀菌曲线,测定甲硝唑或克拉霉素与荆花胃康胶丸、土荆芥及水团花原料药联用与单用时对耐药Hp的时间-杀菌曲线,判断其协同作用的有无。
结果：荆花胃康胶丸原料药和土荆芥原料药在1/2倍MIC即对临床耐药Hp具有较为明显的体外杀菌作用,其杀菌效果随剂量和时间增加而增强。荆花胃康胶丸和土荆芥在和抗生素联用后,对临床耐药Hp的体外杀菌作用得到了加强。荆花胃康胶丸另一成分水团花在体外对耐药Hp的杀菌作用不明显。
结论：荆花胃康胶丸和土荆芥原料药在体外对耐药Hp具有杀灭作用,其杀菌效果随剂量和时间增加而增强,与抗生素联合应用时可加强抗生素的杀菌效果。
实验二土荆芥提取物对耐药幽门螺杆菌主动外排泵hefABC基因表达的作用
目的：研究荆花胃康胶丸的主要成分土荆芥对幽门螺杆菌主动外排泵hefABC基因表达的影响,探索土荆芥抗耐药Hp的分子机制。
方法：实验菌株北京大学第一医院消化科实验室保存的幽门螺杆菌标准菌株NCTC11637,临床耐药菌株9株,均经E-test (AB Biodisk, Solna, Sweden)药敏试验检测对常用抗生素的耐药情况。通过琼脂稀释法测定土荆芥挥发油对幽门螺杆菌的最低抑菌浓度(MIC),收取培养48-72h的新鲜幽门螺杆菌于含10%胎牛血清的布氏肉汤中,于37℃微需氧环境中进行振荡培养,将菌液分为6份,其中5份分别加入土荆芥,使所含土荆芥浓度分别1/8、1/4、1/2、1、2倍MIC。继续于上述环境中培养3h后,收集菌液。RNA的提取RNA提取按Trizol提取试剂盒操作说明书进行。提取的RNA质量由A260/A280比值和1.5%琼脂糖凝胶电泳鉴定。以Oligo dT为引物进行RT反转录。通过荧光定量PCR反应测定各样本中hefA、hefB、hefC的基因表达量,以2-△△Ct表示。
结果：与对照组相比,耐药Hp菌株在加入土荆芥原料药后其主动外排泵基因hefA、hefB、 hefC基因表达均呈不同程度的下调,且在土荆芥原料药的亚抑菌浓度时对细菌外排泵基因的抑制最为明显。
结论：土荆芥原料药可下调耐药幽门螺杆菌外排泵hefABC基因的表达,可能是其对耐药幽门螺杆菌产生抑制杀灭作用的分子机制。
Systematic Review:Meta-analysis of Jinghua Weikang capsules combined PPI triple therapy on Helicobacter pylori infection
Objective:Systematic review of the difference of efficacy and adverse reactionsbetween Jing Hua Wei Kang capsule combined PPI triple therapy and triple therapy alone on Helicobacter pylori infection.
Methods:We searched PubMed, Cochrane Library, EMBASE, Web of Science, CNKI, VIP and the Chinese Medical Association digital journal library for randomized controlled trial comparing Jinghua Weikang Capsules combined triple therapy vs. triple therapy alone, with retrieval time from the built of the library till February2013, and traced the literature references. According to the inclusion criteria literatures were selected independently by two researchers and data was extracted. The methodological quality of the included studies were evaluated according to the Jadad scoring criteria. Meta-analysis was conducted with RevMan5.0software.
Results:A total of14studies and1619patients were included. Meta-analysis showed:H. pylori eradication rate of Jinghua Weikang capsules combined PPI triple therapy vs. PPI triple therapy alone [OR=3.29,95%CI (2.44,4.44), P<0.00001];8studies reported incidence of adverse reactions, incidence of adverse reactions of the two groups was no significant difference; adverse reactions reported were mild.
Conclusion:The present studies showed that the Helicobacter pylori infection eradication rate of Jinghua Weikang capsules with PPI triple therapy was better than PPI triple with mild adverse reactions.
Experiment1:The bactericidal action of pharmaceutical raw materials of Jinghua Weikang Capsule and its main components on resistant Helicobacter pylori in vitro
Objective:To confirm the bactericidal action of pharmaceutical raw materials of Jing Weikang Capsule and its main components on resistant Helicobacter pylori, and their synergistic effect when combining with antibiotics.
Methods:E-test method was used for screening of resistance of clinical isolates.The minimum inhibitory concentration (MIC) of Jing WeikangCapsule and its main ingredients drug Chenopodium ambrosioides L. and pilular adinawere determined with the agar dilution method.By the way of in vitro bactericidal experiments, time-killing curveof Jinghua Weikangand its main ingredients Chenopodium ambrosioides L. and pilular adina alone on resistant Hp were measured at different concentrations.The synergy effect of metronidazoleor clarithromycin combined with Jinghua Weikang Capsule, Chenopodium ambrosioides L. or pilular adina were also analyzed with time-killing curve.
Results:Jinghua Weikang Capsuleand Chenopodium ambrosioides L. had an obvious bactericidal effecton clinical drug resistant Hp in vitro at1/2times of the MIC concentration.The bactericidal effect increasedin dose and time dependent manner. In combination withJinghua Weikangor Chenopodium ambrosioides L., the in vitro bactericidal effect of metronidazole or clarithromycin on clinical resistantHp has been strengthened. The bactericidal effect of Jinghua Weikang's another ingredient pilular adina is not obvious.
Conclusion:Jinghua Weikang Capsule and Chenopodium ambrosioides L. APIs had a bactericidal effect on resistant Hp, and its bactericidal effect increased with dose and time, andthe strengthen the bactericidal effect was enhanced in combination with the antibiotic.
Experiment2:Role ofChenopodium ambrosioides L. extract on efflux pump hefABCgene expression of drug-resistant Helicobacter pylori strains
Objective:To study Jinghua Weikang capsule's main component Chenopodium ambrosioides L.on efflux pump hefABC gene expression of drug-resistant Helicobacter pylori strains, explore molecular mechanisms of Chenopodium ambrosioides L. anti-drug-resistant H pylori.
METHODS:The experiment strains H. pylori NCTC11637and three clinical strains were selected from the department of gastroenterology laboratory of Peking University First Hospital saved strains, the clinical drug-resistant strains were confirmed by E-test (AB Biodisk Solna, Sweden) susceptibility test for detection of resistance to commonly used antibiotics. The minimum inhibitory concentration (MIC) of the Chenopodium ambrosioides L. volatile oil on H. pylori were determined byagar dilution method.Put fresh H. pylori strains cultured about48-72h intobrucella broth containing10%fetal bovine serum for shaking culturing, at37°C, in micro-aerobic environment. The broth was divided into6parts. Chenopodium ambrosioides L. were added into5parts, andthe concentration of the drug were as follows respectively,1/8,1/4,1/2,1and2times of the MIC. Collected the strains at3h after culturing. RNA extraction RNA was extracted by Trizol extraction kit Operating Instructions. The quality of the extracted RNA was identified by the A260/A280ratio and1.5%agarose gel electrophoresis. Oligo dT primers were used in RT reverse transcription. The amount of gene expression of each sample's hefA, hefB and hefC were determinated by quantitative PCR reaction, which were expressed by2-△△Ct.
Results:Compared with the control group, when added of Chenopodium ambrosioides L.,the amount of genes expression of hefA, hefB and hefC decreased in each group. The genes expression were inhibited obviouslyat1/2MIC concentration of Chenopodium ambrosioides L.
Conclusion:Chenopodium ambrosioides L. can downgradegene expression of resistant Helicobacter pylori efflux pump hefABC, which may be the molecular mechanism of the drug anti resistant Helicobacter pylori strains.
引文
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