抗幽门螺杆菌抗菌药左氧氟沙星经胃和胆汁转运、分布特点的研究
摘要
背景
应用抗菌药有效根除HP具有十分重要的临床意义。由于HP特异性定植于胃粘液及其下方黏膜表面,因此,Hp根除成功与否理应取决于治疗部位局部抗菌药的浓度。只有抗菌药在其定植部位浓度达到所需杀菌浓度方可起效。抗菌药口服后由血转运至胃,这是抗菌药胃内局部浓度升高的决定性因素,是HP根除成功的关键问题。抗菌药胃内转运具有特殊的药代动力学特点,存在胃内直接分布及肠道吸收后由血转运至胃组织的跨膜转运。研究抗菌药胃内转运、分布特点可为根除HP方案中抗菌药的选择提供试验数据。
近年来HP耐药情况日益严重,经典的三联疗法根除失败率逐年升高。临床研究发现,含左氧氟沙星为基础的治疗方案是目前根除率较为理想的治疗方案。但针对左氧氟沙星胃内转运分布情况的基础研究尚未见报道,缺乏左氧氟沙星胃内区域药动学资料。另外,胃内pH值可影响抗菌药的胃内转运、分布。因此,联用PPI是否影响左氧氟沙星胃内转运、分布尚不明确。由于解剖结构的毗邻关系,胆总管直接开口于十二指肠,胆汁内抗菌药也可随胆汁返流入胃,从而影响胃内局部抗菌药浓度。研究胆汁内左氧氟沙星的药动学过程,有助于阐明左氧氟沙星抗Hp作用。
目的
本课题拟在建立研究抗菌药胃内和胆汁转运、分布的动物模型基础上,初步探讨左氧氟沙星在大鼠胃内和胆汁转运、分布特点;观察联合应用雷贝拉唑对上述胃内过程的影响;同时,结合动物实验研究结果,初步探讨左氧氟沙星在人体胃内、胆汁内浓度情况,从而为临床应用左氧氟沙星根除HP过程中的临床药理学优势提供实验依据。
方法
⑴建立抗菌药胃内转运、分布的动物模型:Wistar大鼠术前禁食,麻醉开腹行胆总管置管。在十二指肠距幽门2cm处,经切口橡胶软管通过幽门插入胃内冲洗,以备胃液收集。试验结束时,采用水泡法剥离胃黏膜,拭干、称重后研磨匀浆,用于测定药物浓度;胃粘液层厚度采用冰冻切片PAS/AB染色法进行测量。
⑵建立不同生物样本中左氧氟沙星检测的HPLC方法:大鼠和人血清、胃液、胃黏膜和胆汁样本采用三氯乙酸或甲醇沉淀蛋白,取上清液测定左氧氟沙星浓度。HPLC条件:流动相乙腈-50mmol/l柠檬酸-1mol/l醋酸铵(19:80:1;v/v),Kromosil C18分析柱,柱温50℃,流速1ml/min,检测波长295nm。评价选择性、线性、准确度、精密度、稳定性和灵敏度;
⑶大鼠左氧氟沙星胃内转运、分布研究:Wistar大鼠随机分为左氧氟沙星50mg/kg组、左氧氟沙星50mg/kg+雷贝拉唑组、左氧氟沙星100mg/kg组、左氧氟沙星100mg/kg+雷贝拉唑组共4组。静脉给药后2小时内按15min间隔取血处死动物,收集不同时点胃液、胃黏膜样本,检测左氧氟沙星浓度,了解大鼠左氧氟沙星胃内转运、分布特点;
⑷大鼠左氧氟沙星胆汁分布研究:Wistar大鼠随机分为左氧氟沙星20mg/kg组, 50mg/kg组,100mg/kg组共3个剂量组。术中行颈动脉置管术及胆总管置管术,分别在静脉给药后12小时按1小时间隔,收集不同时点血液及胆汁样本,检测左氧氟沙星浓度,了解大鼠左氧氟沙星胆汁分布特点;
⑸人体左氧氟沙星胃内分布研究:4例HP感染患者,采用口服雷贝拉唑10mg bid +左氧氟沙星500mg qd +阿莫西林1.0 bid方案治疗,第10天行胃镜检查,留取胃粘液标本后,自下而上分别留取胃窦、胃体、胃底各部位胃黏膜样本,检测左氧氟沙星浓度,了解人体左氧氟沙星胃内分布特点;⑹人体左氧氟沙星胆汁分布研究:17例因胆系疾病行胆道探查术后留置T管的患者,分别静滴左氧氟沙星200mg、400mg和500mg。给药结束后24小时,按1h, 2h, 4h, 8h, 12h, 24h时间点留取血标本,按1小时间隔留取胆汁样本,检测左氧氟沙星浓度,了解人体左氧氟沙星胆汁分布特点。
结果
⑴对研究抗菌药胃内和胆汁转运、分布的动物模型中所涉及的胃液收集方法、胃黏膜剥离方法以及胃粘液层测量方法等关键实验方法和不同生物样本中左氧氟沙星HPLC检测方法进行验证,证明动物模型和HPLC检测方法具有可靠、简便的技术要求。
⑵大鼠左氧氟沙星胃内转运、分布:比较左氧氟沙星50mg/kg组和左氧氟沙星100mg/kg组不同时点各部位药物浓度发现,给药后45-60min左右,胃液药物浓度逐渐高于血药浓度,不同时间点胃体、胃窦、腺胃药物浓度均高于血药浓度及前胃药物浓度,但胃体和胃窦药物浓度无差异。比较单用左氧氟沙星组和左氧氟沙星+雷贝拉唑联用组结果发现,联用雷贝拉唑组的胃液、前胃、胃体、胃窦和腺胃不同时点药物浓度均高于单用左氧氟沙星组,但统计学无显著差异。左氧氟沙星50mg/kg组、左氧氟沙星50mg/kg+雷贝拉唑组、左氧氟沙星100mg/kg组、左氧氟沙星100mg/kg+雷贝拉唑组左氧氟沙星胃内转运分数分别为2.36,2.42,2.52,2.55。
⑶大鼠左氧氟沙星胆汁分布:左氧氟沙星20mg/kg,50mg/kg,100mg/kg各剂量组胆汁药位浓度Cmax分别为57.42mg/l,88.81 mg/l,137.60 mg/l。经统计分析发现,各剂量组各时点胆汁药物浓度均有差异。
⑷人体左氧氟沙星胃内分布:人胃液左氧氟沙星浓度为2.26±1.32μg/ml,胃底、胃体、胃窦样本左氧氟沙星浓度分别为5.51±1.46μg/ml,9.99±4.01μg/ml,8.52±2.45μg/ml,均高于胃液左氧氟沙星浓度。
⑸人体左氧氟沙星胆汁分布:左氧氟沙星200mg,400mg,500mg各剂量组胆汁药物浓度Cmax分别为11.92mg/l,16.52mg/l,20.53mg/l,经统计分析发现,各剂量组Cmax有差异。比较各剂量组各时间点胆汁药浓度,发现不同剂量组几乎在不同时间点胆汁药浓度均有差异。
结论
本课题通过研究大鼠左氧氟沙星胃内和胆汁转运、分布情况及其联用雷贝拉唑的影响,以及初步探讨人体左氧氟沙星胃内和胆汁分布情况,得出以下结论:
⑴在大鼠体内,随给药时间延长胃液左氧氟沙星浓度高于血药浓度,提示左氧氟沙星胃内存在主动转运过程。
⑵大鼠胃窦左氧氟沙星浓度高于前胃,并具有随给药剂量增大而局部浓度增大趋势,联用PPI对左氧氟沙星胃内药物浓度及分布影响较小。
⑶大鼠与人胆汁内左氧氟沙星浓度较高,提示胆汁是左氧氟沙星一个重要的排泄过程。
⑷在人体试验中初步发现,胃黏膜中左氧氟沙星浓度高于胃液药物浓度,其中胃窦和胃体局部浓度较高,提示左氧氟沙星可聚集于Hp特异性定植部位。
Background
It has a very important clinical significance to effectively eradicate Hp by using the antibiotics. The specificity of Hp is colonized at gastric mucus and its lower gastric mucosa surface, therefore, the success of eradication Hp depends on the concentration of local antibiotic in treatment position. The antibiotic works only when the concentration of antibiotic reached the required bactericidal concentration at the colonized position. The antibiotic will be transported into stomach from blood after oral administration, which is the decisive factor that the local concentration of antibiotic in stomach is raised and the key problem to successfully eradicate Hp. The transport of antibiotic in stomach has the feature of pharmacokinetics, transmembrane transport exists from blood to stomach organization after direct distribution in stomach and intestinal absorption. The research on the transport of antibiotic in stomach and distribution features can provide the data for the selection of antibiotic in Hp eradication scheme.
Recently, the drug resistance of Hp is more and more serious, and the failure rate of classical triple therapy for eradiation increases yearly. Clinical researches show that the eradication scheme contained with levofloxacin is a comparatively ideal treatment in eradication rate at present. However, the basic research aimed at the transport and distribution condition of levofloxacin in stomach has not been reported so far, and the pharmacokinetic data of levofloxacin in stomach lacks. In addition, the pH in stomach may affect the transport and distribution of antibiotics in stomach. Therefore, whether the PPI will influence the transport and distribution of levofloxacin in stomach is not clear. Due to the neighborhood relationship of anatomical structure, the common bile duct is directly opened at duodenum, and the antibiotics in bile also can back flow to stomach with bile, so as to affect the local antibiotics concentration in stomach. Studying the pharmacokinetic process of levofloxacin in bile is helpful to explain the anti- Helicobacter pylori function of levofloxacin.
Purpose
To discuss the transport and distribution characteristic of levofloxacin in stomach and bile of rat, on the basis of building the animal model for the transport and distribution of antibiotics in stomach and bile; to observe the effect of treatment combined with rebeprazole on above process in stomach; at the same time, combining with the results of experiments, to preliminarily discuss the concentration condition of levofloxacin in human stomach and bile, so as to provide the experimental basis for clinical pharmacology during the process of eradication Hp by using levofloxacin.
Methods
⑴Build the animal model for transport and distribution of antibiotic in the stomach: carried out the fasting for Wistar rats before operation, and after anaesthesia, carried out the indwelling tube operation in bile duct. At 2cm of duodenum from pylorus, insert the rubber hose into the stomach through the pylorus and collected the gastric juice after intraoperative irrigation of stomach. Determined the concentration of drug by stripping of stomach mucosa of rat with method of blistering at the end of experiment, and then wiped off water and weighed, and finally grinded and homogenated; and the thickness of gastric mucus layer was measured by frozen-section PAS/AB staining method.
⑵Establish the HPLC method for detection of levofloxacin in different biological samples: Trichloroacetic acid or methanol was used to precipitate proteins in rats/human serum, gastric juice, stomach mucosa and bile, then 20μl filtrates were injected for determining the concentration of levofloxacin. HPLC conditions: A Kromosil C18 column was used as chromatographic column, whose temperature was maintained at 50℃. The mobile phase was prepared as follow: cetonitrile-50mmol/l citric acid-1mol/l ammonium acetate (19:80:1, v/v) with the flow rate of 1.0 ml/min. The detection wavelength was 295nm. The parameters of selectivity, linearity, accuracy, precision, stability, sensitivity were evaluated for method validation.
⑶Study on transport and distribution of levofloxacin in rat stomach: divided Wistar rats randomly into 4 groups: levofloxacin 50mg/kg, levofloxacin 50mg/kg + rabeprazole, levofloxacin 100mg/kg, levofloxacin 100mg/kg + rabeprazole. Within 2 hours after intravenous administration, collected the serum, gastric juice, stomach mucosa samples at an interval of 15min and detected the concentration of levofloxacin of all the samples to find out the feature of transport and distribution of levofloxacin in rat stomach.
⑷Study on distribution of levofloxacin in rat bile: divided Wistar rats randomly into 3 dose groups: levofloxacin 20mg/kg, 50mg/kg, 100mg/kg. Carried out the indwelling tube in carotid artery and common bile duct during operation, then respectively collected blood and bile samples at different time points every 1 hour in 12 hours after intravenous administration and detected the concentration of levofloxacin to find out the feature of distribution of levofloxacin in rat bile;
⑸Study on distribution of levofloxacin in human stomach: 4 cases of Hp infected patients, treat by the scheme of oral rabeprazole 10mg bid + levofloxacin 500mg qd + amoxicillin 1.0g bid, carried out gastroscopy in the 10th day, collected gastric juice samples, take gastric mucosa samples from top to bottom at gastric antrum, gastric corpus and gastric fundus, and detected the concentration of levofloxacin, so as to find out the feature of distribution of levofloxacin in human stomach;
⑹Study on distribution of levofloxacin in human bile: 17 cases of patients with biliary disease and indwelling T-tube after exploration of biliary tract, took an intravenous drip of 200mg, 400mg and 500mg levofloxacin. At 24 hours after administration, collected blood samples at 1h, 2h, 4h, 8h, 12h, 24h time points, collected the bile samples at an interval of 1h, and detected the concentration of levofloxacin, so as to find out the feature of distribution of levofloxacin in human bile.
Results
⑴Through verifying key experimental methods involved in the study of animal model of transport and distribution of antibiotics in the stomach, such as the gastric juice collection method, gastric mucosa stripping method and gastric secretion layer measurement method, and HPLC detection method of levofloxacin in different biological samples, it was proved that the animal model and HPLC detection method were reliable, simple and convenient for the technical requirements.
⑵Transport and distribution of levofloxacin in rat stomach: from comparison of the drug concentration of levofloxacin 50mg/kg group and 100mg/kg group in each part at different time points, it was found, after administration for about 45-60 minutes, that the drug concentration of gastric juice was gradually higher than the drug concentration of serum, and the drug concentrations of gastric corpus, gastric antrum and glandular stomach at different time points were higher than the drug concentration of serum and the drug concentration of forestomach, however, there was no difference in the drug concentration of gastric corpus and the gastric antrum. Comparison of the results of group of levofloxacin and the group of levofloxacin combined with rabeprazole indicated that the drug concentrations of gastric juice, forestomach, gastric corpus, gastric antrum and glandular stomach at different time points for the group of levofloxacin combined with rabeprazole were all higher than that of the group of levofloxacin, but there was no significant difference in statistics. The levofloxacin transport fraction in the stomach for levofloxacin 50mg/kg group, levofloxacin 50mg/kg + rabeprazole group, levofloxacin 100mg/kg group, and levofloxacin 100mg/kg + rabeprazole group is respectively 2.36, 2.42, 2.52 and 2.55.
(3) Distribution of levofloxacin in rat bile: the Cmax of bile for levofloxacin 20mg/kg, 50mg/kg and 100mg/kg dose group was 57.42mg/l, 88.81mg/l and 137.60mg/l separately. The statistical analysis showed that there was difference of the drug concentration of the bile for all doses at all time points.
⑷Distribution of levofloxacin in human stomach: the levofloxacin concentration of human gastric juice was 2.26±1.32μg/ml, and the levofloxacin concentration of samples of gastric fundus, gastric corpus and gastric antrum was 5.51±1.46μg/ml, 9.99±4.01μg/ml and 8.52±2.45μg/ml separately, which were all higher than the levofloxacin concentration of gastric juice.
⑸Distribution of levofloxacin in human bile: the Cmax for levofloxacin 200mg, 400mg and 500mg dose groups was respectively 11.92mg/l, 16.52mg/l and 20.53mg/l, and the statistics showed that there was Cmax difference in all dose groups. Besides, through comparing the drug concentration of the bile of all dose groups at each time point, it was found that the difference of drug concentration of the bile exist nearly in all time points and all dose groups.
Conclusions
Through the study of transport and distribution of levofloxacin in rat stomach and bile, study of the effect of combining with rabeprazole, as well as preliminary discussion of distribution of levofloxacin in human stomach and bile, then obtained the following conclusions:
⑴In the rat body, along with the extension of administration time, the levofloxacin concentration of gastric juice gets higher than the serum concentration, indicating that there is an active transport process for the levofloxacin in the stomach.
⑵The levofloxacin concentration of the gastric antrum of rats is higher than that of the forestomach, there is a rising trend partially with increase of administration dose, and combining with PPI has a slight influence on the drug concentration and distribution of levofloxacin in the stomach.
⑶Higher levofloxacin concentration in the bile of both rats and human indicates that the bile is an important excretory process for levofloxacin.
⑷It is preliminarily found in the human body test that the levofloxacin concentration of gastric mucosa is higher than the drug concentration of gastric juice, and partially higher concentration of gastric antrum and gastric corpus indicates that the levofloxacin may gather at Hp specificity colonization areas.
应用抗菌药有效根除HP具有十分重要的临床意义。由于HP特异性定植于胃粘液及其下方黏膜表面,因此,Hp根除成功与否理应取决于治疗部位局部抗菌药的浓度。只有抗菌药在其定植部位浓度达到所需杀菌浓度方可起效。抗菌药口服后由血转运至胃,这是抗菌药胃内局部浓度升高的决定性因素,是HP根除成功的关键问题。抗菌药胃内转运具有特殊的药代动力学特点,存在胃内直接分布及肠道吸收后由血转运至胃组织的跨膜转运。研究抗菌药胃内转运、分布特点可为根除HP方案中抗菌药的选择提供试验数据。
近年来HP耐药情况日益严重,经典的三联疗法根除失败率逐年升高。临床研究发现,含左氧氟沙星为基础的治疗方案是目前根除率较为理想的治疗方案。但针对左氧氟沙星胃内转运分布情况的基础研究尚未见报道,缺乏左氧氟沙星胃内区域药动学资料。另外,胃内pH值可影响抗菌药的胃内转运、分布。因此,联用PPI是否影响左氧氟沙星胃内转运、分布尚不明确。由于解剖结构的毗邻关系,胆总管直接开口于十二指肠,胆汁内抗菌药也可随胆汁返流入胃,从而影响胃内局部抗菌药浓度。研究胆汁内左氧氟沙星的药动学过程,有助于阐明左氧氟沙星抗Hp作用。
目的
本课题拟在建立研究抗菌药胃内和胆汁转运、分布的动物模型基础上,初步探讨左氧氟沙星在大鼠胃内和胆汁转运、分布特点;观察联合应用雷贝拉唑对上述胃内过程的影响;同时,结合动物实验研究结果,初步探讨左氧氟沙星在人体胃内、胆汁内浓度情况,从而为临床应用左氧氟沙星根除HP过程中的临床药理学优势提供实验依据。
方法
⑴建立抗菌药胃内转运、分布的动物模型:Wistar大鼠术前禁食,麻醉开腹行胆总管置管。在十二指肠距幽门2cm处,经切口橡胶软管通过幽门插入胃内冲洗,以备胃液收集。试验结束时,采用水泡法剥离胃黏膜,拭干、称重后研磨匀浆,用于测定药物浓度;胃粘液层厚度采用冰冻切片PAS/AB染色法进行测量。
⑵建立不同生物样本中左氧氟沙星检测的HPLC方法:大鼠和人血清、胃液、胃黏膜和胆汁样本采用三氯乙酸或甲醇沉淀蛋白,取上清液测定左氧氟沙星浓度。HPLC条件:流动相乙腈-50mmol/l柠檬酸-1mol/l醋酸铵(19:80:1;v/v),Kromosil C18分析柱,柱温50℃,流速1ml/min,检测波长295nm。评价选择性、线性、准确度、精密度、稳定性和灵敏度;
⑶大鼠左氧氟沙星胃内转运、分布研究:Wistar大鼠随机分为左氧氟沙星50mg/kg组、左氧氟沙星50mg/kg+雷贝拉唑组、左氧氟沙星100mg/kg组、左氧氟沙星100mg/kg+雷贝拉唑组共4组。静脉给药后2小时内按15min间隔取血处死动物,收集不同时点胃液、胃黏膜样本,检测左氧氟沙星浓度,了解大鼠左氧氟沙星胃内转运、分布特点;
⑷大鼠左氧氟沙星胆汁分布研究:Wistar大鼠随机分为左氧氟沙星20mg/kg组, 50mg/kg组,100mg/kg组共3个剂量组。术中行颈动脉置管术及胆总管置管术,分别在静脉给药后12小时按1小时间隔,收集不同时点血液及胆汁样本,检测左氧氟沙星浓度,了解大鼠左氧氟沙星胆汁分布特点;
⑸人体左氧氟沙星胃内分布研究:4例HP感染患者,采用口服雷贝拉唑10mg bid +左氧氟沙星500mg qd +阿莫西林1.0 bid方案治疗,第10天行胃镜检查,留取胃粘液标本后,自下而上分别留取胃窦、胃体、胃底各部位胃黏膜样本,检测左氧氟沙星浓度,了解人体左氧氟沙星胃内分布特点;⑹人体左氧氟沙星胆汁分布研究:17例因胆系疾病行胆道探查术后留置T管的患者,分别静滴左氧氟沙星200mg、400mg和500mg。给药结束后24小时,按1h, 2h, 4h, 8h, 12h, 24h时间点留取血标本,按1小时间隔留取胆汁样本,检测左氧氟沙星浓度,了解人体左氧氟沙星胆汁分布特点。
结果
⑴对研究抗菌药胃内和胆汁转运、分布的动物模型中所涉及的胃液收集方法、胃黏膜剥离方法以及胃粘液层测量方法等关键实验方法和不同生物样本中左氧氟沙星HPLC检测方法进行验证,证明动物模型和HPLC检测方法具有可靠、简便的技术要求。
⑵大鼠左氧氟沙星胃内转运、分布:比较左氧氟沙星50mg/kg组和左氧氟沙星100mg/kg组不同时点各部位药物浓度发现,给药后45-60min左右,胃液药物浓度逐渐高于血药浓度,不同时间点胃体、胃窦、腺胃药物浓度均高于血药浓度及前胃药物浓度,但胃体和胃窦药物浓度无差异。比较单用左氧氟沙星组和左氧氟沙星+雷贝拉唑联用组结果发现,联用雷贝拉唑组的胃液、前胃、胃体、胃窦和腺胃不同时点药物浓度均高于单用左氧氟沙星组,但统计学无显著差异。左氧氟沙星50mg/kg组、左氧氟沙星50mg/kg+雷贝拉唑组、左氧氟沙星100mg/kg组、左氧氟沙星100mg/kg+雷贝拉唑组左氧氟沙星胃内转运分数分别为2.36,2.42,2.52,2.55。
⑶大鼠左氧氟沙星胆汁分布:左氧氟沙星20mg/kg,50mg/kg,100mg/kg各剂量组胆汁药位浓度Cmax分别为57.42mg/l,88.81 mg/l,137.60 mg/l。经统计分析发现,各剂量组各时点胆汁药物浓度均有差异。
⑷人体左氧氟沙星胃内分布:人胃液左氧氟沙星浓度为2.26±1.32μg/ml,胃底、胃体、胃窦样本左氧氟沙星浓度分别为5.51±1.46μg/ml,9.99±4.01μg/ml,8.52±2.45μg/ml,均高于胃液左氧氟沙星浓度。
⑸人体左氧氟沙星胆汁分布:左氧氟沙星200mg,400mg,500mg各剂量组胆汁药物浓度Cmax分别为11.92mg/l,16.52mg/l,20.53mg/l,经统计分析发现,各剂量组Cmax有差异。比较各剂量组各时间点胆汁药浓度,发现不同剂量组几乎在不同时间点胆汁药浓度均有差异。
结论
本课题通过研究大鼠左氧氟沙星胃内和胆汁转运、分布情况及其联用雷贝拉唑的影响,以及初步探讨人体左氧氟沙星胃内和胆汁分布情况,得出以下结论:
⑴在大鼠体内,随给药时间延长胃液左氧氟沙星浓度高于血药浓度,提示左氧氟沙星胃内存在主动转运过程。
⑵大鼠胃窦左氧氟沙星浓度高于前胃,并具有随给药剂量增大而局部浓度增大趋势,联用PPI对左氧氟沙星胃内药物浓度及分布影响较小。
⑶大鼠与人胆汁内左氧氟沙星浓度较高,提示胆汁是左氧氟沙星一个重要的排泄过程。
⑷在人体试验中初步发现,胃黏膜中左氧氟沙星浓度高于胃液药物浓度,其中胃窦和胃体局部浓度较高,提示左氧氟沙星可聚集于Hp特异性定植部位。
Background
It has a very important clinical significance to effectively eradicate Hp by using the antibiotics. The specificity of Hp is colonized at gastric mucus and its lower gastric mucosa surface, therefore, the success of eradication Hp depends on the concentration of local antibiotic in treatment position. The antibiotic works only when the concentration of antibiotic reached the required bactericidal concentration at the colonized position. The antibiotic will be transported into stomach from blood after oral administration, which is the decisive factor that the local concentration of antibiotic in stomach is raised and the key problem to successfully eradicate Hp. The transport of antibiotic in stomach has the feature of pharmacokinetics, transmembrane transport exists from blood to stomach organization after direct distribution in stomach and intestinal absorption. The research on the transport of antibiotic in stomach and distribution features can provide the data for the selection of antibiotic in Hp eradication scheme.
Recently, the drug resistance of Hp is more and more serious, and the failure rate of classical triple therapy for eradiation increases yearly. Clinical researches show that the eradication scheme contained with levofloxacin is a comparatively ideal treatment in eradication rate at present. However, the basic research aimed at the transport and distribution condition of levofloxacin in stomach has not been reported so far, and the pharmacokinetic data of levofloxacin in stomach lacks. In addition, the pH in stomach may affect the transport and distribution of antibiotics in stomach. Therefore, whether the PPI will influence the transport and distribution of levofloxacin in stomach is not clear. Due to the neighborhood relationship of anatomical structure, the common bile duct is directly opened at duodenum, and the antibiotics in bile also can back flow to stomach with bile, so as to affect the local antibiotics concentration in stomach. Studying the pharmacokinetic process of levofloxacin in bile is helpful to explain the anti- Helicobacter pylori function of levofloxacin.
Purpose
To discuss the transport and distribution characteristic of levofloxacin in stomach and bile of rat, on the basis of building the animal model for the transport and distribution of antibiotics in stomach and bile; to observe the effect of treatment combined with rebeprazole on above process in stomach; at the same time, combining with the results of experiments, to preliminarily discuss the concentration condition of levofloxacin in human stomach and bile, so as to provide the experimental basis for clinical pharmacology during the process of eradication Hp by using levofloxacin.
Methods
⑴Build the animal model for transport and distribution of antibiotic in the stomach: carried out the fasting for Wistar rats before operation, and after anaesthesia, carried out the indwelling tube operation in bile duct. At 2cm of duodenum from pylorus, insert the rubber hose into the stomach through the pylorus and collected the gastric juice after intraoperative irrigation of stomach. Determined the concentration of drug by stripping of stomach mucosa of rat with method of blistering at the end of experiment, and then wiped off water and weighed, and finally grinded and homogenated; and the thickness of gastric mucus layer was measured by frozen-section PAS/AB staining method.
⑵Establish the HPLC method for detection of levofloxacin in different biological samples: Trichloroacetic acid or methanol was used to precipitate proteins in rats/human serum, gastric juice, stomach mucosa and bile, then 20μl filtrates were injected for determining the concentration of levofloxacin. HPLC conditions: A Kromosil C18 column was used as chromatographic column, whose temperature was maintained at 50℃. The mobile phase was prepared as follow: cetonitrile-50mmol/l citric acid-1mol/l ammonium acetate (19:80:1, v/v) with the flow rate of 1.0 ml/min. The detection wavelength was 295nm. The parameters of selectivity, linearity, accuracy, precision, stability, sensitivity were evaluated for method validation.
⑶Study on transport and distribution of levofloxacin in rat stomach: divided Wistar rats randomly into 4 groups: levofloxacin 50mg/kg, levofloxacin 50mg/kg + rabeprazole, levofloxacin 100mg/kg, levofloxacin 100mg/kg + rabeprazole. Within 2 hours after intravenous administration, collected the serum, gastric juice, stomach mucosa samples at an interval of 15min and detected the concentration of levofloxacin of all the samples to find out the feature of transport and distribution of levofloxacin in rat stomach.
⑷Study on distribution of levofloxacin in rat bile: divided Wistar rats randomly into 3 dose groups: levofloxacin 20mg/kg, 50mg/kg, 100mg/kg. Carried out the indwelling tube in carotid artery and common bile duct during operation, then respectively collected blood and bile samples at different time points every 1 hour in 12 hours after intravenous administration and detected the concentration of levofloxacin to find out the feature of distribution of levofloxacin in rat bile;
⑸Study on distribution of levofloxacin in human stomach: 4 cases of Hp infected patients, treat by the scheme of oral rabeprazole 10mg bid + levofloxacin 500mg qd + amoxicillin 1.0g bid, carried out gastroscopy in the 10th day, collected gastric juice samples, take gastric mucosa samples from top to bottom at gastric antrum, gastric corpus and gastric fundus, and detected the concentration of levofloxacin, so as to find out the feature of distribution of levofloxacin in human stomach;
⑹Study on distribution of levofloxacin in human bile: 17 cases of patients with biliary disease and indwelling T-tube after exploration of biliary tract, took an intravenous drip of 200mg, 400mg and 500mg levofloxacin. At 24 hours after administration, collected blood samples at 1h, 2h, 4h, 8h, 12h, 24h time points, collected the bile samples at an interval of 1h, and detected the concentration of levofloxacin, so as to find out the feature of distribution of levofloxacin in human bile.
Results
⑴Through verifying key experimental methods involved in the study of animal model of transport and distribution of antibiotics in the stomach, such as the gastric juice collection method, gastric mucosa stripping method and gastric secretion layer measurement method, and HPLC detection method of levofloxacin in different biological samples, it was proved that the animal model and HPLC detection method were reliable, simple and convenient for the technical requirements.
⑵Transport and distribution of levofloxacin in rat stomach: from comparison of the drug concentration of levofloxacin 50mg/kg group and 100mg/kg group in each part at different time points, it was found, after administration for about 45-60 minutes, that the drug concentration of gastric juice was gradually higher than the drug concentration of serum, and the drug concentrations of gastric corpus, gastric antrum and glandular stomach at different time points were higher than the drug concentration of serum and the drug concentration of forestomach, however, there was no difference in the drug concentration of gastric corpus and the gastric antrum. Comparison of the results of group of levofloxacin and the group of levofloxacin combined with rabeprazole indicated that the drug concentrations of gastric juice, forestomach, gastric corpus, gastric antrum and glandular stomach at different time points for the group of levofloxacin combined with rabeprazole were all higher than that of the group of levofloxacin, but there was no significant difference in statistics. The levofloxacin transport fraction in the stomach for levofloxacin 50mg/kg group, levofloxacin 50mg/kg + rabeprazole group, levofloxacin 100mg/kg group, and levofloxacin 100mg/kg + rabeprazole group is respectively 2.36, 2.42, 2.52 and 2.55.
(3) Distribution of levofloxacin in rat bile: the Cmax of bile for levofloxacin 20mg/kg, 50mg/kg and 100mg/kg dose group was 57.42mg/l, 88.81mg/l and 137.60mg/l separately. The statistical analysis showed that there was difference of the drug concentration of the bile for all doses at all time points.
⑷Distribution of levofloxacin in human stomach: the levofloxacin concentration of human gastric juice was 2.26±1.32μg/ml, and the levofloxacin concentration of samples of gastric fundus, gastric corpus and gastric antrum was 5.51±1.46μg/ml, 9.99±4.01μg/ml and 8.52±2.45μg/ml separately, which were all higher than the levofloxacin concentration of gastric juice.
⑸Distribution of levofloxacin in human bile: the Cmax for levofloxacin 200mg, 400mg and 500mg dose groups was respectively 11.92mg/l, 16.52mg/l and 20.53mg/l, and the statistics showed that there was Cmax difference in all dose groups. Besides, through comparing the drug concentration of the bile of all dose groups at each time point, it was found that the difference of drug concentration of the bile exist nearly in all time points and all dose groups.
Conclusions
Through the study of transport and distribution of levofloxacin in rat stomach and bile, study of the effect of combining with rabeprazole, as well as preliminary discussion of distribution of levofloxacin in human stomach and bile, then obtained the following conclusions:
⑴In the rat body, along with the extension of administration time, the levofloxacin concentration of gastric juice gets higher than the serum concentration, indicating that there is an active transport process for the levofloxacin in the stomach.
⑵The levofloxacin concentration of the gastric antrum of rats is higher than that of the forestomach, there is a rising trend partially with increase of administration dose, and combining with PPI has a slight influence on the drug concentration and distribution of levofloxacin in the stomach.
⑶Higher levofloxacin concentration in the bile of both rats and human indicates that the bile is an important excretory process for levofloxacin.
⑷It is preliminarily found in the human body test that the levofloxacin concentration of gastric mucosa is higher than the drug concentration of gastric juice, and partially higher concentration of gastric antrum and gastric corpus indicates that the levofloxacin may gather at Hp specificity colonization areas.
引文
1 Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet, 1984,1:1311-1315.
2 Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer. Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol, 1997,24:2-17.
3 Lam SK. Aetiological factors of peptic ulcer. Perspectives of epidemiological observations this century. J Gastroenterol Hepatol, 1994,9:S93-8.
4 Hopkins RJ, Girardi LS, Truney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology, 1996,110:1244-52.
5 Sonnenberg A, Olson CA, Zhang J. The effect of antibiotic therapy on bleeding from duodenal ulcer. Am J Gastroenterol, 1999,94.
6 Ng TM, Fock KM, Khor JL, et al. Non-steroidal anti-inflammatory drugs, Helicobacter pylori and bleeding gastric ulcer. Aliment Pharmacol Ther, 2000,14:203-9.
7 Malfertheiner P. Megraud F, O'Morain C, et al. European Helicobacter Pylori Study Group (EHPSG). Gurrent concepts in the management of Helicobacter pylori infection-the Masstricht 2-2000 Consensus Report. Aliment Pharmacol Ther, 2002,16:167-180.
8 Goddard, A. F, Spiller, R. C. The effect of omeprazole on gastric juice viscocity, pH and bacterial counts. Aliment Pharmacol Ther, 1996,10:105-109.
9 Megraud, F. Rationale for the choice of antibiotics for the eradication of Helicobacter pylori. Eur. J. Gastroenterol. Hepatol, 1996,7(Suppl.1):S49-54.
10 A.F. Goddard. Review article: factors influencing antibiotic transfer across the gastric mucosa. Aliment Pharmacol Ther, 1998,12:1175-1184.
11 Erah PO, Goddard AF, Barrett DA, et al. The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. Antimicrob Chemother, 1997,39:5-12.
12 Gustavson LE, Kaiser JF, Edmonds AL, et al. Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother, 1995,39:2078-2083.
13中华医学会消化病学分会幽门螺杆菌学组/全国幽门螺杆菌科研协作组.中国幽门螺杆菌耐药状况以及耐药对治疗的影响.胃肠病学, 2007,12:525-530.
14 Carothers JJ, Bruce MG, Hennessy TW, et al. The relationship between previous fluoroquinolone use and levofloxacin resistance in Helicobacter pylori infection. Clin Infect Dis, 2007,44:e5-8.
15 Miyachi H, Miki I, Aoyama N, et al. Primary levofloxacin resistance and gyrA/B mutations among Helicobacter pylori in Japan. Helicobacter, 2006,11:243-249.
16 Bogaerts P, Berhin C, Nizet H, et al. Prevalence and mechanisms of resistance to fluoroquinolones in Helicobacter pylori strains from patients living in Belgium. Helicobacter, 2006,11:441-445.
17 Cattoir V, Nectoux J, Lascols C, et al. Update on fluoroquinolone resistance in Helicobacter pylori: new mutations leading to resistance and first description of a gyrA polymorphism associated with hypersusceptibility. Int J Antimicrob Agents, 2007,29:389-396.
18 Matsumoto Y, Miki I, Aoyama N, Shirasaka D, et al. Levofloxacin- versus metronidazole-based rescue therapy for H. pylori infection in Japan. Dig Liver Dis, 2005,37:821-5.
19 Coelho LG, Moretzsohn LD, Vieira WL, et al. New once-daily, highly effectiverescue triple therapy after multiple Helicobacter pylori treatment failures: a pilot study. Aliment Pharmacol Ther, 2005,21:783-7.
20 Giannini EG, Bilardi C, Dulbecco P et al. A study of 4- and 7-day triple therapy with rabeprazole, high-dose levofloxacin and tinidazole rescue treatment for Helicobacter pylori eradication. Aliment Pharmacol Ther, 2006,23:281-7.
21 Lee JH, Hong SP, Kwon CI, et al. The efficacy of levofloxacin based triple therapy for Helicobacter pylori eradication. Korean J Gastroenterol, 2006,48:19-24.
22 Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther, 2006,23:35-44.
23 Gisbert JP, Castro-Fernández M, Bermejo F, et al. Third-line rescue therapy with levofloxacin after two H. pylori treatment failures. Am J Gastroenterol, 2006,101:243-7.
24 Gisbert JP, Bermejo F, Castro-Fernández M, et al. Second-line rescue therapy with levofloxacin after H. pylori treatment failure: a Spanish multicenter study of 300 patients. Am J Gastroenterol, 2008,103:71-6.
25 Gisbert JP, Gisbert JL, Marcos S, et al. Third-line rescue therapy with levofloxacin is more effective than rifabutin rescue regimen after two Helicobacter pylori treatment failures. Aliment Pharmacol Ther, 2006,24:1469-74.
26中华医学会消化病学分会,幽门螺杆菌学组/幽门螺杆菌科研协作组.第三次全国幽门螺杆菌感染若干问题共识报告.胃肠病学, 2008,13:42-46.
27 William D. Chey,Benjamin C.Y. Wong, and the Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection.Am J Gastroenterol, 2007,102:1808-1825.
28柏树令.系统解剖学,2005.
29许国铭,侯晓华等.胆汁返流相关性疾病.上海:上海科学技术出版社,2002.
30 Goddard A, Jessa M, Barrett D, et al. Effect of omeprazole on the distribution of metronidazole, amoxicillin and clarithromycin in human gastric juice. Gastroenterology, 1996,111:358-367.
31 Sherwood P, Wibawa J, Atherton J, et al. Impact of acid secretion, gastritis and mucus thickness on gastric transfer of antibiotics in rats. Gut, 2002,51:490-494.
32 G. H. Curtis, D. G. Gall. Macromolecular transport by rat gastric mucosa. Am J Physiol, 1992,262:1033-1040.
33 Nicola Jordan, Julia Newton, Jefferey Pearson. A novel method for the visualization of the in situ mucus layer in rat and man. Clinical Science, 1998,95:97-105.
34张君仁,臧恒昌.体内药物分析.北京:化学工业出版社,2002.
35 Jessa MJ, Goddard AF, Barrett DA, et.al. The effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in human plasma, saliva and gastric juice. Br J Clin Pharmacol, 1997,44:245-253.
36赵香兰.临床药理学.广州:中山大学出版社,2007.
37 Dawson AB, Ivy AC. Contributions to the physiology of gastric secretion. Am J Physiol, 1925,73:304-314.
38 Kobayashi K. Experimental studies on absorption, secretion and excretion. Acta Scholae Med, 1926:465-488.
39 Cooke M, Davenport HW, Goodman LS. The mechanism of the secretion of sulfonamide drugs in gastric juice. Yale J Biol Med, 1941,14:13-28.
40 Shore PA, Brodie BB, Hogben CAM. The gastric secretion of drugs: a pH partition hypothesis. J Pharmacol Exp Ther, 1956,119:361-369.
41 Mcnulty CAM, Dent JC, Ford GA, et.al. Inhibitory antimicrobial concentrations against Campylobacter pylori in gastric mucosa. J Antimicrob Chemother, 1988,22:729-738.
42 Cooreman MP, Krausgrill P, Hengels KJ. Local gastric and serum amoxicillin concentrations after different oral application forms. Antimicrob Agents Chemother, 1993,37:1506-1059.
43 Lambert JR, Loncar B, Schembri MA, et.al. Luminal amoxycillin determines gastric mucosal concentraions. Gastroenterology, 1991,100:A104.
44 Cardaci G, Lambert JR, King RG, et.al. Reduced amoxicillin uptake into human gastric mucosa when gastric juice pH is high. Antimicrob Agents Chemother, 1995,39:2084-7.
45 Veldhuyzen van Zanten SJO, Goldie J, Hollingsworth J, Sillettec, et.al. Secretion of intravenously administrated antibiotics in gastric juice: Implications for management of Helicobacter pylori. J Clin Pathol, 1992,45:225-7.
46 Durex DE, Westblum TU. Clindamycin secretion across human gastric mucosa. J Clin Gastroenterol, 1989,11:601-602.
47 Idstrom J-P, Wrangstadh M, Bergstrand R, et.al. Antibiotics in gastric juice after i.v. injection. Gastroenterology, 1994,106:A98.
48 Veldhuyzen van Zanten SJ, PJollack PT, Kapoor H, et.al. Effect of omeprazole on the movement of intravenously administered metronidazole into gastric juice and its significance in treatment of Helicobacter pylori. Dig Dis Sci, 1996,41:1845-52.
49 Westblum Tu, Duriex DE, Madan E, et.al. Guinea-pig model for antibiotic transport across gastric mucosa:inhibitory tissue concentrations of clindamycin against Helicobacter pylori following two separate dose regimens. Antimicrob Agents Chemother, 1990,34:25-8.
50 Westblum TU, Duriex DE. Enhancement of antibiotic concentrations in gastric mucasa by H2-receptor antagonist. Implications for the treatment of Helicobacter pylori infections. Dig Dis Sci, 1991,36:25-8.
51 Kareemi M, Veldhuyzen van Zanten SJ, Pollack PT,et.al. The effect of pH on MTZ absorption across the gastric mucosa. Gut, 1997,41:A128.
52 Goddard AF, Spiller RC. In vitro assessment of gastric mucosal transfer of anti-Helicobacter therapeutic agents. Antimicrob Agents Chemother, 1997,41:1246-9.
53 Westblum TU, Duriex DE. Antibiiotic concntrations in gastric mucosa: The guinea pig model. Helicobacter pylori, 1990:157-61.
54 Kihira K, Satoh K, Saifuku K, et al. Endoscopic topical therapy for the treatment of Helicobacter pylori infection. J Gastroenterol, 1996,31:66-68.
55 Pedrazzoli J, Calafatti SA, Ortiz RAM, et al. Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pylori-infected individuals. Scand J Gastroenterol, 2001,36:1248-1253.
56 Alain Lozniewski, Michele Weber, Jean-Dominique De Korwin, et.al. Use of Cryomicrotomy To Study Gastric Diffusion of Amoxicillin in Guinea Pigs. Antimicrobial Agents and Chemotherapy, 1995,39:766-768.
57湛先保,李兆申,许国铭等.厚片法测定大鼠胃壁粘液凝胶层的厚度.第二军医大学学报, 2000,21:594.
58 Tanaka S, Tache Y, Kaneko, et.al. Central vagal activation increases mucus gel thickness and surface cell intracellular pH in rat stomach. Gastroenterology, 1997,112:409-417.
59 Ota, H, Katsuyama, T. Alternating laminated array of two types of mucin in the human gastric surface mucous layer. Histochemical J, 1992,24:86-89.
60 Schade, C, Flemstrom, G. and Holm, L. Hydrogen ion concentration in themucus layer on top of acid-stimulated and inhibited rat gastric mucosa. Gastroenterology, 1994,107:180-188.
61 Sababi M, Nilsson E, Holm L, et .al. Mucus and alkali secretion in the rat duodenum; effects of indomethacin, N-omega-nitro-L-arginine, and luminal acid. Gastroenterology, 1995,109:1526-1534.
62李见春,马涛,祝晓光等.盐酸左氧氟沙星胶囊在健康志愿者中生物利用度.蚌埠医学院学报, 2006,31:417-419.
63 J. Atkinson. Principles of clinical pharmaology:Elsevier Inc,2007.
64杨世杰.药理学:人民卫生出版社,2005.
65 Lozniewski A, de Korwin JD, Muhale F, Jehl F. Gastric diffusion of antibiotics used against H. pylori. Int J Antimicrob Agent, 1998,9:181-193.
66 Goddard AF, Erah PO, Barrett DA, et al. The effect of protein binding and lipophilicity of penicillins on their in vitro flux across gastric mucosa. J Antimicrob Chemother, 1998,41:231-236.
67 Goddard AF, Spiller RC. The effect of omeprazole on gastric juice viscosity, pH and bacterial counts. Aliment Pharmacol Ther, 1996,10:105-109.
68 A.F. GODDARD. Review article: factors influencing antibiotic transfer across the gastric mucosa. Aliment Pharmacol Ther, 1998,12:1175-1184.
69 Jung Mogg Kima, Joo Sung Kimb, Nayoung Kimb, et.al. Comparison of primary and secondary antimicrobial minimum inhibitory concentrations for Helicobacter pylori isolated from Korean patients. International Journal of Antimicrobial Agents, 2006,28:6-13.
70 Sugita K, Katouno Y, Uchida H, Kobayashi Y. Comparative in vitro activities of several antimicrobial agents against Helicobacter pylori. Jpn J Antibiot, 2002,55:771-7.
71邹军,杨昭徐,覃卓明.左旋氧氟沙星抗幽门螺杆菌的实验室评价和临床研究.中华医学杂志, 2003,83:1778-1781.
72 CLSI Document M100-S16. Performance Standards for Antimicrobioal Susceptibility Testing,2006.
73唐建国.氟喹诺酮药物左氧氟沙星.国外医药抗生素分册, 1996,17:380-382.
74 Wimer SM, Schoonover L, Garrison MW. Levofloxacin: a therapeutic review. Clin Ther, 1998,20:1049-1053.
75 Annette Lubasch, Ivonne Keller, & Klaus Borner et.al. Comparative Pharmacokinetics of Ciprofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Trovafloxacin, and Moxifloxacin after Single Oral Administration in Healthy Volunteers. Antimicrobial Agents And Chemotherapy, 2000,44:2600-2603.
76 Fish, D. N. & Chow, A. T. The clinical pharmacokinetics of levofloxacin. Clinical Pharmacokinetics, 1997,32:283-90.
77 Ohtomo T, Saito H, Inotsume N, Yasuhara M, Inui KI. Transport of levofloxacin in a kidney epithelial cell line, LLC-PK1: interaction with organic cation transporters in apical and basolateral membranes. J Pharmacol Exp Ther, 1996,276:1143-8.
78 Takeshi Hiranoa, Satoru Yasudaa, Yuki Osakaa. Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells. Biochimica et Biophysica Acta (BBA) - Biomembranes, 2006,1758:1743-1750.
79 Umiko Matsuo,Ikuko Yano, Tatsuya Ito, et.al. Transport of Quinolone Antibacterial Drugs in a Kidney Epithelial Cell Line, LLC-PK1. The Journal of Pharmacology and Experimental Thearpeutics, 1998,287:672-678.
80 Mario Furlanut, Loris Brollo, Emilio Lugatti, et.al. Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential intravenous/oral therapy in patients with lower respiratory tract infections. Journal of AntimicrobialChemotherapy, 2003,51:101-106.
81 Shu-Chean Chien, Mark C. Rogge, Lee G.Gisclon et.al. Pharmacokinetic Profile of Levofloxacin following Once-Daily 500-Milligram Oral or Intravenous Doses. Antimicrobial Agents and Chemotherapy, 1997,41:2256-2260.
82 Christopher J. Destache, Catherine B. Pakiz, Chris Larsen, et.al. Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model. Antimicrobial Agents and Chemotherapy, 2001,47:611-615.
83 Takasuna K, Kasai Y, Usui C, et.al. General pharmacology of the new quinolone antibacterial agent levofloxacin. Arzneimittelforschung, 1992,43:408-418.
84 Federico Pea, Federica Pavan, Ennio Nascimben, et.al. Levofloxacin Disposition in Cerebrospinal Fluid in Patients with External Ventriculostomy. Antimicrobial geents and chemotherapy, 2003,47:3104-3108.
85张贵军,李可欣,刘蕾等.不同剂量国产甲磺酸左氧氟沙星在健康志愿者体内药动学研究.中国药学杂志, 2000,34:394-396.
86姜希凌,孙建国,王广基等.反相高效液相色谱法测定犬血浆中左氧氟沙星浓度及其犬体内药代动力学.中国临床药理学与治疗学, 2004,669-672.
87宋坤改,孙涛,林赴田等.甲磺酸左氧氟沙星大鼠体内分布和血清蛋白结合率.中国抗生素杂志, 1999,24:208-210.
88孙航,杨淑群,周远大等.静注左氧氟沙星在兔血与眼组织中的药动学.中国医院药学杂志, 2005,25:19-21.
89 Shu-Chean Chien, Frank A. Wong, Cynthia L. Fowler, et.al. Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily
750-milligram and 1-gram doses of levofloxacin in healthy volunteers. Antimicrobial Agents and Chemotherapy, 1998,42:885-888.
90 Qiuhong Li, Kohji Naora, Hidenari Hirano, et.al. Comparative Study on Salivary Distribution of Fluoroquinolones in Rats. Biol. Pharm. Bull, 2002,25:1084-1089.
91 Tanaka K, Iwamoto M, Maesaki S, et.al. Laboratory and clinical studies on levofloxacin. Jpn J Antibiot, 1992,45:548-550.
92 S. Swoboda, K. Oberdorfer, & F. Klee et.al. Tissue and serum concentrations of levofloxacin 500 mg administered intravenously or orally for antibiotic prophylaxis in biliary surgery. Journal of Antimicrobial Chemotherapy, 2003,51:459-462.
93 Chow AT, Chen A, Lattime H, et.al. Penetration of levofloxacin into skin tissue after oral administration of multiple 750 mg once-daily doses. J Clin Pharm Ther, 2002,27:143-150.
94 O. Murillo, A. Domenech , A. Garcia,et.al. Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus. Antimicrobial Agents And Chemotherapy, 2006,50:4011-4017.
95 A. Lozniwski, J.D. de Korwin, F. Muhale, F. Jehl. Gastric diffusion of antibiotics used agasit Helicobacter pylori. International Journal of Antimicrobial Agents, 1998,9:181-193.
96 Masahiko Nakamura, Robin C. Spiller, David A. Barrett, et.al. Gastric juice, gastric tissue and blood antibiotic concentration following omeprazole, amoxicillin and clarithromycin triple therapy. Helicobacter, 2003,8:294-300.
97 Une. T. Fujimoto, T, Sato, K. & Osada, Y. In vitro activity of DR-3355, an optically active ofloxacin. Agents and Chemotherapy, 1988,32:1336–40.
98 Eliopoulos, G. M, C. B. Wennersten, & R. C. Moellering. Comparative in vitro activity of levofloxacin and ofloxacin against gram-positive bacteria. Diagnostic Microbiology and Infectious Disease, 1996,25:35-41.
99 Fujimoto, T, and S. Mitsuhashi. In vitro antibacterial activity of DR-3355, the S-(2) isomer of ofloxacin. Chemotherapy, 1990,36:268-276.
100 Andriole, V. T. The quinolones: prospects. The quinolones. 2nd ed ed. San Diego, Calif:Academic Press, Inc,1998. 417-429.
101 Saad RJ, Schoenfeld P, Kim HM, et al. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol, 2006,101:488-496.
102 Malfertheiner P, Megraud F, O'Morain C, et.al. Current concepts in the management of Helicobacter pylori infection—The Maastricht III Consensus Report. Gut, 2007,56:772-781.
103 Christopher J. Destache, Catherine B. Pakiz, Chris Larsen, et.al. Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model. Jouranl of Antimicrobial Chemotherapy, 2001,47:611-615.
104 Lcung JWC, Chan RCY, Cheung SW, et.al. The effect of obstruction o the biliary excretion of cefoperazone and ceftazidime. J Antimciro Chemother, 1990,25:399-402.
105 Westphal JF, Blickle JF, Brogard JM, et.al. Management of biliary tract infections:potential role of the quionlones. J Antimicrob Chemother, 1991,28:486-451.
1刘文忠.幽门螺杆菌研究进展.上海:上海科学技术文献出版社,2001.
2 Linz B, Balloux F, Moodley Y, et.al. An African origin for the intimate association between humans and Helicobacter pylori. Nature, 2007,445:915-918.
3 Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet, 1984,1:1311-1315.
4 Malfertheiner P, Megraud F, O'Morain C, et.al. Current concepts in the management of Helicobacter pylori infection-The Maastricht III Consensus Report. Gut, 2007,56.
5 William D. Chey,Benjamin C.Y. Wong, and the Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am J Gastroenterol, 2007,102:1808-1825.
6 Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology, 2005,129:1756-1780.
7中华医学会消化病学分会,幽门螺杆菌学组/幽门螺杆菌科研协作组.第三次全国幽门螺杆菌感染若干问题共识报告.胃肠病学, 2008,13:42-46.
8 Megraud, F. Rationale for the choice of antibiotics for the eradication of Helicobacter pylori. Eur. J. Gastroenterol. Hepatol, 1996,7(Suppl.1):S49-54.
9 Cockburn J, Gibberd RW, Reid AL, et al. Determinants of noncompliance with short-term antibiotic regimens. Br Med J, 1987,295:814-818.
10 Goddard A. Review article: factors influencing antibiotic transfer across the gastric mucosa. Aliment Pharmacol Ther, 1998,12:1175-1184.
11 Erah P, Goddard A, Barrett D, et al. The stability of amoxicillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. J Antimicrob Chemother, 1997,39:5-12.
12 Sherwood P, Wibawa J, Atherton J, et al. Impact of acid secretion, gastritis andmucus thickness on gastric transfer of antibiotics in rats. Gut, 2002,51:490-494.
13 Kihira K, Satoh K, Saifuku K, et al. Endoscopic topical therapy for the treatment of Helicobacter pylori infection. J Gastroenterol, 1996,31:66-68.
14 Goddard A, Jessa M, Barrett D, et al. Effect of omeprazole on the distribution of metronidazole, amoxicillin and clarithromycin in human gastric juice. Gastroenterology, 1996,111:358-367.
15 Gustavson L, Kaiser J, Edmonds AM, Locke C, et al. Effect of omeprazole on gastric concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother, 1992,36:1147-1150.
16 Pedrazzoli J, Calafatti S, Ortiz R, et al. Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pylori-infected individuals. Scand J Gastroenterol, 2001,36:1248-1253.
17萧树东,刘文忠.幽门螺杆菌感染的治疗现状.世界华人消化杂志, 1999,7:3-4.
18 Laine L, Estrada R, Trujillo M, et al. Randomized comparison of differing periods of twice a day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther, 1996,10:1029-1033.
19 Vakil N, Lanza F, Schwartz H, et al. Seven-day therapy for Helicobacter pylori in the United States. Aliment Pharmacol Ther, 2004,20:99-107.
20 Zagari RM, Bianchi-Porro G, Fiocca R, et al. Comparison of 1 and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication: the HYPER Study. Gut, 2007,56:475-479.
21 Ford A, Moayyedi P. How can the current strategies for Helicobacter pylori eradication therapy be improved?. Can J Gastroenterol, 2003,17:36-40.
22 Katelaris PH, Forbes GM, Talley NJ, et al. A randomized comparison of quadruple and triple therapies for Helicobacter pylori eradication: the QUADRATE Study. Gastroenterology, 2002,123:1763-1769.
23 Calvet X, Ducons J, Guardiola J, et al. One-week triple vs.quadruple therapy for Helicobacter pylori infection—a randomized trial. Aliment Pharmacol Ther,2002,16:1261-1267.
24 Fischbach LA, van Zanten S, Dickason J. Meta-analysis: the efficacy, adverse events, and adherence related to first-line anti-Helicobacter pylori quadruple therapies. Aliment Pharmacol Ther, 2004,20:1071-1082.
25 Gene E. Calvet X, Azagra R, et al. Triple vs. quadruple therapy for treating Helicobacter pylori infection: a meta-analysis. Aliment Pharmacol Ther, 2003,17:1137-1143.
26 Gisbert JP, Gisbert JL, Marcos S, et al. Helicobacter pylori first-line treatment and rescue options in patients allergic to penicillin. Aliment Pharmacol Ther, 2005,22:1041-1046.
27 Bochenek WJ, Peters S, Fraga PD, et al. Eradication of Helicobacter pylori by 7-day triple-therapy regimens combining pantoprazole with clarithromycin, metronidazole, or amoxicillin in patients with peptic ulcer disease: results of two doubleblind, randomized studies. Helicobacter, 2003,8:626-642.
28 Rinaldi V, Zullo A, Pugliano F, et al. The management of failed dual or triple therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther, 1997,17:719-726.
29 Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther, 2003,17:719-726.
30 Hassan C, De Francesco V, Zullo A, et al. Sequential treatment for Helicobacter pylori eradication in duodenal ulcer patients:improving the cost of pharmacotherapy. Aliment Pharmacol Ther, 2003,18:641-646.
31 De Francesco V, Della Valle N, Stoppino V, et al. Effectiveness and pharmaceutical cost of sequential treatment for Helicobacter pylori in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther, 2004,19:993-998.
32 De Francesco V, Zullo A, Hassan C, et al. The prolongation of triple therapy for Helicobacter pylori does not allow reaching therapeutic outcome of sequential scheme: a prospective, randomized study. Dig Liver Dis, 2004,36:322-326.
33 Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drugtherapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med, 2007,146:556-563.
34 De Francesco V, Margiotta M, Zullo A, et al. Clarithromycinresistant genotypes and eradication of Helicobacter pylori. Ann Intern Med, 2006,144:94-100.
35 Vakil N. Helicobacter pylori treatment: a practical approach. Am J Gastroenterol, 2006,101:497-499.
36 Lamouliatte H, Megraud F, Delchier JC, et al. Second-line treatment for failure to eradicate Helicobacter pylori: a randomized trial comparing four treatment strategies. Aliment Pharmacol Ther, 2003,18:791-797.
37 Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther, 2006,23:35-44.
38 Saad RJ, Schoenfeld P, Kim HM, et al. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol, 2006,101:488-496.
39 Miehlke S, Hansky K, Schneider-Brachert W, et al. Randomized trial of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of Helicobacter pylori resistant to both metronidazole and clarithromycin. Aliment Pharmacol Ther, 2006,24:395-403.
40 Gisbert JP, Gisbert JL, Marcos S, et al. Third-line rescue therapy with levofloxacin is more effective than rifabutin rescue regimen after two Helicobacter pylori treatment failures. Aliment Pharmacol Ther, 2006,24:1469-1474.
41 Wong WM, Wong BC, Lu H, et al. One-week omeprazole, furazolidone and amoxicillin rescue therapy after failure of Helicobacter pylori eradication with standard triple therapies. Aliment Pharmacol Ther, 2002,16:793-798.
42 Qasim A, Sebastian S, Thornton O, et al. Rifabutin- and furazolidone-based Helicobacter pylori eradication therapies after failure of standard first- and second-line eradication attempts in dyspepsia patients. Aliment Pharmacol Ther,2005,21:91-96.
43 Ford A, Delaney B, Forman D, et al. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev, 2006:CD003840.
44 Gisbert JP, de la Morena F, Abraira V. Accuracy of monoclonal stool antigen test for the diagnosis of H. pylori infection: a systematic review and meta-analysis. Am J Gastroenterol, 2006,101:1921-1930.
45 Vaira D, Vakil N, Menagatti M, et al. The stool antigen test for the detection of Helicobacter pylori after eradication therapy. Ann Intern Med, 2002,136:280-287.
46 Houben M, van de Beek D, Hensen E, et al. A systematic review of helicobacter eradication therapy—the impact of antimicrobial resistance on eradication rates. Aliment Pharmacol Ther, 1999,13:1047-1055.
47 Mégraud F. H. pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut, 2004,53:1374.
48 Padol S, Yuan Y, Thabane M, et al. The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis. Am J Gastroenterol, 2006,101:1467-1475.
49 Suzuki T, Matsuo K, Ito H, et al. Smoking increases the treatment failure for Helicobacter pylori eradication. Am J Med, 2006,119:217-224.
50 Gisbert J, Hermida C, Pajares J. Are 12 days of omeprazole, amoxcillin and clarithromycin better than 6 days for treating H pylori infection in peptic ulcer and non-ulcer dyspepsia?. Hepatogastroenterology, 2001,48:1383-1388.
51 Gisbert JP. The recurrence of Helicobacter pylori infection: incidence and variables influencing it. Am J Gastroenterol, 2005,100:2083-2099.
52 Kwon DH, Lee M, Kim JJ, et al. Furazolidone- and nitrofurantoinresistant Helicobacter pylori: prevalence and role of genes involved in metronidazole resistance. Antimicrob Agents Chemother, 2001,45:306-308.
53 Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobialsusceptibility testing. Clin Microbiol Rev, 2007,20:280-322.
54 Schabereiter-Gurtner C, Hirschl AM, Dragosics B, et al. Novel real-time PCR assay for detection of Helicobacter pylori infection and simultaneous clarithromycin susceptibility testing of stool and biopsy specimens. J Clin Microbiol, 2004,42:4512-4518.
55 Trebesius K, Adler K, Vieth M, et al. Specific detection and prevalence of Helicobacter heilmannii-like organisms in the human gastric mucosa by fluorescent in situ hybridization and partial 16S ribosomal DNA sequencing. J Clin Microbiol, 2001,39:1510-1516.
56 Duck WM, Sobel J, Pruckler JM, et al. Antimicrobial resistance incidence and risk factors among Helicobacter pylori-infected persons, United States. Emerg Infect Dis, 2004,10:1088-1094.
57 Bruce MG, Bruden DL, McMahon BJ, et al. Alaska sentinel surveillance for antimicrobial resistance in Helicobacter pylori isolates from Alaska native persons, 1999-2003. Helicobacter, 2006,11:581-588.
58 Glupczynski Y, Megraud F, Lopez Brea M, et al. European multicentre survey of in vitro antimicrobial resistance in Helicobacter pylori. Eur J Clin Microbiol Infect Dis, 2001,20:820-823.
59 Storskrubb T, Aro P, Ronkainen J, et al. Antimicrobial susceptibility of Helicobacter pylori strains in a random adult Swedish population. Helicobacter, 2006,11:224-230.
60 Janssen MJ, Hendrikse L, de Boer SY, et al. Helicobacter pylori antibiotic resistance in a Dutch region: trends over time. Neth J Med, 2006,64:191-195.
61 Petersen AM, Gjode P, Vinge OD, et al. Helicobacter pylori antimicrobial resistance and risk factors in Denmark 1998-2004: no need for concern?. Helicobacter, 2006,11:210-211.
62 Koivisto TT, Rautelin HI, Voutilainen ME, et al. Primary Helicobacter pylori resistance to metronidazole and clarithromycin in the Finnish population. Aliment Pharmacol Ther, 2004,19:1009-1017.
63 Boyanova L, Nikolov R, Lazarova E, et al. Antibacterial resistance in Helicobacter pylori strains isolated from Bulgarian children and adult patients over 9 years. J Med Microbiol, 2006,55:65-68.
64 De Francesco V, Margiotta M, Zullo A, et al. Prevalence of primary clarithromycin resistance in Helicobacter pylori strains over a 15-year period in Italy. J Antimicrob Chemother, 2007,59:783-785.
65 Mohammadi M, Doroud D, Mohajerani N, et al. Helicobacter pylori antibiotic resistance in Iran. World J Gastroenterol, 2005,11:6009-6013.
66 Albert JM, Al-Mekhaizeem K, Neil L, et al. High prevalence and level of resistance to metronidazole, but lack of resistance to other antimicrobials in Helicobacter pylori, isolated from a multiracial population in Kuwait. Aliment Pharmacol Ther, 2006,24:1359-1366.
67成虹,胡伏莲.北京地区幽门螺杆菌耐药情况及其耐药趋势.中华医学杂志, 2005,85:2754-2757.
68 Lwai-Lume L, Ogutu EO, Amayo EO, et al. Drug susceptibility pattern of Helicobacter pylori in patients with dyspepsia at the Kenyatta National Hospital, Nairobi. East Afr Med J, 2005,82:603-608.
69 Koletzko S, Richy F, Bontems P, et al. Prospective multicentre study on antibiotic resistance of Helicobacter pylori strains obtained from children living in Europe. Gut, 2006,55:1711-1716.
70 Masuda H, Hiyama T, Yoshihara M, et al. Characteristics and trends of clarithromycin-resistant Helicobacter pylori isolates in Japan over a decade. Pathobiology, 2004,71:159-163.
71胡伏莲.幽门螺杆菌耐药研究进展.现代消化及介入治疗, 2005,10:218-222.
72 Carothers JJ, Bruce MG, Hennessy TW, et al. The relationship between previous fluoroquinolone use and levofloxacin resistance in Helicobacter pylori infection. Clin Infect Dis, 2007,44:e5-8.
73 Miyachi H, Miki I, Aoyama N, et al. Primary levofloxacin resistance and gyrA/B mutations among Helicobacter pylori in Japan. Helicobacter, 2006,11:243-249.
74 Bogaerts P, Berhin C, Nizet H, et al. Prevalence and mechanisms of resistance to fluoroquinolones in Helicobacter pylori strains from patients living in Belgium. Helicobacter, 2006,11:441-445.
75 Cattoir V, Nectoux J, Lascols C, et al. Update on fluoroquinolone resistance in Helicobacter pylori: new mutations leading to resistance and first description of a gyrA polymorphism associated with hypersusceptibility. Int J Antimicrob Agents, 2007,29:389-396.
76 Lopes AI, Oleastro M, Palha A, et al. Antibiotic-resistant Helicobacter pylori strains in Portuguese children. Pediatr Infect Dis J, 2005,24:404-409.
77 Fujimura S, Kato S, Iinuma K, et al. In vitro activity of fluoroquinolone and the gyrA gene mutation in Helicobacter pylori strains isolated from children. J Med Microbio, 2004,53:1019-1022.
78 Nishizawa T, Suzuki H, Kurabayashi K, et al. Gatifloxacin resistance and mutations in gyrA after unsuccessful Helicobacter pylori eradication in Japan. Antimicrob Agents Chemother, 2006,50:1538-1540.
79 Nahar S, Mukhopadhyay AK, Khan R, et al. Antimicrobial susceptibility of Helicobacter pylori strains isolated in Bangladesh. J Clin Microbiol, 2004,42:4856-4858.
80 Glocker E, Bogdan C, Kist M. Characterization of rifampicinresistant clinical Helicobacter pylori isolates from Germany. J Antimicrob Chemother, 2007,59:874-879.
2 Kurata JH, Nogawa AN. Meta-analysis of risk factors for peptic ulcer. Nonsteroidal anti-inflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol, 1997,24:2-17.
3 Lam SK. Aetiological factors of peptic ulcer. Perspectives of epidemiological observations this century. J Gastroenterol Hepatol, 1994,9:S93-8.
4 Hopkins RJ, Girardi LS, Truney EA. Relationship between Helicobacter pylori eradication and reduced duodenal and gastric ulcer recurrence: a review. Gastroenterology, 1996,110:1244-52.
5 Sonnenberg A, Olson CA, Zhang J. The effect of antibiotic therapy on bleeding from duodenal ulcer. Am J Gastroenterol, 1999,94.
6 Ng TM, Fock KM, Khor JL, et al. Non-steroidal anti-inflammatory drugs, Helicobacter pylori and bleeding gastric ulcer. Aliment Pharmacol Ther, 2000,14:203-9.
7 Malfertheiner P. Megraud F, O'Morain C, et al. European Helicobacter Pylori Study Group (EHPSG). Gurrent concepts in the management of Helicobacter pylori infection-the Masstricht 2-2000 Consensus Report. Aliment Pharmacol Ther, 2002,16:167-180.
8 Goddard, A. F, Spiller, R. C. The effect of omeprazole on gastric juice viscocity, pH and bacterial counts. Aliment Pharmacol Ther, 1996,10:105-109.
9 Megraud, F. Rationale for the choice of antibiotics for the eradication of Helicobacter pylori. Eur. J. Gastroenterol. Hepatol, 1996,7(Suppl.1):S49-54.
10 A.F. Goddard. Review article: factors influencing antibiotic transfer across the gastric mucosa. Aliment Pharmacol Ther, 1998,12:1175-1184.
11 Erah PO, Goddard AF, Barrett DA, et al. The stability of amoxycillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. Antimicrob Chemother, 1997,39:5-12.
12 Gustavson LE, Kaiser JF, Edmonds AL, et al. Effect of omeprazole on concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother, 1995,39:2078-2083.
13中华医学会消化病学分会幽门螺杆菌学组/全国幽门螺杆菌科研协作组.中国幽门螺杆菌耐药状况以及耐药对治疗的影响.胃肠病学, 2007,12:525-530.
14 Carothers JJ, Bruce MG, Hennessy TW, et al. The relationship between previous fluoroquinolone use and levofloxacin resistance in Helicobacter pylori infection. Clin Infect Dis, 2007,44:e5-8.
15 Miyachi H, Miki I, Aoyama N, et al. Primary levofloxacin resistance and gyrA/B mutations among Helicobacter pylori in Japan. Helicobacter, 2006,11:243-249.
16 Bogaerts P, Berhin C, Nizet H, et al. Prevalence and mechanisms of resistance to fluoroquinolones in Helicobacter pylori strains from patients living in Belgium. Helicobacter, 2006,11:441-445.
17 Cattoir V, Nectoux J, Lascols C, et al. Update on fluoroquinolone resistance in Helicobacter pylori: new mutations leading to resistance and first description of a gyrA polymorphism associated with hypersusceptibility. Int J Antimicrob Agents, 2007,29:389-396.
18 Matsumoto Y, Miki I, Aoyama N, Shirasaka D, et al. Levofloxacin- versus metronidazole-based rescue therapy for H. pylori infection in Japan. Dig Liver Dis, 2005,37:821-5.
19 Coelho LG, Moretzsohn LD, Vieira WL, et al. New once-daily, highly effectiverescue triple therapy after multiple Helicobacter pylori treatment failures: a pilot study. Aliment Pharmacol Ther, 2005,21:783-7.
20 Giannini EG, Bilardi C, Dulbecco P et al. A study of 4- and 7-day triple therapy with rabeprazole, high-dose levofloxacin and tinidazole rescue treatment for Helicobacter pylori eradication. Aliment Pharmacol Ther, 2006,23:281-7.
21 Lee JH, Hong SP, Kwon CI, et al. The efficacy of levofloxacin based triple therapy for Helicobacter pylori eradication. Korean J Gastroenterol, 2006,48:19-24.
22 Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther, 2006,23:35-44.
23 Gisbert JP, Castro-Fernández M, Bermejo F, et al. Third-line rescue therapy with levofloxacin after two H. pylori treatment failures. Am J Gastroenterol, 2006,101:243-7.
24 Gisbert JP, Bermejo F, Castro-Fernández M, et al. Second-line rescue therapy with levofloxacin after H. pylori treatment failure: a Spanish multicenter study of 300 patients. Am J Gastroenterol, 2008,103:71-6.
25 Gisbert JP, Gisbert JL, Marcos S, et al. Third-line rescue therapy with levofloxacin is more effective than rifabutin rescue regimen after two Helicobacter pylori treatment failures. Aliment Pharmacol Ther, 2006,24:1469-74.
26中华医学会消化病学分会,幽门螺杆菌学组/幽门螺杆菌科研协作组.第三次全国幽门螺杆菌感染若干问题共识报告.胃肠病学, 2008,13:42-46.
27 William D. Chey,Benjamin C.Y. Wong, and the Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection.Am J Gastroenterol, 2007,102:1808-1825.
28柏树令.系统解剖学,2005.
29许国铭,侯晓华等.胆汁返流相关性疾病.上海:上海科学技术出版社,2002.
30 Goddard A, Jessa M, Barrett D, et al. Effect of omeprazole on the distribution of metronidazole, amoxicillin and clarithromycin in human gastric juice. Gastroenterology, 1996,111:358-367.
31 Sherwood P, Wibawa J, Atherton J, et al. Impact of acid secretion, gastritis and mucus thickness on gastric transfer of antibiotics in rats. Gut, 2002,51:490-494.
32 G. H. Curtis, D. G. Gall. Macromolecular transport by rat gastric mucosa. Am J Physiol, 1992,262:1033-1040.
33 Nicola Jordan, Julia Newton, Jefferey Pearson. A novel method for the visualization of the in situ mucus layer in rat and man. Clinical Science, 1998,95:97-105.
34张君仁,臧恒昌.体内药物分析.北京:化学工业出版社,2002.
35 Jessa MJ, Goddard AF, Barrett DA, et.al. The effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in human plasma, saliva and gastric juice. Br J Clin Pharmacol, 1997,44:245-253.
36赵香兰.临床药理学.广州:中山大学出版社,2007.
37 Dawson AB, Ivy AC. Contributions to the physiology of gastric secretion. Am J Physiol, 1925,73:304-314.
38 Kobayashi K. Experimental studies on absorption, secretion and excretion. Acta Scholae Med, 1926:465-488.
39 Cooke M, Davenport HW, Goodman LS. The mechanism of the secretion of sulfonamide drugs in gastric juice. Yale J Biol Med, 1941,14:13-28.
40 Shore PA, Brodie BB, Hogben CAM. The gastric secretion of drugs: a pH partition hypothesis. J Pharmacol Exp Ther, 1956,119:361-369.
41 Mcnulty CAM, Dent JC, Ford GA, et.al. Inhibitory antimicrobial concentrations against Campylobacter pylori in gastric mucosa. J Antimicrob Chemother, 1988,22:729-738.
42 Cooreman MP, Krausgrill P, Hengels KJ. Local gastric and serum amoxicillin concentrations after different oral application forms. Antimicrob Agents Chemother, 1993,37:1506-1059.
43 Lambert JR, Loncar B, Schembri MA, et.al. Luminal amoxycillin determines gastric mucosal concentraions. Gastroenterology, 1991,100:A104.
44 Cardaci G, Lambert JR, King RG, et.al. Reduced amoxicillin uptake into human gastric mucosa when gastric juice pH is high. Antimicrob Agents Chemother, 1995,39:2084-7.
45 Veldhuyzen van Zanten SJO, Goldie J, Hollingsworth J, Sillettec, et.al. Secretion of intravenously administrated antibiotics in gastric juice: Implications for management of Helicobacter pylori. J Clin Pathol, 1992,45:225-7.
46 Durex DE, Westblum TU. Clindamycin secretion across human gastric mucosa. J Clin Gastroenterol, 1989,11:601-602.
47 Idstrom J-P, Wrangstadh M, Bergstrand R, et.al. Antibiotics in gastric juice after i.v. injection. Gastroenterology, 1994,106:A98.
48 Veldhuyzen van Zanten SJ, PJollack PT, Kapoor H, et.al. Effect of omeprazole on the movement of intravenously administered metronidazole into gastric juice and its significance in treatment of Helicobacter pylori. Dig Dis Sci, 1996,41:1845-52.
49 Westblum Tu, Duriex DE, Madan E, et.al. Guinea-pig model for antibiotic transport across gastric mucosa:inhibitory tissue concentrations of clindamycin against Helicobacter pylori following two separate dose regimens. Antimicrob Agents Chemother, 1990,34:25-8.
50 Westblum TU, Duriex DE. Enhancement of antibiotic concentrations in gastric mucasa by H2-receptor antagonist. Implications for the treatment of Helicobacter pylori infections. Dig Dis Sci, 1991,36:25-8.
51 Kareemi M, Veldhuyzen van Zanten SJ, Pollack PT,et.al. The effect of pH on MTZ absorption across the gastric mucosa. Gut, 1997,41:A128.
52 Goddard AF, Spiller RC. In vitro assessment of gastric mucosal transfer of anti-Helicobacter therapeutic agents. Antimicrob Agents Chemother, 1997,41:1246-9.
53 Westblum TU, Duriex DE. Antibiiotic concntrations in gastric mucosa: The guinea pig model. Helicobacter pylori, 1990:157-61.
54 Kihira K, Satoh K, Saifuku K, et al. Endoscopic topical therapy for the treatment of Helicobacter pylori infection. J Gastroenterol, 1996,31:66-68.
55 Pedrazzoli J, Calafatti SA, Ortiz RAM, et al. Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pylori-infected individuals. Scand J Gastroenterol, 2001,36:1248-1253.
56 Alain Lozniewski, Michele Weber, Jean-Dominique De Korwin, et.al. Use of Cryomicrotomy To Study Gastric Diffusion of Amoxicillin in Guinea Pigs. Antimicrobial Agents and Chemotherapy, 1995,39:766-768.
57湛先保,李兆申,许国铭等.厚片法测定大鼠胃壁粘液凝胶层的厚度.第二军医大学学报, 2000,21:594.
58 Tanaka S, Tache Y, Kaneko, et.al. Central vagal activation increases mucus gel thickness and surface cell intracellular pH in rat stomach. Gastroenterology, 1997,112:409-417.
59 Ota, H, Katsuyama, T. Alternating laminated array of two types of mucin in the human gastric surface mucous layer. Histochemical J, 1992,24:86-89.
60 Schade, C, Flemstrom, G. and Holm, L. Hydrogen ion concentration in themucus layer on top of acid-stimulated and inhibited rat gastric mucosa. Gastroenterology, 1994,107:180-188.
61 Sababi M, Nilsson E, Holm L, et .al. Mucus and alkali secretion in the rat duodenum; effects of indomethacin, N-omega-nitro-L-arginine, and luminal acid. Gastroenterology, 1995,109:1526-1534.
62李见春,马涛,祝晓光等.盐酸左氧氟沙星胶囊在健康志愿者中生物利用度.蚌埠医学院学报, 2006,31:417-419.
63 J. Atkinson. Principles of clinical pharmaology:Elsevier Inc,2007.
64杨世杰.药理学:人民卫生出版社,2005.
65 Lozniewski A, de Korwin JD, Muhale F, Jehl F. Gastric diffusion of antibiotics used against H. pylori. Int J Antimicrob Agent, 1998,9:181-193.
66 Goddard AF, Erah PO, Barrett DA, et al. The effect of protein binding and lipophilicity of penicillins on their in vitro flux across gastric mucosa. J Antimicrob Chemother, 1998,41:231-236.
67 Goddard AF, Spiller RC. The effect of omeprazole on gastric juice viscosity, pH and bacterial counts. Aliment Pharmacol Ther, 1996,10:105-109.
68 A.F. GODDARD. Review article: factors influencing antibiotic transfer across the gastric mucosa. Aliment Pharmacol Ther, 1998,12:1175-1184.
69 Jung Mogg Kima, Joo Sung Kimb, Nayoung Kimb, et.al. Comparison of primary and secondary antimicrobial minimum inhibitory concentrations for Helicobacter pylori isolated from Korean patients. International Journal of Antimicrobial Agents, 2006,28:6-13.
70 Sugita K, Katouno Y, Uchida H, Kobayashi Y. Comparative in vitro activities of several antimicrobial agents against Helicobacter pylori. Jpn J Antibiot, 2002,55:771-7.
71邹军,杨昭徐,覃卓明.左旋氧氟沙星抗幽门螺杆菌的实验室评价和临床研究.中华医学杂志, 2003,83:1778-1781.
72 CLSI Document M100-S16. Performance Standards for Antimicrobioal Susceptibility Testing,2006.
73唐建国.氟喹诺酮药物左氧氟沙星.国外医药抗生素分册, 1996,17:380-382.
74 Wimer SM, Schoonover L, Garrison MW. Levofloxacin: a therapeutic review. Clin Ther, 1998,20:1049-1053.
75 Annette Lubasch, Ivonne Keller, & Klaus Borner et.al. Comparative Pharmacokinetics of Ciprofloxacin, Gatifloxacin, Grepafloxacin, Levofloxacin, Trovafloxacin, and Moxifloxacin after Single Oral Administration in Healthy Volunteers. Antimicrobial Agents And Chemotherapy, 2000,44:2600-2603.
76 Fish, D. N. & Chow, A. T. The clinical pharmacokinetics of levofloxacin. Clinical Pharmacokinetics, 1997,32:283-90.
77 Ohtomo T, Saito H, Inotsume N, Yasuhara M, Inui KI. Transport of levofloxacin in a kidney epithelial cell line, LLC-PK1: interaction with organic cation transporters in apical and basolateral membranes. J Pharmacol Exp Ther, 1996,276:1143-8.
78 Takeshi Hiranoa, Satoru Yasudaa, Yuki Osakaa. Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells. Biochimica et Biophysica Acta (BBA) - Biomembranes, 2006,1758:1743-1750.
79 Umiko Matsuo,Ikuko Yano, Tatsuya Ito, et.al. Transport of Quinolone Antibacterial Drugs in a Kidney Epithelial Cell Line, LLC-PK1. The Journal of Pharmacology and Experimental Thearpeutics, 1998,287:672-678.
80 Mario Furlanut, Loris Brollo, Emilio Lugatti, et.al. Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential intravenous/oral therapy in patients with lower respiratory tract infections. Journal of AntimicrobialChemotherapy, 2003,51:101-106.
81 Shu-Chean Chien, Mark C. Rogge, Lee G.Gisclon et.al. Pharmacokinetic Profile of Levofloxacin following Once-Daily 500-Milligram Oral or Intravenous Doses. Antimicrobial Agents and Chemotherapy, 1997,41:2256-2260.
82 Christopher J. Destache, Catherine B. Pakiz, Chris Larsen, et.al. Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model. Antimicrobial Agents and Chemotherapy, 2001,47:611-615.
83 Takasuna K, Kasai Y, Usui C, et.al. General pharmacology of the new quinolone antibacterial agent levofloxacin. Arzneimittelforschung, 1992,43:408-418.
84 Federico Pea, Federica Pavan, Ennio Nascimben, et.al. Levofloxacin Disposition in Cerebrospinal Fluid in Patients with External Ventriculostomy. Antimicrobial geents and chemotherapy, 2003,47:3104-3108.
85张贵军,李可欣,刘蕾等.不同剂量国产甲磺酸左氧氟沙星在健康志愿者体内药动学研究.中国药学杂志, 2000,34:394-396.
86姜希凌,孙建国,王广基等.反相高效液相色谱法测定犬血浆中左氧氟沙星浓度及其犬体内药代动力学.中国临床药理学与治疗学, 2004,669-672.
87宋坤改,孙涛,林赴田等.甲磺酸左氧氟沙星大鼠体内分布和血清蛋白结合率.中国抗生素杂志, 1999,24:208-210.
88孙航,杨淑群,周远大等.静注左氧氟沙星在兔血与眼组织中的药动学.中国医院药学杂志, 2005,25:19-21.
89 Shu-Chean Chien, Frank A. Wong, Cynthia L. Fowler, et.al. Double-blind evaluation of the safety and pharmacokinetics of multiple oral once-daily
750-milligram and 1-gram doses of levofloxacin in healthy volunteers. Antimicrobial Agents and Chemotherapy, 1998,42:885-888.
90 Qiuhong Li, Kohji Naora, Hidenari Hirano, et.al. Comparative Study on Salivary Distribution of Fluoroquinolones in Rats. Biol. Pharm. Bull, 2002,25:1084-1089.
91 Tanaka K, Iwamoto M, Maesaki S, et.al. Laboratory and clinical studies on levofloxacin. Jpn J Antibiot, 1992,45:548-550.
92 S. Swoboda, K. Oberdorfer, & F. Klee et.al. Tissue and serum concentrations of levofloxacin 500 mg administered intravenously or orally for antibiotic prophylaxis in biliary surgery. Journal of Antimicrobial Chemotherapy, 2003,51:459-462.
93 Chow AT, Chen A, Lattime H, et.al. Penetration of levofloxacin into skin tissue after oral administration of multiple 750 mg once-daily doses. J Clin Pharm Ther, 2002,27:143-150.
94 O. Murillo, A. Domenech , A. Garcia,et.al. Efficacy of High Doses of Levofloxacin in Experimental Foreign-Body Infection by Methicillin-Susceptible Staphylococcus aureus. Antimicrobial Agents And Chemotherapy, 2006,50:4011-4017.
95 A. Lozniwski, J.D. de Korwin, F. Muhale, F. Jehl. Gastric diffusion of antibiotics used agasit Helicobacter pylori. International Journal of Antimicrobial Agents, 1998,9:181-193.
96 Masahiko Nakamura, Robin C. Spiller, David A. Barrett, et.al. Gastric juice, gastric tissue and blood antibiotic concentration following omeprazole, amoxicillin and clarithromycin triple therapy. Helicobacter, 2003,8:294-300.
97 Une. T. Fujimoto, T, Sato, K. & Osada, Y. In vitro activity of DR-3355, an optically active ofloxacin. Agents and Chemotherapy, 1988,32:1336–40.
98 Eliopoulos, G. M, C. B. Wennersten, & R. C. Moellering. Comparative in vitro activity of levofloxacin and ofloxacin against gram-positive bacteria. Diagnostic Microbiology and Infectious Disease, 1996,25:35-41.
99 Fujimoto, T, and S. Mitsuhashi. In vitro antibacterial activity of DR-3355, the S-(2) isomer of ofloxacin. Chemotherapy, 1990,36:268-276.
100 Andriole, V. T. The quinolones: prospects. The quinolones. 2nd ed ed. San Diego, Calif:Academic Press, Inc,1998. 417-429.
101 Saad RJ, Schoenfeld P, Kim HM, et al. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol, 2006,101:488-496.
102 Malfertheiner P, Megraud F, O'Morain C, et.al. Current concepts in the management of Helicobacter pylori infection—The Maastricht III Consensus Report. Gut, 2007,56:772-781.
103 Christopher J. Destache, Catherine B. Pakiz, Chris Larsen, et.al. Cerebrospinal fluid penetration and pharmacokinetics of levofloxacin in an experimental rabbit meningitis model. Jouranl of Antimicrobial Chemotherapy, 2001,47:611-615.
104 Lcung JWC, Chan RCY, Cheung SW, et.al. The effect of obstruction o the biliary excretion of cefoperazone and ceftazidime. J Antimciro Chemother, 1990,25:399-402.
105 Westphal JF, Blickle JF, Brogard JM, et.al. Management of biliary tract infections:potential role of the quionlones. J Antimicrob Chemother, 1991,28:486-451.
1刘文忠.幽门螺杆菌研究进展.上海:上海科学技术文献出版社,2001.
2 Linz B, Balloux F, Moodley Y, et.al. An African origin for the intimate association between humans and Helicobacter pylori. Nature, 2007,445:915-918.
3 Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet, 1984,1:1311-1315.
4 Malfertheiner P, Megraud F, O'Morain C, et.al. Current concepts in the management of Helicobacter pylori infection-The Maastricht III Consensus Report. Gut, 2007,56.
5 William D. Chey,Benjamin C.Y. Wong, and the Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection. Am J Gastroenterol, 2007,102:1808-1825.
6 Talley NJ, Vakil NB, Moayyedi P. American Gastroenterological Association technical review on the evaluation of dyspepsia. Gastroenterology, 2005,129:1756-1780.
7中华医学会消化病学分会,幽门螺杆菌学组/幽门螺杆菌科研协作组.第三次全国幽门螺杆菌感染若干问题共识报告.胃肠病学, 2008,13:42-46.
8 Megraud, F. Rationale for the choice of antibiotics for the eradication of Helicobacter pylori. Eur. J. Gastroenterol. Hepatol, 1996,7(Suppl.1):S49-54.
9 Cockburn J, Gibberd RW, Reid AL, et al. Determinants of noncompliance with short-term antibiotic regimens. Br Med J, 1987,295:814-818.
10 Goddard A. Review article: factors influencing antibiotic transfer across the gastric mucosa. Aliment Pharmacol Ther, 1998,12:1175-1184.
11 Erah P, Goddard A, Barrett D, et al. The stability of amoxicillin, clarithromycin and metronidazole in gastric juice: relevance to the treatment of Helicobacter pylori infection. J Antimicrob Chemother, 1997,39:5-12.
12 Sherwood P, Wibawa J, Atherton J, et al. Impact of acid secretion, gastritis andmucus thickness on gastric transfer of antibiotics in rats. Gut, 2002,51:490-494.
13 Kihira K, Satoh K, Saifuku K, et al. Endoscopic topical therapy for the treatment of Helicobacter pylori infection. J Gastroenterol, 1996,31:66-68.
14 Goddard A, Jessa M, Barrett D, et al. Effect of omeprazole on the distribution of metronidazole, amoxicillin and clarithromycin in human gastric juice. Gastroenterology, 1996,111:358-367.
15 Gustavson L, Kaiser J, Edmonds AM, Locke C, et al. Effect of omeprazole on gastric concentrations of clarithromycin in plasma and gastric tissue at steady state. Antimicrob Agents Chemother, 1992,36:1147-1150.
16 Pedrazzoli J, Calafatti S, Ortiz R, et al. Transfer of clarithromycin to gastric juice is enhanced by omeprazole in Helicobacter pylori-infected individuals. Scand J Gastroenterol, 2001,36:1248-1253.
17萧树东,刘文忠.幽门螺杆菌感染的治疗现状.世界华人消化杂志, 1999,7:3-4.
18 Laine L, Estrada R, Trujillo M, et al. Randomized comparison of differing periods of twice a day triple therapy for the eradication of Helicobacter pylori. Aliment Pharmacol Ther, 1996,10:1029-1033.
19 Vakil N, Lanza F, Schwartz H, et al. Seven-day therapy for Helicobacter pylori in the United States. Aliment Pharmacol Ther, 2004,20:99-107.
20 Zagari RM, Bianchi-Porro G, Fiocca R, et al. Comparison of 1 and 2 weeks of omeprazole, amoxicillin and clarithromycin treatment for Helicobacter pylori eradication: the HYPER Study. Gut, 2007,56:475-479.
21 Ford A, Moayyedi P. How can the current strategies for Helicobacter pylori eradication therapy be improved?. Can J Gastroenterol, 2003,17:36-40.
22 Katelaris PH, Forbes GM, Talley NJ, et al. A randomized comparison of quadruple and triple therapies for Helicobacter pylori eradication: the QUADRATE Study. Gastroenterology, 2002,123:1763-1769.
23 Calvet X, Ducons J, Guardiola J, et al. One-week triple vs.quadruple therapy for Helicobacter pylori infection—a randomized trial. Aliment Pharmacol Ther,2002,16:1261-1267.
24 Fischbach LA, van Zanten S, Dickason J. Meta-analysis: the efficacy, adverse events, and adherence related to first-line anti-Helicobacter pylori quadruple therapies. Aliment Pharmacol Ther, 2004,20:1071-1082.
25 Gene E. Calvet X, Azagra R, et al. Triple vs. quadruple therapy for treating Helicobacter pylori infection: a meta-analysis. Aliment Pharmacol Ther, 2003,17:1137-1143.
26 Gisbert JP, Gisbert JL, Marcos S, et al. Helicobacter pylori first-line treatment and rescue options in patients allergic to penicillin. Aliment Pharmacol Ther, 2005,22:1041-1046.
27 Bochenek WJ, Peters S, Fraga PD, et al. Eradication of Helicobacter pylori by 7-day triple-therapy regimens combining pantoprazole with clarithromycin, metronidazole, or amoxicillin in patients with peptic ulcer disease: results of two doubleblind, randomized studies. Helicobacter, 2003,8:626-642.
28 Rinaldi V, Zullo A, Pugliano F, et al. The management of failed dual or triple therapy for Helicobacter pylori eradication. Aliment Pharmacol Ther, 1997,17:719-726.
29 Zullo A, Vaira D, Vakil N, et al. High eradication rates of Helicobacter pylori with a new sequential treatment. Aliment Pharmacol Ther, 2003,17:719-726.
30 Hassan C, De Francesco V, Zullo A, et al. Sequential treatment for Helicobacter pylori eradication in duodenal ulcer patients:improving the cost of pharmacotherapy. Aliment Pharmacol Ther, 2003,18:641-646.
31 De Francesco V, Della Valle N, Stoppino V, et al. Effectiveness and pharmaceutical cost of sequential treatment for Helicobacter pylori in patients with non-ulcer dyspepsia. Aliment Pharmacol Ther, 2004,19:993-998.
32 De Francesco V, Zullo A, Hassan C, et al. The prolongation of triple therapy for Helicobacter pylori does not allow reaching therapeutic outcome of sequential scheme: a prospective, randomized study. Dig Liver Dis, 2004,36:322-326.
33 Vaira D, Zullo A, Vakil N, et al. Sequential therapy versus standard triple-drugtherapy for Helicobacter pylori eradication: a randomized trial. Ann Intern Med, 2007,146:556-563.
34 De Francesco V, Margiotta M, Zullo A, et al. Clarithromycinresistant genotypes and eradication of Helicobacter pylori. Ann Intern Med, 2006,144:94-100.
35 Vakil N. Helicobacter pylori treatment: a practical approach. Am J Gastroenterol, 2006,101:497-499.
36 Lamouliatte H, Megraud F, Delchier JC, et al. Second-line treatment for failure to eradicate Helicobacter pylori: a randomized trial comparing four treatment strategies. Aliment Pharmacol Ther, 2003,18:791-797.
37 Gisbert JP, Morena F. Systematic review and meta-analysis: levofloxacin-based rescue regimens after Helicobacter pylori treatment failure. Aliment Pharmacol Ther, 2006,23:35-44.
38 Saad RJ, Schoenfeld P, Kim HM, et al. Levofloxacin-based triple therapy versus bismuth-based quadruple therapy for persistent Helicobacter pylori infection: a meta-analysis. Am J Gastroenterol, 2006,101:488-496.
39 Miehlke S, Hansky K, Schneider-Brachert W, et al. Randomized trial of rifabutin-based triple therapy and high-dose dual therapy for rescue treatment of Helicobacter pylori resistant to both metronidazole and clarithromycin. Aliment Pharmacol Ther, 2006,24:395-403.
40 Gisbert JP, Gisbert JL, Marcos S, et al. Third-line rescue therapy with levofloxacin is more effective than rifabutin rescue regimen after two Helicobacter pylori treatment failures. Aliment Pharmacol Ther, 2006,24:1469-1474.
41 Wong WM, Wong BC, Lu H, et al. One-week omeprazole, furazolidone and amoxicillin rescue therapy after failure of Helicobacter pylori eradication with standard triple therapies. Aliment Pharmacol Ther, 2002,16:793-798.
42 Qasim A, Sebastian S, Thornton O, et al. Rifabutin- and furazolidone-based Helicobacter pylori eradication therapies after failure of standard first- and second-line eradication attempts in dyspepsia patients. Aliment Pharmacol Ther,2005,21:91-96.
43 Ford A, Delaney B, Forman D, et al. Eradication therapy for peptic ulcer disease in Helicobacter pylori positive patients. Cochrane Database Syst Rev, 2006:CD003840.
44 Gisbert JP, de la Morena F, Abraira V. Accuracy of monoclonal stool antigen test for the diagnosis of H. pylori infection: a systematic review and meta-analysis. Am J Gastroenterol, 2006,101:1921-1930.
45 Vaira D, Vakil N, Menagatti M, et al. The stool antigen test for the detection of Helicobacter pylori after eradication therapy. Ann Intern Med, 2002,136:280-287.
46 Houben M, van de Beek D, Hensen E, et al. A systematic review of helicobacter eradication therapy—the impact of antimicrobial resistance on eradication rates. Aliment Pharmacol Ther, 1999,13:1047-1055.
47 Mégraud F. H. pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut, 2004,53:1374.
48 Padol S, Yuan Y, Thabane M, et al. The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis. Am J Gastroenterol, 2006,101:1467-1475.
49 Suzuki T, Matsuo K, Ito H, et al. Smoking increases the treatment failure for Helicobacter pylori eradication. Am J Med, 2006,119:217-224.
50 Gisbert J, Hermida C, Pajares J. Are 12 days of omeprazole, amoxcillin and clarithromycin better than 6 days for treating H pylori infection in peptic ulcer and non-ulcer dyspepsia?. Hepatogastroenterology, 2001,48:1383-1388.
51 Gisbert JP. The recurrence of Helicobacter pylori infection: incidence and variables influencing it. Am J Gastroenterol, 2005,100:2083-2099.
52 Kwon DH, Lee M, Kim JJ, et al. Furazolidone- and nitrofurantoinresistant Helicobacter pylori: prevalence and role of genes involved in metronidazole resistance. Antimicrob Agents Chemother, 2001,45:306-308.
53 Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobialsusceptibility testing. Clin Microbiol Rev, 2007,20:280-322.
54 Schabereiter-Gurtner C, Hirschl AM, Dragosics B, et al. Novel real-time PCR assay for detection of Helicobacter pylori infection and simultaneous clarithromycin susceptibility testing of stool and biopsy specimens. J Clin Microbiol, 2004,42:4512-4518.
55 Trebesius K, Adler K, Vieth M, et al. Specific detection and prevalence of Helicobacter heilmannii-like organisms in the human gastric mucosa by fluorescent in situ hybridization and partial 16S ribosomal DNA sequencing. J Clin Microbiol, 2001,39:1510-1516.
56 Duck WM, Sobel J, Pruckler JM, et al. Antimicrobial resistance incidence and risk factors among Helicobacter pylori-infected persons, United States. Emerg Infect Dis, 2004,10:1088-1094.
57 Bruce MG, Bruden DL, McMahon BJ, et al. Alaska sentinel surveillance for antimicrobial resistance in Helicobacter pylori isolates from Alaska native persons, 1999-2003. Helicobacter, 2006,11:581-588.
58 Glupczynski Y, Megraud F, Lopez Brea M, et al. European multicentre survey of in vitro antimicrobial resistance in Helicobacter pylori. Eur J Clin Microbiol Infect Dis, 2001,20:820-823.
59 Storskrubb T, Aro P, Ronkainen J, et al. Antimicrobial susceptibility of Helicobacter pylori strains in a random adult Swedish population. Helicobacter, 2006,11:224-230.
60 Janssen MJ, Hendrikse L, de Boer SY, et al. Helicobacter pylori antibiotic resistance in a Dutch region: trends over time. Neth J Med, 2006,64:191-195.
61 Petersen AM, Gjode P, Vinge OD, et al. Helicobacter pylori antimicrobial resistance and risk factors in Denmark 1998-2004: no need for concern?. Helicobacter, 2006,11:210-211.
62 Koivisto TT, Rautelin HI, Voutilainen ME, et al. Primary Helicobacter pylori resistance to metronidazole and clarithromycin in the Finnish population. Aliment Pharmacol Ther, 2004,19:1009-1017.
63 Boyanova L, Nikolov R, Lazarova E, et al. Antibacterial resistance in Helicobacter pylori strains isolated from Bulgarian children and adult patients over 9 years. J Med Microbiol, 2006,55:65-68.
64 De Francesco V, Margiotta M, Zullo A, et al. Prevalence of primary clarithromycin resistance in Helicobacter pylori strains over a 15-year period in Italy. J Antimicrob Chemother, 2007,59:783-785.
65 Mohammadi M, Doroud D, Mohajerani N, et al. Helicobacter pylori antibiotic resistance in Iran. World J Gastroenterol, 2005,11:6009-6013.
66 Albert JM, Al-Mekhaizeem K, Neil L, et al. High prevalence and level of resistance to metronidazole, but lack of resistance to other antimicrobials in Helicobacter pylori, isolated from a multiracial population in Kuwait. Aliment Pharmacol Ther, 2006,24:1359-1366.
67成虹,胡伏莲.北京地区幽门螺杆菌耐药情况及其耐药趋势.中华医学杂志, 2005,85:2754-2757.
68 Lwai-Lume L, Ogutu EO, Amayo EO, et al. Drug susceptibility pattern of Helicobacter pylori in patients with dyspepsia at the Kenyatta National Hospital, Nairobi. East Afr Med J, 2005,82:603-608.
69 Koletzko S, Richy F, Bontems P, et al. Prospective multicentre study on antibiotic resistance of Helicobacter pylori strains obtained from children living in Europe. Gut, 2006,55:1711-1716.
70 Masuda H, Hiyama T, Yoshihara M, et al. Characteristics and trends of clarithromycin-resistant Helicobacter pylori isolates in Japan over a decade. Pathobiology, 2004,71:159-163.
71胡伏莲.幽门螺杆菌耐药研究进展.现代消化及介入治疗, 2005,10:218-222.
72 Carothers JJ, Bruce MG, Hennessy TW, et al. The relationship between previous fluoroquinolone use and levofloxacin resistance in Helicobacter pylori infection. Clin Infect Dis, 2007,44:e5-8.
73 Miyachi H, Miki I, Aoyama N, et al. Primary levofloxacin resistance and gyrA/B mutations among Helicobacter pylori in Japan. Helicobacter, 2006,11:243-249.
74 Bogaerts P, Berhin C, Nizet H, et al. Prevalence and mechanisms of resistance to fluoroquinolones in Helicobacter pylori strains from patients living in Belgium. Helicobacter, 2006,11:441-445.
75 Cattoir V, Nectoux J, Lascols C, et al. Update on fluoroquinolone resistance in Helicobacter pylori: new mutations leading to resistance and first description of a gyrA polymorphism associated with hypersusceptibility. Int J Antimicrob Agents, 2007,29:389-396.
76 Lopes AI, Oleastro M, Palha A, et al. Antibiotic-resistant Helicobacter pylori strains in Portuguese children. Pediatr Infect Dis J, 2005,24:404-409.
77 Fujimura S, Kato S, Iinuma K, et al. In vitro activity of fluoroquinolone and the gyrA gene mutation in Helicobacter pylori strains isolated from children. J Med Microbio, 2004,53:1019-1022.
78 Nishizawa T, Suzuki H, Kurabayashi K, et al. Gatifloxacin resistance and mutations in gyrA after unsuccessful Helicobacter pylori eradication in Japan. Antimicrob Agents Chemother, 2006,50:1538-1540.
79 Nahar S, Mukhopadhyay AK, Khan R, et al. Antimicrobial susceptibility of Helicobacter pylori strains isolated in Bangladesh. J Clin Microbiol, 2004,42:4856-4858.
80 Glocker E, Bogdan C, Kist M. Characterization of rifampicinresistant clinical Helicobacter pylori isolates from Germany. J Antimicrob Chemother, 2007,59:874-879.