Lansoprazole inhibits the cysteine protease legumain by binding to the active site

Proton pump inhibitors (PPIs) are prodrugs used in the treatment of peptic ulcer diseases. Once activated by acidic pH, the PPIs subsequently inhibit the secretion of gastric acid by covalently forming disulphide bonds with the SH groups of the parietal proton pump, that is the H⁺/K⁺‐ATPase. Long‐term use of PPIs has been associated with numerous adverse effects, including bone fractures. Considering the mechanism of activation, PPIs could also be active in acidic micro‐environments such as in lysosomes, tumours and bone resorption sites. We suggested that the SH group in the active site of cysteine proteases could be susceptible for inhibition by PPIs. In this study, the inhibition by lansoprazole was shown on the cysteine proteases legumain and cathepsin B by incubating purified proteases or cell lysates with lansoprazole at different concentrations and pH conditions. The mechanism of legumain inhibition was shown to be a direct interaction of lansoprazole with the SH group in the active site, and thus blocking binding of the legumain‐selective activity‐based probe MP‐L01. Lansoprazole was also shown to inhibit both legumain and cathepsin B in various cell models like HEK293, monoclonal legumain over‐expressing HEK293 cells (M38L) and RAW264.7 macrophages, but not in human bone marrow‐derived skeletal (mesenchymal) stem cells (hBMSC‐TERT). During hBMSC‐TERT differentiation to osteoblasts, lansoprazole inhibited legumain secretion, alkaline phosphatase activity, but had no effects on in vitro mineralization capacity. In conclusion, lansoprazole acts as a direct covalent inhibitor of cysteine proteases via disulphide bonds with the SH group in the protease active site. Such inhibition of cysteine proteases could explain some of the off‐target effects of PPIs.     

兰索拉唑双相释药微丸胶囊的制备

目的：研究兰索拉唑双相释药微丸胶囊剂的制备方法。方法采用离心造粒法制备兰索拉唑含药微丸,用流化床包衣法分别制备兰索拉唑肠溶微丸和肠溶脉冲微丸,然后将两种微丸按固定比例填充至空心胶囊内。用体外释放度法观察肠溶微丸累计释放量。结果优化处方：载药丸心中碳酸镁用量15%,低取代羟丙纤维素（L-HPC）用量20%;肠溶微丸中隔离衣层增重9%~10%,肠溶衣层增重＞41%;肠溶脉冲微丸溶胀层包衣增重50%~60%,控释层包衣增重50%,肠溶衣层增重＞41%,后干燥时间为4h。结论以肠溶微丸技术制备兰索拉唑双相释药微丸胶囊,工艺可行,重复性良好,质量稳定可靠。     

小柴胡汤合平胃散治疗胃食管反流随机平行对照研究

[目的]观察小柴胡汤合平胃散治疗胃食管反流疗效。[方法]使用随机平行对照方法,将65例住院患者按病志号抽签法简单随机分为两组。对照组30例兰索拉唑,20mg/次,2次/d,饭前口服;莫沙比利,10mg/次,3次/d,饭前口服;磷酸铝,20g/次,3次/d,饭前口服。治疗组35例小柴胡汤合平胃散(柴胡15g,黄芩、制半夏各10g,党参12g,苍术6g,厚朴9g,陈皮6g,甘草5g,九节茶20g,蒲公英15g,郁金10g;热甚口苦、口干加黄连、白花蛇舌草、栀子;腹胀甚加枳实、香附;纳呆加麦芽炒、谷芽、莱菔子;久病不愈舌底脉络青紫瘀曲加丹参、檀香、砂仁),1剂/d,水煎300m L,餐前30min早晚口服。连续治疗56d为1疗程。观测临床症状、食管黏膜、不良反应。治疗1疗程,判定疗效。[结果]治疗组痊愈18例,显效11例,有效4例,无效2例,总有效率94.28%。对照组痊愈10例,显效8例,有效4例,无效8例,总有效率71.33%。治疗组疗效优于对照组(P0.05)。[结论]小柴胡汤合平胃散治疗胃食管反流效果显著,值得推广。     

注射用盐酸头孢替安与注射用兰索拉唑存在配伍禁忌

注射用盐酸头孢替安为第二代头孢菌素,用于敏感菌所致的术后感染、烧伤感染、皮肤软组织感染及耳、鼻、喉感染等。注射用兰索拉唑主要用于胃溃疡、十二指肠溃疡、吻合口溃疡、幽门螺杆菌感染及反流性食管炎、胃泌素瘤等。我科在临床工作     

高效毛细管电泳法测定血浆中兰索拉唑对映体浓度

目的建立测定血浆中兰索拉唑对映体浓度的高效毛细管电泳分析方法,并用于兰索拉唑在人体内立体选择性药代动力学研究。方法用乙醚作提取溶剂提取血浆中兰索拉唑。采用高效毛细管电泳法测定6名健康男性受试者经口给予兰索拉唑片后不同时刻血浆中药物对映体浓度,绘制血药浓度-时间曲线,并计算主要药动学参数。结果 S—与R—兰索拉唑对映体的主要药动学参数如下:ρmax分别为(0.538±0.039)mg.L-1和(1.050±0.250)mg.L-1,tmax为(1.8±0.7)h和(1.8±0.7)h,t1/2分别为(1.6±0.7)h和(2.7±1.0)h,用梯形法计算,AUC0-t分别为(1.49±0.36)mg.h.L-1和(4.35±1.52)mg.h.L-1。结论兰索拉唑两对映体在人体内的代谢过程具有立体选择性。     

兰索拉唑肠溶胶囊中杂质的结构确证、检查及控制

目的:建立兰索拉唑肠溶胶囊中杂质的检查方法,进行稳定性考察,确证杂质的结构。方法:采用液相色谱进行杂质检查的方法学研究及稳定性考察;采用Supelcosil LC–ABZ色谱柱(250 mm×3.0 mm,5μm),Diamond C18色谱柱(250 mm×4.6mm,5μm),流动相为1.67%三乙胺水溶液(用磷酸调pH至6.2)-乙腈(65:35),等度洗脱,流速1.0 mL·min-1,检测波长285 nm,柱温30℃。采用液–质联用技术及标准杂质对照法进行杂质的结构确证。通过相对分子质量(Mr)、分子离子峰(m/z)及液相色谱保留时间(tR)三方面的信息进行杂质的结构确证。结果:供试品经强制破坏后各杂质峰与主峰均能达到基线分离。最低检测限0.05 ng(S/N=3)。不同放置时间主峰峰面积的RSD=0.67%(n=5);改变流动相pH,主峰峰面积的RSD=0.14%(n=3);改变柱温,主峰峰面积的RSD=1.4%(n=3)。杂质E的浓度在1.60～6.40μg·mL-1范围内线性良好(r=0.9999)。主峰及各杂质对照峰的峰纯度良好。结论:确证了供试品中杂质的结构,建立了杂质检查的方法,此法简便易行,耐用性好,专属性强,灵敏,准确,适用于兰索拉唑肠溶胶囊剂中杂质的确证、检查及控制。     

Pharmacokinetics of lansoprazole and its main metabolites after single intravenous doses in healthy Chinese subjects

1. The aim of the study was to evaluate the pharmacokinetics (PK) of lansoprazole (LPZ) and its main metabolites 5′-hydroxy lansoprazole (HLPZ) and lansoprazole sulphone (LPZS) after single intravenous (i.v.) doses of LPZ in healthy Chinese subjects, and the relationship between the cytochrome P450 (CYP) 2C19 phenotypes and the plasma concentrations of LPZS at the time-points in the elimination phase of LPZ.

2. Twelve subjects were given lansoprazole by i.v. infusion. Blood samples were collected at designated time points up to 24 h. Plasma concentrations of LPZ, HLPZ and LPZS were quantified by a selective and sensitive liquid chromatography-tandem mass spectrometric (LC-MS/MS) method.

3. After single i.v. doses of 15, 30 and 60 mg LPZ, C_max and area under the plasma concentration-time curve (AUC_0-t) of LPZ were 725 ± 151, 1480 ± 190, 3130 ± 480 µg·L^?1 and 1690 ± 1210, 3630 ± 2530, 8080 ± 4550 µg·h·L^?1, respectively. LPZ was generally well tolerated in healthy Chinese subjects, and displayed linear PK in the range of 15–60 mg.

4. There were significant differences in the elimination of LPZ and the formation of LPZS between the single CYP2C19 poor metabolizer (PM) and the CYP2C19 extensive metabolizers (EM). The concentration of LPZS at the time-points in the elimination phase of LPZ could be monitored for CYP2C19 phenotyping. As a probe drug for CYP2C19 phenotyping, LPZ for injection might be more suitable than LPZ oral formulations.

     

Ethnic differences in drug therapy: a pharmacogenomics perspective

This study was presented at the American College of Chest Physicians meeting in Pittsburgh (PA, USA) in October 2011. The study objective was to evaluate the association of proton pump inhibitors (PPIs) and community-acquired pneumonia (CAP). The design was a meta-analysis of nine case–controlled and cohort studies. 120,863 pneumonia cases from 1987 to 2006 were included in the meta-analysis. PubMed and Ovid Medline were searched from inception through May 2011 by two investigators independently using keywords: PPI, pneumonia, CAP, anti-ulcer, antacid, omeprazole, esomeprazole, lansoprazole, pantoprazole and rabeprazole. This meta-analysis only included case–controlled and cohort studies that were published in full in English and evaluated PPI use and CAP incidence. Studies were excluded if they included the following patients: pediatric, Helicobacter pylori treatment and critically ill. Bibliographies of recent review articles and systematic reviews were hand-searched. Quality of studies was assessed using the Newcastle–Ottawa Quality Assessment Scale. Two investigators independently extracted data into standardized data collection forms that were confirmed by a third investigator. Data were analyzed based on current use of PPIs, duration of PPI use (<30 days or >180 days) and PPI dose (high vs low). Overall association of PPI and CAP was analyzed using the random effects model (Comprehensive Meta analysis^® Version 2.0). Nine studies met all criteria for the primary outcome. Newcastle–Ottawa Quality Assessment Scale scores ranged from 4 to 8 out of 9. Current use of PPIs (odds ratio [OR]: 1.39; 95% CI: 1.09–1.76), PPI use <30 days (OR: 1.65; 95% CI: 1.25–2.19), PPI high dose (OR: 1.50; 95% CI: 1.33–1.68) and PPI low dose (OR: 1.17; 95% CI: 1.11–1.24) were significantly associated with CAP. There was no association between CAP and PPI use >180 days (OR: 1.10; 95% CI: 1.00–1.21). In conclusion, patients currently receiving PPIs, particularly <30 days or high dose, showed an association with CAP. Practitioners need to be vigilant about adverse effects of PPIs and consider alternative therapies.     

外科病区注射用兰索拉唑合理用药调查分析

目的促进医院注射用兰索拉唑的合理应用。方法制订质子泵抑制剂用药评价标准,组织抽查小组,对2012年2月外科病区病历进行抽查,对注射用兰索拉唑的适应证、用法用量等进行合理性分析。结果共抽查100份病例,存在不合理用药病例49例,合格率为51．00％。存在问题有使用无明确指征和用药疗程过长等。结论外科住院患者注射用质子泵抑制剂存在不舍理用药情况,医院应加快制订质子泵抑制剂使用标准或规范,以提高医院注射用质子泵抑制剂使用的合理性。