Relative potency of proton-pump inhibitors—comparison of effects on intragastric pH

Aim  Comparative potency of proton-pump inhibitors (PPIs) is an important clinical issue. Most available trials have compared the different PPIs at one or a few selected specific dosages, making it difficult to derive quantitative equivalence dosages. Here we derived PPI dose equivalents based on a comprehensive assessment of dose-dependent effects on intragastric pH. Methods  All available clinical studies reporting the effects of PPIs on mean 24-h intragastric pH were sought from electronic databases including Medline. Studies included were restricted to those targeting the Caucasian population, and healthy volunteers or gastroesophageal reflux disease (GERD) patients. The dose-effect relationships for mean 24-h intragastric pH and for percentage of time with pH > 4 in 24 h were analyzed for each PPI using pharmacodynamic modeling with NONMEM and a model integrating all available data. Results  Fifty-seven studies fulfilled the inclusion criteria. Based on the mean 24-h gastric pH, the relative potencies of the five PPIs compared to omeprazole were 0.23, 0.90, 1.00, 1.60, and 1.82 for pantoprazole, lansoprazole, omeprazole, esomeprazole, and rabeprazole, respectively. Compared with healthy volunteers, patients with GERD needed a 1.9-fold higher dose and Helicobacter pylori-positive individuals needed only about 20% of the dose to achieve a given increase in mean 24-h intragastric pH. Conclusion  The present meta-analysis provides quantitative estimates on clinical potency of individual PPIs that may be helpful when switching between PPIs and for assessing the cost-effectiveness of specific PPIs. However, our estimates must be viewed with caution because only a limited dose range has been tested and not exactly the same study conditions were applied for the different substances.     

甘羟铝片联合四联药物治疗复发性消化性溃疡的疗效观察

目的观察甘羟铝片联合四联药物（质子泵抑制剂、枸橼酸铋钾、呋喃唑酮、阿莫西林）治疗复发性消化性溃疡的疗效。方法选取复发性消化性溃疡患者84例,随机分治疗组和对照组,分别给予甘羟铝片联合四联疗法或以四联疗法治疗,总疗程均为14d。结果疗程结束时,治疗组总有效率为97．6％,对照组总有效率为88．1％,两组疗效差异无统计学意义（P〉0．05）,但是治疗组症状完全缓解天数少于对照组（P〈0．05）。两组幽门螺杆菌转阴率和溃疡愈合率差异无统计学意义（P〉0．05）。结论以甘羟铝片联合四联疗法与以四联疗法治疗复发性消化性溃疡均安全、有效,但是以甘羟铝片联合四联疗法缓解症状更快,依从性更好,是治疗复发性消化性溃疡较好的方案。     

Development and validation of an enantioselective and chemoselective HPLC method using a Chiralpak IA column to simultaneously quantify (R)-(+)- and (S)-(−)-lansoprazole enantiomers and related impurities

An accurate and reproducible high-performance liquid chromatographic (HPLC) method has been developed and validated for the direct separation of individual enantiomers of lansoprazole, a potent proton pump inhibitor belonging to the family of the substituted benzimidazoles. The enantiomers were resolved on a Chiralpak IA by using a mobile phase consisting of methyl-tert-butyl ether (MtBE)–ethyl acetate (EA)–ethanol (EtOH)–diethylamine (DEA) in the ratio 60:40:5:0.1 (v/v/v/v). Baseline separation of the enantiomers of lansoprazole was obtained with a resolution factor of 8.14. The standard curves for the two enantiomers were linear (r² > 0.999) in the concentration range of 10–80 μg/ml with a working concentration of about 60 μg/ml for each enantiomer. Apparent recovery was 100.8% with a relative standard deviation less than 2%. The limit of quantization for each enantiomer of lansoprazole was 0.22 μg/ml. The intra-day precisions were in the range of 0.21–0.36 and 0.59–0.66 while the inter-day precisions were in the range of 0.55–1.24 and 0.66–1.19% in terms of retention times and area response RSD% for (R)-(+)- and (S)-(−)-lansoprazole, respectively. The method was also able to resolve impurities from the enantiomers of lansoprazole.     

探讨胃镜下兰索拉唑与凝血酶联合治疗消化性溃疡出血的临床疗效

目的：探讨胃镜下兰索拉唑与凝血酶联合治疗消化性溃疡出血的临床疗效,并为临床开展高效、科学的治疗方案提供指导。方法选取平江县第一人民医院2010年4月～2012年8月收治的104例消化性溃疡伴出血患者为研究对象,利用随机数字表法均分为研究组和对照组（n=52）。对照组给予冰冻生理盐水加去甲肾上腺素联合治疗,研究组给予兰索拉唑与凝血酶联合治疗。记录2组患者在5 min、8 h和24 h内有效止血例数及再出血发生率,并进行比较。结果研究组患者在5 min、8 h和24 h内有效止血分别为38例（73.1%）、12例（23.1%）、2例（3.85%）,而对照组分别为17例（32.7%）、12例（23.1%）、10例（19.2%）,2组有效止血率比较,差异有统计学意义（P〈0.05）。研究组再出血为6例（11.5%）,对照组为17例（32.7%）,2组比较,差异有统计学意义（P〈0.05）。结论对于消化性溃疡出血患者而言,给予兰索拉唑与凝血酶联合治疗可以提高患者的有效止血率,降低再出血发生率,取得较为满意的临床效果。     

Reversible lansoprazole-induced interstitial lung disease showing improvement after drug cessation.

Lansoprazole is an acid proton-pump inhibiting drug that is used for the treatment of duodenal or gastric ulcers, H. pylori infection, gastroesophageal reflux disease or Zollinger-Ellison syndrome. Although lansoprazole is well known for its gastrointestinal and dermatologic adverse effects, mild pulmonary symptoms are also known to develop from taking this drug. There have been no reports about lansoprazole-induced interstitial lung disease. We report here a case of lansoprazole-induced interstitial lung disease that developed in a 66-year-old man.     

Determination of Lansoprazole by Direct Injection of Plasma and High Performance Liquid Chromatography with Column Switching

建立了用柱切换测定血浆中兰索拉唑的方法。血样用蒸馏水简单稀释后注入填充ＬｉＣｈｒｏｍｐｒｅｐＲＰ２（２５～４０μｍ）的预柱上。用蒸馏水冲洗出血浆中蛋白质和其它极性成分。切换后，浓缩在预柱上的兰索拉唑被流动相甲醇０２ｍｏｌ·Ｌ１醋酸铵（６５：３５）反冲到分析柱ＳｈｉｍｐａｃｋＣＬＣＯＤＳ上进行分析。预柱用净化液进行消除和再生。本法有很好的精密度和回收率，检测限为０００５ｍｇ·Ｌ１，日内和日间测定相对标准差小于２５％和５３％。此分析方法已成功地用于测定自愿受试者的兰索拉唑药代动力学     

Proton pump inhibitor treatment of patients with gastroesophageal reflux-related chronic cough： A comparison between two different daily doses of lansoprazole

AIM:To compare two different daily doses oflansoprazole given for 12 weeks and to assess the roleof gastrointestinal (GI) investigations as criteria forselecting patients.METHODS:Out of 45 patients referred for unexplainedchronic persistent cough,36 had at least one of theGI investigations (endoscopy,24-h esophageal pH-metry and a 4-week trial of proton pump inhibitor (PPI)therapy) positive and were randomly assigned to receiveeither 30 mg lansoprazole o.d.or 30 mg lansoprazoleb.i.d,for 12 weeks.Symptoms were evaluated atbaseline (visit 1) after the PPI test (visit 2) and after the12-week lansoprazole treatment period (visit 3).RESULTS:Thirty-five patients completed the studyprotocol.Twenty-one patients (60.0%) reportedcomplete relief from their cough with no differencebetween the two treatment groups (58.8% and 61.1%had no cough in 30 mg lansoprazole and 60 mglansoprazole groups,respectively).More than 80% ofthe patients who had complete relief from their cough atthe end of the treatment showed a positive response tothe PPI test.CONCLUSION:Twelve weeks of lansoprazole treatmenteven at a standard daily dose,is effective in patientswith chronic persistent cough.A positive response to aninitial PPI test seems to be the best criterion for selectingpatients who respond to therapy.     

Long-Term Efficacy of Lansoprazole in Preventing Relapse of Erosive Reflux Esophagitis

In a phase III study of lansoprazole treatment, patients with healed or unhealed erosive esophagitis entered a titrated open-label treatment period and received lansoprazole for ≤6 years to assess long-term maintenance therapy. Doses were adjusted depending on symptom response. Endoscopy was performed yearly. One hundred ninety-five subjects received lansoprazole for <1 to 72 months; most received daily doses of ≤30 mg. Lansoprazole maintained erosive esophagitis remission in 75% of subjects receiving treatment for ≤72 months, with 39 subjects experiencing 50 recurrences. Most subjects (94–95%) had no or mild symptoms of day or night heartburn at study end, and 77% were asymptomatic at first erosive esophagitis recurrence. The most common treatment-related adverse events included diarrhea (10%), headache (8%), and abdominal pain (6%), and were mild or moderate in severity. Long-term lansoprazole is effective and well tolerated when used to maintain erosive esophagitis remission for ≤6 years.     

高效液相色谱法测定人血浆中奥美拉唑与兰索拉唑

目的：建立高效液相色谱法测定人血浆中奥关拉唑和兰索拉唑血药浓度的方法。方法：在血浆中同时加入奥美拉唑、兰索拉唑及内标物泮托拉唑,以叔丁基甲醚提取。流动相为甲醇-乙腈-水（2：29：69）,流速为1．0ml·min^-1;检测波长为285nm,柱温为30℃。结果：奥美拉唑、兰索拉唑与内标物泮托拉唑分离良好,在0．02-4．0μg·ml^-1浓度范围为奥美拉唑线性方程为Y=6．889X-5．787×10^-4,r=0．9999;兰索拉唑线性方程为Y=10．758X＋6．667×10^-3,r=0．9998,奥美拉唑与兰索拉唑日内、日问精密度RSD均小于10％。结论：该法简单、准确、灵敏,适用于测定人血浆中奥美拉唑及兰索拉唑浓度。     

Cytochrome P450 enzyme activity and protein expression in primary porcine enterocyte and hepatocyte cultures

1. A method for the isolation and cultivation of porcine hepatocytes and porcine duodenal enterocytes for the investigation of drug oxidation reactions has been established. 2. Hepatocytes as well as enterocytes metabolized ethoxyresorufin (EROD) and ethoxycoumarin (ECOD) effectively, the rate being 31 +/- 17 pmol/h dish (EROD) and 9530 +/- 4062 pmol/h dish (ECOD) in the case of hepatocytes, and 9 +/- 4 pmol/h dish (EROD) and 510 +/- 467 pmol/h dish (ECOD) in the case of enterocytes. Diazepam, another CYP monooxygenase substrate, was also metabolized by porcine hepatocytes but not with porcine enterocytes, thus indicating differences in the metabolic competence of the liver and the gut. 3. The ability to induce enzymes responsible for the metabolism of ethoxyresorufin and ethoxycoumarin was investigated in vitro on treatment of the cell cultures with either 50 muM 3-methylcholanthrene (3-MC) or 50 muM beta-naphthoflavone (beta-NF). With enterocyte cultures, ECOD activity was inducible up to 20-fold, whereas EROD remained unchanged following treatment with either 3-MC or beta-NF. 4. Western blotting provided additional evidence for the expression of CYP1A1 and CYP3A4 at the protein level and treatment of cultured enterocytes with 30 muM Aroclor 1254 or 50 muM beta-NF resulted in enhanced expression of the CYP1A protein, and CYP3A4 protein expression was induced following treatment with 50 muM DEX, 2 mM PB, 30 muM Aroclor 1254 or 50 muM beta-NF. 5. The metabolism of diazepam was also investigated with baculovirus-expressed human CYP enzymes (2C8, 2C9-ARG, 2C9-CYS, 2C19, 3A4, 3A4+cytochrome b₅ and 3A5) and evidence was obtained to suggest the formation of temazepam and oxazepam by enzymes of the CYP3A subfamily. Small amounts (32 +/- 12 ng/ml) of desmethyldiazepam were additionally recovered in microsomal preparations of all CYP-transfected cell lines. 6. In conclusion, porcine duodenal enterocytes can successfully be cultured for a short period and may be used as a tool for studying intestinal metabolism, whereas porcine hepatocytes can be cultured for prolonged periods (&gt; 10 days) reliably to investigate hepatic drug oxidation reactions.