Is the required therapeutic effect always achieved by racemic switch of proton-pump inhibitors?

Many of the drugs currently used in medical practice are racemates. The enantiomers of a racemic drug differ in pharmacodynamics and/or pharmacokinetics, thus in some cases it is preferable to develop pure enantiomers by racemic switch. In a recent study by Pai et al, dexrabeprazole [R(+)-rabeprazole] (10 mg) was found to be more effective than rabeprazole (20 mg) in the treatment of gastroesophageal reflux disease. We read with great interest in this study and discussed whether such racemic switch would be applicable to other proton-pump inhibitors (PPIs). A literature review indicates that stereoselective pharmacokinetics, rather than stereoselective pharmacological activity, is the main cause of differences in clinical efficacy between pure enantiomer and racemic PPI. Racemic switches of PPI provide the therapeutic advantages such as reducing metabolic load on the body, simplifying pharmacokinetics, providing benefit to the non-responders to standard dose of racemate, more homogenous response to treatment and better efficacy with equal safety. Further studies in quantitative structure-activity relationships (QSARs) are needed to address the fact that the preferred enantiomer of PPI is not always in the same absolute configuration, i.e., S-form is for omeprazole, pantoprazole and tenatoprazole whereas R-form is for lansoprazole and rabeprazole.

Evidence-based assessment of proton-pump inhibitors in Helicobacter pylori eradication: A systematic review

Peptic ulcer disease continues to be issue especially due to its high prevalence in the developing world.Helicobacter pylori(H.pylori)infection associated duodenal ulcers should undergo eradication therapy.There are many regimens offered for H.pylori eradication which include triple,quadruple,or sequential therapy regimens.The central aim of this systematic review is to evaluate the evidence for H.pylori therapy from a meta-analytical outlook.The consequence of the dose,type of proton-pump inhibitor,and the length of the treatment will be debated.The most important risk factor for eradication failure is resistance to clarithromycin and metronidazole.

Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms

Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia （PPIH） has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective,controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the feld of PPIH and the proposed mechanisms of this effect.

A Pharmacist-Led Medication Use Evaluation of Proton-Pump Inhibitors

Objective： To determine whether patients maintain symptom control after discontinuation of PPI （proton-pump inhibitor） therapy through intervention of a pharmacist-led medication utilization program and determine annual clinic cost-savings per prescription. Design： The study was conducted as a prospective, medication use evaluation. Using an electronic medical record system at a clinic, reports generated all patients receiving PP1 therapy from January 2013-June 2015. Patients were encouraged to participate in a PPI discontinuation trial through a pharmacist-led educational session. Participants were followed-up three months post enrollment to assess their quality of life through a survey assessing severity and frequency of symptoms. Participants unable to maintain symptom control after the intervention were referred back to their primary care physician for further evaluation. Results： Of one hundred participants, 25% （n = 25） were able to discontinue the use of PPI by lifestyle modifications, 43% （n = 43） refused to discontinue PP1 therapy and lifestyle changes due to the severity of their symptoms, 17% （n = 17） switched to over-the-counter H2 receptor antagonist daily to control their symptoms, 9% （n = 9） used PPIs only as needed, and 6% （n = 6） of participants were dropped from the study after three failed communication attempts. The clinic saved approximately $11 thousand annually for every one prescription of PPI＇s. Conclusions： Discontinuation of PPI or step-down therapy was possible for patients with mild-moderate GERD （Gastroesophageal Reflux Disease） symptoms when mediated by pharmacist counseling and follow-up. Also, the annual PPI expenditure at this clinic will decrease due to participant＇s discontinuation of therapy.

Optimized sequential therapy vs 10- and 14-d concomitant therapy for eradicating Helicobacter pylori: A randomized clinical trial

BACKGROUND A cure for Helicobacter pylori(H.pylori)remains a problem of global concern.The prevalence of antimicrobial resistance is widely rising and becoming a challenging issue worldwide.Optimizing sequential therapy seems to be one of the most attractive strategies in terms of efficacy,tolerability and cost.The most common sequential therapy consists of a dual therapy[proton-pump inhibitors(PPIs)and amoxicillin]for the first period(5 to 7 d),followed by a triple therapy for the second period(PPI,clarithromycin and metronidazole).PPIs play a key role in maintaining a gastric pH at a level that allows an optimal efficacy of antibiotics,hence the idea of using new generation molecules.This open-label prospective study randomized 328 patients with confirmed H.pylori infection into three groups(1:1:1):The first group received quadruple therapy consisting of twice-daily(bid)omeprazole 20 mg,amoxicillin 1 g,clarith-romycin 500 mg and metronidazole 500 mg for 10 d(QT-10),the second group received a 14 d quadruple therapy following the same regimen(QT-14),and the third group received an optimized sequential therapy consisting of bid rabe-prazole 20 mg plus amoxicillin 1 g for 7 d,followed by bid rabeprazole 20 mg,clarithromycin 500 mg and metronidazole 500 mg for the next 7 d(OST-14).AEs were recorded throughout the study,and the H.pylori eradication rate was determined 4 to 6 wk after the end of treatment,using the 13C urea breath test.RESULTS In the intention-to-treat and per-protocol analysis,the eradication rate was higher in the OST-14 group compared to the QT-10 group:(93.5%,85.5%P=0.04)and(96.2%,89.5%P=0.03)respectively.However,there was no statist-ically significant difference in eradication rates between the OST-14 and QT-14 groups:(93.5%,91.8%P=0.34)and(96.2%,94.4%P=0.35),respectively.The overall incidence of AEs was significantly lower in the OST-14 group(P=0.01).Furthermore,OST-14 was the most cost-effective among the three groups.CONCLUSION The optimized 14-d sequential therapy is a safe and effective alternative.Its eradication rate is comparable to that of the 14-d concomitant therapy while causing fewer AEs and allowing a gain in terms of cost.

雷公藤红素对内皮细胞E-selectin和ICAM-1及CD31表达的实验研究

目的通过研究雷公藤红素对细胞因子表达的影响探讨其体外抑制血管生成的机制。方法应用RT-PCR检测一定浓度雷公藤红素作用下的内皮细胞株ECV304 E-selectin和ICAM-1的表达,采用流式细胞仪检测不同浓度雷公藤红素作用下内皮细胞株ECV304表面CD31的表达。结果RT-PCR的结果表明,经过雷公藤红素处理后,内皮细胞株ECV304 ICAM-1的表达明显地降低,而E-selectin和CD31并未见表达。结论雷公藤红素在体外可能通过影响内皮细胞粘附分子ICAM-1等的表达,从而抑制血管生成。

一种复合缓蚀剂对碳钢的协同缓蚀作用研究

用失重法、表面观察法研究了NaH2 PO4、ZnSO4、十二胺在 0 .0 5MNa2 SO4溶液中对 2 0 #碳钢的协同缓蚀效应。结果发现 :室温下 ,NaH2 PO4,ZnSO4、十二胺的浓度分别为 10 0ppm ,10 0ppm ,10ppm时 ,具有最佳的协同缓蚀效果 .

致癌剂DEN、促癌剂巴豆油对大鼠肝α_1抑制因子3基因表达的影响

本文对致癌剂二乙基亚硝胺(DEN)和促癌剂巴豆油对大鼠肝α_1-抑制因子3(α_1- I_s)基因表达的影响进行了观察。结果表明:在腹腔注射DEN(200mg/kg·b.w.)后2h,α_1- I_3 RNA水平即显著下降;4h左右有所回升,约为正常水平的四分之一;然后又下降至极低水平,并一直保持该水平至24h。同时,c-myc RNA在2h则被诱导,约为正常水平的2-3倍;之后,即在4至24h内虽有波动,但基本处于正常水平。在腹腔注射巴豆油(18mg/kg.b.w.)后1h,α_1-I_3RNA水平即下降,约为正常水平的1/8,此后有所回升,约为正常水平的1/3-1/4;在同样条件下,ODC和C-fos RNA能被巴豆油诱导而增加。我们以前的工作表明,在大多数(75％,12/16)由DEN所诱发的大鼠肝癌中,α_1- I_3RNA水平显著下降,且基因结构发生了变化。综合这些结果,说明α_1- I_3基因或与该基因表达有关的蛋白调控因子可能是致癌剂DEN或促癌剂TPA的作用靶分子。该基因表达异常的意义及机理正在深入研究中。

SGLT-2抑制剂研究进展

钠-葡萄糖协同转运蛋白抑制剂具有独特的不依赖于胰岛素分泌的降糖途径,使过量的葡萄糖从尿液中排出,进而降低血糖。因其作用机制,该药在2型糖尿病(type 2 diabetes mellitus,T2DM)任何阶段均可使用。除降糖作用外,该类药物已被证实具有减轻体重、血压、尿白蛋白/肌酐比值,还被证实能降低不良心血管疾病风险。目前研究表明,钠-葡萄糖协同转运蛋白抑制剂具有良好的药效和耐受性,可成为2型糖尿病患者新的药物选择。

阻化剂性能评价的氧化增重法研究

硫化矿石氧化阻化材料的性能评价是一个难题。首次探讨了一种实验评价的新方法氧化增重法 ,并将该方法应用于实际 ,取得了良好的效果 ,从而验证了该方法的可行性和有效性。

氨茶碱与乌司他丁合用在婴幼儿体外循环中的肺保护作用

目的探讨氨茶碱与乌司他丁合用对体外循环（CPB）所致肺损伤的保护作用。方法选取体重≤7kg的单纯室间隔缺损新生儿及低体重婴幼儿60例，采用随机化分组表分为氨茶碱组（A组）、乌司他丁组（U组）、联合组（AU组）和对照组（C组），每组各15例。A组麻醉诱导后静脉注射氨茶碱5mg／kg，并在体外循环过程中按每小时0．5mg／kg维持；U组在CPB过程中应用10000U／k乌司他丁；AU组联合应用上述两种药物；C组未给予氨茶碱及乌司他丁。选取CPB启动前（t1）、CPB结束后1h（t2）和CPB结束后24h（t3）计算胸肺顺应性（Cs）、动态肺顺应性（Cd）以及呼吸指数（RI）。结果术后对照组1例因多器官功能衰竭死亡，乌司他丁组1例因严重心律失常死亡。手术后1h，AU组Cs优于A组、C组，RI优于A组、U组；手术后24h，AU组Cs和RI优于其他组，Cd优于A组、U组。结论氨茶碱和乌司他丁可减轻体外循环引起的急性炎症反应和CPB导致的肺损伤；两者联合应用有协同作用。

新型锌锰干电池无汞缓蚀剂的研究

通过用椭圆偏振技术观测锌在电池电解液中的腐蚀情况，经椭圆法实验和数据拟合，得出锌表面腐蚀防护层的生长规律；用铅盐、ＺＬ－０１（有机缓蚀剂）及其混合物替代ＨｇＣｌ２装配电池，对电池性能进行检测，其性能指标接近于含汞电池。

What are the effects of proton pump inhibitors on the small intestine?

Generally, proton-pump inhibitors(PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury.Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth(SIBO) compared to patients who lack the aforementioned conditions.Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, nonalcoholic fatty liver disease, and autoimmune diseases.When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked.

Treatment and prevention of gastrointestinal bleeding in patients receiving antiplatelet therapy

Antiplatelet therapy is the standard of care for the secondary prevention of acute coronary syndrome and ischemic stroke, especially after coronary intervention. However, this therapy is associated with bleeding complications such as gastrointestinal bleeding, which is one of the most common life-threatening complications. Early endoscopy is recommended for most patients with acute upper gastrointestinal bleeding. After successful endoscopic hemostasis, immediate resumption of antiplatelet therapy with proton-pump inhibitors(PPIs) is recommended to prevent further ischemic events. PPI prophylaxis during antiplatelet therapy reduces the risk of upper gastrointestinal bleeding. The potential negative metabolic interaction between PPIs and clopidogrel is still unclear.

Stress ulcer prophylaxis guidelines:Are they being implemented in Lebanese health care centers?

AIM:To evaluate the current practice of stress ulcer prophylaxis (SUP) in Lebanese Health care centers.METHODS:A multi-center prospective chart review study was conducted over 8 mo.A questionnaire was distributed to pharmacy students who collected data on demographics,SUP medications,dose,route,duration and associated risk factors.The appropriateness of SUP use was determined as per American Society of Health-System Pharmacists guidelines.Institutional review board approval was obtained from each hospital center.RESULTS:A total of 1004 patients were included.67% of the patients who received prophylaxis did not have an indication for SUP.The majority (71.6%) of the patients who were administered parenteral drugs can tolerate oral medications.Overall,the regimen of acid-suppressant drugs was suboptimal in 87.6% of the sample.This misuse was mainly observed in non-teaching hospitals.CONCLUSION:This study highlighted the need,in Lebanese hospitals,to establish clinical practice guidelines for the use of SUP;mainly in non-critical care settings.

A randomized open-label trial of on-demand rabeprazole vs ranitidine for patients with non-erosive reflux disease

AIM： To compare the efficacy of the proton-pump inhibitor, rabeprazole, with that of the H2-receptor antagonist, ranitidine, as on-demand therapy for relieving symptoms associated with non-erosive reflux disease （NEED）.METHODS： This is a single center, prospective, randomized, open-label trial of on-demand therapy with rabeprazole （group A） vs ranitidine （group B） for 4 wk. Eighty-three patients who presented to the American University of Beirut Medical Center with persistent gas- troesophageal reflux disease （GERD） symptoms and a normal upper gastrointestinal endoscopy were eligible for the study. Patients in group A （n = 44） were al-lowed a maximum rabeprazole dose of 20 mg twice daily, while those in group B （n = 39） were allowed a maximum ranitidine dose of 300 mg twice daily. Ef- ficacy was assessed by patient evaluation of global symptom relief, scores of the SF-36 quality of life （QoL） questionnaires, total number of pills used, and number of medication-free days.RESULTS： Among the 83 patients who were enrolled in the study, 76 patients （40 in the rabeprazole group and 36 in the ranitidine group） completed the 4-wk trial. Baseline characteristics were comparable between both groups. After 4 wk, there was no significant difference in the subjective global symptom relief between the rabeprazole and the ranitidine groups （71.4% vs 65.4%, respectively; P = 0.9）. There were no statistically significant differences between mean cumulative scores of the SF-36 QoL questionnaire for the two study groups （rabeprazole 22.40±27.53 vs ranitidine 17.28 ± 37.06; P = 0.582）. There was no significant difference in the mean number of pills used （rabeprazole 35.70±29.75 vs ranitidine 32.86±26.98; P = 0.66）. There was also no statistically significant difference in the mean number of medication-free days between both groups.CONCLUSION： Rabeprazole has a comparable efficacy compared to ranitidine when given on-demand for the treatment of NERD. Both medications were associated with improved quality of life.

Poor awareness of preventing aspirin-induced gastrointestinal injury with combined protective medications

AIM:To investigate prescribing pattern in low-dose aspirin users and physician awareness of preventing aspirin-induced gastrointestinal(GI) injury with combined protective medications.METHODS:A retrospective drug utilization study was conducted in the 2nd Affiliated Hospital,School of Medicine,Zhejiang University.The hospital has 2300 beds and 2.5 million outpatient visits annually.Data mining was performed on all aspirin prescriptions for outpatients and emergency patients admitted in 2011.Concomitant use of proton-pump inhibitors(PPIs),histamine 2-receptor antagonists(H2RA) and mucoprotective drugs(MPs) were analyzed.A defined daily dose(DDD) methodology was applied to each MP.A further investigation was performed in aspirin users on combination use of GI injurious medicines [non-steoid anti-inflammatory drugs(NSAIDs),corticosteroids and clopidogrel and warfarin] or intestinal protective drugs(misoprostol,rebamipide,teprenone and gefarnate).Data of major bleeding episodes were derived from medical records and adverse drug reaction monitoring records.The annual incidence of major GI bleeding due to low-dose aspirin was estimated for outpatients.RESULTS:Prescriptions for aspirin users receiving PPIs,H2RA and MPs(n = 1039) accounted for only 3.46% of total aspirin prescriptions(n = 30 015).The ratios of coadministration of aspirin/PPI,aspirin/H2RA,aspirin/MP and aspirin/PPI/MP to the total aspirin prescriptions were 2.82%,0.12%,0.40% and 0.12%,respectively.No statistically significant difference was observed in age between patients not receiving any GI protective medications and patients receiving PPIs,H2RA or MPs.The combined medication of aspirin and PPI was used more frequently than that of aspirin and MPs(2.82% vs 0.40%,P < 0.05) and aspirin/H2RA(2.82% vs 0.12%,P < 0.05).The values of DDDs of MPs in descending order were as follows:gefarnate,hydrotalcite > teprenone > sucralfate oral suspension > L-glutamine and sodium gualenate granules > rebamipide > sucralfate chewable tablets.The ratio of MP plus aspirin prescriptions to the total MP prescriptions was as follows:rebamipide(0.47%),teprenone(0.91%),L-glutamine and sodium gualenate granules(0.92%),gefarnate(0.31%),hydrotalcite(1.00%) and sucralfate oral suspension(0.13%).Percentages of prescriptions containing aspirin and intestinal protective drugs among the total aspirin prescriptions were:rebamipide(0.010%),PPI/rebamipide(0.027%),teprenone(0.11%),PPI/teprenone(0.037%),gefarnate(0.017%),and PPI/gefarnate(0.013%).No prescriptions were found containing coadministration of aspirin and other NSAIDs.Among the 3196 prescriptions containing aspirin/clopidogrel,3088(96.6%) prescriptions did not contain any GI protective medicines.Of the 389 prescriptions containing aspirin/corticosteroids,236(60.7%) contained no GI protective medicines.None of the prescriptions using aspirin/warfarin(n = 22) contained GI protective medicines.Thirty-five patients were admitted to this hospital in 2011 because of acute hemorrhage of upper digestive tract induced by low-dose aspirin.The annual incidence rates of major GI bleeding were estimated at 0.25% for outpatients taking aspirin and 0.5% for outpatients taking aspirin/warfarin,respectively.CONCLUSION:The prescribing pattern of low-dose aspirin revealed a poor awareness of preventing GI injury with combined protective medications.Actions should be taken to address this issue.

Management of gastro-esophageal reflux disease:Practice-oriented answers to clinical questions

Gastro-esophageal reflux disease(GERD)is a condition which is frequently faced by primary care physicians and gastroenterologists.Improving management of GERD is crucial to maximise both patient care and resource utilization.In fact,the management of patients with GERD is complex and poses several questions to the clinician who faces them in clinical practice.For instance,many aspects should be considered,including the appropriateness of indication to endoscopy,the quality of the endoscopic examination,the use and interpretation of ambulatory reflux testing,and the choice and management of anti-reflux treatments,i.e.,protonpump inhibitors and surgery.Aim of the present review was to provide a comprehensive update on the clinical management of patients with GERD,through a literature review on the diagnosis and management of patients with GER symptoms.In details,we provide practice-oriented concise answers to clinical questions,with the aim of optimising patient management and healthcare resource use.

Clinical Analysis of the Pharmacological Interactions of Clopidogrel and Gender Differences: A Case-Control Study

Background: Clopidogrel is a prodrug metabolized by cytochrome P450-2C19. Drugs inhibiting this enzyme might reduce its antiplatelet activity. In order to reduce gastrointestinal bleedings, proton-pump inhibitors are usually prescribed in association with clopidogrel. The study aims at assessing the clinical importance of interactions between clopidogrel and inhibitors of CYP2C19. It also aims to evaluate any possible factors that may reduce the therapeutic efficacy of the drug. Particular attention was devoted to possible gender differences in responsiveness to treatment with clopidogrel or clopidogrel plus proton-pump inhibitors. This analysis is a retrospective case-control observational study carried out by the University Hospital of Ferrara. Methods: Subjects were patients who had received clopidogrel from 01-01-2008 to 31-12-2008. For them, we analysed hospital admissions and data of drug prescriptions relative to dispensing of drugs cytochrome P-450-2C19 inhibitors. Patients were subdivided into case and control groups based on the occurrence or not of cardiovascular or cerebrovascular secondary events during therapy with clopidogrel. Results: The study focused on 781 patients, 20.1% of which (n.157) experienced secondary effects. The mean age is 70 years old. Men (67% of the analyzed population) experienced secondary events more than women (OR 1.54;CI 95% 1.04 - 2.28;p < 0.03). 70% of patients took PPIs and we noticed that the risk of secondary events increased by 2.2% with respect to the remaining patients (20.77% vs 18.57%;OR 1.15;CI 0.78 - 1.70;p = NS). Among PPIs, lansoprazole is the most used. For this subgroup the risk is 5.2% higher (risk in those exposed of 23.75% vs 18.57% in those not exposed;or 1.37, 95% CI 0.92 - 2.03;p = NS). The interaction with PPIs is particularly interesting only among women, with a risk 6.3% higher (17.46% exposed, 11.11% non exposed). The risk remains the same among men. Conclusions: Analyzed data show an increase in cardiovascular or cerebral secondary events for patients exposed to PPIs. It also demonstrated the existence of differrent gender in therapeutic response to clopidogrel.

中国糖尿病患者胰岛功能的困境与出路

胰岛功能障碍是2型糖尿病的重要发病机制之一,是2型糖尿病治疗的重要靶点,而现有治疗手段保护β细胞功能作用有限。最新的研究发现,基于肠促胰素的药物包括胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)受体激动剂及二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂,不仅能够改善β细胞功能,而且能够避免低血糖、体重增加等不良反应,是治疗2型糖尿病的新途径。