Rabeprazole- versus esomeprazole-based eradication regimens for H. pylori infection

BACKGROUND: Different kinds of proton pump inhibitor-based triple therapies could result in different Helicobacter pylori eradication rates. AIM: The aims of this study were to compare the efficacy and safety of rabeprazole- and esomeprazole-based triple therapy in primary treatment of H. pylori infection in Taiwan. PATIENTS AND METHODS: From June 2005 to March 2007, 420 H. pylori-infected patients were randomly assigned to receive a 7-day eradication therapy with either esomeprazole 40 mg daily (EAC group, n = 209) or rabeprazole 20 mg b.i.d. (RAC group, n = 211) in combination with amoxicillin 1 g b.i.d. and clarithromycin 500 mg b.i.d.. Follow-up endoscopy with biopsy was done 12-16 weeks after completion of eradication therapy. Those who refused endoscopic exams underwent (13)C-urea breath test to assess the treatment response. RESULTS: Intention-to-treat analysis revealed that the eradication rate was 89.4% in the EAC group and 90.5% in RAC groups (p-value = .72). All of the subjects returned for assessment of compliance (100% in EAC group vs. 99.5% in RAC group, p-value = .32) and adverse events (3.83% in EAC group vs. 6.16% in RAC group, p-value = .27). Sixty (28.7%) and 37 (17.6%) patients in EAC and RAC group, respectively, refused endoscopy and underwent a (13)C-urea breath test to determine the treatment effect. CONCLUSION: In conclusion, rabeprazole- and esomeprazole-based primary therapies for H. pylori infection are comparable in efficacy and safety.     

Conformational spaces of the gastrointestinal antisecretory chiral drug omeprazole: stereochemistry and tautomerism

A study of the conformational spaces of the chiral proton pump inhibitor (PPI) drug omeprazole by semiempirical, ab-initio, and DFT methods is described. In addition to the chiral center at the sulfinyl sulfur atom, the chiral axis at the pyridine ring (due to the hindered rotation of the 4-methoxy substituents) was considered. The results were analyzed in terms of the 5-methoxy and 6-methoxy tautomers and the two pairs of enantiomers (R,P)/(S,M) and (R,M)/(S,P). Five torsion angles were systematically explored: the backbone rotations defined by D1 (N3-C2-S10-O11), D2 (C2-S10-C12-C13), and D3 (S10-C12-C13-N14) and two methoxy rotations defined by D4 (C6-C5-O8-C9) and D5 (C16-C17-O19-C20). Significant energy differences were revealed between the 5- and 6-methoxy tautomers, the extended and folded conformations, and the (S,M) and (S,P) diastereomers. The "extended M" conformation of the 6-methoxy tautomer of (S)-omeprazole was found to be the most stable conformer.     

四联疗法治疗幽门螺杆菌阳性胃溃疡的疗效观察

目的：观察埃索美拉唑联合瑞巴派特、阿莫西林、克拉霉素治疗幽门螺杆菌阳性胃溃疡临床疗效。方法：60例确诊的Hp阳性胃溃疡患者随机分为对照组（30例）和治疗组（30例）,其中对照组患者给予奥美拉唑＋阿莫西林＋克拉霉素三联法治疗,实验组给予埃索美拉唑＋瑞巴派特＋阿莫西林＋克拉霉素四联法治疗。观察比较两组患者临床症状缓解情况,溃疡愈合率、Hp根除率及溃疡复发率。结果：①经过治疗,所有患者腹痛、腹胀、反酸、暧气等临床症状积分均显著降低（P〈0.01）,且治疗组下降程度大于对照组,两组间差异有统计学意义（P〈0.05）。②治疗组患者痊愈率为60.00%、总有效率为93.33%,明显高于对照组痊愈率（43.33%）和总有效率（80.00%）,两组间差异有统计学意义（P〈0.05）。③治疗组S2期获得率、溃疡愈合率和Hp根除率分别为93.33%、96.67%和93.33%,显著高于对照组60.00%的S2期获得率、70.00%的愈合率和83.33%的根除率（P〈0.01或0.05）。④随访1年后,治疗组患者溃疡复发率为11.54%,与对照组32.00%的复发率比较差异有显著性（P〈0.05）。结论：四联疗法治疗幽门螺杆菌阳性胃溃疡可有效缓解患者临床症状,提高溃疡愈合质量,根除Hp感染,减少复发,效果优于三联疗法。     

四联疗法治疗幽门螺杆菌阳性胃溃疡的疗效观察

目的:观察埃索美拉唑联合瑞巴派特、阿莫西林、克拉霉素治疗幽门螺杆菌阳性胃溃疡临床疗效。方法:60例确诊的Hp阳性胃溃疡患者随机分为对照组(30例)和治疗组(30例),其中对照组患者给予奥美拉唑+阿莫西林+克拉霉素三联法治疗,实验组给予埃索美拉唑+瑞巴派特+阿莫西林+克拉霉素四联法治疗。观察比较两组患者临床症状缓解情况,溃疡愈合率、Hp根除率及溃疡复发率。结果:①经过治疗,所有患者腹痛、腹胀、反酸、暧气等临床症状积分均显著降低(P<0.01),且治疗组下降程度大于对照组,两组间差异有统计学意义(P<0.05)。②治疗组患者痊愈率为60.00%、总有效率为93.33%,明显高于对照组痊愈率(43.33%)和总有效率(80.00%),两组间差异有统计学意义(P<0.05)。③治疗组S2期获得率、溃疡愈合率和Hp根除率分别为93.33%、96.67%和93.33%,显著高于对照组60.00%的S2期获得率、70.00%的愈合率和83.33%的根除率(P<0.01或0.05)。④随访1年后,治疗组患者溃疡复发率为11.54%,与对照组32.00%的复发率比较差异有显著性(P<0.05)。结论:四联疗法治疗幽门螺杆菌阳性胃溃疡可有效缓解患者临床症状,提高溃疡愈合质量,根除Hp感染,减少复发,效果优于三联疗法。     

One-week once-daily triple therapy with esomeprazole, moxifloxacin, and rifabutin for eradication of persistent Helicobacter pylori resistant to both metronidazole and clarithromycin

Aim: To investigate a 1‐week once‐daily triple therapy with esomeprazole, moxifloxacin, and rifabutin for rescue therapy of Helicobacter pylori infection. Methods: Consecutive patients (n = 103) with at least one previous treatment failure and H. pylori infection resistant to both metronidazole and clarithromycin were treated with esomeprazole 40 mg, moxifloxacin 400 mg, and rifabutin 300 mg, given once daily for 7 days. Eradication was confirmed by histology and culture. CYP2C19 status was determined by polymerase chain reaction‐restriction fragment length polymorphism. Results: Intention‐to‐treat and per‐protocol eradication rates were 77.7% (68.4–85.3) and 83.3% (74.4–90.2). Five patients discontinued prematurely (4.8%). Eradication was achieved in 93.1% of poor/intermediate metabolizers and in 78.8% of homozygous extensive metabolizers (p = .14). Eradication rates in patients with one, two, three, and four or more previous failures were 78.3%, 89.6%, 68.6%, and 88.9%, respectively (p = .21). The regimen was effective in seven of nine patients who previously failed quadruple therapy. Post‐treatment resistance to moxifloxacin and rifabutin was detected in two (12.5%) and five (31%) patients after treatment failure. Conclusion: Once‐daily triple therapy with esomeprazole, moxifloxacin, and rifabutin is a promising, safe, and convenient regimen for rescue therapy of H. pylori infection that may serve as a valuable alternative to quadruple therapy, particularly for patients with intolerance to amoxicillin.     

Use of (S)‐BINOL as NMR chiral solvating agent for the enantiodiscrimination of omeprazole and its analogs

The application of (S)‐1,1′‐binaphthyl‐2,2′‐diol as NMR chiral solvating agent (CSA) for omeprazole, and three of its analogs (lanso‐, panto‐, and rabe‐prazole) was investigated. The formation of diastereomeric host–guest complexes in solution between the CSA and the racemic substrates produced sufficient NMR signal splitting for the determination of enantiomeric excesses by ¹H‐ or ¹⁹F‐NMR spectroscopy. Using of hydrophobic deuterated solvents was mandatory for obtaining good enantiodiscrimination, thus suggesting the importance of intermolecular hydrogen bonds in the stabilization of the complexes. The method was applied to the fast quantification of the enantiomeric purity of in‐process samples of S‐omeprazole. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Enhanced spectrofluorimetric determination of esomeprazole and pantoprazole in dosage forms and spiked human plasma using organized media

A simple, sensitive and rapid spectrofluorimetric method was developed for the determination of esomeprazole (EMZ) and pantoprazole (PRZ) in their pharmaceutical formulations and human plasma. The proposed method is based on the fluorescence spectral behavior of EMZ in methanol in the presence of 0.1 m NaOH containing 0.5% methyl cellulose (MC) at 306/345 nm. The fluorescence intensity of EMZ was enhanced about 1.3‐fold and good linearity in the range 0.4–4.0 µg/mL with a lower detection limit of 0.04 µg/mL and lower quantification limit of 0.14 µg/mL. For PRZ, its methanolic solution exhibited marked native fluorescence at 290/325 nm after enhancement (about 2.1‐ or 1.4‐fold) using either 0.025% sodium dodecyl sulfate (SDS) or 0.05% MC in the presence of 0.2 m borate buffer of pH 9.5. The fluorescence–concentration plots of PRZ were rectilinear over the ranges 0.2–2.0 and 0.3–3.0 µg/mL with lower detection limits of 0.02 and 0.03 µg/mL and lower quantification limits of 0.07 and 0.09 µg/mL using sodium dodecyl sulfate and MC, respectively. The method was successfully applied to the analysis of EMZ and PRZ in their commercial dosage forms and the results were in good agreement with those obtained with the comparison method. Furthermore, in a preliminary investigation, the proposed method was extended to the in vitro determination of the two drugs in spiked human plasma and the results were satisfactory. Copyright © 2014 John Wiley & Sons, Ltd.     

Extracellular acidity strengthens mesenchymal stem cells to promote melanoma progression

Mesenchymal stem cells (MSC) participate to tumor stroma development and several evidence suggests that they play a role in facilitating cancer progression. Because melanoma often shows extracellular pH low enough to influence host cell as tumor cell behavior, the aim of this study is to elucidate whether acidity affects cross talk between MSC and melanoma cells to disclose new liaisons promoting melanoma progression, and to offer new therapeutic opportunities. We found that MSC grown in a low pH medium (LpH-MSC) stimulate melanoma xenografts more than MSC grown in a standard pH medium. LpH-MSC express a higher level of TGFβ that is instrumental of epithelial-to-mesenchymal transition (EMT)-like phenotype induction in melanoma cells. LpH-MSC profile also shows a switching to an oxidative phosphorylation metabolism that was accompanied by a forced glycolytic pathway of melanoma cells grown in LpH-MSC-conditioned medium. Metformin, an inhibitor of mitochondrial respiratory chain was able to reconvert oxidative metabolism and abrogate TGFβ expression in LpH-MSC. In addition, esomeprazole, a proton pump inhibitor activated in acidosis, blocked TGFβ expression in LpH-MSC through the downregulation of IkB. Both agents, metformin and esomeprazole, inhibited EMT profile in melanoma cells grown in LpH-MSC medium, and reduced glycolytic markers. Thus, acidosis of tumor microenvironment potentiates the pro-tumoral activity of MSC and orchestrates for a new potential symbiosis, which could be target to limit melanoma progression.     

Spectroscopic and molecular modeling approaches to investigate the binding of proton pump inhibitors to human serum albumin

The interaction between two proton pump inhibitors viz., omeprazole (OME) and esomeprazole (EPZ) with human serum albumin (HSA) was studied by fluorescence, absorption, circular dichroism (CD), Fourier transform infrared spectroscopy (FT-IR), voltammetry, and molecular modeling approaches. The Stern–Volmer quenching constants (K_sv) for OME-HSA and EPZ-HSA systems obtained at different temperatures revealed that both OME and EPZ quenched the intensity of HSA through dynamic mode of quenching mechanism. The binding constants of OME-HSA and EPZ-HSA increased with temperature, indicating the increased stability of these systems at higher temperatures. Thermodynamic parameters viz., ?H^°, ?S^°, and ?G^° were determined for both systems. These values revealed that both systems were stabilized by hydrophobic forces. The competitive displacement and molecular docking studies suggested that OME/EPZ was bound to Sudlow’s site I in subdomain IIA in HSA. The extent of energy transfer from HSA to OME/EPZ and the distance of separation in tryptophan (Trp214) Trp214-OME and Trp214-EPZ was determined based on the theory of fluorescence resonance energy transfer. UV absorption, 3D fluorescence, and CD studies indicated that the binding of OME/EPZ to HSA has induced micro environmental changes around the protein which resulted changes in its secondary structure.