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J Am Soc Mass Spectrom. 2008 Feb 7;
Van De Steene JC, Lambert WE
When developing an LC-MS/MS-method matrix effects are a major issue. The effect of co-eluting compounds arising from the matrix can result in signal enhancement or suppression. During method development much attention should be paid to diminishing matrix effects as much as possible.The present work evaluates matrix effects from aqueous environmental samples in the simultaneous analysis of a group of 9 specific pharmaceuticals with HPLC-ESI/MS/MS and UPLC-ESI/MS/MS: flubendazole, propiconazole, pipamperone, cinnarizine, ketoconazole, miconazole, rabeprazole, itraconazole and domperidone. When HPLC-MS/MS is used, matrix effects are substantial and can not be compensated for with analogue internal standards. For different surface water samples different matrix effects are found. For accurate quantification the standard addition approach is necessary. Due to the better resolution and more narrow peaks in UPLC, analytes will co-elute less with interferences during ionisation, so matrix effects could be lower, or even eliminated. If matrix effects are eliminated with this technique, the standard addition method for quantification can be omitted and the overall method will be simplified. Results show that matrix effects are almost eliminated if internal standards (structural analogues) are used. Instead of the time-consuming and labour-intensive standard addition method, with UPLC the internal standardization can be used for quantification and the overall method is substantially simplified.
Aliment Pharmacol Ther. 2008 Feb 27;
Sinn DH, Kim JH, Kim S, Son HJ, Kim JJ, Rhee JC, Rhee PL
Background Although the etiology of globus remains unclear, gastroesophageal reflux disease (GERD) is associated with globus. Short-term trial with high-dose proton pump inhibitor (PPI) has been shown to be a sensitive tool for diagnosing GERD. Aim To see whether patients with globus symptom responded to short-term high-dose rabeprazole trial and find out predictors of symptom response. Methods Sixty-four patients with globus symptom were analyzed. Patients received rabeprazole 20 mg bid for 14 days. Patients completed a daily diary assessing the severity and frequency of globus. Results Forty-one patients (64%) were diagnosed with GERD. Based on the pH testing and endoscopy, the prevalence of GERD was 22% (14 of 64). The globus symptom score was significantly higher in patients with GERD compared to patients without GERD (p = 0.004). Two patients (3.1%) had complete resolution and 22 (34.4%) had more than a 50% improvement in the globus symptom score. Endoscopic findings (p = 0.714), pathologic acid exposure on pH testing (p = 0.741), or baseline GERD symptoms (p = 0.606) were not associated with improvement of globus symptom. Conclusions While GERD may be an aggravating factor in patients with globus, it does not appear to be sole cause of globus symptom.
Gastrointest Endosc. 2008 Feb 28;
Wills JC, Hilden K, Disario JA, Fang JC
BACKGROUND: Lower esophageal (Schatzki's) rings are a common cause of solid food dysphagia. Standard treatment involves passage of a single large bougie to disrupt the ring, but symptoms recur in the majority of patients. Electrosurgical incision of the ring may provide a longer duration of symptom improvement. There are no data on the treatment of Schatzki's rings in the presence of acid suppression treatment. OBJECTIVE: Our purpose was to compare the efficacy of bougie dilation with electrosurgical incision of symptomatic Schatzki's rings at 1-year follow-up in the presence of rabeprazole treatment. DESIGN: Randomized, prospective trial. SETTING: University of Utah Health Sciences Center and the Veterans Affairs Salt Lake. PATIENTS: Fifty patients referred for endoscopic evaluation of dysphagia between January 2002 and March 2005. MAIN OUTCOME MEASUREMENTS: Symptom-free survival time (in months), dysphagia, and GERD scores. RESULTS: Twenty-five patients each underwent bougie dilation and electrical incision and were followed up for 12 months. Symptom-free survival times were significantly longer in the incision group (7.99 months) compared with the bougie dilation group (5.86 months) (P = .03). Dysphagia and GERD scores significantly improved in each group comparing baseline with each time interval. The incision group had greater relief of dysphagia at 1 month (P = .05) compared with the bougie group. There was no difference between GERD scores in both groups. LIMITATIONS: Dysphagia and GERD symptoms were self-reported. CONCLUSIONS: Electrosurgical incision of Schatzki's rings is safe and offers longer symptom-free survival compared with bougie dilation. The addition of rabeprazole offered significant improvement in GERD scores in both groups.
J Pharm Biomed Anal. 2007 Dec 23;
Belaz KR, Coimbra M, Barreiro JC, Montanari CA, Cass QB
The enantiomers of sulfoxide proton pump inhibitors - omeprazole, lansoprazole, rabeprazole and Ro 18-5364 - were enantiomerically separated by liquid chromatography at multimilligram scale on a polysaccharide-based chiral stationary phase using normal and polar organic conditions as mobile phase. The values of the recovery and production rate were significant for each enantiomer; better results were achieved using a solid-phase injection system. However, this system was applied just for the enantiomeric separation of omeprazole to demonstrate the applicability of this injection mode at milligram scale. The chiroptical characterization of the compounds was performed using a polarimeter and a circular dichroism detector. The higher enantiomeric purity obtained for the isolated enantiomers suggests that the methods here described should be considered as a simple and rapid way to obtain enantiomeric pure standards for analytical purpose.
Br J Clin Pharmacol. 2008 Jan 30;
Hunfeld NG, Mathot RA, Touw DJ, van Schaik RH, Mulder PG, Franck PF, Kuipers EJ, Geus WP
WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT * The influence of CYP2C19 on the kinetics and dynamics of omeprazole, lansoprazole and rabeprazole has been studied in Japanese subjects. * It has been suggested that subjects with *1/*1 genotype might need stronger acid suppression than *1/*2 and *2/*2 subjects. This suggestion comes from data in Japanese subjects and has not been confirmed in Caucasians. * Furthermore, a novel CYP2C19 mutation, *17, which mainly occurs in Caucasians has been discovered. This mutation has been associated with clinical failure, but its relevance for therapy with PPIs has not been studied yet. WHAT THIS STUDY ADDS * In this study, the influence of CYP2C19 on both the pharmacokinetics and dynamics in Caucasian subjects after single and repeated dosing has been investigated. * This is the first study showing that Caucasian subjects with *1/*1 and *1/*17 mutations need stronger acid-inhibition. In this study three proton pump inhibitors (omeprazole, lansoprazole and pantoprazole, in different doses) were studied of which pantoprazole had not been studied before in this setting, not even in Japanese. AIMS To investigate the impact of CYP2C19 mutations *2-*6 and *17 on acid-inhibition and pharmacokinetics of lansoprazole (L15), omeprazole (O10, O20) and pantoprazole (P40) in Caucasians. METHODS CYP2C19 genotyping for *2-*6 and *17 mutations was assessed in subjects who were H. pylori negative in two randomized crossover trials. The influence of CYP2C19 mutations on single and repeated administration of L15 and O10 (study A) and O20 and P40 (study B) was investigated. Pharmacokinetics and the cumulative percentage of time with intragastric pH above 4 (% > pH 4) were assessed on day 1 and 6. RESULTS For study A CYP2C19 genotyping found five *1/*1, four *1/*2, one *1/*17 and one *2/*17. For study B the results were six *1/*1, two *1/*2, six *1/*17, one *2/*2 and one *2/*17. For all PPIs AUC was highest in *2/*2 and lowest in *1/*17. On day 1, all PPIs significantly increased percentage >pH 4 compared with baseline. *1/*1 genotype showed no significant acid-inhibition after L15, O10 and O20. *1/*17 genotype showed no significant acid-inhibition after O20 and P40. *1/*2 genotype showed significant acid-inhibition after L15 and O10. On day 6, all four PPIs showed significantly increased acid-inhibition. *1/*1 and *1/*17 showed a significantly increased percentage > pH 4 after treatment with O20 and P40. However, in *1/*1 subjects percentage > pH 4 was not significantly increased after L15 and O10. *1/*2 genotype showed a significant acid-inhibitory effect after repeated dosing with L15 and O10. CONCLUSIONS Caucasian subjects with *1/*1 and *1/*17 genotype need stronger acid-suppression therapy, especially during the first days of treatment or with on-demand therapy.
J Chromatogr A. 2008 Feb 29; 1182(2): 153-60
Van De Steene JC, Lambert WE
This paper reports the development and validation of a quantitative LC-electrospray (ESI)-MS/MS method for the simultaneous analysis of nine basic pharmaceuticals (flubendazole, pipamperone, cinnarizine, ketoconazole, miconazole, rabeprazole, itraconazole, domperidone and propiconazole) in environmental waters. Sample preparation consisted of solid-phase extraction on a Speedisk phenyl and a NH(2) solid-phase extraction tube for sample clean-up. Chromatography was performed on a pentafluorophenyl column in a total run time of 24min. Due to different matrix effects measured in different surface water samples, standard addition was the only method to perform accurate quantification. Limits of detection and quantification were in the range of
Recent advances in chirally pure proton pump inhibitors.
J Indian Med Assoc. 2007 Aug; 105(8): 469-70, 472, 474
Pai V, Pai N
Chirality is a ubiquitous natural phenomenon resulting because of a differential spatial orientation of molecules around its chiral centre. This leads to the existence of two or more spatially dissimilar forms, known as stereoisomers or enantiomers, which are non-superimposable images of each other and may significantly differ from each other with respect to pharmacokinetic and pharmacodynamic properties and molecular interaction. Thus one isomer may offer significant pharmacokinetic and therapeutic advantages as compared to the other isomer or the racemic mixture (mixture containing both enantiomers). Proton pump inhibitors are a class of drugs which have been very effective in the management of acid-related disorders. The proton pumps currently available in the market including omeprazole, pantoprazole, rabeprazole and lansoprazole are racemic mixtures of the S and R isomers. Chirally pure forms of proton pump inhibitors show a superior metabolic and pharmacokinetic profile as compared to their racemates. The therapeutic efficacy is also superior to the parent racemate. This has been clearly demonstrated with the development of esomeprazole- the S-isomer of omeprazole. S-pantoprazole and dexrabeprazole also offer therapeutic advantages as compared to racemic pantoprazole and racemic rabeprazole respectively. This article reviews the chiral developments in the proton pump inhibitors and their clinical applications.
Ther Drug Monit. 2008 Feb; 30(1): 46-51
Miura M, Satoh S, Inoue K, Kagaya H, Saito M, Suzuki T, Habuchi T
Peptic ulcer disease is a common complication after organ transplantation, and long-term administration of antiulcer agents is needed in many renal transplant recipients. Although several drug interactions with mycophenolic acid (MPA), the active metabolite of the prodrug mycophenolate mofetil (MMF), have been reported, little is known about the interaction between MPA and proton pump inhibitors (PPIs). The present study investigated the drug interaction between MMF and lansoprazole or rabeprazole and the impact of cytochrome (CYP) 2C19, and multidrug resistance (MDR)1 C3435T polymorphisms on these drug interactions at 1 year after renal transplantation. Retrospectively, 61 recipients were divided into 3 groups: MMF and tacrolimus as combination immunosuppressive therapy, together with either 30 mg lansoprazole (n = 22) or 10 mg rabeprazole (n = 17), or without PPI (n = 22). One year after transplantation, plasma concentrations of MPA were measured by high-performance liquid chromatography. The mean dose-unadjusted and -adjusted Cmax of MPA with 30 mg lansoprazole were significantly lower than those without PPI (11.8 vs. 17.8 microg/mL, P = 0.0197, and 22.6 vs. 33.1 ng/mL/mg MMF, P = 0.0222, respectively). In recipients having the CYP2C19 *1/*2+*1/*3 or MDR1 C3435T CC genotype, the mean dose-adjusted AUC0-12 of MPA with 30 mg lansoprazole was significantly smaller than that with 10 mg rabeprazole or without PPI. The plasma concentration of MPA was influenced by 30 mg lansoprazole but not 10 mg rabeprazole. Because of the greater gastric acid secretion-inhibitory effect of 30 mg lansoprazole in recipients having the CYP2C19 *1/*2+*1/*3 (intermediate metabolizer) or MDR1 C3435T CC genotype, the elution and hydrolysis of MMF might be decreased. Although the clinical relevance might be minor, the fact that administration of 30 mg lansoprazole in patients having the CYP2C19 *2 or *3 allele or the MDR1 C3435T CC genotype diminishes the absorption of MPA in the maintenance stage after renal transplantation should be taken into consideration with regard to the MPA pharmacokinetics.
A Novel Rat Model to Determine Interaction between Reflux Esophagitis and Bronchial Asthma.
Gut. 2008 Jan 25;
Sugawa T, Fujiwara Y, Yamagami H, Watanabe K, Tanigawa T, Shiba M, Watanabe T, Tominaga K, Oshitani N, Higuchi K, Arakawa T
BACKGROUND: Several studies have shown a strong association between reflux esophagitis (RE) and bronchial asthma (BA). The precise mechanisms of interaction between RE and BA are uncertain, possibly due to lack of animal models. AIMS: We established a novel rat model and examined pathogenic interaction of RE and BA. METHODS: RE and BA were induced in Brown-Norway rats by ligating the transitional region between the forestomach and the glandular portion and wrapping the duodenum near the pylorus, and by ovalbumin (OVA) sensitization and challenge with OVA aerosol. Rats were divided into four groups: control, RE, BA, and RE+BA. OVA-induced airway inflammation was assessed by number of infiltrating cells and cytokine levels in bronchoalveolar lavage fluid (BALF). Esophageal lesion index, histology, and cytokine mRNA expression as determined by real-time RT-PCR were also examined. RESULTS: Significant increases in number of cells, especially eosinophils, and IL-13 but not IFN-gamma concentration in BALF were observed in the RE+BA group compared with the BA group. These enhancements of OVA-induced airway inflammation were prevented by treatment with rabeprazole. Although the esophagitis lesion index in the RE+BA group did not differ from that in the RE group, eosinophilic infiltration in the esophageal submucosa and levels of mRNA expression of cytokines such as IL-5, IL-10, IL-13, and RANTES were significantly increased. CONCLUSION: We established a novel rat model of RE and BA, and found significant interactions of the two diseases. This model thus appears to be useful for examining the association between gastroesophageal reflux disease and bronchial asthma.
J Chromatogr Sci. 2008 Jan; 46(1): 10-4
Patel BH, Suhagia BN, Patel MM, Patel JR
Simple, sensitive high-performance liquid chromatography (HPLC) and thin-layer chromatography (TLC) methods are developed for the quantitative estimation of rabeprazole and mosapride in their combined pharmaceutical dosage forms. In HPLC, rabeprazole and mosapride are chromatographed using 0.01M 6.5 pH ammonium acetate buffer-methanol-acetonitrile (40:20:40, v/v, pH 5.70+/-0.02) as the mobile phase at a flow rate of 1.0 mL/min. In TLC, the mobile phase is ethyl acetate-methanol-benzene (2:0.5:2.5, v/v). Both the drugs are scanned at 276 nm. The retention times of rabeprazole and mosapride are found to be 4.93+/-0.01 and 9.79+/-0.02, respectively. The Rf values of rabeprazole and mosapride are found to be 0.42+/-0.02 and 0.61+/-0.02, respectively. The linearities of rabeprazole and mosapride are in the range of 400-2000 ng/mL and 300-1500 ng/mL, respectively, for HPLC; in TLC, the linearities of rabeprazole and mosapride are in the range of 400-1200 ng/spot and 300-900 ng/spot, respectively. The limit of detection is found to be 97.7 ng/mL for rabeprazole and 97.6 ng/mL for mosapride in HPLC; in TLC the limit of detection is found to be 132.29 ng/spot for rabeprazole and 98.25 ng/spot for mosapride. The proposed methods can be applied to the determination of rabeprazole and mosapride in combined pharmaceutical products.