Proton Pump Inhibitor Rabeprazole Research Articles

The effect of rabeprazole on the secretory and motor function of the gastrointestinal tract

Parietal cell proton pump inhibitors (PPIs) have become firmly established in clinician practice. When discussing the features of their action, as a rule, researchers focus on their antisecretory effect. In the available literature, we found only a single report on the effect of PPIs on the motor-evacuation function of the gastrointestinal tract (GIT). We have found that the PPI rabeprazole not only has an antisecretory effect, but also normalizes the motor-evacuation function of all parts of the gastrointestinal tract. In this regard, it can be used in patients with gastric hypersecretion in functional gastrointestinal disorders (FGID) with impaired motor-evacuation function. Aim. To study the effect of the antisecretory drug rabeprazole on the state of gastrointestinal motility in patients suffering from FGID of the gastrointestinal tract and overlap syndrome (overlap syndrome) with functional dyspepsia (FD) with gastric hypersecretion and irritable bowel syndrome (IBS). Material and methods. We examined 30 patients suffering from FGID of the gastrointestinal tract and cross syndrome - FD with gastric hypersecretion and IBS. To relieve clinical symptoms of FD, the drug rabeprazole 20 mg was prescribed once a day for 14 days. Before and after the start of treatment, patients were examined with VAS and SF-36 tests, intragastric pH-metry and peripheral electrogastroenterocolography (EGECG) were performed. Results. In all 30 patients with FGID of the gastrointestinal tract with FD and overlap syndrome with IBS, gastric hypersecretion was eliminated within 3 hours after taking 20 mg of rabeprazole. 2 weeks after the start of treatment, abdominal pain and heartburn were completely eliminated in 28 (93.3%) patients. In all (100%) patients with FGID of the gastrointestinal tract with gastric hypersecretion and overlap syndrome, after two weeks of treatment, sour belching disappeared, and nausea disappeared in 23 (77%) patients. Rabeprazole therapy in the examined individuals was accompanied by a marked improvement in the quality of life in all assessed SF-36 parameters. 2 weeks after starting rabeprazole, in patients with FGID of the gastrointestinal tract and overlap syndrome of FD and IBS, the frequency of bowel movements and stool quality were normalized, and according to the results of EGECG, the relative myoelectric activity (P(i)/PS) of the gastrointestinal tract and the rhythmicity coefficient (Kritm) were normalized. Conclusion. Rabeprazole quickly neutralizes gastric secretion and helps eliminate symptoms of FD. It also has a beneficial effect on the motor-evacuation function of all parts of the gastrointestinal tract, normalizing the frequency of bowel movements, stool quality and myoelectric activity of all parts of the gastrointestinal tract according to EGECG. Rabeprazole can be used in patients with FGID with FD with gastric hypersecretion and overlap syndrome with IBS.

Examination of the Effect of Proton Pump Inhibitors on the Anticancer Activity of Oxaliplatin.

Oxaliplatin (L-OHP) is absorbed by cancer cells via organic cation transporter1-3 (OCT1-3). However, proton pump inhibitors (PPIs) suppress the function of OCT1-3. This study investigated whether PPIs attenuate the antitumor effect of L-OHP. Colorectal cancer patients who received FOLFOX (L-OHP + 5-fluorouracil: 5-FU) + bevacizumab therapy at Nagasaki University Hospital from October 1, 2010 to September 30, 2019 were retrospectively investigated. Patients were categorized into two groups with or without PPIs use. Progression-free survival (PFS) between the two groups was compared using the log-rank test. L-OHP was added to the intestinal epithelial Caco-2 cell line with or without the PPI rabeprazole, and then cell viability was analyzed using the WST-8 cell proliferation assay. The median PFS was 11.4 months in the group with PPIs and 9.7 months in the group without PPIs (p=0.736). No significant effect of 1-10 μM rabeprazole was observed on the antitumor effect of L-OHP. Plasma concentrations of rabeprazole at clinical doses are 1.0-1.3 μM. Even if L-OHP interacts with PPIs, clinical doses of PPIs were considered to have minimal effect on the antitumor effect of L-OHP.

Effectiveness of rebamipide in treatment of erosions in stomach mucosa

The aim. To evaluate the effectiveness of the drug Rebamipide-SZ when used in combination with proton pump inhibitors in the treatment of erosive changes in the gastric mucosa.Materials and methods. 40 patients were monitored who had erosive lesions of the stomach: 20 patients (group 1) with erosive gastritis not associated with Helicobacter pylori, 20 patients (group 2) with erosive changes in the gastric mucosa while taking nonsteroidal anti-inflammatory drugs (NSAIDs). Before the start of therapy and after the end of treatment, patients underwent a comprehensive examination: assessment of complaints according to the survey data, assessment of the severity of dyspepsia on the GIS scale, assessment of gastroenterological complaints on the GSRS scale, assessment of the effectiveness of treatment on the visual-analog scales of abdominal pain and general well-being, assessment of quality of life (questionnaire SF-36), upper gastro-intestinal endoscopy with biopsy (one biopsy from the stomach body, one biopsy from the antrum of the stomach) for verification of Helicobacter pylori infection (rapid urease test) and histological examination, assessment of side effects. All patients were prescribed therapy: Rebamipide-SZ one tablet three times a day after meals for a month and a proton pump inhibitor (rabeprazole) 20 mg two times a day for 15–30 minutes before meals for a month. Results. There was a complete relief of epigastric pain and a significant decrease or complete relief of dyspeptic complaints. When assessing the dynamics of endoscopic changes after usage of Rebamipide-SZ therapy, there was a regression of hyperemia of the gastric mucosa and complete epithelization of erosions in the stomach in almost all patients. Histological analysis of the gastric mucosa before and after treatment showed a decrease in the severity of acute and chronic inflammatory changes. There were no adverse events, no new complaints, no negative changes in clinical and biochemical blood tests during treatment. No allergic reactions were observed.Conclusion. The intake of Rebamipide-SZ is highly effective and safe for patients with various etiology erosive lesions of the gastric mucosa, including those caused by taking NSAIDs. Rebamipide-SZ can be recommended for course use in the complex therapy of patients with various pathologies of the upper gastrointestinal tract as a gastroprotective agent that helps restore the permeability of the gastric mucosa.

Treatment of gastroesophageal reflux disease with autonomic dystonia syndrome with combination of proton pump inhibitor Rabeprazole and neuroleptic sulpiride

According to the results of the study in the main group of patients who received complex treatment (IPP and neuroleptic), there was a significant positive dynamics of the main clinical manifestations, compared with the control group. All patients reported a significant decrease in the intensity of heartburn and pain.The use of probulin with vegetative-corrective action in the complex treatment of patients with GERD with vegetative dystonia syndrome allowed to more effectively stop the painful manifestations and reduce the emotional experience of bodily discomfort, improve the emotional state and mental health of patients, as well as improve their quality of life.

DNA unchained: two assays to discover and study inhibitors of the DNA clustering function of barrier-to-autointegration factor

The protein barrier-to-autointegration factor (BAF) and its interaction partners, the LEM (LAP2B, emerin, MAN1)-domain proteins, constitute a powerful cytoplasmic DNA defense mechanism. Invading DNA molecules are quickly bound by the BAF system and trapped in membrane compartments. This decreases the nuclear uptake of DNA from the cytoplasm. Inhibition of the BAF system is therefore expected to enhance the efficacy of non-viral DNA transfection agents. In this study, we introduced a protocol for the recombinant expression of soluble BAF and developed two ELISA-type assays to discover small molecule inhibitors of BAF-dependent DNA retention by high throughput screening (HTS). The proton pump inhibitor rabeprazole as well as three compounds of the Maybridge library were identified as inhibitors of the LEM-BAF-DNA interaction chain. The inhibition was based on adduct formation with BAF cysteine residues. An enhancing effect of the compounds on cell culture transfection, however, was not observed, which may be attributed to the reducing environment of the cytoplasm that prevents the adduct formation with BAF cysteine residues. The novel assays developed here can provide new tools to further study the biological functions of the BAF system, and may lead to the identification of suitable BAF inhibitors in future HTS campaigns.

Efficacy of <i>Helicobacter pylori</i> eradication followed by the administration of a proton pump inhibitor (PPI) or PPI plus a prokinetic in <i>H. pylori</i>-positive patients with dyspepsia

To investigate whether treatment comprised of Helicobacter pylori eradication followed by the administration of a proton pump inhibitor (PPI) alone and a dual treatment with a PPI plus a prokinetic agent helps relieve symptoms, we treated 26 patients with H. pylori infection and dyspepsia with the sequential treatment and assessed their symptoms. Scores for gastroesophageal reflux disease (GERD) and dyspepsia in a modified F-scale were significantly improved after the eradication of H. pylori, and symptoms were completely relieved in 13 patients. The remaining 13 patients received 4-week treatment with the PPI rabeprazole, and their GERD scores significantly improved after the treatment. The symptoms of five patients completely disappeared ; the other eight patients required dual treatment with a PPI plus the prokinetic acotiamide. Early satiety tended to be relieved after the dual treatment, but the improvement was not significant. Thus, in patients with dyspepsia and an H. pylori infection, the H. pylori should be eradicated first. The administration of a PPI is useful in patients with GERD symptoms, and a PPI+ acotiamide may be beneficial for residual symptoms of early satiety.

Comorbid patient with GERD and cardiovascular disease receiving antiplatelet therapy. The possibilities of choosing a proton pump inhibitor on a case study

The high prevalence of cardiovascular disease and its frequent pathogenetic relationship with various comorbid diseases and conditions lead to polypragmasia and the development of undesirable adverse reactions. Treatment premorbidly disorders requires high clinical expertise and breadth of knowledge in the field of related disciplines that allows you to efficiently prescribe the appropriate drug therapy. It is important to emphasize that a patient with cardiovascular disease often receives antiplatelet therapy, including double, which can lead to adverse reactions from the upper gastrointestinal tract (due to the peculiarities of the mechanism of action of antiplatelet drugs), including from the esophagus, provoking the development or deterioration of gastroesophageal reflux disease (GERD). Proton pump inhibitors (PPI) are used for the prevention and treatment of these adverse events on the part of the gastrointestinal tract. Effective drug therapy for GERD also includes the administration of these drugs. However. Given the polymorbidity of patients and polypragmasia, the practitioner should strive to prescribe drugs with the lowest risk of drug interactions. These requirements are met by PPI rabeprazole, the metabolism of which is predictable. The use of this drug is presented in a clinical case.

Клинические примеры к дорожной карте по ведению первичных пациентов с симптомами диспепсии

The aim. On clinical examples to demonstrate to the Therapist and General practitioner the possibility of using the road-map of management of primary patients with symptoms of dyspepsia at the stage of outpatient care. Fundamentals. Clinical cases of patients with established diagnoses of Functional dyspepsia; Dyspepsia associated with Helicobacter pylori infection; Nonerosive reflux disease; Gastroesophageal reflux disease of I degree with nocturnal acid breakthroughs in combination with functional dyspepsia are presented. The questions of substantiation of preliminary and final diagnoses, approaches of differential diagnosis of diseases using the road-map are considered in the comments. The main methods of diagnosis of diseases and disorders with symptoms of dyspepsia are presented and justified. It is shown that prior to obtaining the results of esophagogastroduodenoscopy, a preliminary diagnosis Uninvestigated Dyspepsia “K 31.9 Disease of stomach and duodenum, unspecified” should be made. After elimination of the organic cause of dyspepsia, treatment is carried out using proton pump inhibitors (omeprazole or rabeprazole 20 mg/day) in combination with a prokinetic (domperidone 30 mg/day). Rational use of a fixed combination of omeprazole 20 mg with modified release domperidone 30 mg / day (Omez®DSR). Conclusion. Compliance with the algorithm of management of primary patients with symptoms of dyspepsia in a wide clinical practice will avoid errors in the diagnosis, the appointment of unreasonable research, irrational treatment, which will improve the quality of life and prognosis of patients with dyspeptic disorders.

A review of medical therapy for proton pump inhibitor nonresponsive gastroesophageal reflux disease.

Up to 40% of patients report persistent gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy. This review outlines the evidence for medical therapy for PPI nonresponsive GERD. A literature search for GERD therapies from 2005 to 2015 in PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews identified 2928 unique citations. Of those, 40 unique articles specific to the impact of PPI metabolizer genotype on PPI response and the use adjunctive medical therapies were identified. Thirteen articles reported impacts on CYP genotypes on PPI metabolism demonstrating lower endoscopic healing rates in extensive metabolizers; however, outcomes across genotypes were more uniform with more CYP independent PPIs rabeprazole and esomeprazole. Twenty-seven publications on 11 adjunctive medications showed mixed results for adjunctive therapies including nocturnal histamine-2 receptor antagonists, promotility agents, transient lower esophageal sphincter relaxation inhibitors, and mucosal protective agents. Utilizing PPI metabolizer genotype or switching to a CYP2C19 independent PPI is a simple and conservative measure that may be useful in the setting of incomplete acid suppression. The use of adjunctive medications can be considered particularly when the physiologic mechanism for PPI nonresponse is suspected. Future studies using adjunctive medications with improved study design and patient enrollment are needed to better delineate medical management options before proceeding to antireflux interventions.

The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib‐induced small bowel injury

Simultaneous use of proton pump inhibitors (PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injury. To investigate whether polymorphisms of the cytochrome P450 2C19 gene (CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. Study participants included 55 healthy Japanese volunteers, who participated in the PPI-NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole.

Meal Effects Confound Attempts to Counteract Rabeprazole-Induced Hypochlorhydria Decreases in Atazanavir Absorption.

Clinically relevant pharmacokinetic interactions exist between gastric acid-reducing agents and certain weakly basic drugs that rely on acidic environments for optimal oral absorption. In this study, we examine whether the administration of betaine hydrochloride under fed conditions can enhance the absorption of atazanavir, an HIV-1 protease inhibitor, during pharmacologically-induced hypochlorhydria. In this randomized, single-dose, 3 period, crossover study healthy volunteers received ritonavir-boosted atazanavir (atazanavir/ritonavir 300/100mg) alone, following pretreatment with the proton pump inhibitor rabeprazole (20mg twice daily), and with 1500mg of betaine HCl after rabeprazole pretreatment. Atazanavir was administered with a light meal and gastric pH was monitored using the Heidelberg Capsule. Pretreatment with rabeprazole resulted in significant reductions in atazanavir Cmax (p < 0.01) and AUC0-last (p < 0.001) (71 and 70%, respectively), and modest decreases in ritonavir Cmax and AUClast (p < 0.01) (40% and 41%, respectively). The addition of betaine HCl restored 13% of ATV Cmax and 12% of AUClast lost due to rabeprazole. The co-administration of rabeprazole with atazanavir resulted in significant decreases in atazanavir exposure. The addition of betaine HCl did not sufficiently mitigate the loss of ATV exposure observed during RAB-induced hypochlorhydria. Meal effects lead to a marked difference in the outcome of betaine HCl on atazanavir exposure than we previously reported for dasatanib under fasting conditions.

Effects of rabeprazole on bone metabolic disorders in a gastrectomized rat model.

Proton pump inhibitors (PPIs) are frequently prescribed to patients with gastroesophageal reflux disease; however, the number of bone fractures reportedly increased in these patients. Although PPIs have been shown to inhibit the bone resorption by osteoclasts, the effect of PPIs on skeletal metabolism remains controversial. The aim of the present study was to determine the effect of the PPI rabeprazole on skeletal metabolism using gastrectomized rats. Male Wistar rats were divided into four groups: i) Sham-surgery (n=15); ii) total gastrectomy (TG) control (n=20); iii) TG plus rabeprazole (n=20); and iv) TG plus the bisphosphonate minodronic acid (n=20). Twenty-two weeks after TG, the rats were sacrificed, and bone mineral density (BMD), bone strength and markers for bone metabolism were measured. Compared with the control group (50.0±8.1%), the TG-induced decrease in BMD was significantly ameliorated in the rabeprazole group (56.5±7.5%) and the minodronic acid group (59.0±6.0%). However, rabeprazole did not improve bone strength. In conclusion, rabeprazole does not appear to exacerbate bone metabolic disorders in gastrectomized rats, but rather ameliorates the TG-induced BMD decrease.

Proton Pump Inhibitors Increase Incidence of Nonsteroidal Anti-Inflammatory Drug-Induced Small Bowel Injury: ARandomized, Placebo-Controlled Trial.

Some studies have reported a high incidence of small bowel injuries in 60%-80% of subjects who take nonselective nonsteroidal anti-inflammatory drugs and PPIs simultaneously. We performed a randomized, double-blind, controlled study to determine whether proton pump inhibitors (PPIs) exacerbate nonsteroidal anti-inflammatory drug-induced small bowel injury. Fifty-seven healthy subjects were randomly assigned groups given the cyclooxygenase (COX) 2inhibitor celecoxib (200 mg, twice daily) plus placebo for 2 weeks (COX-2+ placebo group, n= 30), or celecoxib plus the PPI rabeprazole (20 mg, once daily) for 2 weeks (COX-2+ PPI group, n= 27). The study was performed from October 2012 through September 2013 at a tertiary medical center in Japan. All subjects were evaluated by capsule endoscopy at the start of the study and then after 2 weeks administration of celecoxib with rabeprazole or placebo. The incidence rates and the numbers of small bowel injuries (ulcers and erosions) that were observed under capsule endoscopy were compared between groups. The primary endpoint was the incidence of mucosal injuries at the second capsule endoscopy examination. A significantly higher proportion of subjects in the COX-2+ PPI group developed small bowel injury (12 of 27 subjects; 44.4%) than in the COX-2+ placebo group (5 of 30 subjects; 16.7%; P= .04). Subjects in the COX-2+ PPI group had a significant increase in risk of small bowel injury compared with the COX-2+ placebo group (relative risk, 2.67; 95% confidence interval, 1.08-6.58). The number of erosions in each member of the COX-2+ PPI group was greater thanin each member of the COX-2+ placebo group (P= .02). The number of ulcers did not differ between groups. Twenty-six percent of subjects in the COX-2+ PPI group developed mucosal injury in the jejunum, compared with none of the subjects in the COX-2+ placebo group (P= .003); no such trend was found in the ileum. In a randomized, controlled trial, PPIs increased the risk of short-term nonsteroidal anti-inflammatory drug-induced small bowel injury. UMIN clinical trial registry number: UMIN000008883.

Characterization of 8-Deuterium Substituted Proton Pump Inhibitors by Nuclear Magnetic Resonance and Electrospray Ionization Mass Spectrometry

Nuclear magnetic resonance (NMR) was employed to characterize the hydrogen-deuterium exchange for the proton pump inhibitors pantoprazole sodium, esomeprazole sodium, rabeprazole sodium, lansoprazole, and ilaprazole in methanol-d4. The results showed that the 1H and 13C signals of 8-CH2 (labeled as H8a, H8b, and C8) next to the sulfinyl (S˭O) group of the proton pump inhibitors decreased significantly. Electrospray ionization mass spectrometry showed the presence of deuterated products. Basing on the NMR data, H8a and H8b of proton pump inhibitors were more active for the hydrogen-deuterium exchange. The most significant parameter governing the exchange was the salt-formation of the benzimidazole group. Therefore, the influence of salt-formation on hydrogen-deuterium exchange was characterized for ilaprazole; replacement of NH by N–Na on the benzimidazole group accelerated the exchange process. Tandem mass spectrometry showed that CH˭S–OH was formed by tautomerism involving sulfinyl and CH2 groups in methanol-d4.

Development and validation of HPLC-DAD method for the simultaneous determination of amoxicillin, metronidazole and rabeprazole sodium. Application to spiked simulated intestinal fluid samples

This work deals with the development, validation and application of an HPLC-DAD method for the determination of a ternary mixture containing amoxicillin (AX), metronidazole (MZ) and the proton pump inhibitor rabeprazole sodium (RB). This triple therapy is used for treatment of Helicobacter pylori infection. Effective chromatographic separation between the three drugs was achieved using Thermo Hypersil BDS-C8 (4.6×250mm, 5μm particle size) column and a mobile phase composed of phosphate buffer pH 7 and acetonitrile (70: 30, by volume). The mobile phase was pumped isocratically at a flow rate of 1mL/min. Quantification of the analytes was based on measuring their peak areas at 230nm for both AX and RB, and at 319nm for MZ. AX, MZ and RB eluted at retention times 2.36, 3.55 and 8.72min respectively. The reliability and analytical performance of the proposed HPLC procedure were statistically validated with respect to linearity, ranges, precision, accuracy, selectivity, robustness, detection and quantification limits. The linear dynamic ranges were 25-250, 25-250 and 5-50μg/mL for AX, MZ and RB respectively with correlation coefficients>0.9998. The validated method was successfully applied to the analysis of several laboratory-prepared mixtures as well as simulated intestinal fluid samples spiked with the three drugs.

Clinical efficacy observation on BanxiaxiexinTang combined with rabeprazole in treatment of peptic ulcer

Objective To explore the clinical efficacy of traditional Chinese medicine preparation BanxiaxiexinTang combined with proton pump inhibitor rabeprazole for the treatment of peptic ulcer.Methods In our hospital from January 2010 to May 2013 78 cases of peptic ulcer patients treated taking treatment modality contrast,were randomly divided into two groups,one treatment group of BanxiaxiexinTang combined with drug rabeprazole combination therapy,the control group used the drug treatment alone,rabeprazole-based,two groups were compared the efficacy and incidence of adverse reactions.Results The cure rates of treatment and control groups were 87.18％ and 76.92％,total effective rates were 94.87％ and 87.18％ respectively,showing statistically significant difference (P ＜ 0.05).The adverse reaction rate of treatment group (2.56％) was much lower than that of control group (7.69％).Conclusion BanxiaxiexinTang combined with rabeprazole has more precise treatment for peptic ulcer,with lower incidence probability of adverse reaction. Key words: Rabeprazole; BanxiaxiexinTang; Peptic ulcer; Combination therapy

Impact of Food and the Proton Pump Inhibitor Rabeprazole on the Pharmacokinetics of GDC-0941 in Healthy Volunteers: Bench to Bedside Investigation of pH-Dependent Solubility

GDC-0941 is an orally administered potent, selective pan-inhibitor of phosphatidylinositol 3-kinases (PI3Ks) with good preclinical antitumor activity in xenograft models and favorable pharmacokinetics and tolerability in phase 1 trials, and it is currently being investigated in phase II clinical trials as an anti-cancer agent. In vitro solubility and dissolution studies suggested that GDC-0941, a weak base, displays significant pH-dependent solubility. Moreover, preclinical studies conducted in famotidine-induced hypochlorhydric dog suggested that the pharmacokinetics of GDC-0941 may be sensitive to pharmacologically induced hypochlorhydria. To investigate the clinical significance of food and pH-dependent solubility on GDC-0941 pharmacokinetics a four-period, two-sequence, open-label, randomized, crossover study was conducted in healthy volunteers. During the fasting state, GDC-0941 was rapidly absorbed with a median Tmax of 2 h. The presence of a high-fat meal delayed the absorption of GDC-0941, with a median Tmax of 4 h and a modest increase in AUC relative to the fasted state, with an estimated geometric mean ratio (GMR, 90% CI) of fed/fasted of 1.28 (1.08, 1.51) for AUC0-∞ and 0.87 (0.70, 1.06) for Cmax. The effect of rabeprazole (model PPI) coadministration on the pharmacokinetics of GDC-0941 was evaluated in the fasted and fed state. When comparing the effect of rabeprazole + GDC-0941 (fasted) to baseline GDC-0941 absorption in a fasted state, GDC-0941 median Tmax was unchanged, however, both Cmax and AUC0-∞ decreased significantly after pretreatment with rabeprazole, with an estimated GMR (90% CI) of 0.31 (0.21, 0.46) and 0.46 (0.35, 0.61), respectively for both parameters. When rabeprazole was administered in the presence of the high-fat meal, the impact of food did not fully reverse the pH effect; the overall effect of rabeprazole on AUC0-∞ was somewhat attenuated by the high-fat meal (estimate GMR of 0.57, with 90% CI, 0.50, 0.65) but unchanged for the Cmax (estimate of 0.43, with 90% CI, 0.37, 0.50). The results of the current investigations emphasize the complex nature of physicochemical interactions and the importance of gastric acid for the dissolution and solubilization processes of GDC-0941. Given these findings, dosing of GDC-0941 in clinical trials was not constrained relative to fasted/fed states, but the concomitant use of ARAs was restricted. Mitigation strategies to limit the influence of pH on exposure of molecularly targeted agents such as GDC-0941 with pH-dependent solubility are discussed.

The association of insomnia with gastroesophageal reflux symptoms in biopsy-proven nonalcoholic fatty liver disease

It is suggested that nonalcoholic fatty liver disease (NAFLD), including nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH), can be associated with insomnia and gastro-esophageal reflux disease (GERD). The relationship between GERD and insomnia in subjects with biopsy-proven NAFLD was investigated. This study enrolled 123 patients with biopsy-proven NAFLD. Insomnia was assessed by the Athens Insomnia Scale (AIS), a self-assessment psychometric instrument designed to quantify sleep difficulty based on ICD-10 criteria; AIS scores ≥ 6 were considered positive for insomnia. GERD symptoms were evaluated using a frequency scale for the symptoms of GERD (FSSG); FSSG scores ≥ 8 were considered positive. Logistic regression models were used to evaluate the association of insomnia with GERD, after adjusting for potential confounders. Thirteen patients with GERD were treated with the proton pump inhibitor rabeprazole (RPZ; 10 mg/day), for 12 weeks. Of the 123 patients, 76 (62%) were female and 87 (71%) were obese, with 34 (28%) having AIS scores ≥ 6 and 31 (25%) having FSSG scores ≥ 8. Liver biopsy revealed that 40 patients (33%) had NAFL and 83 (67%) had NASH. FSSG and AIS scores were similar in the two groups. HOMA-IR, FSSG scores and γGT (GGT) concentrations were significantly higher in insomniacs than in non-insomniacs. Logistic regression analysis demonstrated that FSSG score and GGT concentration were independently associated with insomnia. RPZ treatment resulted in significantly reductions in both AIS and FSSG scores. Nearly 30% of patients with biopsy-proven NAFLD had insomnia, which was related to GGT and GERD and could be relieved by RPZ treatment.

Sa1903 Efficacy of Clarithromycin-Susceptibility Based Tailored Helicobacter pylori Eradication Treatment Maintaining Acid Secretion for a Full 24 Hours

Background: Over the years, the eradication rate of Helicobacter pylori during treatment has gradually decreased for two reasons: increased prevalence of clarithromycin (CAM)-resistant strains and acid inhibition during treatment, as insufficient acid inhibition during treatment makes antimicrobial agents unstable and leads to their degradation in stomach. During treatment, when respective percent time of pH , 4.0 and 24-h pH values of , 10% and . 6.0 were attained, most cases of infection were able to be resolved, irrespective of bacterial susceptibility. However, the optimum regimen of proton pump inhibitors (PPIs) is unknown at present. We therefore assessed acid inhibitory effects of multiple PPI dosing methods with respect to CYP2C19 genotype status and efficacy of CAM-susceptibility-based H. pylori eradication efforts by maintaining acid secretion for a full 24 h. Methods: [Study 1] Using pHmonitoring, we evaluated the efficacy of multiple dosing regimenswith the PPI rabeprazole (40 mg sid, 20 mg bid, and 10 mg qid). [Study 2] A total of 200 H. pylori-positive patients were randomly assigned to the standard regimen group (rabeprazole 10 mg bid, amoxicillin (AMPC) 750 mg bid and CAM 400 mg bid for 1 week) or the tailored regimen group based on bacterial susceptibility to CAM. Patients infected with CAM-sensitive H. pylori were treated with rabeprazole 10 mg qid, AMPC 500 mg qid and CAM 400 mg bid for 1 week, and patients infected with CAM-resistant H. pylori were treated with rabeprazole 10 mg qid, AMPC 500 mg qid, and metronidazole (MNZ) 250 mg bid for 1 week. Results: [Study 1] Respective median 24-h pH values for rabeprazole 40 mg sid, 20 mg bid, and 10 mg qid were 4.8 (3.6-6.4), 5.7 (4.1-7.4), and 6.6 (4.9-8.4). Increasing the dosing times effectively increased pH throughout a 24-h period. In CYP2C19 poor metabolizers, acid inhibition by a PPI was enhanced in comparison with that in CYP2C19 intermediate or rapid metabolizers. Further, rabeprazole 10 mg qid maintained pH . 4 for 24 h in rapid metabolizers. [Study 2] The intention-to-treat eradication rate in tailored regimen group was 96.0% (95% confidence interval [CI]: 90.1%-98.9%, 96/100), which was significantly higher than that in the standard regimen group (70.0%, 95% CI: 60.0%-78.8%, 70/100) (P , 0.001). In the tailored regimen group, the eradication rate in the PPI/AMPC/CAM regimen was 93.2% (95% CI: 83.5%98.1%, 55/59), and that in the PPI/AMPC/MNZ regimen was 100% (95% CI: 93.0%-100%, 41/41). Discussion: Four-times daily dosing of rabeprazole 10 mg achieved potent acid inhibition, including at night, in CYP2C19 rapid metabolizers, suggesting its potential usefulness in patients refractory to PPI therapeutic regimens. Using this PPI qid treatment for all patients made CAM-susceptibility-based H. pylori eradication treatment effective, with an eradication rate exceeding 95%.

What is the Best Regimen forHelicobacter pyloriEradication in Canadian Arctic Aboriginals?

Canadian Aboriginal populations have a high prevalence of Helicobacter pylori infection and an increased risk for the development of gastric cancer (1). Thus, there is a need to identify effective H pylori eradication regimens in this at-risk population. In the current issue of the Journal, Morse et al (2) (pages 701–706) report results from a randomized controlled trial comparing sequential versus standard clarithromycin-containing triple therapy in H pylori-infected adults from the community of Aklavik (Northwest Territories) (2). The study was part of a participatory research project focusing on community-identified research goals investigating the burden of H pylori disease in Arctic Aboriginal communities. In the study by Morse et al (2), H pylori-infected patients >15 years of age were randomly assigned to either a 10-day treatment of standard triple therapy consisting of a proton pump inhibitor (rabeprazole), amoxillicin and clarithromycin, or sequential therapy. Antibiotic resistance rates to clarithromycin and metronidazole were available for almost one-half of the subjects, allowing tailored treatment. If clarithromycin resistance was detected, patients were randomly assigned to sequential therapy or quadruple therapy. Several important points are noteworthy in this study. First, as identified in other Canadian Aboriginal populations, the prevalence of H pylori infection remains high in this community despite a diminishing H pylori prevalence in most segments of the Canadian population. Second, the prevalence of precancerous lesions, gastric atrophy and intestinal metaplasia were high, supporting the increased risk for development of gastric cancer in this population and underscoring the need for effective H pylori eradication regimens. When outcomes were assessed by the more stringent intention-to-treat analysis, the effectiveness of both therapies was disappointing, with only 55% efficacy with triple therapy and 57% with sequential therapy. With these poor outcomes, it is important to consider why the results were suboptimal. The success of treatment for H pylori is determined, in large part, by the presence of antibiotic resistance and patient adherence (3). In the study by Morse et al (2), of the 50 subjects who underwent sensitivity testing, the rates of clarithromycin and metronidazole resistance were 10% and 26%, respectively. Thus, it is likely that similar resistance rates were present in the remaining subjects who were randomly assigned to triple versus sequential therapy. The updated Maastricht guidelines (4) do not recommend clarithromycin therapy if the local clarithromycin resistance rate is >15%. Thus, one potential explanation for the poor efficacy is antibiotic resistance. Poor adherence to therapy is an additional important determinant of efficacy (3). In the study by Morse et al, the overall adherence levels were suboptimal (60%). In fact, even in the group who underwent antibiotic sensitivity-directed therapy, the eradication rates were still low. However, in subjects with 100% compliance, treatment effectiveness increased in both the triple therapy and sequential therapy groups to 65% and 75%, respectively. Thus, the combination of antibiotic resistance and decreased adherence likely account for the poor efficacy of both triple therapy and sequential therapy. Although sequential therapy was initially regarded as superior to triple therapy, follow-up studies indicate that the efficacy of sequential therapy is not as good as the original studies suggested. Sequential therapy loses efficacy in the presence of clarithromycin and metronidaz-ole resistance (3). In the study by Morse et al, even when assessed by per-protocol analyses, efficacy of sequential therapy was well below the recommended cure rates of 80% to 90%, suggesting that this regimen is not an optimal choice in this particular community unless adherence can be improved. Morse et al should be commended for providing key information concerning H pylori infection in a Canadian Aboriginal Arctic community. This study shows that, in this at-risk population, the efficacies of two currently recommended eradication regimens are suboptimal, likely due to both antibiotic resistance and poor compliance. These findings support further studies aimed at identifying effective therapies by focusing on both optimized regimens based on known antibiotic susceptibility rates in the community and promoting adherence.