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Medical research on esomeprazole
Cell Tissue Res. 2008 Jul 1;
Bernsand M, Zhao CM, Håkanson R, Stenström B, Chen D, Norlén P
Histamine in the rat stomach resides in enterochromaffin-like (ECL) cells and mast cells. The ECL cells are peptide-hormone-producing endocrine cells known to release histamine and chromogranin-A-derived peptides (such as pancreastatin) in response to gastrin. Ischemia (induced by clamping of the celiac artery or by gastric submucosal microinfusion of the vasoconstrictor endothelin) mobilizes large amounts of ECL-cell histamine in a burst-like manner. This report examines the ECL-cell response to ischemia and compares it with that induced by gastrin in rats. Arterial clamping (30 min) and gastric submucosal microinfusion (3 h) of endothelin, vasopressin, or adrenaline caused ischemia, manifested as a raised lactate/pyruvate ratio and mucosal damage. Whereas microinfusion of gastrin released both histamine and pancreastatin, ischemia mobilized histamine only. The mucosal concentrations of histamine and pancreastatin, the number and immunostaining intensity of the ECL cells, and the ultrastructure of the ECL cells were unchanged following ischemia. The long-term effects of ischemia and reperfusion (60-90 min) on gastric mucosa were examined in rats treated with the proton pump inhibitor omeprazole for 4 days. The activity of the ECL cells was suppressed (reflected in low histamine-forming capacity) but returned to normal within 1 week, illustrating the ability of the ECL cells to recover. We suggest that ischemia mobilizes cytosolic ECL-cell histamine without affecting the storage of histamine (and pancreastatin) in the secretory organelles and without causing lasting ECL-cell impairment.
Eur J Clin Pharmacol. 2008 Jun 26;
Rocha A, Coelho EB, Moussa SA, Lanchote VL
OBJECTIVE: This study compares midazolam with omeprazole as marker drugs for the evaluation of CYP3A activity in nine healthy self-reported white Brazilian volunteers. METHODS: Omeprazole was also used to evaluate the CYP2C19 phenotype. The volunteers received p.o. 20 mg omeprazole, and blood samples were collected 3.5 h after drug administration. After a washout period of 10 days, the volunteers received p.o. 15 mg midazolam maleate, and serial blood samples were collected up to 6 h after administration of the drug. CYP2C19 was genotyped for the allelic variants CYP2C19*1, CYP2C19*2, CYP2C19*3, and CYP2C19*17. Analysis of omeprazole, hydroxyomeprazole, omeprazole sulfone, and midazolam in plasma was carried out by LC-MS/MS. RESULTS: The volunteers genotyped as CYP2C19*1*17, CYP2C19*17*17, CYP2C19*1*1 (n = 8), or CYP2C19*17*2 (n = 1) presented a median hydroxylation index (omeprazole/hydroxyomeprazole) of 1.35, indicating that all of them were extensive metabolizers of CYP2C19. The volunteers (n = 9) presented a 0.12 log of the omeprazole/sulfone ratio and a median oral clearance of midazolam of 17.89 ml min(-1) kg(-1), suggesting normal CYP3A activity. CONCLUSIONS: Orthogonal regression analysis between midazolam clearance and log of the plasma concentrations of the omeprazole/omeprazole sulfone ratio (R = -0.7544, P < 0.05) suggests that both midazolam and omeprazole can be used as markers of CYP3A activity in the population investigated.
J Chromatogr B Analyt Technol Biomed Life Sci. 2008 Jun 7;
Olsson J, Blomberg LG
The present paper demonstrates the enantiomeric separation of omeprazole and its metabolite 5-hydroxyomeprazole performed with open tubular capillary electrochromatography (OT-CEC). The protein avidin was used as the chiral selector. Avidin was immobilized by a Schiffs base type of reaction where the protein was via glutaraldehyde covalently bonded to the amino-modified wall of a fused-silica capillary, 50mum i.d. Both racemates were baseline resolved. Resolution was 1.9 and 2.3, respectively, using ammonium acetate buffer, pH 5.8, 5% methanol, with UV-detection. These values of resolution using OT-CEC are higher than earlier published results regarding chiral separation of omeprazole and 5-hydroxyomeprazole on packed CEC. The number of theoretical plates also indicated good separation efficiency.
Eur J Pharmacol. 2008 May 27;
Campbell CA, Gaskin PJ, Darton J, Chiu P, Lee K, McLean PG
Identification of novel drug molecules requires the extensive evaluation in vitro and in vivo. Following in vitro evaluation it is necessary to efficiently screen numerous novel molecules in vivo using relatively simple methodology that requires small numbers of animals, is rapid to perform, and provides results that can definitely discriminate potential candidates for further investigation. Herein, we describe the results of three standard compounds (omeprazole, a proton pump inhibitor; cimetidine, an histamine H(2) receptor antagonist; and AR-H047108, a potassium competitive acid blocker) in the rat aspiration model (under both basal and stimulated conditions), and compared the effects with those in the pyloric ligation model with a view to comparing the results in terms of sensitivity, robustness and simplicity of the methodology. In the aspiration model, drug or vehicle was administered orally 1 h prior to administration of pentagastrin or dimaprit. Ten minutes later 0.9% NaCl was administered orally and immediately recovered by aspiration. In the pyloric ligation model, drugs or vehicle were administered orally 2 h before ligation in a volume of 10 ml/kg. For each model, the volume of each sample was measured and the acidity was determined. In the aspiration model under basal acid secretion or following stimulation with pentagastrin omeprazole, cimetidine and AR-H047108 produced dose related inhibition of acidity. Omeprazole and cimetidine inhibited acid secretion following stimulation with dimaprit. In the pyloric ligation model omeprazole, cimetidine and AR-H047108 inhibited acid secretion. The profile of each of 3 inhibitors of acid secretion exhibited similar effects irrespective of the degree of stimulation (dimaprit, pentagastrin or pyloric ligation). Thus, based on these robust effects and ease of methodology we would recommend the use of the rat aspiration model with pentagastrin stimulation of gastric acid secretion as the primary in vivo methodology to screen novel inhibitors of acid secretion.
Adv Ther. 2008 Jun 23;
Atug O, Giral A, Kalayci C, Dolar E, Isitan F, Oguz D, Ovunc O, Ozgur O, Soykan I, Simsek I, Unal S, Yenice N
INTRODUCTION: THE AIM OF THIS STUDY WAS TO ASSESS THE EFFICACY AND SAFETY OF ESOMEPRAZOLE 40 MG ONCE DAILY (Q.D.) IN HEALING REFLUX OESOPHAGITIS AT 4 AND 8 WEEKS, AND THE EFFICACY OF ESOMEPRAZOLE 20 MG Q.D. FOR 12 WEEKS IN THE MAINTENANCE OF REMISSION: METHODS: A TOTAL OF 235 PATIENTS WITH ENDOSCOPICALLY PROVEN REFLUX OESOPHAGITIS WERE ENROLLED IN THIS STUDY, WHICH CONSISTED OF TWO PHASES (HEALING AND MAINTENANCE THERAPY). PATIENTS WHO SHOWED COMPLETE ENDOSCOPIC AND SYMPTOMATIC HEALING AT THE END OF 4 OR 8 WEEKS WERE SWITCHED TO MAINTENANCE TREATMENT WITH ESOMEPRAZOLE 20 MG Q.D. FOR 12 WEEKS. THE PRIMARY EFFICACY ENDPOINT WAS HEALING OF REFLUX OESOPHAGITIS AT WEEK 8. SECONDARY ASSESSMENTS INCLUDED THE PROPORTION OF PATIENTS WITH SYMPTOMATIC RELAPSE IN THE MAINTENANCE PHASE: RESULTS: AT THE END OF WEEK 8, 88% (95% LIFE-TABLE CONFIDENCE INTERVALS [CI]: 84%, 92%) OF PATIENTS WERE HEALED ENDOSCOPICALLY AND 90.6% OF THE PATIENTS WERE ASYMPTOMATIC. PATIENT AGE, GENDER AND HELICOBACTER PYLORI STATUS HAD NO EFFECT ON THE EFFICACY OF TREATMENT. DURING THE 12-WEEK MAINTENANCE TREATMENT PHASE, SYMPTOMATIC RELAPSE RATIOS WERE 0.5%, 2.2%, AND 0%, FOR THE FIRST, SECOND, AND THIRD 4-WEEK PERIODS, RESPECTIVELY. THE PROPORTIONS OF PATIENTS SATISFIED WITH TREATMENT WERE 95% AND 99.4% AT THE END OF ACUTE AND MAINTENANCE TREATMENT, RESPECTIVELY. THE MOST COMMON ADVERSE EFFECTS WERE HEADACHE, UPPER RESPIRATORY TRACT INFECTION AND ABDOMINAL PAIN: CONCLUSIONS: ESOMEPRAZOLE IS EFFECTIVE IN THE HEALING OF REFLUX OESOPHAGITIS, THE RESOLUTION OF HEARTBURN, AND IN MAINTAINING SYMPTOMATIC REMISSION. THE EFFECTIVENESS OF ESOMEPRAZOLE IN PATIENTS WITH GASTROESOPHAGEAL REFLUX DISEASE IS NOT AFFECTED BY THE PRESENCE OF H. PYLORI :
Endoscopic ablation of Barrett's esophagus: a multicenter study with 2.5-year follow-up.
Gastrointest Endosc. 2008 Jun 16;
Fleischer DE, Overholt BF, Sharma VK, Reymunde A, Kimmey MB, Chuttani R, Chang KJ, Lightdale CJ, Santiago N, Pleskow DK, Dean PJ, Wang KK
BACKGROUND: For patients with Barrett's esophagus (BE), life-long surveillance endoscopy is recommended because of an elevated risk for developing dysplasia and esophageal adenocarcinoma. Various endoscopic therapies have been used to eradicate BE. Recently circumferential radiofrequency ablation has been used with encouraging short-term results. OBJECTIVE: To provide longer follow-up and to assess the long-term safety and efficacy of step-wise circumferential ablation with the addition of focal ablation for BE. DESIGN: Prospective, multicenter clinical trial (NCT00489268). SETTING: Eight U.S. centers, between May 2004 and February 2007. PATIENTS: Seventy subjects with 2 to 6 cm of BE and histologic evidence of intestinal metaplasia (IM). INTERVENTIONS: Circumferential ablation was performed at baseline and repeated at 4 months if there was residual IM. Follow-up biopsy specimens were obtained at 1, 3, 6, 12, and 30 months. Specimens were reviewed by a central pathology board. Focal ablation was performed after the 12-month follow-up for histological evidence of IM at the 12-month biopsy (absolute indication) or endoscopic appearance suggestive of columnar-lined esophagus (relative indication). Subjects received esomeprazole for control of esophageal reflux. MAIN OUTCOME MEASUREMENTS: Complete absence of IM per patient from biopsy specimens obtained at 12 and 30 months, defined as complete remission-IM (CR-IM). RESULTS: At 12 months, CR-IM was achieved in 48 of 69 available patients (70% per protocol [PP], 69% intention to treat [ITT]). At 30 months after additional focal ablative therapy, CR-IM was achieved in 60 of 61 available patients (98% PP, 97% ITT). There were no strictures or buried glandular mucosa detected by the standardized biopsy protocol at 12 or 30 months, and there were no serious adverse events. LIMITATIONS: This was an uncontrolled clinical trial with 2.5-year follow-up. CONCLUSION: Stepwise circumferential and focal ablation resulted in complete eradication of IM in 98% of patients at 2.5-year follow-up.
Drug Saf. 2008; 31(7): 627-36
Estborn L, Joelson S
BACKGROUND: A potential causal association between an increase in gastric pH and a risk of community-acquired respiratory tract infection (RTI), specifically pneumonia, has been debated in relation to the use of potent gastric acid-suppressive medication. OBJECTIVE: To investigate the occurrence of community-acquired RTI, including pneumonia, in patients receiving esomeprazole versus placebo and other acid-suppressive agents in randomized clinical trials. METHODS: The AstraZeneca ARIADNE safety database was searched for comparative, controlled phase II-IV randomized, blinded clinical studies with esomeprazole and standard reporting of all adverse events (AEs). Pooled AE data were presented according to treatment comparison (esomeprazole versus placebo, esomeprazole 40 mg versus 20 mg daily, esomeprazole versus omeprazole, lansoprazole and/or ranitidine, respectively). Frequency and relative risk (RR), with 99% confidence interval (CI) and adjustment for time on treatment, were calculated for the following four AE categories: all RTIs; signs and symptoms potentially indicating RTI; lower RTI; and pneumonia. RESULTS: Thirty-one studies were identified, in which 16 583 patients received esomeprazole and 12 044 patients received either placebo or comparator acid-suppressive drugs. The occurrence of all four categories of AEs was similar between esomeprazole and placebo (all RTIs: 9.2% versus 8.5%; signs and symptoms of RTI: 1.8% versus 1.8%; lower RTI: 1.6% versus 1.5%; and pneumonia: 0.2% in both groups). The RR estimates were as follows: all RTIs, 0.93 (99% CI 0.78, 1.11); signs and symptoms of RTI, 0.85 (99% CI 0.57, 1.27); lower RTI, 0.92 (99% CI 0.59, 1.42); and pneumonia, 0.94 (99% CI 0.29, 3.07). The distribution of RTIs by patient sex and age showed a similar pattern in esomeprazole and placebo-treated patients. The comparisons of esomeprazole with the other comparator acid-suppressive drugs showed a similar pattern with only minor numerical differences in the occurrence of RTI between the drugs. There were no significant between-group differences with esomeprazole versus placebo for all four categories of AEs according to esomeprazole dosage, treatment indication and duration of treatment. CONCLUSIONS: This pooled analysis found no causal association between acid-suppressive therapy with esomeprazole and increased risk of community-acquired RTI, including pneumonia, in patients receiving this agent for gastric acid-related disorders.
Am J Gastroenterol. 2008 Jun 12;
Garrean CP, Zhang Q, Gonsalves N, Hirano I
OBJECTIVES: Studies have shown that extended pH recording improves the sensitivity of esophageal pH monitoring. Controversy exists as to whether pH studies are optimally done off or on proton pump inhibitor (PPI) therapy. The aim of this study was to incorporate periods both off and on PPI therapy in a single, extended pH test and describe the effect of PPI therapy on symptom-reflux associations. METHODS: Sixty patients underwent 4-day pH recordings using two separate receivers calibrated to a single wireless pH capsule. Patients were off PPI therapy for days 1 and 2. Either rabeprazole 20 mg twice daily or omeprazole/sodium bicarbonate 40 mg twice daily were administered on days 3 and 4. Symptom-reflux correlation was determined by the symptom index (SI), symptom sensitivity index (SSI), and symptom association probability (SAP). RESULTS: Twenty studies were excluded due to premature detachment (9) or incomplete data capture for >6 of the 96-h period (11). Off therapy, 14 patients (35%) had abnormal esophageal acid exposure values. On day 4, 39 patients (98%) had normal acid exposure. The number of symptoms and acid reflux events were significantly higher off PPI therapy. Furthermore, the percentage of patients with a positive SI fell from 50% off PPI to 9% on PPI (P < 0.01), whereas 63% of patients symptomatic off PPI therapy became asymptomatic on PPI therapy and could not have an SI calculated. Similarly, the SAP was abnormal in 45% of patients off PPI therapy but only 10% on PPI therapy (P < 0.01). CONCLUSIONS: Extended pH recording improves the detection of abnormal acid reflux and increases the number of recorded symptoms and acid reflux events. Combined off and on PPI therapy pH testing enhances the interpretation of pH monitoring and symptom-reflux correlations, which can be helpful in the management of patients with PPI-unresponsive gastroesophageal acid reflux symptoms.
J Pharm Pharmacol. 2008 Jul; 60(7): 843-51
Lee DY, Jung YS, Shin HS, Lee I, Kim YC, Lee MG
It has been reported that omeprazole is mainly metabolized via hepatic cytochrome P450 (CYP) 1A1/2, CYP2D1 and CYP3A1/2 in male Sprague-Dawley rats, and the expression of hepatic CYP3A1 is increased in male Sprague-Dawley rats with acute renal failure induced by uranyl nitrate (U-ARF rats). Thus, the metabolism of omeprazole would be expected to increase in U-ARF rats. After intravenous administration of omeprazole (20 mgkg(-1)) to U-ARF rats, the area under the plasma concentration-time curve from time zero to infinity (AUC) was significantly reduced (371 vs 494 mugminmL(-1)), possibly due to the significantly faster non-renal clearance (56.6 vs 41.2 mL min(-1) kg(-1)) compared with control rats. This could have been due to increased expression of hepatic CYP3A1 in U-ARF rats. After oral administration of omeprazole (40 mgkg(-1)) to U-ARF rats, the AUC was also significantly reduced (89.3 vs 235 mug minmL(-1)) compared with control rats. The AUC difference after oral administration (62.0% decrease) was greater than that after intravenous administration (24.9% decrease). This may have been primarily due to increased intestinal metabolism of omeprazole caused by increased expression of intestinal CYP1A and 3A subfamilies in U-ARF rats, in addition to increased hepatic metabolism.
Chem Res Toxicol. 2008 Jun 13;
Ma L, Wen B, Ruan Q, Zhu M
The present study describes a novel integrated approach for rapid analysis of reactive metabolites with a linear ion trap mass spectrometer (LTQ). In this approach, an isotope pattern-dependent scanning method was applied to the data acquisition of glutathione (GSH)-trapped reactive metabolites. Recorded full-scan MS and MS/MS data sets were further processed with neutral loss filtering, product ion filtering, and extracted ion chromatographic analysis to search for protonated molecules and MS/MS spectra of GSH adducts. To evaluate the effectiveness and reliability of the approach, GSH adducts of carbamazepine, diclofenac, 4-ethylphenol, acetaminophen, p-cresol, and omeprazole were analyzed, which were formed in human liver microsome incubations fortified with a mixture of nonlabeled GSH and stable isotope-labeled GSH at a 1:0.8 ratio. Results demonstrate that the combination of the isotope pattern-dependent scanning with the postacquisition data mining was very effective in detecting low levels of GSH adducts, regardless of their fragmentation patterns. As compared to a neutral loss scanning method performed with a triple quadrupole mass spectrometer, the LTQ-based approach had several major advantages, including the superior selectivity and sensitivity in detecting different classes of GSH adducts and the higher throughput capability of the detection and MS/MS spectral acquisition of GSH adducts in a single LC/MS run. Overall, this analytical approach provides a simple and efficient means for screening for reactive metabolites using a linear ion trap LC/MS platform.