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J Gastroenterol. 2008 Jun; 43(6): 429-433
Usta Y, Saltik-Temizel IN, Demir H, Uslu N, Ozen H, Gurakan F, Yuce A
BACKGROUND: Research regarding the optimal therapeutic approach to Helicobacter pylori infection in children is ongoing. There is no consensus as to duration of treatment or second-line therapy. The purpose of this study was compare the efficacy of 7-day and 14-day triple therapies and report the results of second-line quadruple therapy in children. METHODS: A total of 275 consecutive H. pylori-infected patients were enrolled into two groups. Group 1 (n = 180) received triple therapy with 14 days of amoxicillin and clarithromycin and 21 days of proton pump inhibitor. Group 2 (n = 95) received triple therapy including 7 days of amoxicillin and clarithromycin with 21 days of proton pump inhibitor. Subsequently, 89 patients not responding to the triple therapies received quadruple therapy comprising omeprazole (14 days), bismuth subcitrate (7 days), doxycycline (7 days), and metronidazole (7 days). Eradication was evaluated by (13)C-urea breath test. RESULTS: The per-protocol eradication rates in groups 1 and 2 were 60.5% and 55.8%, respectively (P = 0.44). In the second interview with 227 patients, severe symptoms were reported to have disappeared in 59% and decreased notably in 34.8%. Helicobacter pylori was eradicated in 66.7% of patients at the end of the quadruple therapy. In the third interview with 75 patients, severe symptoms had decreased in 38.6% and disappeared in 56%. CONCLUSIONS: The different duration of the two treatment regimens had no impact on eradication rates. Furthermore, quadruple therapy was necessary to achieve H. pylori eradication after triple therapy. However, the eradication rate with quadruple therapy was still insuf-ficient. Consequently, a new therapeutic approach to H. pylori infection in children is needed.
Inflammopharmacology. 1999; 7(2): 163-77
Slomiany BL, Piotrowski J, Slomiany A
Aims:Helicobacter pylori lipopolysaccharide is a primary virulence factor responsible for eliciting acute mucosal inflammatory responses associated withH. pylori infection. In this study, we investigated the activity of a key apoptotic protease, caspase-3, and the expression of inducible nitric oxide synthase (NOS-2) duringH. pylori lipopolysaccharide-induced acute gastritis, and evaluated the effect of anti-ulcer agents, omeprazole and sucralfate, on this process.Methods: Rats, pretreated twice daily with omeprazole at 40 mg/kg, sucralfate at 100 mg/kg, or the vehicle, were subjected to intragastric application ofH. pylori lipopolysaccharide at 50 mug/animal, and after 4 additional days on the anti-ulcer drug or vehicle regimen their mucosal tissue was used for histologic assessment, assays of epithelial cells apoptosis, and the measurements of caspase-3 and NOS-2 activities.Results: In the absence of anti-ulcer agents,H. pylori lipopolysaccharide induced acute reaction characterized by the inflammatory infiltration of the lamina propria, hyperemia, and epithelial hemorrhage. This was accompanied by an 11.2-fold increase in epithelial cell apoptosis, a 6.5-fold induction in mucosal expression of NOS-2, and a 5.4-fold increase in caspase-3 activity. Treatment with proton pump inhibitor, omeprazole, produced a 39.6% reduction in the extent of mucosal inflammatory changes elicited byH. pylori lipopolysaccharide and a 75.5% decrease in the epithelial cells apoptosis, while the activity of caspase-3 decreased by 26.8% and that of NOS-2 showed a 46.7% decline. The gastroprotective agent, sucralfate, evoked a 62.3% reduction in the extent of mucosal inflammatory changes caused by the lipopolysaccharide, epithelial cell apoptosis decreased by 85.8%, and NOS-2 showed a 68.2% decline, while the activity of caspase-3 decreased by 39.7%.Conclusions: Our findings implicate caspase-3 involvement in gastric mucosal inflammatory responses toH. pylori lipopolysaccharide, and point towards participation of NOS-2 in the amplification of the cell death-signaling cascade. We also show that anti-ulcer agents, omeprazole and sucralfate, are capable of suppressing the H. pylori-induced mucosal inflammatory responses by interfering with the events propagated by NOS-2 and caspase-3.
Dig Dis Sci. 2008 Jul 2;
Taghavi SA, Jafari A, Eshraghian A
This study compared a new regimen (group A: doxycycline, co-amoxiclav, omeprazole) and two routinely prescribed regimens (group B: amoxicillin, omeprazole, furazolidone, bismuth; group C: amoxicillin, clarithromycin, omeprazole) to find an acceptable first-line treatment option for Helicobacter pylori. The study population consisted of 189 patients who referred to our clinic to undergo endoscopy due to ulcer-like dyspepsia. The H. pylori eradication rate was 68% in group A, 56% in group B, and 70% in group C according to per-control analysis. There was no statistically significant difference in H. pylori eradication between groups A and B (P = 0.187), groups A and C (P = 0.857), and groups B and C (P = 0.15). In conclusion, although none of the three eradication regimens can be recommended as a first-line eradication treatment, the new regimen is at least as effective and probably better tolerated than the two routinely applied regimens.
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.
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.