omeprazole, Prilosec
Induction of tumor necrosis factor-alpha and apoptosis in gastric mucosal injury by indomethacin: effect of omeprazole and ebrotidine.

Slomiany BL, Piotrowski J, Slomiany A.

University of Medicine and Dentistry of New Jersey, Newark 07103-2400, USA.

BACKGROUND: The gastric injury associated with nonsteroidal anti-inflammatory drug (NSAID) therapy has been linked to the detrimental effects of the agents on the processes of prostaglandin generation, leukocyte adherence, superoxides production, and mucosal cell proliferation. In the present study we investigated the expression of tumor necrosis factor-alpha (TNF-alpha) and epithelial cell apoptosis during indomethacin-induced gastric mucosal injury and evaluated the effect of two antiulcer agents on this process. METHODS: The experiments were carried out with groups of rats subjected to intragastric pretreatment with 40 mg/kg omeprazole, 100 mg/kg ebrotidine, or vehicle, followed 30 min later by an intragastric dose of indomethacin at 60 mg/kg. After 2 h the animals were killed, and the gastric mucosal tissue used for macroscopic damage assessment, quantitation of TNF-alpha expression, and the assay of epithelial cell apoptosis. RESULTS: In the absence of antiulcer drugs, indomethacin caused extensive multiple hemorrhagic lesions accompanied by a 47% increase in mucosal expression of TNF-alpha and a dramatic (> 300-fold) enhancement in gastric epithelial cell apoptosis. Pretreatment with a proton pump inhibitor, omeprazole, produced only marginal (6-8%) reduction in the extent of mucosal damage caused by indomethacin, whereas the mucosal expression of TNF-alpha decreased by 15% and the apoptotic DNA fragmentation by 10-13%. In contrast, the H2-receptor antagonist ebrotidine, also known for its gastroprotective effects, not only successfully prevented (98.3%) the enhancement in mucosal TNF-alpha expression caused by indomethacin but also caused a 54% reduction in the epithelial cell apoptosis. These effects of ebrotidine were, furthermore, reflected in a 90.2% prevention in the gastric mucosal damage. CONCLUSIONS: Our findings provide new insights into the mechanism of gastric injury caused by NSAIDs and show that ebrotidine protection against indomethacin-induced mucosal damage occurs through the inhibition of epithelial cell apoptosis triggered by the enhancement in the mucosal TNF-alpha expression. Our data also show that omeprazole does not possess antiapoptotic properties.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9246701&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Unhealed duodenal ulcers despite Helicobacter pylori eradication.

Gisbert JP, Boixeda D, Martin De Argila C, Alvarez Baleriola I, Abraira V, Garcia Plaza A.

Dept. of Gastroenterology, Hospital Ramon y Cajal, University of Alcala de Henares, Madrid, Spain.

BACKGROUND: Our aims were 1) to study the influence of several factors (age, sex, smoking, previous ulcer disease, ulcer size, chronic gastritis, serum gastrin and pepsinogen I levels, therapy regimen and, especially, eradication of Helicobacter pylori) on duodenal ulcer healing; 2) to evaluate the frequency of duodenal ulcer healing failure despite eradication of H. pylori, to study why this failure occurs, and to verify its evolution without antisecretory therapy; and 3) to confirm whether a week's prescription of omeprazole is sufficient to obtain ulcer healing. METHODS: Three-hundred and eight patients (mean age, 45 +/- 13 years; 71% males) with duodenal ulcer and H. pylori infection were studied prospectively. Biopsy specimens were obtained at initial endoscopy, and serum gastrin and pepsinogen I levels were measured. A repeat endoscopy (with biopsies) was performed 1 month after eradication therapy had been completed, and a 13C-urea breath test was also carried out. Three eradication therapies were used: omeprazole plus amoxycillin for 2 weeks (OA group, n = 61); 'classic' triple therapy (with bismuth; CTT group, n = 65); and 'new' triple therapies for 1 week (NTT group, n = 182): omeprazole plus two of the following antibiotics: clarithromycin, metronidazole, and amoxycillin. When the ulcer did not heal despite successful H. pylori eradication, antacids were prescribed on an as-needed basis, and endoscopy was repeated 1 month later (2nd control endoscopy). If the ulcer was still present, the acid output (basal and pentagastrin-stimulated) was measured, a secretin test was performed, and a final endoscopy (3rd control endoscopy) was carried out after an additional month. The statistical method used was multiple logistic regression. RESULTS: Overall eradication was achieved in 69% (n = 212) of the patients, and ulcer healing in 76% (n = 233): 57% in the OA group, 80% in the CTT group, and 81% in the NTT group (P < 0.01 when comparing the OA group with the others). Ulcer healing was achieved in 90% of H. pylori-eradicated patients and in only 45% of patients with eradication therapy failure (P < 0.001). Similar results were obtained when only patients treated with NTT were considered: ulcer healing in 90% of patients with the organisms eradicated. Eradication of H. pylori (odds ratio (OR), 11.8; 95% confidence interval (CI), 6.3-22) and sex (OR, 2.5; 95% CI, 1.2-5.1) were the only variables that correlated with ulcer healing in the multivariate analysis. The ulcer persisted despite successful eradication of H. pylori in 22 patients. The duodenal ulcer had healed spontaneously in 73% of these patients at the 2nd control endoscopy. Finally, by the 3rd control endoscopy, only three patients still had duodenal ulcer. Therefore, ulcer healing was finally achieved in 98.1% (95-99%) of patients in whom H. pylori was eradicated. Gastrin, pepsinogen I, acid output, and the secretin test had normal values in all patients. CONCLUSIONS: Eradication of H. pylori favours ulcer healing, which is achieved in most patients in whom the organism is eradicated. Just 1 week of omeprazole therapy (that is, the antibiotic administration period in the new triple therapies) is enough to obtain a high ulcer healing rate. Most duodenal ulcers that do not heal initially despite H. pylori eradication will ultimately do so after several weeks without additional therapy.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9246702&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Alterations in gastrin cells induced by short-term omeprazole treatment in the rat antrum: an immunocytochemical and in situ hybridization study.

Bolkent S, Yilmazer S.

Department of Medical Biology, Cerrahpasa Faculty of Medicine, University of Istanbul, Turkey.

Gastrin is a hormonal regulator of gastric acid secretion and a trophic stimulant of acid-producing gastric mucosa. The blockage of acid secretion has been reported to cause hypergastrinaemia and gastrin cell hyperplasia. These findings suggest that achlorhydria may stimulate gastrin gene expression in gastrin cells. In this study, we aimed to determine the alterations of gastrin mRNA by non-radioactive in situ hybridization, and also to compare the localization of transcripts and protein products of the same gene by immunocytochemistry in an acid inhibition environment provided by omeprazole. Female Sprague-Dawley rats, weighing 200-250 g, were divided into three groups. The first group was the control group (eight rats). The second group (eight rats) was given 20 mg kg-1 day-1 omeprazole as intragastric instillations for 4 days. The third group (eight rats) was given 100 mg kg-1 day-1 omeprazole as in the second group. Serum gastrin levels in the two groups treated with omeprazole showed a statistically significant increase (P < 0.001) compared with the control group. The omeprazole-treated groups also showed an increase in the number of immunoreactive gastrin cells in the pyloric mucosa and an enhancement in the intensity of immunoreaction. Cells containing gastrin mRNA signals were observed in the upper regions of the pyloric glands in the pyloric sections of the control group and in both experimental groups.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9248855&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Basis for the selective antibacterial activity in vitro of proton pump inhibitors against Helicobacter spp.

Sjostrom JE, Kuhler T, Larsson H.

Department of Cell Biology, Preclinical Research and Development, Astra Hassle AB, Molndal, Sweden.

Proton pump inhibitors of the benzimidazole type exert a specific antibacterial activity against Helicobacter pylori in vitro. In the present study, the basis for this selectivity was investigated, and in particular, various factors affecting the in vitro antibacterial activity of sulfide analogs of benzimidazoles were studied. Upon preincubation of omeprazole for a period of up to 72 h in a buffer at pH 7, a product was formed that was bactericidal for H. pylori but had no effect on urease activity. Sulfide constitutes the main end product of degradation. The sulfide analog of omeprazole (H 168/22) exerted a bactericidal activity specifically against both resting (in buffer) and growing (in broth) Helicobacter spp., and time-kill in buffer at pH 5 was enhanced compared to that at pH 7. There was no or very low covalent binding of 3H-labeled H 168/22 to Helicobacter spp. or to other gram-negative and gram-positive bacteria. In the presence of fetal calf serum (FCS) under the same conditions, binding was only slightly lowered while the killing activity was markedly reduced, indicating a probably nonspecific interaction with proteins and/or protection of bacterial target(s) by FCS. Addition of H 168/22 (four times the minimum bactericidal concentration [MBC]) to exponentially growing H. pylori immediately stopped growth, and after an incubation period of 20 h viable counts were reduced by >7 log10. One-hour exposure of H. pylori to the drug followed by repeated washing retarded growth by about 2 h, indicating that the effect is reversible after short-term exposure. MICs and MBCs of various sulfide structures were lower than those obtained in broth after the addition of the corresponding sulfoxide. Thus, the MBC of the sulfide structure of omeprazole against 140 clinical isolates of H. pylori ranged from 8 to 32 microg/ml, compared to an MBC of omeprazole of 32 to 128 microg/ml. A similar potency was also recorded against other helicobacters. In conclusion, formation of sulfides of benzimidazoles in culture media is the reason for the selective antibacterial effect against H. pylori. The sulfides rapidly exerted a reversible antibacterial activity, which was specific against both resting and growing Helicobacter spp. without any covalent protein binding.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9257764&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Chicken parathyroid hormone gene expression in response to gastrin, omeprazole, ergocalciferol, and restricted food intake.

Gagnemo-Persson R, Samuelsson A, Hakanson R, Persson P.

Department of Pharmacology, University of Lund, Solvegatan 10, S-223 62 Lund, Sweden.

Treatment with omeprazole, a long-acting proton pump inhibitor of acid secretion, induces hypergastrinemia. In chickens, omeprazole induces growth not only of the acid-producing mucosa (probably reflecting the trophic action of gastrin), but also of the parathyroid glands (hypertrophy + hyperplasia), while suppressing bone density and body weight gain without affecting blood calcium. The first part of the present study was concerned with the effect of omeprazole, ergocalciferol (vitamin D2), and restricted food intake on the gene expression of parathyroid hormone (PTH) in the parathyroid glands of the chicken. Chickens were treated with omeprazole (400 micromol/kg/day, I.M.), food restriction, omeprazole + food restriction, ergocalciferol (250 000 IU/kg/day, S.C.), or ergocalciferol + omeprazole for 5 weeks. The weight gain of the chickens was monitored, and the weights of the parathyroid glands and femurs were determined at sacrifice. PTH mRNA in the parathyroid glands was analyzed by Northern blot. The second part of the study examined the effect of 3 weeks of continuous gastrin infusion (chicken gastrin 20-36, 5 nmol/kg/hour, S.C.) on the expression of PTH mRNA in the parathyroid glands. Omeprazole reduced the body weight and femur density (ash weight per volume) while greatly increasing the weight of the parathyroid glands and the PTH gene expression. Food restriction alone and ergocalciferol alone (at a dose that raised blood Ca2+) were without effect, but food restriction greatly enhanced the omeprazole-evoked increase in parathyroid gland weight and PTH gene expression. Gastrin increased the weight of the parathyroid glands and reproduced the effect of omeprazole on PTH gene expression. Hence, it seems likely that the effect of omeprazole reflects the ensuing hypergastrinemia.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9262512&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Regulation by gastric acid of the processing of progastrin-derived peptides in rat antral mucosa.

Macro JA, Bate GW, Varro A, Vaillant C, Seidah NG, Dimaline R, Dockray GJ.

Physiological Laboratory, University of Liverpool, UK.

1. Inhibition of gastric acid secretion by proton pump inhibitors like omeprazole increases the synthesis and secretion of the pyloric antral hormone gastrin. We report here how omeprazole influences the conversion of the gastrin precursor to its final products, and the abundance of mRNAs encoding proteins associated with progastrin processing in rat antral mucosa. 2. Progastrin processing was studied using a pulse-chase protocol in antral mucosa, incubated in vitro, from rats treated with omeprazole for up to 5 days. Labelled peptides were detected by on-line scintillation counting after immunoprecipitation and HPLC. The mRNAs encoding prohormone-processing enzymes were identified by Northern blot, polymerase chain reaction or ribonuclease protection assay, and their cellular origins identified by immunocytochemistry. 3. Cleavage of [3H]- and [35S]-labelled progastrins at Arg-94-95 or Arg-57-58, and amidation at Phe-92 were not influenced by pretreatment with omeprazole. In contrast, cleavage of G34 (the thirty-four amino acid amidated gastrin) at Lys-74-75 to give G17 (the seventeen amino acid amidated gastrin), and of G34-Gly to G17-Gly (G34 and G17 with COOH-terminal glycine), was increased 3-fold after treatment with omeprazole for either 1 or 5 days. 4. Approximately 20% of newly synthesized amidated and Gly-extended gastrins were secreted within 240 min of the labelling period in omeprazole-treated samples, but secretion of labelled gastrins from control tissue was undetectable over a comparable period. 5. The amidating enzyme, peptidyglycine alpha-amidating mono-oxygenase (PAM), the prohormone convertases PC1/3, PC2, PC5 and the PC2 chaperone 7B2 were localized to rat antral gastrin cells by immunocytochemistry. The relative abundance of mRNA species encoding 7B2, PC5 and PAM were unchanged after treatment with omeprazole for 5 days, whereas gastrin, PC1/3 and PC2 mRNAs are known to increase at this time. 6. The main consequence of increased cleavage at Lys-74-75 is the production of G17 and G17-Gly at the expense of G34 and G34-Gly, respectively. The latter have longer plasma half-lives, and so their increased cleavage may serve to limit the rise in plasma gastrin concentration after inhibition of acid secretion. Changes in the abundance of mRNAs encoding prohormone-processing enzymes cannot account for the rapidity of the changes in cleavage of progastrin at Lys residues after omeprazole.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9263920&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Stability of omeprazole in an extemporaneously prepared oral liquid.

Quercia RA, Fan C, Liu X, Chow MS.

Department of Pharmacy Services, Hartford Hospital, CT 06102, USA. hhdicchow aol.com

The stability of omeprazole 2 mg/mL. in an extemporaneously prepared oral liquid was studied. The contents of five 20-mg omeprazole capsules were mixed with 50 mL of 8.4% sodium bicarbonate solution in a Luer-Lok syringe. Three vials of this liquid were prepared for storage at 24, 5, and -20 degrees C. A 3-mL. sample of each was taken initially and on days 1, 2, 3, 4, 6, 8, 10, 12, 14, 18, 22, 26, and 30 and assayed by high-performance liquid chromatography. The liquids stored at 5 degrees C and at -20 degrees C did not change color during the study period, but the color of the liquid stored at 24 degrees C changed from white to brown. There were no significant changes in the omeprazole concentrations of the liquids stored at 5 and -20 degrees C during the study period, but the omeprazole concentration of the liquid stored at 24 degrees C was < 90% of the initial concentration on day 18. Omeprazole 2 mg/mL in an oral liquid compounded extemporaneously from capsules and sodium bicarbonate injection was stable for up to 14 days at 24 degrees C and for up to 30 days at 5 and -20 degrees C.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9269520&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Omeprazole, other antiulcer drugs and newly diagnosed gout.

Meier CR, Jick H.

The Boston Collaborative Drug Surveillance Program, Boston University Medical Center, Lexington, Massachusetts 02173, USA.

AIMS: Case-reports describing patients who developed a first episode of acute gout while being treated with the proton pump inhibitor omeprazole led us to compare incidence rates of newly diagnosed gout cases among omeprazole, ranitidine and cimetidine users. METHODS: We conducted a cohort study with a nested case-control analysis using the UK-based General Practitioner Research Database (GPRD). The study encompassed a cohort of more than 53,000 subjects who received some 185,000 prescriptions for the three study drugs. RESULTS: Neither current omeprazole vs recent use (age- and sex-adjusted relative risk 1.1, 95% CI 0.5-2.1), nor current omeprazole use in comparison with current use of the two histamine H2-receptor blockers was associated with an increased risk of developing newly diagnosed gout. Higher age (RR 2.4, 95% CI 1.5-3.9), male gender (RR 5.4, 95% CI 2.8-10.3), high body mass index (OR 3.3, 95% CI 1.0-10.9) and hypertension (OR 4.5, 95% CI 1.6-12.9) were all important risk factors for gout. CONCLUSIONS: While other known risk factors were significantly associated with gout, current omeprazole use was not materially associated with an increased gout incidence.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9278205&dopt=Abstract omeprozole Prilosec