omeprazole, Prilosec
Effect of inhibition of pentagastrin-stimulated acid secretion on gastric mucosal gland luminal pressure.

Synnerstad I, Persson AE, Holm L.

Department of Physiology and Medical Biophysics, Uppsala University, Sweden.

We demonstrated previously that hydrochloric acid secreted from the gastric glands traverses the mucus layer in channels above the gland openings. The driving force for creation of these channels is most probably the hydrostatic pressure generated in the gastric gland lumen during stimulation of acid secretion. Here we investigated the effect of total inhibition of acid secretion on gland luminal pressure. Glandular pressure was measured in vivo with a pressure-sensitive microelectrode technique in Inactin-anaesthetized Sprague Dawley or Lewis x DA F1 rats. Glandular pressure was significantly reduced after ranitidine inhibition of acid secretion, from 17.2 +/- 2.1 mmHg during pentagastrin stimulation to 11.2 +/- 1.2 mmHg. This was also true when pentagastrin infusion was continued after inhibition of secretion with ranitidine. Omeprazole, however, did not significantly alter gland luminal pressure although it totally inhibited acid secretion. With continuation of pentagastrin infusion after omeprazole inhibition, glandular pressure increased significantly from 17.6 +/- 3.4 to 20.1 +/- 3.3 mmHg. In conclusion, total inhibition of acid secretion with ranitidine reduces but does not abolish gland luminal pressure. After omeprazole inhibition of acid secretion the gastric gland luminal pressure persisted or even increased. Since the volume secretion is lower after omeprazole administration than during pentagastrin stimulation, the outflow resistance most probably had increased after omeprazole injection. Suggestions for increased outflow resistance are narrowing in the upper part of the gland lumen by conformational changes of the cells or muscle contractions, and/or an increase in mucus secretion or viscosity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9179318&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
[One-week treatment with omeprazole, clarithromycin and amoxicillin: high efficacy in the eradication of Helicobacter pylori and cicatrization of duodenal ulcer]

[Article in Spanish]

Gisbert JP, Mur M, Boixeda D, Cena G, Martin de Argila C, Alvarez Baleriola I, Abraira V, Garcia Plaza A.

Servicio de Gastroenterologia, Hospital Ramon y Cajal, Madrid.

BACKGROUND: To evaluate the efficacy of one-week therapy with omeprazole, clarithromycin and amoxycillin in eradicating Helicobacter pylori and healing duodenal ulcer. PATIENTS AND METHODS: One-hundred and thirty-four consecutive duodenal ulcer patients (mean age 47 +/- 13 yrs, 66% males) with H. pylori infection were prospectively studied. At endoscopy, biopsies from both gastric antrum and body were obtained for histologic study (H/E). A 15C-urea breath test was also performed in 98 patients. Omeprazole 20 mg b.i.d., amoxycillin 1 g b.i.d., and clarithromycin 500 mg b.i.d. were administered only for 1 week, and no therapy was administered thereafter. Endoscopy with biopsies and breath test were repeated 1 month after completing therapy. RESULTS: Eradication was achieved in 87.3% of patients (n = 93; 95% CI = 82-93%). In the multivariate analysis the variables which influenced H. pylori eradication were: time of evolution of ulcer disease (p = 0.002) and active chronic gastritis in the antrum (p = 0.04) (chi 2 model = 15.8; p = 0.001). Ulcer healing was demonstrated in 89.5% of patients (84-95%), and healing rate was higher when eradication was achieved (94%; 90-98%) than in H. pylori-positive patients (59%; 36-78%) (p < 0.001). In the multivariate analysis the variables which influenced ulcer healing were: age (p = 0.02) and H. pylori eradication (p = 0.001) (chi 2 model = 21.2; p = 0.0001). An improvement of histologic gastritis was observed when eradication was achieved (p < 0.001). Compliance of therapy was complete in all patients but one and no relevant adverse effects were reported. CONCLUSION: One-week triple therapy with omeprazole, clarithromycin and amoxycillin administered on a twice daily basis achieves a high efficacy in eradicating H. pylori and healing duodenal ulcer. Moreover, this therapy regimen is simple and is associated with a low incidence of adverse effects and a low cost.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9190436&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Comparative study of plasma gastrin levels in rats after two months of ebrotidine administration.

Romero A, Gomez F, Villamayor F, Ballesta A, Sacristan A, Ortiz JA.

Department of Toxicology, Centro de Investigacion Farmaceutica Grupo Ferrer, Barcelona, Spain.

Four groups of male rats were orally administered for 60 days with daily doses of ebrotidine (N-[(E)-[[2-[[[2-[(diaminoethylene) amino]-4-thiazolyl]methyl]thio]ethyl]amino]methylene]-4-bromo- benzenesulfonamide, CAS 100981-43-9, FI-3542) (500 mg/kg), ranitidine (500 mg/kg), cimetidine (500 mg/kg) and omeprazole (43.5 mg/kg). A fifth group received no treatment and was used as control. The curve of gastrinemia was obtained on days 1, 15 and 60 of administration. On each of these days gastrinemia was assessed at 0, 1, 5, 8, and 24 h on day 1, and 1, 5, 8, 10 and 24 h on days 15 and 60. The purpose of this study was to compare the plasma gastrin level profile in association with the administration of test drugs on days 1, 15 and 60 of treatment. The results showed a significant difference in the duration of hypergastrinemia of H2-receptor antagonists as compared to proton pump blockers. Although peak plasma gastrin levels were attained for all products between 5 and 8 h after day 1 of administration, H2-receptor antagonists, unlike omeprazole, achieved recovery of gastrin baseline levels within 24 h. On days 15 and 60 of ebrotidine, treatment, plasma gastrin levels returned to normal range at 5 and 8 h after administration, respectively. After ranitidine and cimetidine, hypergastrinemia was still present at this time, but normal levels were attained before 24 h. With omeprazole plasma gastrin levels did not return to normal range within 24 h after each administration, and a cumulative effect occurred during treatment. The omeprazole treated group showed the highest and more sustained plasma gastrin levels. It was concluded that ebrotidine was the antisecretory agent with the lowest hypergastrinemic effect during long-term treatment. With ebrotidine daily baseline gastrin levels were more rapidly recovered after each administration.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9205757&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Successful low-dose amoxycillin, metronidazole and omeprazole combination therapy in a population with a high frequency of metronidazole-resistant Helicobacter pylori.

Breuer T, Kim JG, Gurer IE, Graham DP, Osato M, Genta RM, Graham DY.

Department of Medicine, Veterans Affairs Medical Center, Houston, Texas 77030, USA.

AIM: Effective anti-Helicobacter pylori therapies with few side-effects are needed. We studied the effectiveness of a low-dose combination of metronidazole, amoxycillin and omeprazole for treatment of ulcer patients in Seoul, Korea. METHODS: Patients with gastric or duodenal ulcer received metronidazole (125 mg b.d.), amoxycillin (500 mg b.d.) and omeprazole (20 mg at bedtime) for 2 weeks. Endoscopic examinations were performed before treatment and at least 6 weeks after completion of antimicrobial therapy. H. pylori status was confirmed by histological examination of two gastric biopsies using the Genta stain. RESULTS: Seventy-nine patients (64 men, 15 women, mean age 46 years) with peptic ulcer were enrolled. H. pylori infection was cured in 56 (71%) 95% CI: 60-81%). The cure rate in non-smokers was significantly higher than in smokers (88% vs. 65%, P = 0.035). Twelve pre-treatment isolates were available and metronidazole resistance was noted in all; H. pylori infection was cured in 10. Thirty-six patients cured of H. pylori have been followed for 1 year (mean of 361 days) and 2 cases became reinfected (5.5%, 95% CI: 1-18%). CONCLUSIONS: The low-dose combination of metronidazole, amoxycillin and omeprazole was effective even the in face of metronidazole resistance. Recurrence of H. pylori infection is infrequent even in countries with a high prevalence of H. pylori infection.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9218076&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Exploring an antifungal target in the plasma membrane H(+)-ATPase of fungi.

Seto-Young D, Monk B, Mason AB, Perlin DS.

Public Health Research Institute, New York, NY 10016, USA.

The plasma membrane H(+)-ATPase is a promising new antifungal target that is readily probed with the sulfhydryl-reactive reagent omeprazole. Inhibition of the H(+)-ATPase by omeprazole is closely linked to cell killing, and it has been suggested that enzyme inhibition may result from a covalent interaction within the first two transmembrane segments (M1 and M2) (Monk et al. (1995) Biochim. Biophys. Acta 1239, 81-90). In this study, the molecular nature of this interaction was examined by screening a series of 26 well-characterized pma1 mutations residing in the first two transmembrane segments of the H(+)-ATPase from Saccharomyces cerevisiae. Only two pma1 mutants, A135G and G158D,G156C, were found to significantly decrease the sensitivity of cells for omeprazole. In contrast, enhanced sensitivity was observed at a number of positions, with D140C(A) and M128C producing the most significant increases in sensitivity. The introduction of cysteine at various locations within this region only marginally affected omeprazole sensitivity, suggesting that this region was not a direct site of covalent modification. Rather, its conformation influences omeprazole binding at some other locus. In order to determine the sidedness of the omeprazole interaction, a novel in vitro assay system was exploited that utilized liposomes co-reconstituted with the H(+)-ATPase and the light-driven proton pump bacteriorhodopsin. Omeprazole was found to completely inhibit proton transport by the H(+)-ATPase at 50 microM in this system. An asymmetrically-distributed chemical trap system involving glutathione was used to demonstrate that this inhibition appears localized to the extracellular portion of the enzyme. This work indicates that omeprazole can inhibit the H(+)-ATPase from its extracellular face, and this inhibition is influenced by changes in the M1, M2 region of the protein.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9218555&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
Evaluation of omeprazole and lansoprazole as inhibitors of cytochrome P450 isoforms.

Ko JW, Sukhova N, Thacker D, Chen P, Flockhart DA.

Department of Medicine, Georgetown University Medical Center, Washington, DC 20007, USA.

The human clearance of omeprazole and lansoprazole is conducted primarily by the hepatic cytochrome P450 (CYP) system. Efficacy data indicate few differences between these two drugs, but they may exhibit discrete drug interaction profiles. To compare the potency and specificity of these drugs as inhibitors of CYP isoforms, we performed in vitro studies with human liver microsomal preparations. Both drugs were potent, competitive inhibitors of CYP2C19, as measured by the conversion of S-mephenytoin to 4-hydroxymephenytoin (k(i) = 3.1 +/- 2.2 microM for omeprazole, K(i) = 3.2 +/- 1.3 microM for lansoprazole). For omeprazole, the highest concentration at which >70% inhibition of CYP2C19 was observed with no significant inhibitory effect on other isoforms was at least 20 times greater than K(i). Both drugs were competitive inhibitors of CYP2C9-catalyzed conversion of tolbutamide to 4-hydroxytolbutamide (K(i) = 40.1 +/- 14.8 microM for omeprazole, K(i) = 52.1 +/- 1.4 microM for lansoprazole) and were noncompetitive inhibitors of CYP3A-catalyzed conversion of dextromethorphan to 3-methoxymorphinan (K(i) = 84.4 +/- 4.0 microM for omeprazole, K(i) = 170.4 +/- 7.1 microM for lansoprazole). Lansoprazole was at least 5 times more potent (K(i) = 44.7 +/- 22.0 microM) than omeprazole (k(i) = 240.7 +/- 102.0 microM) as an inhibitor of CYP2D6-mediated conversion of dextromethorphan to dextrorphan. No inhibition of CYP1A2, assessed by measuring the conversion of phenacetin to acetaminophen, was noted. Our data suggest that whereas the inhibitory profiles of these two drugs are similar, lansoprazole may be the more important in vitro inhibitor of CYP2D6. Since its inhibition is very potent and has a broad "window of selectivity," omeprazole seems to be a useful, selective inhibitor of CYP2C19.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9224780&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
An immuno- and enzyme cytochemical study of the H(+)-K+ ATPase in human parietal cells after administration of tetragastrin and omeprazole.

Kobayashi A, Araki K, Ando T, Ogata T.

Department of Surgery, Kochi Medical School, Japan.

The presence of subunit proteins, 1H9 for the alpha-subunit and 2B6 for the beta-subunit, of H(+)-K+ ATPase and its activity in tubulovesicles and intracellular canaliculi of gastric parietal cells were immunocytochemically and enzyme cytochemically examined. Specimens were taken from healthy human volunteers by endoscopic biopsy in resting, tetragastrin-stimulated and omeprazole-inhibited conditions. H(+)-K+ ATPase was present in both intracellular canaliculi and tubulovesicles in these three conditions. Gold particles of the alpha-subunit decreased in number, and those showing the beta-subunit increased under both gastrin-stimulating and omeprazole-inhibiting conditions compared with parietal cells in the resting state. We suggest that the administration of tetragastrin and omeprazole alter the turnover rate of each subunit of H(+)-K+ ATPase, resulting in the difference of the proportions of alpha- and beta-subunits. Moreover, the activity of H(+)-K+ ATPase was detected strongly beneath the membrane of microvilli and weakly in that of tubulovesicles under these three conditions. After 7 days of daily oral omeprazole intake, H(+)-K+ ATPase in parietal cells were detected in intracellular canaliculi and tubulovesicles. However, the H(+)-K+ ATPase activity in tubulovesicles was diminished 1 h after omeprazole intake, and the activity in intracellular canaliculi was completely inhibited even 3 h after omeprazole administration. These results show that omeprazole inhibited the H(+)-K+ ATPase activity in both intracellular canaliculi and tubulovesicles.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9232184&dopt=Abstract omeprozole Prilosec



omeprazole, Prilosec
The effect of omeprazole pretreatment on acetaminophen metabolism in rapid and slow metabolizers of S-mephenytoin.

Sarich T, Kalhorn T, Magee S, al-Sayegh F, Adams S, Slattery J, Goldstein J, Nelson S, Wright J.

Department of Pharmacology, Faculty of Medicine, University of British Columbia, Vancouver, Canada.

Omeprazole, a widely used and potent gastric proton pump inhibitor, induces cytochrome P450 (CYP) 1A2 in humans. Induction is most pronounced in slow metabolizers of S-mephenytoin because CYP2C19 (S-mephenytoin hydroxylase) is responsible for the elimination of omeprazole. Acetaminophen (INN, paracetamol), a widely used and effective analgesic and antipyretic agent, causes serious hepatic and renal toxicity at high doses by conversion of acetaminophen to the toxic intermediate N-acetyl-p-benzoquinone imine (NAPQI) through CYP1A2, CYP2E1, and CYP3A4. This study evaluated whether omeprazole pretreatment in five rapid and five slow metabolizers of S-mephenytoin could increase thioether (an estimate of NAPQI production) metabolite formation from acetaminophen. The results of this study show that, despite induction of CYP1A2 activity in slow metabolizers (a 75% increase in plasma clearance of caffeine), the formation of NAPQI from acetaminophen was not increased after 7 days of omeprazole administration (40 mg/day). This suggests that induction of CYP1A2 activity by omeprazole is unlikely to increase the risk of acetaminophen hepatotoxicity.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9246016&dopt=Abstract omeprozole Prilosec