In Vivo Effect of Omeprazole on HLA-DR Expression and the Nonocyte-Macrophage Function in Patis with Duodenal Ulcer Disease

Kountouras, Jannis; Boura, Panagiota; Apostolides, G.; Zaharioudaki, E.; Tsapas, G.

doi:10.3109/08923979409007103

Cited by 8 publications

(7 citation statements)

References 16 publications

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“…Moreover, PPI are commonly administered to millions of subjects affected by peptic diseases, with minimal side effects and few drug interactions (19,20). Consistently, omeprazole did not inhibit functions of human macrophages and lymphocytes in long-term treated patients (46). We know that PPI are weak bases, and the active protonated form of the drug will necessarily accumulate into acidic compartments (33).…”

Section: Discussionmentioning

confidence: 99%

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

et al. 2007

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Proton pumps like the vacuolar-type H + ATPase (V-ATPase) are involved in the control of cellular pH in normal and tumor cells. Treatment with proton pump inhibitors (PPI) induces sensitization of cancer cells to chemotherapeutics via modifications of cellular pH gradients. It is also known that low pH is the most suitable condition for a full PPI activation. Here, we tested whether PPI treatment in unbuffered culture conditions could affect survival and proliferation of human B-cell tumors. First, we showed that PPI treatment increased the sensitivity to vinblastine of a pre-B acute lymphoblastic leukemia (ALL) cell line. PPI, per se, induced a dose-dependent inhibition of proliferation of tumor B cells, which was associated with a dose-and time-dependent apoptotic-like cytotoxicity in B-cell lines and leukemic cells from patients with pre-B ALL. The effect of PPI was mediated by a very early production of reactive oxygen species (ROS), that preceded alkalinization of lysosomal pH, lysosomal membrane permeabilization, and cytosol acidification, suggesting an early destabilization of the acidic vesicular compartment. Lysosomal alterations were followed by mitochondrial membrane depolarization, release of cytochrome c, chromatin condensation, and caspase activation. However, inhibition of caspase activity did not affect PPI-induced cell death, whereas specific inhibition of ROS by an antioxidant (N-acetylcysteine) significantly delayed cell death and protected both lysosomal and mitochondrial membranes. The proapoptotic activity of PPI was consistent with a clear inhibition of tumor growth following PPI treatment of B-cell lymphoma in severe combined immunodeficient mice. This study further supports the importance of acidity and pH gradients in tumor cell homeostasis and suggests new therapeutic approaches for human B-cell tumors based on PPI. [Cancer Res 2007;67(11):5408-17]

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Section: Discussionmentioning

confidence: 99%

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

et al. 2007

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“…Reports as to the immunomodulatory actions of proton pump inhibitors are inconsistent. 31,32 Lansoprazole has been reported to suppress activation on peripheral blood mononuclear cells, 31 whereas omeprazole increases both the number of activated HLA-DR T cells and the expression of activation makers on blood monocytes. 32 The study by Torgano et al, 14 who used a similar regimen against H pylori and clarithromycin to treat C pneumoniae infection, is important in this context.…”

Section: Discussionmentioning

confidence: 99%

“…31,32 Lansoprazole has been reported to suppress activation on peripheral blood mononuclear cells, 31 whereas omeprazole increases both the number of activated HLA-DR T cells and the expression of activation makers on blood monocytes. 32 The study by Torgano et al, 14 who used a similar regimen against H pylori and clarithromycin to treat C pneumoniae infection, is important in this context. The effect of treatment on fibrinogen was similar in subjects with either C pneumoniae or H pylori treated with clarithromycin alone or clarithromycin as part of a triple regimen including omeprazole, suggesting no additional benefit from this agent.…”

Section: Discussionmentioning

confidence: 99%

Effect of Treatment for Chlamydia pneumoniae and Helicobacter pylori on Markers of Inflammation and Cardiac Events in Patients With Acute Coronary Syndromes

et al. 2002

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Background-Infection with Helicobacter pylori and Chlamydia pneumoniae is associated with coronary heart disease.We conducted an intervention study using antibiotics against these bacteria in patients with acute coronary syndromes to determine whether antibiotics reduce inflammatory markers and adverse cardiac events. Methods and Results-Patients (nϭ325) admitted with acute myocardial infarction or unstable angina (acute coronary syndromes) were randomized to receive a 1-week course of 1 of 3 treatment regimens: (1) placebo; (2) amoxicillin (500 mg twice daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily); or (3) azithromycin (500 mg once daily), metronidazole (400 mg twice daily), and omeprazole (20 mg twice daily). Serum fibrinogen, white cell count, and high-sensitivity C-reactive protein were measured at study entry and at 1, 3, and 12 months during follow-up. Cardiac death and readmission with acute coronary syndrome were considered clinical end points. Patients were followed for 1 year. C-reactive protein levels were reduced (Pϭ0.03) in unstable angina patients receiving amoxicillin, and fibrinogen was reduced in both patient groups receiving antibiotics (Pϭ0.06). There were 17 cardiac deaths and 71 readmissions with acute coronary syndrome. No difference in frequency or timing of end points was observed between the 2 antibiotic groups. At 12 weeks, there was a 36% reduction in all end points in patients receiving antibiotics compared with placebo (Pϭ0.02). This reduction persisted during the 1-year follow-up. Neither C pneumoniae nor H pylori antibody status was significantly related to response to treatment. Conclusions-Antibiotic treatment significantly reduced adverse cardiac events in patients with acute coronary syndromes, but the effect was independent of H pylori or C pneumoniae seropositivity.

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“…The mechanism of action by which omeprazole treatment (20 mg daily for 3 months) in duodenal ulcer patients increased the percentage of HLA-DR-positive peripheral blood lymphocytes as well as random migration, directed migration, phagocytosis index and HLA-DR expression in peripheral blood monocytesmacrophages [54] is unknown. Although both Wandall [43] and Suzuki et al [48] on the one hand, and Kountouras et al [54] on the other, discussed the either inhibitory or stimulatory effects in terms of beneficial properties of omeprazole, we consider either 'anti-inflammatory' or 'immunopotentiating' actions of any PPI as unwanted effects.…”

Section: Biological In Vitro Correlates For Ph Selectivitymentioning

confidence: 99%

“…Although both Wandall [43] and Suzuki et al [48] on the one hand, and Kountouras et al [54] on the other, discussed the either inhibitory or stimulatory effects in terms of beneficial properties of omeprazole, we consider either 'anti-inflammatory' or 'immunopotentiating' actions of any PPI as unwanted effects. Actually, they indicate effects probably at moderately acidic targets in cells other than the parietal cell.…”

Section: Biological In Vitro Correlates For Ph Selectivitymentioning

confidence: 99%

Differences in pH-Dependent Activation Rates of Substituted Benzimidazoles and Biological in vitro Correlates

Kromer

Krüger²,

Huber³

et al. 1998

Pharmacology

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Gastric proton pump inhibitors (PPIs) are substituted benzimidazole prodrugs that require an acid-induced activation. Its rate depends on the reactivity of the molecule relative to the environmental pH and determines the drug’s tissue selectivity. Factors affecting the exposure of moderately acidic tissues to the activated PPI are the area under the serum concentration-time curve (AUC), serum protein binding, the partition coefficient logP and the serum elimination half-life relative to the chemical activation half-life at a critical tissue pH of about 5. These parameters have therefore been determined in a comparative fashion in the present study. The data shows that pantoprazole is less likely to undergo unwanted activation at moderately acidic targets as opposed to the parietal cell, compared to omeprazole. Actually, although 40 mg pantoprazole (steady state) gave a slightly higher serum AUC of the total parent compound than 40 mg omeprazole (10.5 vs. 7.1 µmol × h × l^–1), a higher serum protein binding of pantoprazole versus omeprazole (98 vs. 96%) reversed the AUC values for the free drug in favor of a lower value for pantoprazole (0.19 vs. 0.28 µmol × h × 1^–1). It is the free parent compound that equilibrates across cell membranes to be activated in acidic tissue compartments. At pH 5.1, the activation half-life of pantoprazole was 4.7 versus 1.4 h for omeprazole, the latter being in the order of the common serum elimination half-life determined in an intraindividual comparison (1.24 vs. 1.25 h). Thus, pantoprazole is eliminated faster from blood than it is activated at a pH of about 5, while omeprazole is as quickly activated at this pH as it is eliminated from blood. Biological in vitro experiments confirmed that pantoprazole displays a lower liability to interfere with unwanted biological targets. This has been demonstrated in vitro for inhibition of both renal Na⁺/K⁺-ATPase, lysosomal acidification and the production of reactive oxygen species by neutrophils.

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In Vivo Effect of Omeprazole on HLA-DR Expression and the Nonocyte-Macrophage Function in Patis with Duodenal Ulcer Disease

Cited by 8 publications

References 16 publications

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

Proton Pump Inhibitors Induce Apoptosis of Human B-Cell Tumors through a Caspase-Independent Mechanism Involving Reactive Oxygen Species

Effect of Treatment for Chlamydia pneumoniae and Helicobacter pylori on Markers of Inflammation and Cardiac Events in Patients With Acute Coronary Syndromes

Differences in pH-Dependent Activation Rates of Substituted Benzimidazoles and Biological in vitro Correlates

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