47 results on '"Lansoprazole pharmacology"'
Search Results
2. Letter to the editor: lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris .
- Author
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Zhu M, Wang H, Zhang Y, and Pan F
- Subjects
- Humans, Candidiasis drug therapy, Candidiasis microbiology, Proton Pump Inhibitors pharmacology, Lansoprazole pharmacology, Amphotericin B pharmacology, Antifungal Agents pharmacology, Drug Resistance, Multiple, Fungal, Drug Synergism, Microbial Sensitivity Tests, Candida auris drug effects, Candida auris genetics
- Abstract
The study investigates the potential of lansoprazole, a proton pump inhibitor, to interfere with fungal respiration and enhance the antifungal activity of amphotericin B against multidrug-resistant Candida auris. The authors administered lansoprazole at concentrations significantly higher than typical therapeutic doses, which demonstrated promising results but also raised concerns about potential toxicity. We suggest incorporating a control group, monitoring toxicity indicators, performing pathological examinations, and conducting cellular assays to improve the study's rigor and reliability. We also highlight the need for further research into the mechanisms of lansoprazole's antifungal activity, its long-term effects on amphotericin B resistance, and potential drug-drug interactions with amphotericin B. Addressing these concerns is crucial for the clinical translation of lansoprazole as an adjuvant to amphotericin B.
- Published
- 2024
- Full Text
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3. Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris .
- Author
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Salama EA, Elgammal Y, Wijeratne A, Lanman NA, Utturkar SM, Farhangian A, Li J, Meunier B, Hazbun TR, and Seleem MN
- Subjects
- Animals, Mice, Candida auris, Lansoprazole pharmacology, Respiration, Cytochromes, Amphotericin B pharmacology, Antifungal Agents pharmacology, Candidiasis
- Abstract
Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc
1 ). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.- Published
- 2024
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4. Contribution of human organic anion transporter 3-mediated transport of a major linezolid metabolite, PNU-142586, in linezolid-induced thrombocytopenia.
- Author
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Wang D, Ikemura K, Hasegawa T, Yamane F, and Okuda M
- Subjects
- Humans, HEK293 Cells, Animals, Male, Female, Middle Aged, Retrospective Studies, Aged, Rats, Proton Pump Inhibitors adverse effects, Proton Pump Inhibitors pharmacology, Lansoprazole pharmacology, Biological Transport, Rats, Sprague-Dawley, Risk Factors, Adult, Organic Anion Transporters, Sodium-Independent metabolism, Linezolid adverse effects, Linezolid pharmacokinetics, Thrombocytopenia chemically induced, Thrombocytopenia metabolism
- Abstract
Thrombocytopenia, a common adverse effect of linezolid, often occurs in patients lacking typical risk factors. In this study, we investigated the key risk factors for linezolid-induced thrombocytopenia using two real-world clinical databases and explored its underlying mechanism through in vitro and in vivo experiments. In a retrospective analysis of 150 linezolid-treated patients, multivariate analysis identified coadministration of lansoprazole, a proton pump inhibitor, as a significant independent risk factor for thrombocytopenia (odds ratio: 2.33, p = 0.034). Additionally, analysis of the Food and Drug Administration Adverse Event Reporting System database revealed a reporting odds ratio of thrombocytopenia for lansoprazole of 1.64 (95% CI: 1.25-2.16). In vitro studies showed that the uptake of PNU-142586, a major linezolid metabolite, was significantly higher in human organic anion transporter 3-expressing HEK293 (HEK-hOAT3) cells compared to HEK-pBK cells. The apparent IC
50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38 µM. In a pharmacokinetic study using rats, coadministration of linezolid with lansoprazole intravenously resulted in approximately a 1.7-fold increase in the area under the plasma concentration-time curve of PNU-142586, but not linezolid and PNU-142300. Moreover, PNU-142586, but not linezolid, exhibited concentration-dependent cytotoxicity in a human megakaryocytic cell line. These findings suggest that linezolid-induced thrombocytopenia should be due to delayed elimination of PNU-142586. Furthermore, delayed elimination of PNU-142586 due to renal failure and hOAT3-mediated transport inhibition by lansoprazole should exacerbate linezolid-induced thrombocytopenia., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
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5. Lansoprazole protects hepatic cells against cisplatin-induced oxidative stress through the p38 MAPK/ARE/Nrf2 pathway.
- Author
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Yamagishi N, Yamamoto Y, Nishi T, Ito T, and Kanai Y
- Subjects
- Animals, Rats, Cisplatin adverse effects, NF-E2-Related Factor 2 genetics, Lansoprazole pharmacology, Oxidative Stress, Hepatocytes, Antioxidants pharmacology, p38 Mitogen-Activated Protein Kinases, Mitogen-Activated Protein Kinase 14
- Abstract
Lansoprazole, a proton pump inhibitor, can exert antioxidant effects through the induction of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, independently of the inhibition of acid secretion in the gastrointestinal tract. Lansoprazole has been reported to provide hepatoprotection in a drug-induced hepatitis animal model through the Nrf2/heme oxygenase-1 (HO1) pathway. We sought to investigate the molecular mechanism of cytoprotection by lansoprazole. An in vitro experimental model was conducted using cultured rat hepatic cells treated with lansoprazole to analyze the expression levels of Nrf2 and its downstream genes, the activity of Nrf2 using luciferase reporter assays, cisplatin-induced cytotoxicity, and signaling pathways involved in Nrf2 activation. Lansoprazole treatment of rat liver epithelial RL34 cells induced transactivation of Nrf2 and the expression of the Nrf2-dependent antioxidant genes encoding HO1, NAD(P)H quinone oxidoreductase-1, and glutathione S-transferase A2. Furthermore, cycloheximide chase experiments revealed that lansoprazole prolongs the half-life of the Nrf2 protein. Notably, cell viability was significantly increased by lansoprazole treatment in a cisplatin-induced cytotoxicity model. Moreover, the siRNA knockdown of Nrf2 fully abolished the cytoprotective effect of lansoprazole, whereas the inhibition of HO1 by tin-mesoporphyrin only partially abolished this. Finally, lansoprazole promoted the phosphorylation of p38 mitogen-activated protein kinase (MAPK) but not that of the extracellular signal-regulated kinase or the c-Jun N-terminal kinase. Using SB203580, a specific inhibitor for p38 MAPK, the lansoprazole-induced Nrf2/antioxidant response elements pathway activation and cytoprotective effects were shown to be exclusively p38 MAPK dependent. Lansoprazole was shown by these results to exert a cytoprotective effect on liver epithelial cells against the cisplatin-induced cytotoxicity through the p38 MAPK signaling pathway. This could have potential applications for the prevention and treatment of oxidative injury in the liver., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Yamagishi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
- Published
- 2023
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6. Synergistic Effect of Metformin and Lansoprazole Against Gastric Cancer through Growth Inhibition.
- Author
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Kao HW, Tsai KW, and Lin WC
- Subjects
- Animals, Humans, Lansoprazole pharmacology, Lansoprazole therapeutic use, Proton Pump Inhibitors pharmacology, Proton Pump Inhibitors therapeutic use, Metformin pharmacology, Metformin therapeutic use, Stomach Neoplasms drug therapy, Stomach Neoplasms genetics, Diabetes Mellitus, Type 2
- Abstract
Cancer has been linked to metabolic disorders and diverse gene mutations. Metformin, which is widely used to treat type 2 diabetes, inhibits the growth of cancer cells in animal models. Here we investigated the effects of metformin on human gastric cancer cell lines. We also investigated the synergistic anticancer effect of metformin and proton pump inhibitors. Lansoprazole, a proton pump inhibitor, is effective for treating gastroesophageal reflux disease. Our results revealed that metformin and lansoprazole can significantly inhibit cancer cell growth in a dose-dependent manner by suppressing cell cycle progression and inducing apoptosis. Low concentrations of metformin and lansoprazole have a synergistic effect on AGS cell growth inhibition. In summary, our findings suggest a new and safe treatment protocol for treating stomach cancers., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)
- Published
- 2023
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7. Proton pump inhibitor-induced risk of chronic kidney disease is associated with increase of indoxyl sulfate synthesis via inhibition of CYP2E1 protein degradation.
- Author
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Lu S, Zhao J, Chen X, Xu S, Yang X, Zhang Y, Ma Z, Jiang H, and Zhou H
- Subjects
- Mice, Animals, Indican, Cytochrome P-450 CYP2E1, Proteolysis, Uremic Toxins, Omeprazole pharmacology, Pantoprazole, Lansoprazole pharmacology, Proton Pump Inhibitors adverse effects, Renal Insufficiency, Chronic chemically induced
- Abstract
Proton pump inhibitors (PPIs) are widely used to treat acid-related disorders in the gastrointestinal tract; however, PPI use increases the risk of chronic kidney disease (CKD) through unclear mechanisms. Considering that PPIs disturb the gut microbiome balance, which is involved in the precursor of gut-derived uremic toxin accumulation, and that gut-derived uremic toxins aggravate CKD progression, the aim of this study is to elucidate whether PPIs affect gut-derived uremic toxin metabolism, including indoxyl sulfate (IS), p-cresyl sulfate, and trimethylamine-N-oxide, as a mechanism for causing CKD. The present study showed that 3 week-treatment of PPIs (omeprazole, lansoprazole, and pantoprazole at 30 mg/kg) in mice only increased IS plasma levels among the above three gut-derived uremic toxins. Additionally, lansoprazole increased IS plasma concentrations along with increased exposure dose (7.5-30 mg/kg) and duration (1-3 weeks). However, nephrotoxicity with mild changes in glomerular structure and signs of fibrosis were observed only in groups exposed to a 3-week treatment of PPIs (30 mg/kg). As the concentrations of indole (the precursor of IS from gut metabolism) in the colon were only increased in the pantoprazole-treated group, the mechanism of increased IS exposure remains unclear. Further studies revealed that PPIs (omeprazole and lansoprazole; but not pantoprazole) increased IS production from indole in primary mouse hepatocytes in a concentration-dependent manner. Additionally, the increased protein levels of hepatic CYP2E1 (the key enzyme mediating IS formation) due to suppressed degradation resulted in an increase in IS levels. Although omeprazole and lansoprazole significantly inhibited IS uptake in hOAT1/3 in vitro, 3 weeks of PPI treatment did not reduce IS renal excretion in mice. In conclusion, PPIs induced IS synthesis via increased hepatic CYP2E1 protein level, subsequently leading to increased IS exposure. These findings present a plausible biological mechanism to explain the association of PPI use with the increased risk of CKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
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8. Efficacy of soluble lansoprazole-impregnated beta-tricalcium phosphate for bone regeneration.
- Author
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Mishima K, Okabe YT, Mizuno M, Ohno K, Kitoh H, and Imagama S
- Subjects
- Animals, Humans, Rabbits, Lansoprazole pharmacology, Calcium Phosphates pharmacology, Bone Regeneration, Osteogenesis, Lagomorpha
- Abstract
The proton pump inhibitor lansoprazole has been previously identified to upregulate the expression and transcriptional activity of runt-related transcription factor 2 (Runx2) that promotes lineage commitment and differentiation of osteoprogenitor cells. We could not elicit the expected efficacy of insoluble lansoprazole in enhancing osteogenesis when combined with beta-tricalcium phosphate (β-TCP) bone substitutes. This study aimed to evaluate the effects of soluble lansoprazole on in vitro osteoblastogenesis and new bone formation in vivo. Commercially available human mesenchymal stem cells or patient-derived bone marrow-derived stromal cells were treated with 20 µM of soluble lansoprazole at the beginning of osteogenic induction. Soluble lansoprazole-impregnated β-TCP materials were embedded in the cortical bone defect model of rabbits. Rabbits were sacrificed four weeks postoperatively and undecalcified bone specimens were prepared for evaluation of intra-material new bone formation. Only a 1-day treatment with soluble lansoprazole facilitated osteoblastic differentiation and matrix calcium deposition when added to undifferentiated human mesenchymal stromal cells at the beginning of the osteogenic differentiation. Soluble lansoprazole dose-dependently accelerated intra-material new bone formation when being impregnated with porous β-TCP artificial bones. Local use of soluble lansoprazole can be applicable for fracture and bone defect repair when combined with porous β-TCP scaffolds., (© 2022. The Author(s).)
- Published
- 2022
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9. Lansoprazole and zoledronate delays hard tissue healing of tooth extraction sockets in dexamethasone-treated mice.
- Author
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Yoshioka R, Mine Y, Kaku M, Nikawa H, and Murayama T
- Subjects
- Animals, Dexamethasone adverse effects, Diphosphonates pharmacology, Imidazoles, Lansoprazole pharmacology, Mice, Mice, Inbred C57BL, Tooth Extraction adverse effects, Tooth Socket pathology, X-Ray Microtomography, Zoledronic Acid pharmacology, Bisphosphonate-Associated Osteonecrosis of the Jaw drug therapy, Bisphosphonate-Associated Osteonecrosis of the Jaw etiology, Bisphosphonate-Associated Osteonecrosis of the Jaw pathology, Bone Density Conservation Agents pharmacology
- Abstract
Proton pump inhibitors (PPIs) are among the most commonly prescribed medicines for the management of acid-related gastrointestinal diseases. Osteonecrosis of the jaw (ONJ) is a serious adverse event that is associated with the use of antiresorptive and antiangiogenic agents. According to previous clinical reports, the use of PPIs contributes to the pathogenesis of severe ONJ that requires surgery. Here, we investigated the effects of lansoprazole (LP) or LP in combination with zoledronate (ZOL) on ONJ development in mice. C57BL/6J mice were administered ZOL (125 μg/kg intravenously, twice weekly) and/or LP (10 mg/kg intraperitoneally; 3 weeks of 3 consecutive days followed by 1 day off). One week after initiation of the study, the first molar was atraumatically extracted. Concurrently with ZOL administration, dexamethasone (Dex) was administered (5 mg/kg intraperitoneally, twice weekly). Micro-computed tomography and histological evaluation were performed to characterize femoral structures, tooth extraction sockets, and osteonecrosis areas. The results showed that ZOL/Dex significantly increased bone mass compared to saline/Dex, while the simultaneous administration of LP and ZOL/Dex diminished the ZOL-induced enhancement of bone mass. In the alveolar bone around the tooth extraction socket, necrotic bone was significantly increased in the LP/Dex group compared to the saline/Dex group. However, no signs of more severe ONJ-like lesions were observed following combined administration of LP and ZOL/Dex, other than an increase in the number of non-attached TRAP-positive cells. Our findings in a mouse model suggest that LP use can be a risk factor for the development of ONJ., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2022
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10. Repurposing Lansoprazole and Posaconazole to treat leishmaniasis: Integration of in vitro testing, pharmacological corroboration, and mechanisms of action.
- Author
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Gupta Y, Goicoechea S, Romero JG, Mathur R, Caulfield TR, Becker DP, Durvasula R, and Kempaiah P
- Subjects
- Drug Repositioning, Humans, In Vitro Techniques, Lansoprazole pharmacology, Lansoprazole therapeutic use, Triazoles, Antiprotozoal Agents pharmacology, Antiprotozoal Agents therapeutic use, Leishmania, Leishmaniasis drug therapy, Leishmaniasis parasitology
- Abstract
Leishmaniasis remains a serious public health problem in many tropical regions of the world. Among neglected tropical diseases, the mortality rate of leishmaniasis is second only to malaria. All currently approved therapeutics have toxic side effects and face rapidly increasing resistance. To identify existing drugs with antileishmanial activity and predict the mechanism of action, we designed a drug-discovery pipeline utilizing both in-silico and in-vitro methods. First, we screened compounds from the Selleckchem Bio-Active Compound Library containing ~1622 FDA-approved drugs and narrowed these down to 96 candidates based on data mining for possible anti-parasitic properties. Next, we completed preliminary in-vitro testing of compounds against Leishmania amastigotes and selected the most promising active compounds, Lansoprazole and Posaconazole. We identified possible Leishmania drug targets of Lansoprazole and Posaconazole using several available servers. Our in-silico screen identified likely Lansoprazole targets as the closely related calcium-transporting ATPases (LdBPK_352080.1, LdBPK_040010.1, and LdBPK_170660.1), and the Posaconazole target as lanosterol 14-alpha-demethylase (LdBPK_111100.1). Further validation showed LdBPK_352080.1 to be the most plausible target based on induced-fit docking followed by long (100ns) MD simulations to confirm the stability of the docked complexes. We present a likely ion channel-based mechanism of action of Lansoprazole against Leishmania calcium-transporting ATPases, which are essential for parasite metabolism and infectivity. The LdBPK_111100.1 interaction with Posaconazole is very similar to the known fungal orthologue. Herein, we present two novel anti-leishmanial agents, Posaconazole and Lansoprazole, already approved by the FDA for different indications and propose plausible mechanisms of action for their antileishmanial activity.
- Published
- 2022
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11. Enhanced Antigiardial Effect of Omeprazole Analog Benzimidazole Compounds.
- Author
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Hernández-Ochoa B, Gómez-Manzo S, Sánchez-Carrillo A, Marcial-Quino J, Rocha-Ramírez LM, Santos-Segura A, Ramírez-Nava EJ, Arreguin-Espinosa R, Cuevas-Cruz M, Méndez-Tenorio A, and Calderón-Jaimes E
- Subjects
- Antiprotozoal Agents chemical synthesis, Antiprotozoal Agents chemistry, Benzimidazoles chemical synthesis, Benzimidazoles chemistry, Caco-2 Cells, Cell Death drug effects, Cell Survival drug effects, Circular Dichroism, Drug Design, Drug Evaluation, Preclinical, Enzyme Activation drug effects, Giardia lamblia enzymology, HT29 Cells, Humans, Kinetics, Lansoprazole pharmacology, Molecular Docking Simulation, Omeprazole chemical synthesis, Omeprazole chemistry, Spectrometry, Fluorescence, Triose-Phosphate Isomerase antagonists & inhibitors, Triose-Phosphate Isomerase chemistry, Trophozoites drug effects, Antiprotozoal Agents pharmacology, Benzimidazoles pharmacology, Giardia lamblia drug effects, Omeprazole pharmacology
- Abstract
Giardiasis is a diarrheal disease that is highly prevalent in developing countries. Several drugs are available for the treatment of this parasitosis; however, failures in drug therapy are common, and have adverse effects and increased resistance of the parasite to the drug, generating the need to find new alternative treatments. In this study, we synthesized a series of 2-mercaptobenzimidazoles that are derivatives of omeprazole, and the chemical structures were confirmed through mass,
1 H NMR, and13 C NMR techniques. The in vitro efficacy compounds against Giardia , as well as its effect on the inhibition of triosephosphate isomerase (TPI) recombinant, were investigated, the inactivation assays were performed with 0.2 mg/mL of the enzyme incubating for 2 h at 37 °C in TE buffer, pH 7.4 with increasing concentrations of the compounds. Among the target compounds, H-BZM2 , O2 N-BZM7 , and O2 N-BZM9 had greater antigiardial activity (IC50 : 36, 14, and 17 µM on trophozoites), and inhibited the TPI enzyme ( K2 : 2.3, 3.2, and 2.8 M-1 s-1 ) respectively, loading alterations on the secondary structure, global stability, and tertiary structure of the TPI protein. Finally, we demonstrated that it had low toxicity on Caco-2 and HT29 cells. This finding makes it an attractive potential starting point for new antigiardial drugs.- Published
- 2020
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12. Computational discovery of therapeutic candidates for preventing preterm birth.
- Author
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Le BL, Iwatani S, Wong RJ, Stevenson DK, and Sirota M
- Subjects
- Drug Repositioning, Female, Humans, Infant, Newborn, Pregnancy, Computational Biology, Fetus drug effects, Lansoprazole pharmacology, Premature Birth prevention & control
- Abstract
Few therapeutic methods exist for preventing preterm birth (PTB), or delivery before completing 37 weeks of gestation. In the US, progesterone (P4) supplementation is the only FDA-approved drug for use in preventing recurrent spontaneous PTB. However, P4 has limited effectiveness, working in only approximately one-third of cases. Computational drug repositioning leverages data on existing drugs to discover novel therapeutic uses. We used a rank-based pattern-matching strategy to compare the differential gene expression signature for PTB to differential gene expression drug profiles in the Connectivity Map database and assigned a reversal score to each PTB-drug pair. Eighty-three drugs, including P4, had significantly reversed differential gene expression compared with that found for PTB. Many of these compounds have been evaluated in the context of pregnancy, with 13 belonging to pregnancy category A or B - indicating no known risk in human pregnancy. We focused our validation efforts on lansoprazole, a proton-pump inhibitor, which has a strong reversal score and a good safety profile. We tested lansoprazole in an animal inflammation model using LPS, which showed a significant increase in fetal viability compared with LPS treatment alone. These promising results demonstrate the effectiveness of the computational drug repositioning pipeline to identify compounds that could be effective in preventing PTB.
- Published
- 2020
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13. Proton Pump Inhibitor-Treated H. pylori Adjust Cell Envelope Fatty Acid and Cholesterol Content to Survive.
- Author
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Kadkhodaei S, Siavoshi F, Foroumadi A, Sarrafnejad A, and Kolahdoozan S
- Subjects
- Cell Membrane chemistry, Helicobacter pylori cytology, Lansoprazole pharmacology, Microbial Sensitivity Tests, Microbial Viability drug effects, Pantoprazole pharmacology, Cholesterol analysis, Fatty Acids analysis, Helicobacter pylori drug effects, Proton Pump Inhibitors pharmacology
- Abstract
Background: Proton pump inhibitors (PPIs) with lipophilic nature may interact with lipid components of H. pylori cell membrane, disrupting cell structure and viability. In this study, the effect of PPIs on fatty acid and cholesterol components of H. pylori cell membrane was assessed., Methods: One H. pylori isolate was treated with 1X and 2X MICs (μg/mL) of lansoprazole (LPZ: 8 and 16) and pantoprazole (PAN: 128 and 256) in brain heart infusion broth plus serum. Treated H. pylori was cultured on brucella blood agar (BBA) and tetrazolium egg yolk agar (TEYA). Bacterial cells stained with Live/Dead kit were examined by fluorescent microscopy. Fatty acid and cholesterol contents of treated H. pylori were measured by gas chromatography., Results: PPI-treated H. pylori did not grow on BBA but grew on TEYA. Fluorescent microscopy showed H. pylori stained red. Analyses showed high frequency of saturated fatty acids, C14:0, C16:0 and C18:0. Among unsaturated fatty acids, C18:1 and C18:2c were increased, while five were eliminated and five were synthesized de novo. Cholesteryl-6-O-tetradecanoyl-α-D- glucopyranoside was detected as the only glycosylated cholesterol in treated H. pylori. Growth of PPI-treated H. pylori on cholesterol-rich TEYA showed that occurrence of cholesterol can reverse the growth inhibition by PPIs. Red- bacilli form of H. pylori showed dye entry through damaged cell membrane without lysis., Conclusion: Incorporation of lipophilic PPI into H. pylori cell membrane disrupted lipids and inhibited growth. However, H. pylori adjusted the defected membrane by replacing the lipid components and resisted lysis., (© 2020 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.)
- Published
- 2020
14. Lansoprazole alleviates pressure overload-induced cardiac hypertrophy and heart failure in mice by blocking the activation of β-catenin.
- Author
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Lin H, Li Y, Zhu H, Wang Q, Chen Z, Chen L, Zhu Y, Zheng C, Wang Y, Liao W, Bin J, Kitakaze M, and Liao Y
- Subjects
- Animals, Aorta physiopathology, Aorta surgery, Cell Proliferation drug effects, Cells, Cultured, Constriction, Disease Models, Animal, Fibroblasts drug effects, Fibroblasts metabolism, Fibroblasts pathology, Fibrosis, Glycogen Synthase Kinase 3 beta metabolism, Heart Failure metabolism, Heart Failure pathology, Heart Failure physiopathology, Hypertrophy, Left Ventricular metabolism, Hypertrophy, Left Ventricular pathology, Hypertrophy, Left Ventricular physiopathology, Male, Mice, Inbred C57BL, Myocytes, Cardiac metabolism, Myocytes, Cardiac pathology, Phosphorylation, Proto-Oncogene Proteins c-akt metabolism, Rats, Signal Transduction, beta Catenin metabolism, Heart Failure prevention & control, Hypertrophy, Left Ventricular prevention & control, Lansoprazole pharmacology, Myocytes, Cardiac drug effects, Proton Pump Inhibitors pharmacology, Ventricular Function, Left drug effects, Ventricular Remodeling drug effects, beta Catenin antagonists & inhibitors
- Abstract
Aims: Proton pump inhibitors (PPIs) are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding, but whether PPIs are beneficial for the heart is controversial. Here, we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure, as well as the underlying mechanisms., Methods and Results: Adult male C57 mice were subjected to transverse aortic constriction (TAC) or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks. In addition, cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin II in the presence or absence of lansoprazole. At 5 weeks after TAC, the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice, as was the lung weight/body weight ratio, while left ventricular (LV) fractional shortening and the maximum and minimum rates of change of the LV pressure were higher in lansoprazole-treated mice, along with less cardiac fibrosis. In cultured cardiomyocytes, lansoprazole inhibited angiotensin II-induced protein synthesis and hypertrophy, as well as inhibiting proliferation of fibroblasts. Lansoprazole decreased myocardial levels of phosphorylated Akt, phosphorylated glycogen synthase kinase 3β, and active β-catenin in TAC mice and in angiotensin II-stimulated cardiomyocytes. After overexpression of active β-catenin or knockdown of H+/K+-ATPase α-subunit, lansoprazole still significantly attenuated myocyte hypertrophy., Conclusion: Lansoprazole inhibits cardiac remodelling by suppressing activation of the Akt/GSK3β/β-catenin pathway independent of H+/K+-ATPase inhibition, and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodelling., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2020
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15. Proton pump inhibitors attenuate myofibroblast formation associated with thyroid eye disease through the aryl hydrocarbon receptor.
- Author
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Hammond CL, Roztocil E, Phipps RP, Feldon SE, and Woeller CF
- Subjects
- Actins metabolism, Calcium-Binding Proteins metabolism, Cell Differentiation drug effects, Cells, Cultured, Cicatrix metabolism, Cicatrix pathology, Cicatrix prevention & control, Collagen metabolism, Esomeprazole pharmacology, Fibroblasts drug effects, Fibroblasts metabolism, Graves Ophthalmopathy pathology, HEK293 Cells, Humans, Lansoprazole pharmacology, Microfilament Proteins metabolism, Myofibroblasts metabolism, Receptors, Aryl Hydrocarbon genetics, Transforming Growth Factor beta metabolism, Wnt Signaling Pathway drug effects, Calponins, Graves Ophthalmopathy metabolism, Myofibroblasts drug effects, Proton Pump Inhibitors pharmacology, Receptors, Aryl Hydrocarbon metabolism
- Abstract
Thyroid eye disease (TED) can lead to scar formation and tissue remodeling in the orbital space. In severe cases, the scarring process leads to sight-threatening pathophysiology. There is no known effective way to prevent scar formation in TED patients, or to reverse scarring once it occurs. In this study, we show that the proton pump inhibitors (PPIs), esomeprazole and lansoprazole, can prevent transforming growth factor beta (TGFβ)-mediated differentiation of TED orbital fibroblasts to myofibroblasts, a critical step in scar formation. Both PPIs prevent TGFβ-induced increases in alpha-smooth muscle actin (αSMA), calponin, and collagen production and reduce TED orbital fibroblast cell proliferation and migration. Esomeprazole and lansoprazole exert these effects through an aryl hydrocarbon receptor (AHR)-dependent pathway that includes reducing β-catenin/Wnt signaling. We conclude that PPIs are potentially useful therapies for preventing or treating TED by reducing the myofibroblast accumulation that occurs in the disease., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2019
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16. Helicobacter suis infection is associated with nodular gastritis-like appearance of gastric mucosa-associated lymphoid tissue lymphoma.
- Author
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Takigawa H, Masaki S, Naito T, Yuge R, Urabe Y, Tanaka S, Sentani K, Matsuo T, Matsuo K, Chayama K, and Kitadai Y
- Subjects
- Adult, Amoxicillin pharmacology, Clarithromycin pharmacology, DNA, Bacterial genetics, Drug Therapy, Combination, Gastritis drug therapy, Helicobacter Infections drug therapy, Helicobacter Infections epidemiology, Helicobacter heilmannii drug effects, Helicobacter heilmannii genetics, Humans, Lansoprazole pharmacology, Lymphoma, B-Cell, Marginal Zone drug therapy, Male, Middle Aged, Prevalence, Treatment Outcome, Amoxicillin therapeutic use, Clarithromycin therapeutic use, Gastritis microbiology, Helicobacter Infections diagnosis, Helicobacter heilmannii isolation & purification, Lansoprazole therapeutic use, Lymphoma, B-Cell, Marginal Zone microbiology
- Abstract
Most patients with gastric mucosa-associated lymphoid tissue (MALT) lymphoma are infected with Helicobacter pylori, and eradication therapy is the first-line treatment for localized disease with H pylori infection. However, there were several reports showing effectiveness of eradication therapy in even H pylori negative cases. Gastric MALT lymphomas are endoscopically classified into three common types: superficial, ulcerative, and elevated types. For the past 20 years, we have encountered 200 cases of localized gastric MALT lymphoma. Among them, only 4 cases (2%) showed similar macroscopic findings to those of nodular gastritis (gastric MALT lymphoma with nodular gastritis-like appearance; M-NGA). Here, we compared clinicopathological characteristics and prevalence of non-H pylori Helicobacter (NHPH) infection between M-NGA and other common types of gastric MALT lymphoma. To examine the prevalence of NHPH infection, DNA was extracted from formalin-fixed paraffin-embedded biopsy tissues from four cases of M-NGA, 20 cases of common endoscopic types of gastric MALT lymphoma, and 10 cases of nodular gastritis. We used a highly sensitive polymerase chain reaction assay to detect the presence of five species of NHPH (Helicobacter suis, H felis, H bizzozeronii, H salomonis, and H heilmannii). H suis infection was detected in 4, 2, and 0 of the 4, 20, and 10 cases of M-NGA, other types of gastric MALT lymphoma, and nodular gastritis, respectively. Other NHPH species were not detected in any cases. Complete response rate by eradication therapy was 4/4 in M-NGA cases. Therefore, nodular gastritis-like MALT lymphoma, which shows a very rare phenotype, is closely associated with NHPH infection, and eradication therapy may be the first-choice treatment., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)
- Published
- 2019
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17. Proton pump inhibitors versus Cryptococcus species: effects on in vitro susceptibility and melanin production.
- Author
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Brilhante RS, da Rocha MG, de Oliveira JS, España JD, Pereira VS, Scm Castelo-Branco D, A Pereira-Neto W, Sidrim JJ, A Cordeiro R, and Rocha MF
- Subjects
- Adenosine Triphosphatases, Copper, Copper Sulfate metabolism, Cryptococcus growth & development, Culture Media chemistry, Esomeprazole pharmacology, Glutathione metabolism, Glycine analogs & derivatives, Humans, Lansoprazole pharmacology, Microbial Sensitivity Tests, Omeprazole pharmacology, Pantoprazole pharmacology, Rabeprazole pharmacology, Glyphosate, Antifungal Agents pharmacology, Cryptococcus drug effects, Cryptococcus metabolism, Melanins biosynthesis, Proton Pump Inhibitors pharmacology
- Abstract
Aim: This study aimed to evaluate the effects of proton pump inhibitors (PPIs) on growth and melanin production by Cryptococcus spp. Materials & methods: Minimum inhibitory concentrations (MICs) of omeprazole, esomeprazole, rabeprazole, pantoprazole and lansoprazole against Cryptococcus spp. were determined and the effect of PPIs on melanin production was evaluated, in the presence or absence of copper sulfate or glutathione. Results: PPIs showed MICs ranging from 125-1000 μg/ml and decreased melanization by Cryptococcus cells. Addition of copper sulfate or gluthatione restored melanogenesis of cells grown in the presence of PPIs. The presence of PPIs and glyphosate decreased copper sulfate toxicity (1 mM). Conclusion: PPIs inhibited melanogenesis of Cryptococcus spp., possibly by chelating copper or inhibiting copper ATPase transport.
- Published
- 2019
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18. No Evidence for Acquired Mutations Associated with Cytochrome bc 1 Inhibitor Resistance in 13,559 Clinical Mycobacterium tuberculosis Complex Isolates.
- Author
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Rybniker J, Kohl TA, Barilar I, and Niemann S
- Subjects
- Humans, Lansoprazole analogs & derivatives, Microbial Sensitivity Tests, Mycobacterium tuberculosis isolation & purification, Tuberculosis, Multidrug-Resistant drug therapy, Antitubercular Agents pharmacology, Electron Transport Complex III antagonists & inhibitors, Lansoprazole pharmacology, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis genetics, Tuberculosis, Multidrug-Resistant genetics
- Published
- 2018
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19. Inhibition of Gastric H + ,K + -ATPase Activity in Vitro by Dissolution Media of Original Brand-Name and Generic Tablets of Lansoprazole, a Proton Pump Inhibitor.
- Author
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Phutthatiraphap S, Hayashi Y, Fujii T, Kosugi A, Okada K, Kadozaki T, Ishise T, Sakai H, and Onuki Y
- Subjects
- Adenosine Triphosphatases metabolism, Administration, Oral, Animals, Drugs, Generic, Humans, Lansoprazole chemistry, Proton Pump Inhibitors chemistry, Solubility, Stomach cytology, Stomach enzymology, Swine, Tablets, Therapeutic Equivalency, Adenosine Triphosphatases antagonists & inhibitors, Lansoprazole pharmacology, Proton Pump Inhibitors pharmacology
- Abstract
To investigate the inhibitory effect of a commercial proton pump inhibitor (lansoprazole) on the gastric proton pump H
+ ,K+ -ATPase in vitro, we used orally disintegrating (OD) tablets including original brand-name and generic tablets. In the course of the development of generic products, dissolution and clinical tests are necessary to ensure their bioequivalence to the original brand-name products; by contrast, there is almost no opportunity to demonstrate their activity in vitro. This study initially compared the similarity of the dissolution of test generic tablets with that of the original brand-name tablets. The dissolution tests for 15 and 30-mg lansoprazole tablets found their dissolution properties were similar. Subsequently, the dissolution media were sampled and then their effects on the H+ ,K+ -ATPase activity were measured using tubulovesicles prepared from the gastric mucosa of hogs. We confirmed that the inhibitory effects of the generic tablets on H+ ,K+ -ATPase activity were consistent with those of the original brand-name tablets. Furthermore, lansoprazole contents in each tablet estimated from their inhibitory effects were in good agreement with their active pharmaceutical ingredient content. To our knowledge, this is the first technical report to compare the in vitro biochemical activity of lansoprazole OD tablets between the original brand-name and generic commercial products.- Published
- 2018
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20. Lansoprazole halts contrast induced nephropathy through activation of Nrf2 pathway in rats.
- Author
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Khaleel SA, Alzokaky AA, Raslan NA, Alwakeel AI, Abd El-Aziz HG, and Abd-Allah AR
- Subjects
- Administration, Oral, Animals, Contrast Media toxicity, Fluorescent Antibody Technique, Kidney pathology, Male, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Nephritis chemically induced, Rats, Rats, Wistar, Real-Time Polymerase Chain Reaction, Up-Regulation drug effects, Heme Oxygenase-1 metabolism, Kidney drug effects, Lansoprazole pharmacology, Lansoprazole therapeutic use, NF-E2-Related Factor 2 drug effects, Nephritis drug therapy, Signal Transduction drug effects
- Abstract
Contrast-induced nephropathy (CIN) is an important cause of acute kidney injury characterized by significant mortality and morbidity. To date, there is no successful protective regimen for CIN especially in poor kidney function patients. Lansoprazole has been shown to exert antioxidant action through induction of nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. The aim of the present study is to investigate the potential of lansoprazole to activate Nrf2 pathway in the kidney and consequently to protect against oxidative stress induced by iodinated contrast media. Lansoprazole, at a dose of 100 mg/kg, showed a significant induction of Nrf2 mRNA after 3 h. Administration of contrast media induced significant increase in serum creatinine and blood urea nitrogen, histological deterioration, and reduction in total antioxidant capacity. Moreover, it instigated the defensive Nrf2 gene expression and immunoreactivity. In addition, there were overexpression of HO-1, caspase 3, p53 and IL6 genes and downregulation of Bcl2 gene. Pre-treatment with lansoprazole (100 mg/kg) ameliorated the nephrotoxicity parameters and oxidative stress, improved histological lesions, and hijacked apoptotic and inflammatory markers that were provoked by contrast media. In conclusion, lansoprazole attenuates experimental CIN which might be due to activation of Nrf2 antioxidant defence pathway. These findings highlight the potential benefit of incorporating lansoprazole in the protective regimen against CIN especially for susceptible patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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21. Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects.
- Author
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Keyvanjah K, DiPrimeo D, Li A, Obaidi M, Swearingen D, and Wong A
- Subjects
- Adult, Cross-Over Studies, Female, Healthy Volunteers, Humans, Male, Middle Aged, Protein Kinase Inhibitors adverse effects, Protein Kinase Inhibitors blood, Protein Kinase Inhibitors pharmacokinetics, Proton Pump Inhibitors pharmacology, Quinolines adverse effects, Quinolines blood, Drug Interactions, Lansoprazole pharmacology, Quinolines pharmacokinetics
- Abstract
Aims: To evaluate the effect of lansoprazole, a proton-pump inhibitor, on the absorption, pharmacokinetics, and safety of neratinib, a pan-HER tyrosine kinase inhibitor, in healthy subjects., Methods: This was an open-label, two-period, fixed-sequence study. Fifteen healthy adult subjects received a single oral dose of neratinib 240 mg (Period 1), followed by a washout period, then oral lansoprazole 30 mg once daily for 7 days and a single dose of neratinib 240 mg on Day 5 (Period 2). Pharmacokinetic sampling was performed for 72 h following each neratinib dose. Plasma neratinib concentration-time data were analysed using noncompartmental methods. Geometric mean ratios for AUC
0-t , AUC0-inf , and peak plasma concentrations (Cmax ) for neratinib plus lansoprazole vs. neratinib were used to assess the magnitude of the drug-drug interaction if the 90% confidence intervals were outside 80.00-125.00%., Results: Neratinib geometric least-squares mean (LSM) Cmax was reduced from 84.5 ng ml-1 with neratinib alone to 24.5 ng ml-1 with neratinib plus lansoprazole. The extent of exposure to neratinib was also decreased: geometric LSM AUC0-t was 1478 ng ml-1 h with neratinib vs. 426 ng ml-1 h with neratinib plus lansoprazole, and geometric LSM AUC0-inf was 1557 ng ml-1 h vs. 542 ng ml-1 h, respectively. Mean t½ was similar with both treatments (approximately 14 h). Geometric mean ratios 90% confidence intervals for AUC0-t , AUC0-inf and Cmax fell outside the prespecified equivalence range (80.0-125.0%). Treatment-emergent adverse events, all mild, were reported by five (33%) subjects., Conclusions: Coadministration of lansoprazole with neratinib reduced the rate and extent of neratinib exposure in healthy subjects., (© 2016 The British Pharmacological Society.)- Published
- 2017
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22. Antitumor effect of combination of the inhibitors of two new oncotargets: proton pumps and reverse transcriptase.
- Author
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Lugini L, Sciamanna I, Federici C, Iessi E, Spugnini EP, and Fais S
- Subjects
- Alkynes, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Cyclopropanes, Drug Evaluation, Preclinical, Drug Synergism, Humans, Melanoma drug therapy, Spheroids, Cellular cytology, Spheroids, Cellular drug effects, Tumor Microenvironment drug effects, Antineoplastic Combined Chemotherapy Protocols pharmacology, Benzoxazines pharmacology, Lansoprazole pharmacology, Melanoma metabolism, Proton Pump Inhibitors pharmacology, Reverse Transcriptase Inhibitors pharmacology
- Abstract
Tumor therapy needs new approaches in order to improve efficacy and reduce toxicity of the current treatments. The acidic microenvironment and the expression of high levels of endogenous non-telomerase reverse transcriptase (RT) are common features of malignant tumor cells. The anti-acidic proton pump inhibitor Lansoprazole (LAN) and the non-nucleoside RT inhibitor Efavirenz (EFV) have shown independent antitumor efficacy. LAN has shown to counteract drug tumor resistance. We tested the hypothesis that combination of LAN and EFV may improve the overall antitumor effects. We thus pretreated human metastatic melanoma cells with LAN and then with EFV, both in 2D and 3D spheroid models. We evaluated the treatment effect by proliferation and cell death/apoptosis assays in classical and in pulse administration experiments. The action of EFV was negatively affected by the tumor microenvironmental acidity, and LAN pretreatment overcame the problem. LAN potentiated the cytotoxicity of EFV to melanoma cells and, when administered during the drug interruption period, prevented the replacement of tumor cell growth.This study supports the implementation of the current therapies with combination of Proton Pumps and Reverse Transcriptase inhibitors.
- Published
- 2017
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23. Impact of Long-Term Proton Pump Inhibitor Therapy on Gut Microbiota in F344 Rats: Pilot Study.
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Shin CM, Kim N, Kim YS, Nam RH, Park JH, Lee DH, Seok YJ, Kim YR, Kim JH, Kim JM, Kim JS, and Jung HC
- Subjects
- Animals, Ileum drug effects, Ileum microbiology, Male, Pilot Projects, RNA, Ribosomal, 16S genetics, Rats, Rats, Inbred F344, Sequence Analysis, DNA methods, Time, Gastrointestinal Microbiome drug effects, Lansoprazole pharmacology, Proton Pump Inhibitors pharmacology
- Abstract
Background/aims: To evaluate changes in gut microbiota composition following long-term proton pump inhibitor (PPI) treatment., Methods: Twenty-four-week-old F344 rats were fed diets with (n=6) or without (n=5) lansoprazole for 50 weeks. Profiles of luminal microbiota in the terminal ileum were then analyzed. Pyrosequencing of the 16S rRNA gene was performed using an FLX genome sequencer (454 Life Sciences/Roche)., Results: Rats treated with lansoprazole showed significantly reduced body weights compared to controls (lansoprazole-treated rats and controls, 322.3±15.3 g vs 403.2±5.2 g, respectively, p<0.001). However, stool frequencies and consistencies did not differ between the two groups. The composition of the gut microbiota in lansoprazole-treated rats was quite different from that of the controls. In the controls, the microbiota profiles obtained from the terminal ileum showed a predominance of Proteobacteria (93.9%) due to the abundance of Escherichia and Pasteurella genera. Conversely, lansoprazole-treated rats showed an elevated population of Firmicutes (66.9%), which was attributed to an increased ratio of Clostridium g4 to Lactobacillus genera., Conclusions: This preliminary study suggests that long-term administration of PPI may cause weight loss and changes to the microbiota in the terminal ileum.
- Published
- 2016
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24. Coupling Data Mining and Laboratory Experiments to Discover Drug Interactions Causing QT Prolongation.
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Lorberbaum T, Sampson KJ, Chang JB, Iyer V, Woosley RL, Kass RS, and Tatonetti NP
- Subjects
- Aged, Ceftriaxone adverse effects, Cefuroxime adverse effects, Drug Interactions, Drug-Related Side Effects and Adverse Reactions, Electronic Health Records, Electrophysiologic Techniques, Cardiac, Female, Humans, Lansoprazole adverse effects, Male, Middle Aged, Patch-Clamp Techniques, Proton Pump Inhibitors adverse effects, Ceftriaxone pharmacology, Cefuroxime pharmacology, Data Mining, Lansoprazole pharmacology, Long QT Syndrome chemically induced, Proton Pump Inhibitors pharmacology
- Abstract
Background: QT interval-prolonging drug-drug interactions (QT-DDIs) may increase the risk of life-threatening arrhythmia. Despite guidelines for testing from regulatory agencies, these interactions are usually discovered after drugs are marketed and may go undiscovered for years., Objectives: Using a combination of adverse event reports, electronic health records (EHR), and laboratory experiments, the goal of this study was to develop a data-driven pipeline for discovering QT-DDIs., Methods: 1.8 million adverse event reports were mined for signals indicating a QT-DDI. Using 1.6 million electrocardiogram results from 380,000 patients in our institutional EHR, these putative interactions were either refuted or corroborated. In the laboratory, we used patch-clamp electrophysiology to measure the human ether-à-go-go-related gene (hERG) channel block (the primary mechanism by which drugs prolong the QT interval) to evaluate our top candidate., Results: Both direct and indirect signals in the adverse event reports provided evidence that the combination of ceftriaxone (a cephalosporin antibiotic) and lansoprazole (a proton-pump inhibitor) will prolong the QT interval. In the EHR, we found that patients taking both ceftriaxone and lansoprazole had significantly longer QTc intervals (up to 12 ms in white men) and were 1.4 times more likely to have a QTc interval above 500 ms. In the laboratory, we found that, in combination and at clinically relevant concentrations, these drugs blocked the hERG channel. As a negative control, we evaluated the combination of lansoprazole and cefuroxime (another cephalosporin), which lacked evidence of an interaction in the adverse event reports. We found no significant effect of this pair in either the EHR or in the electrophysiology experiments. Class effect analyses suggested this interaction was specific to lansoprazole combined with ceftriaxone but not with other cephalosporins., Conclusions: Coupling data mining and laboratory experiments is an efficient method for identifying QT-DDIs. Combination therapy of ceftriaxone and lansoprazole is associated with increased risk of acquired long QT syndrome., (Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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25. Lansoprazole Exacerbates Pemetrexed-Mediated Hematologic Toxicity by Competitive Inhibition of Renal Basolateral Human Organic Anion Transporter 3.
- Author
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Ikemura K, Hamada Y, Kaya C, Enokiya T, Muraki Y, Nakahara H, Fujimoto H, Kobayashi T, Iwamoto T, and Okuda M
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carboplatin administration & dosage, Carcinoma, Non-Small-Cell Lung drug therapy, Drug Interactions, Female, Folic Acid Antagonists administration & dosage, Folic Acid Antagonists adverse effects, HEK293 Cells, Humans, Kidney metabolism, Lansoprazole administration & dosage, Lung Neoplasms drug therapy, Male, Middle Aged, Pemetrexed administration & dosage, Pemetrexed adverse effects, Retrospective Studies, Folic Acid Antagonists pharmacology, Hematologic Tests, Kidney drug effects, Lansoprazole pharmacology, Organic Anion Transporters, Sodium-Independent antagonists & inhibitors, Pemetrexed pharmacology, Proton Pump Inhibitors pharmacology
- Abstract
Pemetrexed, a multitargeted antifolate, is eliminated by tubular secretion via human organic anion transporter 3 (hOAT3). Although proton pump inhibitors (PPIs) are frequently used in cancer patients, the drug interaction between PPIs and pemetrexed remains to be clarified. In this study, we examined the drug interaction between pemetrexed and PPIs in hOAT3-expressing cultured cells, and retrospectively analyzed the impact of PPIs on the development of hematologic toxicity in 108 patients who received pemetrexed and carboplatin treatment of nonsquamous non-small cell lung cancer for the first time between January 2011 and June 2015. We established that pemetrexed was transported via hOAT3 (Km = 68.3 ± 11.1 µM). Lansoprazole, rabeprazole, pantoprazole, esomeprazole, omeprazole, and vonoprazan inhibited hOAT3-mediated uptake of pemetrexed in a concentration-dependent manner. The inhibitory effect of lansoprazole was much greater than those of other PPIs and the apparent IC50 value of lansoprazole against pemetrexed transport via hOAT3 was 0.57 ± 0.17 µM. The inhibitory type of lansoprazole was competitive. In a retrospective study, multivariate analysis revealed that coadministration of lansoprazole, but not other PPIs, with pemetrexed and carboplatin was an independent risk factor significantly contributing to the development of hematologic toxicity (odds ratio: 10.004, P = 0.005). These findings demonstrated that coadministration of lansoprazole could exacerbate the hematologic toxicity associated with pemetrexed, at least in part, by competitive inhibition of hOAT3. Our results would aid clinicians to make decisions of coadministration drugs to avoid drug interaction-induced side effects for achievement of safe and appropriate chemotherapy with pemetrexed., (Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.)
- Published
- 2016
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26. Comparison of the effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on intragastrıc pH in extensive metabolizer patients with gastroesophageal reflux disease.
- Author
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Çelebi A, Aydın D, Kocaman O, Konduk BT, Şentürk Ö, and Hülagü S
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles administration & dosage, 2-Pyridinylmethylsulfinylbenzimidazoles pharmacology, Adult, Cross-Over Studies, Double-Blind Method, Esomeprazole administration & dosage, Esomeprazole pharmacology, Female, Gastroesophageal Reflux genetics, Genotype, Humans, Lansoprazole administration & dosage, Lansoprazole pharmacology, Male, Middle Aged, Pantoprazole, Proton Pump Inhibitors administration & dosage, Rabeprazole administration & dosage, Rabeprazole pharmacology, Treatment Outcome, Cytochrome P-450 CYP2C19 metabolism, Gastric Acid chemistry, Gastroesophageal Reflux drug therapy, Hydrogen-Ion Concentration drug effects, Proton Pump Inhibitors pharmacology
- Abstract
Background/aims: Studies on the therapeutic efficacy of proton pump inhibitors (PPIs) in patients with gastroesophageal reflux disease (GERD) have been recently published. In most of these studies, comparison of only two PPIs have been made. There are few studies on the comparison of four or more PPIs. We aimed to compare the acid inhibitory effects of esomeprazole 40 mg, rabeprazole 20 mg, lansoprazole 30 mg, and pantoprazole 40 mg on days 1 and 5 of treatment in patients with GERD, who were extensive metabolizers in regard to the CYP2C19 genotype., Materials and Methods: Helicobacter pylori-negative with typical symptoms of GERD patients were randomly divided into four treatment groups. Efficacy analysis on days 1 and 5 were performed on the four groups which comprised 10 (esomeprazole), 11 (rabeprazole), 10 (lansoprazole), and 10 (pantoprazole) patients., Results: On day 1 of PPI treatment, the mean percentage of time with intragastric Ph>4 were 54%, 58%, 60%, and 35% for the groups, respectively, and on day 5, these values were 67%, 60%, 68%, and 59%, respectively. Esomeprazole, rabeprazole, and lansoprazole were found to be superior to pantoprazole on the first day of treatment., Conclusion: Pantoprazole is a less potent proton pump inhibitor than the other PPIs tested on the first day of treatment. When the time needed to raise the intragatric pH to over 4 was evaluated, esomeprazole was found to have the most rapid action, followed by lansoprazole and rabeprazole.
- Published
- 2016
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27. Inefficacy of triple therapy and comparison of two different bismuth-containing quadruple regimens as a firstline treatment option for helicobacter pylori.
- Author
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Kekilli M, Onal IK, Ocal S, Dogan Z, and Tanoglu A
- Subjects
- Adult, Amoxicillin administration & dosage, Amoxicillin pharmacology, Bismuth pharmacology, Clarithromycin administration & dosage, Clarithromycin pharmacology, Drug Therapy, Combination, Female, Humans, Lansoprazole administration & dosage, Lansoprazole pharmacology, Male, Organometallic Compounds pharmacology, Retrospective Studies, Salicylates pharmacology, Treatment Outcome, Anti-Bacterial Agents administration & dosage, Anti-Bacterial Agents pharmacology, Bismuth administration & dosage, Helicobacter Infections drug therapy, Helicobacter pylori drug effects, Organometallic Compounds administration & dosage, Salicylates administration & dosage
- Abstract
Background/aim: Increasing resistance of Helicobacter pylori to antimicrobials necessitated the development of new regimens and the modification of existing regimens. The present study aimed to compare the efficacy of two bismuth-containing quadruple regimens-one including clarithromycin (C) instead of metronidazole (M) and triple therapy., Patients and Methods: Patients with H. pylori infection given the following regimens were sequentially enrolled in this retrospective study: (1) Triple therapy: Lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., and amoxicillin 1 g b.i.d., (2) bismuth group C: Lansoprazole 30 mg b.i.d., clarithromycin 500 mg b.i.d., amoxicillin 1 g b.i.d., and bismuth subsalicylate 524 mg b.i.d., and (3) bismuth group M: Lansoprazole 30 mg b.i.d., amoxicillin 1 g b.i.d., metronidazole 500 mg t.i.d., and bismuth subsalicylate 524 mg b.i.d. for 14 days. Gastroscopy and 14 C-urea breath test were performed before enrollment, and urea breath test was repeated four weeks after the treatment., Results: At per-protocol analysis, the eradication rates were 64.7% (95% confidence interval 60.4-68.7) with the triple therapy (n = 504), 95.4% (95% confidence interval 91.5-99.4) with the bismuth group C (n = 501), and 93.9% (95% confidence interval 89.7-98.7) with the bismuth group M (n = 505). The eradication rates were similar between the two bismuth groups (P > 0.05) but significantly greater than that of the triple therapy (P < 0.05)., Conclusion: In our study, both of the bismuth-containing quadruple therapies reached high eradication rates, whereas triple therapy was shown to be ineffective. Moreover, clarithromycin may also be a component of bismuth-containing quadruple therapy.
- Published
- 2016
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28. Lansoprazole and carbonic anhydrase IX inhibitors sinergize against human melanoma cells.
- Author
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Federici C, Lugini L, Marino ML, Carta F, Iessi E, Azzarito T, Supuran CT, and Fais S
- Subjects
- Antigens, Neoplasm metabolism, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Carbonic Anhydrase IX metabolism, Carbonic Anhydrase Inhibitors chemical synthesis, Carbonic Anhydrase Inhibitors chemistry, Cell Death drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Dose-Response Relationship, Drug, Drug Screening Assays, Antitumor, Drug Synergism, Humans, Lansoprazole chemical synthesis, Lansoprazole chemistry, Molecular Structure, Structure-Activity Relationship, Antineoplastic Agents pharmacology, Carbonic Anhydrase IX antagonists & inhibitors, Carbonic Anhydrase Inhibitors pharmacology, Lansoprazole pharmacology, Melanoma drug therapy, Melanoma pathology
- Abstract
Context: Proton Pump Inhibitors (PPIs) reduce tumor acidity and therefore resistance of tumors to drugs. Carbonic Anhydrase IX (CA IX) inhibitors have proven to be effective against tumors, while tumor acidity might impair their full effectiveness., Objective: To analyze the effect of PPI/CA IX inhibitors combined treatment against human melanoma cells., Methods: The combination of Lansoprazole (LAN) and CA IX inhibitors (FC9-399A and S4) has been investigated in terms of cell proliferation inhibition and cell death in human melanoma cells., Results: The combination of these inhibitors was more effective than the single treatments in both inhibiting cell proliferation and in inducing cell death in human melanoma cells., Discussion: These results represent the first successful attempt in combining two different proton exchanger inhibitors., Conclusion: This is the first evidence on the effectiveness of a new approach against tumors based on the combination of PPI and CA IX inhibitors, thus providing an alternative strategy against tumors.
- Published
- 2016
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29. Cognitive impact after short-term exposure to different proton pump inhibitors: assessment using CANTAB software.
- Author
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Akter S, Hassan MR, Shahriar M, Akter N, Abbas MG, and Bhuiyan MA
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles pharmacology, Adult, Esomeprazole pharmacology, Female, Humans, Lansoprazole pharmacology, Male, Pantoprazole, Young Adult, Anti-Ulcer Agents pharmacology, Cognition drug effects, Omeprazole pharmacology, Proton Pump Inhibitors pharmacology, Rabeprazole pharmacology, Software
- Abstract
Introduction: Studies have shown that proton pump inhibitors (PPIs) increase the brain burden of amyloid-beta (Aβ) and also create vitamin B12 deficiency. However, these two phenomena have deleterious effect on cognition and Alzheimer's disease (AD). Since the use of PPIs has increased tremendously for the last few years, it is of great public health importance to investigate the cognitive impact of PPIs. Hence, the purpose of this study was to investigate the degree of neuropsychological association of each PPI with different cognitive functions., Methods: Sixty volunteers of either gender were recruited and divided randomly into six groups: five test groups for five classes of PPIs and one control group. All the groups participated in the five computerized neuropsychological tests (nine subtests) of the Cambridge Neuropsychological Test Automated Battery twice: at the beginning of the study and 7 days thereafter., Results: We found statistically and clinically significant impairment in visual memory, attention, executive function, and working and planning function. One-way analysis of variance findings showed that all PPIs had a similar negative impact on cognition. However, paired-samples t tests indicated that omeprazole showed significant (p < 0.05) results in seven subtests; lansoprazole and pantoprazole showed significant results in five subtests; and rabeprazole showed significant results in four subtests. Among five classes of PPIs, esomeprazole showed comparatively less impact on cognitive function with significant results in three subtests., Conclusions: The present study reveals for the first time that different PPIs have varying degrees of influence on different cognitive domains and have associations with AD. These findings should be considered when balancing the risks and benefits of prescribing these medications. A study done for a longer period of time with a larger sample size might yield better results.
- Published
- 2015
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30. Lansoprazole Upregulates Polyubiquitination of the TNF Receptor-Associated Factor 6 and Facilitates Runx2-mediated Osteoblastogenesis.
- Author
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Mishima K, Kitoh H, Ohkawara B, Okuno T, Ito M, Masuda A, Ishiguro N, and Ohno K
- Subjects
- Animals, Bone Morphogenetic Proteins metabolism, Cell Differentiation, Cell Line, Core Binding Factor Alpha 1 Subunit metabolism, Fracture Healing, Fractures, Bone, Humans, Lansoprazole chemistry, MAP Kinase Kinase Kinases metabolism, Male, Mice, Models, Molecular, Molecular Conformation, Osteoblasts cytology, Protein Transport, Proton Pump Inhibitors pharmacology, Rats, Signal Transduction drug effects, Ubiquitination drug effects, Ubiquitins chemistry, Ubiquitins metabolism, p38 Mitogen-Activated Protein Kinases metabolism, Core Binding Factor Alpha 1 Subunit genetics, Lansoprazole pharmacology, Osteoblasts drug effects, Osteoblasts metabolism, Osteogenesis drug effects, Osteogenesis genetics, TNF Receptor-Associated Factor 6 metabolism
- Abstract
The transcription factor, runt-related transcription factor 2 (Runx2), plays a pivotal role in the differentiation of the mesenchymal stem cells to the osteochondroblast lineages. We found by the drug repositioning strategy that a proton pump inhibitor, lansoprazole, enhances nuclear accumulation of Runx2 and induces osteoblastogenesis of human mesenchymal stromal cells. Systemic administration of lansoprazole to a rat femoral fracture model increased osteoblastogenesis. Dissection of signaling pathways revealed that lansoprazole activates a noncanonical bone morphogenic protein (BMP)-transforming growth factor-beta (TGF-β) activated kinase-1 (TAK1)-p38 mitogen-activated protein kinase (MAPK) pathway. We found by in cellulo ubiquitination studies that lansoprazole enhances polyubiquitination of the TNF receptor-associated factor 6 (TRAF6) and by in vitro ubiquitination studies that the enhanced polyubiquitination of TRAF6 is attributed to the blocking of a deubiquitination enzyme, cylindromatosis (CYLD). Structural modeling and site-directed mutagenesis of CYLD demonstrated that lansoprazole tightly fits in a pocket of CYLD where the C-terminal tail of ubiquitin lies. Lansoprazole is a potential therapeutic agent for enhancing osteoblastic differentiation.
- Published
- 2015
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31. Reduced Gut Acidity Induces an Obese-Like Phenotype in Drosophila melanogaster and in Mice.
- Author
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Lin WS, Huang CW, Song YS, Yen JH, Kuo PC, Yeh SR, Lin HY, Fu TF, Wu MS, Wang HD, and Wang PY
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- Acetazolamide pharmacology, Animals, Carbonic Anhydrase Inhibitors pharmacology, Drosophila Proteins metabolism, Drosophila melanogaster, Gastric Acidity Determination, Gastrointestinal Tract drug effects, Lansoprazole pharmacology, Mice, Obesity metabolism, Proton Pump Inhibitors pharmacology, Vacuolar Proton-Translocating ATPases metabolism, Acid-Base Equilibrium genetics, Drosophila Proteins genetics, Gastrointestinal Tract metabolism, Obesity genetics, Phenotype, Vacuolar Proton-Translocating ATPases genetics
- Abstract
In order to identify genes involved in stress and metabolic regulation, we carried out a Drosophila P-element-mediated mutagenesis screen for starvation resistance. We isolated a mutant, m2, that showed a 23% increase in survival time under starvation conditions. The P-element insertion was mapped to the region upstream of the vha16-1 gene, which encodes the c subunit of the vacuolar-type H+-ATPase. We found that vha16-1 is highly expressed in the fly midgut, and that m2 mutant flies are hypomorphic for vha16-1 and also exhibit reduced midgut acidity. This deficit is likely to induce altered metabolism and contribute to accelerated aging, since vha16-1 mutant flies are short-lived and display increases in body weight and lipid accumulation. Similar phenotypes were also induced by pharmacological treatment, through feeding normal flies and mice with a carbonic anhydrase inhibitor (acetazolamide) or proton pump inhibitor (PPI, lansoprazole) to suppress gut acid production. Our study may thus provide a useful model for investigating chronic acid suppression in patients.
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- 2015
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32. Influence of the proton pump inhibitor lansoprazole on distribution and activity of doxorubicin in solid tumors.
- Author
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Yu M, Lee C, Wang M, and Tannock IF
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- Animals, Antibiotics, Antineoplastic pharmacokinetics, Antibiotics, Antineoplastic therapeutic use, Biomarkers, Tumor metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Cell Proliferation drug effects, Doxorubicin therapeutic use, Drug Resistance, Neoplasm drug effects, Female, MCF-7 Cells, Mammary Neoplasms, Animal pathology, Mice, Mice, Nude, Xenograft Model Antitumor Assays, Breast Neoplasms drug therapy, Doxorubicin pharmacokinetics, Lansoprazole pharmacology, Mammary Neoplasms, Animal drug therapy, Proton Pump Inhibitors pharmacology
- Abstract
Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate autophagy, which facilitates survival of stressed cells, and may contribute to drug resistance. Basic drugs (e.g. doxorubicin) are sequestered in acidic endosomes, thereby diverting drugs from their target DNA and decreasing penetration to distal cells. Proton pump inhibitors (PPIs) may raise endosomal pH, with potential to improve drug efficacy and distribution in solid tumors. We determined the effects of the PPI lansoprazole to modify the activity of doxorubicin. To gain insight into its mechanisms, we studied the effects of lansoprazole on endosomal pH, and on the spatial distribution of doxorubicin, and of biomarkers reflecting its activity, using in vitro and murine models. Lansoprazole showed concentration-dependent effects to raise endosomal pH and to inhibit endosomal sequestration of doxorubicin in cultured tumor cells. Lansoprazole was not toxic to cancer cells but potentiated the cytotoxicity of doxorubicin and enhanced its penetration through multilayered cell cultures. In solid tumors, lansoprazole improved the distribution of doxorubicin but also increased expression of biomarkers of drug activity throughout the tumor. Combined treatment with lansoprazole and doxorubicin was more effective in delaying tumor growth as compared to either agent alone. Together, lansoprazole enhances the therapeutic effects of doxorubicin both by improving its distribution and increasing its activity in solid tumors. Use of PPIs to improve drug distribution and to inhibit autophagy represents a promising strategy to enhance the effectiveness of anticancer drugs in solid tumors., (© 2015 The Authors. Cancer Science published by Wiley Publishing Asia Pty Ltd on behalf of Japanese Cancer Association.)
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- 2015
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33. Lansoprazole is an antituberculous prodrug targeting cytochrome bc1.
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Rybniker J, Vocat A, Sala C, Busso P, Pojer F, Benjak A, and Cole ST
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- 2-Pyridinylmethylsulfinylbenzimidazoles, Animals, Cell Line, Drug Discovery methods, Drug Resistance, Bacterial, Electron Transport Complex III antagonists & inhibitors, Fibroblasts, High-Throughput Screening Assays, Humans, Lansoprazole metabolism, Macrophages, Mice, Omeprazole, Pantoprazole, Prodrugs metabolism, Sulfides metabolism, Sulfides pharmacology, Tuberculosis, Multidrug-Resistant, Antitubercular Agents pharmacology, Electron Transport Complex III drug effects, Lansoprazole pharmacology, Mycobacterium tuberculosis drug effects, Prodrugs pharmacology, Proton Pump Inhibitors pharmacology
- Abstract
Better antibiotics capable of killing multi-drug-resistant Mycobacterium tuberculosis are urgently needed. Despite extensive drug discovery efforts, only a few promising candidates are on the horizon and alternative screening protocols are required. Here, by testing a panel of FDA-approved drugs in a host cell-based assay, we show that the blockbuster drug lansoprazole (Prevacid), a gastric proton-pump inhibitor, has intracellular activity against M. tuberculosis. Ex vivo pharmacokinetics and target identification studies reveal that lansoprazole kills M. tuberculosis by targeting its cytochrome bc1 complex through intracellular sulfoxide reduction to lansoprazole sulfide. This novel class of cytochrome bc1 inhibitors is highly active against drug-resistant clinical isolates and spares the human H(+)K(+)-ATPase thus providing excellent opportunities for targeting the major pathogen M. tuberculosis. Our finding provides proof of concept for hit expansion by metabolic activation, a powerful tool for antibiotic screens.
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- 2015
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34. Omeprazole and lansoprazole enantiomers induce CYP3A4 in human hepatocytes and cell lines via glucocorticoid receptor and pregnane X receptor axis.
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Novotna A and Dvorak Z
- Subjects
- Anti-Ulcer Agents adverse effects, Cells, Cultured, Cytochrome P-450 CYP3A genetics, Hep G2 Cells, Hepatocytes metabolism, Humans, Lansoprazole adverse effects, Omeprazole adverse effects, Pregnane X Receptor, Anti-Ulcer Agents pharmacology, Cytochrome P-450 CYP3A metabolism, Hepatocytes drug effects, Lansoprazole pharmacology, Omeprazole pharmacology, Receptors, Glucocorticoid metabolism, Receptors, Steroid metabolism
- Abstract
Benzimidazole drugs lansoprazole and omeprazole are used for treatment of various gastrointestinal pathologies. Both compounds cause drug-drug interactions because they activate aryl hydrocarbon receptor and induce CYP1A genes. In the current paper, we examined the effects of lansoprazole and omeprazole enantiomers on the expression of key drug-metabolizing enzyme CYP3A4 in human hepatocytes and human cancer cell lines. Lansoprazole enantiomers, but not omeprazole, were equipotent inducers of CYP3A4 mRNA in HepG2 cells. All forms (S-, R-, rac-) of lansoprazole and omeprazole induced CYP3A4 mRNA and protein in human hepatocytes. The quantitative profiles of CYP3A4 induction by individual forms of lansoprazole and omeprazole exerted enantiospecific patterns. Lansoprazole dose-dependently activated pregnane X receptor PXR in gene reporter assays, and slightly modulated rifampicin-inducible PXR activity, with similar potency for each enantiomer. Omeprazole dose-dependently activated PXR and inhibited rifampicin-inducible PXR activity. The effects of S-omeprazole were much stronger as compared to those of R-omeprazole. All forms of lansoprazole, but not omeprazole, slightly activated glucocorticoid receptor and augmented dexamethasone-induced GR transcriptional activity. Omeprazole and lansoprazole influenced basal and ligand inducible expression of tyrosine aminotransferase, a GR-target gene, in HepG2 cells and human hepatocytes. Overall, we demonstrate here that omeprazole and lansoprazole enantiomers induce CYP3A4 in HepG2 cells and human hepatocytes. The induction comprises differential interactions of omeprazole and lansoprazole with transcriptional regulators PXR and GR, and some of the effects were enantiospecific. The data presented here might be of toxicological and clinical importance, since the effects occurred in therapeutically relevant concentrations.
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- 2014
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35. Extracellular acidosis contracts coronary but neither renal nor mesenteric artery via modulation of H+,K+-ATPase, voltage-gated K+ channels and L-type Ca2+ channels.
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Niu L, Liu Y, Hou X, Cui L, Li J, Zhang X, and Zhang M
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- Animals, Calcium Channels, L-Type drug effects, Cytosol metabolism, H(+)-K(+)-Exchanging ATPase drug effects, Hydrogen-Ion Concentration, Lansoprazole pharmacology, Male, Mesenteric Arteries physiopathology, Muscle, Smooth, Vascular physiology, Potassium Channels, Voltage-Gated drug effects, Rats, Wistar, Renal Artery physiopathology, Vasoconstriction drug effects, Acidosis physiopathology, Coronary Vessels physiopathology, Vasoconstriction physiology
- Abstract
Extracellular acidosis (EA) jeopardizes the heart, whereas mild extracellular alkalinization is cardioprotective, but it remains elusive how the coronary artery (CA) responses to EA. In the present study, EA was demonstrated to induce contraction in rat coronary artery (RCA) in a manner dependent on extracellular pH (pHo, 7.2-6.6), whereas it did not affect the resting tone of either rat renal interlobe artery (RIA) or mesenteric artery (MA). The amplitude of contraction provoked by pHo 6.8 was approximately equal to that induced by 60 mmol l(-1) KCl at pHo 7.4. Blockade of L-type voltage-gated Ca(2+) channels and inhibition of H(+),K(+)-ATPase attenuated the contraction, whereas inhibition of nitric oxide synthesis and endothelial denudation augmented it. A molecular probe study showed that EA acidified the cytosol of arterial smooth muscle cells (ASMCs) in RIA and MA, but alkalinized it in RCA. Extracellular acidosis elevated the intracellular Ca(2+) concentration exclusively in RCA ASMCs. Patch-clamp studies showed that EA enhanced L-type voltage-gated Ca(2+) channel currents in RCA ASMCs, but depressed the currents in MA ASMCs and did not affect the currents in RIA ASMCs. Extracellular acidosis depressed voltage-gated K(+) channel (KV) currents only in RCA ASMCs. Lansoprazole blunted all these observed effects of EA on RCA. Taken together, the present results demonstrate that the responses of RCA to EA are different from those of RIA and MA and suggest that activation of L-type voltage-gated Ca(2+) channels and H(+),K(+)-ATPase as well as depression of KV may, at least partly, underlie the EA-induced contraction in RCA., (© 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.)
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- 2014
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36. Differential effects of omeprazole and lansoprazole enantiomers on aryl hydrocarbon receptor in human hepatocytes and cell lines.
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Novotna A, Srovnalova A, Svecarova M, Korhonova M, Bartonkova I, and Dvorak Z
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- Cell Line, Hepatocytes metabolism, Humans, Lansoprazole chemistry, Omeprazole chemistry, Proton Pump Inhibitors chemistry, Stereoisomerism, Hepatocytes drug effects, Lansoprazole pharmacology, Omeprazole pharmacology, Proton Pump Inhibitors pharmacology, Receptors, Aryl Hydrocarbon metabolism
- Abstract
Proton pump inhibitors omeprazole and lansoprazole contain chiral sulfur atom and they are administered as a racemate, i.e. equimolar mixture of S- and R-enantiomers. The enantiopure drugs esomeprazole and dexlansoprazole have been developed and introduced to clinical practice due to their improved clinical and therapeutic properties. Since omeprazole and lansoprazole are activators of aryl hydrocarbon receptor (AhR) and inducers of CYP1A genes, we examined their enantiospecific effects on AhR-CYP1A pathway in human cancer cells and primary human hepatocytes. We performed gene reporter assays for transcriptional activity of AhR, RT-PCR analyses for CYP1A1/2 mRNAs, western blots for CYP1A1/2 proteins and EROD assay for CYP1A1/2 catalytic activity. Lansoprazole and omeprazole enantiomers displayed differential effects on AhR-CYP1A1/2 pathway. In general, S-enantiomers were stronger activators of AhR and inducers of CYP1A genes as compared to R-enantiomers in lower concentrations, i.e. 1-10 µM for lansoprazole and 10-100 µM for omeprazole. In contrast, R-enantiomers were stronger AhR activators and CYP1A inducers than S-enantiomers in higher concentrations, i.e. 100 µM for lansoprazole and 250 µM for omeprazole. In conclusion, we provide the first evidence of enantiospecific effects of omeprazole and lansoprazole on AhR signaling pathway.
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- 2014
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37. Nrf2-inducing anti-oxidation stress response in the rat liver--new beneficial effect of lansoprazole.
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Yamashita Y, Ueyama T, Nishi T, Yamamoto Y, Kawakoshi A, Sunami S, Iguchi M, Tamai H, Ueda K, Ito T, Tsuruo Y, and Ichinose M
- Subjects
- Active Transport, Cell Nucleus drug effects, Animals, Antioxidants metabolism, Dose-Response Relationship, Drug, Hepatocytes pathology, Liver pathology, Male, Rats, Rats, Wistar, Thioacetamide toxicity, Up-Regulation drug effects, Cell Nucleus metabolism, Hepatocytes metabolism, Lansoprazole pharmacology, Liver metabolism, NF-E2-Related Factor 2 metabolism, Oxidative Stress drug effects
- Abstract
Lansoprazole is a potent anti-gastric ulcer drug that inhibits gastric proton pump activity. We identified a novel function for lansoprazole, as an inducer of anti-oxidative stress responses in the liver. Gastric administration of lansoprazole (10-100 mg/kg) to male Wistar rats produced a dose-dependent increase in hepatic mRNA levels of nuclear factor, erythroid-derived 2, -like 2 (Nrf2), a redox-sensitive transcription factor, at 3 h and Nrf2 immunoreactivity (IR) in whole hepatic lysates at 6 h. Conversely, the levels of Kelch-like ECH-associated protein (Keap1), which sequesters Nrf2 in the cytoplasm under un-stimulated conditions, were unchanged. Translocation of Nrf2 into the nuclei of hepatocytes was observed using western blotting and immunohistochemistry. Expression of mRNAs for Nrf2-dependent antioxidant and phase II enzymes, such as heme oxygenase 1 (HO-1), NAD (P) H dehydrogenase, quinone 1 (Nqo1), glutathione S-transferase A2 (Gsta2), UDP glucuronosyltransferase 1 family polypeptide A6 (Ugt1a6), were dose-dependently up-regulated at 3 h. Furthermore, the levels of HO-1 IR were dose-dependently increased in hepatocytes at 6 h. Subcutaneous administration of lansoprazole (30 mg/kg/day) for 7 successive days resulted in up-regulation and nuclear translocation of Nrf2 IR in hepatocytes and up-regulation of HO-1 IR in the liver. Pretreatment with lansoprazole attenuated thioacetamide (500 mg/kg)-induced acute hepatic damage via both HO-1-dependent and -independent pathways. Up-stream networks related to Nrf2 expression were investigated using microarray analysis, followed by data mining with Ingenuity Pathway Analysis. Up-regulation of the aryl hydrocarbon receptor (AhR)-cytochrome P450, family 1, subfamily a, polypeptide 1 (Cyp1a1) pathway was associated with up-regulation of Nrf2 mRNA. In conclusion, lansoprazole might have an alternative indication in the prevention and treatment of oxidative hepatic damage through the induction of both phase I and phase II drug-metabolizing systems, i.e. the AhR/Cyp1a1/Nrf2 pathway in hepatocytes.
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- 2014
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38. Exercise prevented the lansoprazole-induced reduction of anti-osteoporotic efficacy of alendronate in androgen deficiency rats.
- Author
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Cegieła U, Pytlik M, Folwarczna J, Miozga R, Piskorz S, and Nowak D
- Subjects
- Animals, Bone Density drug effects, Bone and Bones metabolism, Bone and Bones pathology, Drug Interactions, Male, Orchiectomy, Osteoporosis metabolism, Osteoporosis pathology, Rats, Rats, Wistar, Running, Time Factors, Alendronate pharmacology, Bone Density Conservation Agents pharmacology, Bone and Bones drug effects, Lansoprazole pharmacology, Osteoporosis prevention & control, Physical Exertion, Proton Pump Inhibitors pharmacology, Testosterone deficiency
- Abstract
Clinical studies indicate that proton pump inhibitors (PPIs), used long-term in elderly patients, increase the risk of osteoporotic fractures, and decrease the anti-fracture efficacy of alendronate. The aim of the present study was to examine the effect of physical exercise on the anti-osteoporotic efficacy of alendronate administered concurrently with lansoprazole, a PPI, in male rats with androgen deficiency induced by orchidectomy. Male Wistar rats at 3 months of age were divided into: sham-operated control rats, orchidectomized (ORX) control rats, ORX rats receiving alendronate, ORX rats receiving alendronate and lansoprazole, ORX rats receiving alendronate and subjected to exercise, and ORX rats receiving alendronate and lansoprazole and subjected to exercise. The orchidectomy or sham-operation was performed 7-8 days before the start of drug administration. The rats were subjected to the exercise on the treadmill 1 hour/day for 7 weeks (6 days a week). Alendronate sodium (3 mg/kg p.o.) and lansoprazole (4 mg/kg p.o.) were administered once daily for 7 weeks (6 days a week). Mechanical properties of the tibial metaphysis and femoral neck were assessed. Bone turnover markers, histomorphometric parameters, bone mass and mass of bone mineral were also studied. Lansoprazole weakened the anti-osteoporotic efficacy of alendronate. The exercise increased the alendronate effect. Similar changes were observed in the rats treated with lansoprazole and alendronate, subjected to exercise; no deleterious effects of lansoprazole were observed. In conclusion, the exercise prevented the lansoprazole-induced reduction the anti-osteoporotic efficacy of alendronate in orchidectomized rats.
- Published
- 2014
39. Pharmacodynamic effects of cilostazol versus clopidogrel in stented patients under proton pump inhibitor co-administration: the ACCEL-PARAZOL study.
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Park Y, Jung JM, Tantry US, Kim K, Koh JS, Park JR, Hwang SJ, Kwak CH, Hwang JY, Kim S, Gurbel PA, and Jeong YH
- Subjects
- Cilostazol, Clopidogrel, Female, Follow-Up Studies, Humans, Lansoprazole pharmacology, Male, Middle Aged, Platelet Activation, Platelet Aggregation Inhibitors pharmacology, Platelet Function Tests, Prognosis, Prospective Studies, Stents, Ticlopidine pharmacology, Cardiovascular Diseases drug therapy, Platelet Aggregation drug effects, Proton Pump Inhibitors pharmacology, Renal Insufficiency, Chronic drug therapy, Tetrazoles pharmacology, Ticlopidine analogs & derivatives
- Abstract
Aim: Proton pump inhibitor (PPI) therapy has been shown to attenuate the antiplatelet effects of clopidogrel. The aim of this study was to compare the antiplatelet effects of cilostazol versus clopidogrel in patients co-administered a PPI., Methods: We enrolled PPI-naïve stented patients treated with standard clopidogrel and aspirin therapy for at least six months (n=100). The patients were randomly assigned to receive either cilostazol at a dose of 100mg twice daily (CILO group) or clopidogrel at a dose of 75mg daily (CLPD group) in addition to lansoprazole (30mg daily). The platelet aggregation (PA) determined using light transmittance aggregometry and the platelet reactivity index (PRI) obtained using a vasodilator-stimulated phosphoprotein phosphorylation assay were measured before randomization and at the 14-day follow-up visit. The primary endpoint was the PRI value at follow-up., Results: At follow-up, the CLPD group showed similar values of PRI as the CILO group (66.9±14.0% vs. 63.1±14.1%; mean difference: 3.9%; 95% confidence interval of difference: -1.7% to 9.4%; p=0.174). However, the 6μg/mL collagen- and 0.5mg/mL arachidonic acid-induced PA values in the CLPD group were higher than those observed in the CILO group (mean differences: 9.8% to 11.1%; all p values <0.001). CYP2C19 loss-of-function allele carriage was the major contributing factor associated with the PRI level in the absence of lansoprazole treatment (with a gene-dose effect); this association was not observed in the subjects receiving lansoprazole co-administration in the CLPD group., Conclusions: During lansoprazole co-administration, cilostazol treatment achieves a more favorable platelet function profile than clopidogrel therapy. The use of combination treatment with cilostazol and aspirin deserves further attention with respect to the management of stable stented patients requiring PPI co-administration.
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- 2014
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40. A novel nanoparticulate system for sustained delivery of acid-labile lansoprazole.
- Author
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Alai MS and Lin WJ
- Subjects
- Acrylic Resins, Calorimetry, Differential Scanning, Kinetics, Nanoparticles ultrastructure, Particle Size, Polymers chemistry, Solutions, Solvents chemistry, Spectroscopy, Fourier Transform Infrared, Acids chemistry, Drug Delivery Systems, Lansoprazole pharmacology, Nanoparticles chemistry
- Abstract
In the present study, an effort was made to develop the Eudragit RS100 based nanoparticulate system for sustained delivery of an acid-labile drug, lansoprazole (LPZ). LPZ-loaded Eudragit RS100 nanoparticles (ERSNPs) were prepared by oil-in-water emulsion-solvent evaporation method. The effects of various formulation variables such as polymer concentration, drug amount and solvent composition on physicochemical performance of nanoparticles and in vitro drug release were investigated. All nanoparticles were spherical with particle size 198.9 ± 8.6-376.9 ± 5.6 nm and zeta potential +35.1 ± 1.7 to +40.2 ± 0.8 mV. The yield of nanoparticles was unaffected by change of these three variables. However, the drug loading and encapsulation efficiency were affected by polymer concentration and drug amount. On the other hand, the particle size of nanoparticles was significantly affected by polymer concentration and internal phase composition due to influence of droplet size during emulsification process. All nanoparticles prolonged drug release for 24h which was dominated by a combination of drug diffusion and polymer chain relaxation. The fastest and the slowest release rates were observed in C2-1002-10/0 and C8-4001-10/0, respectively, based on the release rate constant (k). Thus, the developed nanoparticles possessed a potential as a nano-carrier to sustain drug delivery for treatment of acid related disorders., (Copyright © 2013 Elsevier B.V. All rights reserved.)
- Published
- 2013
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41. Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole.
- Author
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Sahara S, Sugimoto M, Uotani T, Ichikawa H, Yamade M, Iwaizumi M, Yamada T, Osawa S, Sugimoto K, Umemura K, Miyajima H, and Furuta T
- Subjects
- Aryl Hydrocarbon Hydroxylases metabolism, Cross-Over Studies, Cytochrome P-450 CYP2C19, Drug Administration Schedule, Esomeprazole pharmacology, Female, Genotype, Humans, Hydrogen-Ion Concentration, Japan, Lansoprazole administration & dosage, Lansoprazole pharmacology, Male, Omeprazole administration & dosage, Omeprazole pharmacology, Polymorphism, Genetic drug effects, Proton Pump Inhibitors pharmacology, Rabeprazole administration & dosage, Rabeprazole pharmacology, Young Adult, Aryl Hydrocarbon Hydroxylases genetics, Esomeprazole administration & dosage, Gastric Acid metabolism, Proton Pump Inhibitors administration & dosage
- Abstract
Background: Twice-daily dosing of proton pump inhibitors (PPIs) is used to treat Helicobacter pylori or acid-related diseases, such as gastro-oesophageal reflux disease (GERD) refractory to standard dose of a PPI. Genetic polymorphisms of CYP2C19 are involved to different extents in the metabolism of four kinds of PPIs (omeprazole, lansoprazole, rabeprazole and esomeprazole) available in Japan., Aim: To compare acid-inhibitory effects of the four PPIs dosed twice daily in relation to CYP2C19 genotype., Methods: We performed 24-h pH monitoring studies on Day 7 of PPI treatment for 40 Japanese H. pylori-negative volunteers [15 CYP2C19 rapid metabolisers (RMs), 15 intermediate metabolisers (IMs) and 10 poor metabolisers (PMs)] using a randomised four-way crossover design: omeprazole 20 mg, esomeprazole 20 mg, lansoprazole 30 mg and rabeprazole 10 mg twice daily., Results: Although median pH values with esomeprazole, omeprazole, lansoprazole and rabeprazole were 5.7 (3.5-7.2), 5.5 (2.4-7.2), 5.5 (3.7-7.3) and 5.2 (2.5-7.3), respectively (no statistically significant differences), CYP2C19 genotype-dependent differences were smaller for esomeprazole and rabeprazole compared with values for omeprazole and lansoprazole. In CYP2C19 RMs, the median pH with esomeprazole [5.4 (3.5-6.8)] was significantly higher than those with omeprazole [5.0 (2.4-5.9), P = 0.018], lansoprazole [4.7 (3.7-5.5), P = 0.017] or rabeprazole [4.8 (2.5-6.4), P = 0.002]. In IMs and PMs, the median pH was >5.0 independent of the PPI., Conclusions: In intermediate and rapid metabolisers of CYP2C19, PPIs dosed twice daily could attain sufficient acid suppression, while in CYP2C19 RMs, esomeprazole 20 mg twice daily caused the strongest inhibition of the four PPIs. Therefore, esomeprazole may be effective in Japanese population when dosed twice daily., (© 2013 John Wiley & Sons Ltd.)
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- 2013
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42. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine.
- Author
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Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, and Cooke JP
- Subjects
- Amidohydrolases metabolism, Animals, Arginine blood, Biomarkers blood, Cells, Cultured, Disease Models, Animal, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Esomeprazole adverse effects, Esomeprazole pharmacology, Esomeprazole therapeutic use, Humans, Lansoprazole adverse effects, Lansoprazole pharmacology, Lansoprazole therapeutic use, Male, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type III metabolism, Proton Pump Inhibitors pharmacology, Risk Factors, Vasodilation drug effects, Arginine analogs & derivatives, Cardiovascular Diseases epidemiology, Cardiovascular Diseases metabolism, Gastroesophageal Reflux drug therapy, Proton Pump Inhibitors adverse effects, Proton Pump Inhibitors therapeutic use
- Abstract
Background: Proton pump inhibitors (PPIs) are gastric acid-suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed., Methods and Results: Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA., Conclusions: We present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.
- Published
- 2013
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43. Defensive effect of lansoprazole in dementia of AD type in mice exposed to streptozotocin and cholesterol enriched diet.
- Author
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Sodhi RK and Singh N
- Subjects
- Acetylcholinesterase metabolism, Alzheimer Disease etiology, Alzheimer Disease physiopathology, Analysis of Variance, Animals, Body Weight drug effects, Brain drug effects, Brain metabolism, Brain pathology, Cholesterol blood, Cholesterol, Dietary adverse effects, Diet, High-Fat adverse effects, Female, Glutathione metabolism, Injections, Intraventricular, Male, Mice, Peroxidase metabolism, Proton Pump Inhibitors pharmacology, Streptozocin administration & dosage, Streptozocin toxicity, Thiobarbituric Acid Reactive Substances metabolism, Alzheimer Disease prevention & control, Lansoprazole pharmacology, Maze Learning drug effects, Memory drug effects
- Abstract
The present study investigates the potential of lansoprazole (a proton pump inhibitor and agonist of liver x receptors) in experimental dementia of AD type. Streptozotocin [STZ, 3 mg/kg, injected intracerebroventricular (i.c.v), and high fat diet (HFD, administered for 90 days)] were used to induce dementia in separate groups of Swiss mice. Morris water maze (MWM) test was performed to assess learning and memory of the animals. A battery of biochemical and histopathological studies were also performed. Extent of oxidative stress was measured by estimating the levels of brain reduced glutathione (GSH) and thiobarbituric acid reactive species (TBARS). Brain acetylcholinestrase (AChE) activity and serum cholesterol levels were also estimated. The brain level of myeloperoxidase (MPO) was measured as a marker of inflammation. STZ and HFD produced a marked decline in MWM performance of the animals, reflecting impairment of learning and memory. STZ/HFD treated mice exhibited a marked accentuation of AChE activity, TBARS and MPO levels along with a fall in GSH levels. Further, the stained micrographs of STZ/HFD treated mice indicated pathological changes, severe neutrophilic infiltration and amyloid deposition. Lansoprazole treatment significantly attenuated STZ and HFD -induced memory deficits, biochemical and histopathological alterations. It also prevented HFD-induced rise in the cholesterol level. Therefore, the findings demonstrate potential of lansoprazole in memory dysfunctions which may probably be attributed to its anti-cholinesterase, anti-oxidative and anti-inflammatory effects. Moreover, both cholesterol-dependent as well as cholesterol-independent effects of lansoprazole appear to play a role. In addition study indicates the role of liver x receptors in dementia.
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- 2013
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44. Antibiotic treatment decreases microbial burden associated with pseudomyxoma peritonei and affects β-catenin distribution.
- Author
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Semino-Mora C, Testerman TL, Liu H, Whitmire JM, Studeman K, Jia Y, McAvoy TJ, Francis J, Nieroda C, Sardi A, Merrell DS, and Dubois A
- Subjects
- Adenocarcinoma, Mucinous drug therapy, Adenocarcinoma, Mucinous surgery, Amoxicillin pharmacology, Amoxicillin therapeutic use, Anti-Bacterial Agents pharmacology, Bacterial Load drug effects, Cell Membrane metabolism, Cell Nucleus, Clarithromycin pharmacology, Clarithromycin therapeutic use, Combined Modality Therapy, Helicobacter pylori genetics, Humans, In Situ Hybridization, Lansoprazole pharmacology, Lansoprazole therapeutic use, Middle Aged, Peritoneal Neoplasms drug therapy, Peritoneal Neoplasms surgery, Protein Transport, Pseudomyxoma Peritonei drug therapy, Pseudomyxoma Peritonei surgery, Treatment Outcome, Adenocarcinoma, Mucinous microbiology, Anti-Bacterial Agents therapeutic use, Helicobacter Infections drug therapy, Peritoneal Neoplasms microbiology, Pseudomyxoma Peritonei microbiology, beta Catenin metabolism
- Abstract
Purpose: Pseudomyxoma peritonei is an understudied cancer in which an appendiceal neoplasm invades the peritoneum and forms tumor foci on abdominal organs. Previous studies have shown that bacteria reside within pseudomyxoma peritonei tumors and mucin. Thus, we sought to analyze the effect of antibiotics on bacterial density and β-catenin expression within pseudomyxoma peritonei samples., Experimental Design: The study included 48 patients: 19 with disseminated peritoneal adenomucinosis (DPAM) and 29 with peritoneal mucinous carcinomatosis (PMCA). Fourteen patients were given antibiotics (30 mg lansoprazole, 1 g amoxicillin, and 500 mg clarithromycin) twice a day for 14 days. One week after completion of therapy, surgery was conducted and specimens were harvested for pathology, bacterial culture, ISH, and immunohistochemistry., Results: ISH showed the presence of bacteria in 83% of the patient samples, with a higher Helicobacter pylori density observed in PMCA versus DPAM. PMCA patients treated with antibiotics had a significantly lower bacterial density and decreased β-catenin levels in the cytoplasm, the cell nuclei, and mucin-associated cells. Although not significant, similar trends were observed in DPAM patients. Cell membrane β-catenin was significantly increased in both DPAM and PMCA patients receiving antibiotics., Conclusions: Bacteria play an important role in pseudomyxoma peritonei. Antibiotic treatment improved the histopathology of tissue, particularly in PMCA patients. In PMCA, antibiotics decreased bacterial density and were associated with a significant β-catenin decrease in the cytoplasm, cell nuclei, and mucin along with a small membrane increase. These results suggest that antibiotics offer potential protection against cell detachment, cellular invasion, and metastasis.
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- 2013
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45. The proton pump inhibitor lansoprazole improves the skeletal phenotype in dystrophin deficient mdx mice.
- Author
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Sali A, Many GM, Gordish-Dressman H, van der Meulen JH, Phadke A, Spurney CF, Cnaan A, Hoffman EP, and Nagaraju K
- Subjects
- Animals, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Drug Synergism, Dystrophin deficiency, Female, Gene Expression, Glucocorticoids pharmacology, Mice, Mice, Inbred mdx, Muscle, Skeletal metabolism, Muscle, Skeletal pathology, Muscular Dystrophy, Animal genetics, Muscular Dystrophy, Animal metabolism, Muscular Dystrophy, Animal pathology, Prednisolone pharmacology, Dystrophin genetics, Lansoprazole pharmacology, Muscle Strength drug effects, Muscle, Skeletal drug effects, Muscular Dystrophy, Animal drug therapy, Proton Pump Inhibitors pharmacology
- Abstract
Background: In Duchenne muscular dystrophy (DMD), loss of the membrane stabilizing protein dystrophin results in myofiber damage. Microinjury to dystrophic myofibers also causes secondary imbalances in sarcolemmic ion permeability and resting membrane potential, which modifies excitation-contraction coupling and increases proinflammatory/apoptotic signaling cascades. Although glucocorticoids remain the standard of care for the treatment of DMD, there is a need to investigate the efficacy of other pharmacological agents targeting the involvement of imbalances in ion flux on dystrophic pathology., Methodology/principal Findings: We designed a preclinical trial to investigate the effects of lansoprazole (LANZO) administration, a proton pump inhibitor, on the dystrophic muscle phenotype in dystrophin deficient (mdx) mice. Eight to ten week-old female mice were assigned to one of four treatment groups (n = 12 per group): (1) vehicle control; (2) 5 mg/kg/day LANZO; (3) 5 mg/kg/day prednisolone; and (4) combined treatment of 5 mg/kg/day prednisolone (PRED) and 5 mg/kg/day LANZO. Treatment was administered orally 5 d/wk for 3 months. At the end of the study, behavioral (Digiscan) and functional outcomes (grip strength and Rotarod) were assessed prior to sacrifice. After sacrifice, body, tissue and organ masses, muscle histology, in vitro muscle force, and creatine kinase levels were measured. Mice in the combined treatment groups displayed significant reductions in the number of degenerating muscle fibers and number of inflammatory foci per muscle field relative to vehicle control. Additionally, mice in the combined treatment group displayed less of a decline in normalized forelimb and hindlimb grip strength and declines in in vitro EDL force after repeated eccentric contractions., Conclusions/significance: Together our findings suggest that combined treatment of LANZO and prednisolone attenuates some components of dystrophic pathology in mdx mice. Our findings warrant future investigation of the clinical efficacy of LANZO and prednisolone combined treatment regimens in dystrophic pathology.
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- 2013
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46. Comparison of the effect of a single dose of omeprazole or lansoprazole on intragastric pH in Japanese participants: a two-way crossover study.
- Author
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Funaki Y, Tokudome K, Izawa S, Tamura Y, Kondo Y, Iida A, Mizuno M, Ogasawara N, Sasaki M, and Kasugai K
- Subjects
- Adult, Cross-Over Studies, Gastric Acidity Determination, Gastric Mucosa metabolism, Humans, Hydrogen-Ion Concentration, Male, Prospective Studies, Gastric Mucosa drug effects, Lansoprazole pharmacology, Omeprazole pharmacology, Proton Pump Inhibitors pharmacology
- Abstract
Background: It is known that the pharmacokinetic profile of proton pump inhibitors (PPIs) after postprandial administration may differ among PPIs. The purpose of this study was to compare the inhibitory effects of gastric acid secretion by PPIs administered after a meal, based on a 24-hour intragastric pH monitoring., Methods: Ten healthy men who provided written informed consent participated in the study. They were given a 20-mg omeprazole tablet and a 30-mg lansoprazole orally dispersing tablet in a two-way crossover manner. At baseline, the anti-HP-IgG antibody levels in blood and the pepsinogen (PG) I/II ratio were measured. Participants were given a standardized meal and 200 mL of water at 9:30 am, 13:30 pm, and 18.30 pm. Participants took the PPI after breakfast., Results: Two of the ten participants tested positive for Helicobacter pylori infection. The PG I/II ratio indicated negative gastric atrophy in all the participants. The percentage 24-hour intragastric pH > 4 holding times (median, range) with omeprazole and lansoprazole were 29.3, 19.3-50.0% and 27.8, 13.0-42.3%, respectively, which shows that with the administration of omeprazole, the pH was maintained at >4 for a longer period (p < 0.05). Each median intragastric pH value per hour at 3, 17, and 18 hours after a dose of omeprazole was significantly higher than that of lansoprazole (p < 0.05)., Conclusion: Compared with lansoprazole, a single postprandial dose of omeprazole showed a more rapid and sustained acid-inhibitory effect., (Copyright © 2012. Published by Elsevier B.V.)
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- 2013
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47. Reaction of proton pump inhibitors with model peptides results in novel products.
- Author
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Watson C, Zhu L, Guan S, Machen TE, and Forte JG
- Subjects
- 2-Pyridinylmethylsulfinylbenzimidazoles chemistry, 2-Pyridinylmethylsulfinylbenzimidazoles pharmacology, Catalytic Domain, Enzyme Inhibitors, H(+)-K(+)-Exchanging ATPase, Hydrogen-Ion Concentration, Lansoprazole chemistry, Lansoprazole pharmacology, Mass Spectrometry, Molecular Structure, Omeprazole chemistry, Omeprazole pharmacology, Pantoprazole, Pyridones, Sulfamerazine, Cysteine chemistry, Peptides chemistry, Proton Pump Inhibitors chemistry, Proton Pump Inhibitors pharmacology
- Abstract
The proposed mechanism for proton pump inhibitors (PPIs) is that PPIs are activated at low pH to the sulfenamide form, which reacts with the sulfhydryl group of cysteine(s) at the active site of the proton pump, to produce reducible disulfide-bonded PPI-proton pump conjugates. However, this mechanism cannot explain the observations that some PPI-protein conjugates are irreducible. This study was designed to investigate the chemistry of the irreducible conjugates by mass spectrometry, using three PPIs and 17 cysteine-containing peptides. While some peptides favored the formation of reducible PPI-peptide adduct, the other peptides mainly produced irreducible adducts. Characterization of the irreducible adduct revealed that the irreducible bonding required the participation of both a sulfhydryl group and a nearby primary amino group. High resolution mass spectrometry suggested a molecular structure of the irreducible adduct. These results suggested a reaction mechanism in which the PPI pyridone form reacted with an amino group and a sulfhydryl group to form an irreducible adduct. The irreducible adduct becomes the dominant product over time because of the irreversible nature of the pyridone-mediated reaction. These findings may explain the irreducible inhibition of H/K-ATPase by PPIs and their relatively slow biological turnover in vivo. [Supplementary materials: available only at http://dx.doi.org/10.1254/jphs.13058FP].
- Published
- 2013
- Full Text
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