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Molecular mechanism and functional consequences of lansoprazole-mediated heme oxygenase-1 induction.World Journal of Gastroenterology Sep 2009To investigate the molecular mechanism and functional consequences of heme oxygenase-1 (HO-1) activation by lansoprazole in endothelial cells and macrophages.
AIM
To investigate the molecular mechanism and functional consequences of heme oxygenase-1 (HO-1) activation by lansoprazole in endothelial cells and macrophages.
METHODS
Expression of HO-1 mRNA was analyzed by Northern blotting. Western blotting was used to determine the HO-1 and ferritin protein levels. NADPH-dependent reactive oxygen species (ROS) formation was measured with lucigenin-enhanced chemiluminescence. HO-1 promoter activity in mouse fibroblasts, stably transfected with a 15-kb HO-1 gene that drives expression of the reporter gene luciferase, was assessed using in vivo bioluminescence imaging.
RESULTS
Lansoprazole increased HO-1 mRNA levels in endothelial cells and HO-1 protein levels in macrophages. In addition, lansoprazole-induced ferritin protein levels in both cell systems. Moreover, induction of the antioxidant proteins HO-1 and ferritin by lansoprazole was followed by a decrease in NADPH-mediated ROS formation. The radical scavenging properties of lansoprazole were diminished in the presence of the HO inhibitor, chromium mesoporphyrin IX. Induction of HO-1 gene expression by lansoprazole was not related to oxidative stress or to the activation of the mitogen-activated protein kinase pathway. However, the phosphatidylinositol 3-kinase inhibitor LY294002 showed a concentration-dependent inhibition of HO-1 mRNA and promoter activity.
CONCLUSION
Activation of HO-1 and ferritin may account for the gastric protection of lansoprazole and is dependent on a pathway blocked by LY294002.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Animals; Antioxidants; Blotting, Northern; Blotting, Western; Cells, Cultured; Endothelial Cells; Enzyme Activation; Enzyme Inhibitors; Ferritins; Gene Expression Regulation, Enzymologic; H(+)-K(+)-Exchanging ATPase; Heme Oxygenase-1; Lansoprazole; Luminescence; Macrophages; Mice; Promoter Regions, Genetic; Proton Pump Inhibitors; RNA, Messenger; Reactive Oxygen Species
PubMed: 19764090
DOI: 10.3748/wjg.15.4392 -
Acta Medica Indonesiana Apr 2013to assess the safety and effectiveness of lansoprazole injection (Prosogan®) in patients with upper gastrointestinal bleeding due to peptic ulcers or erosive gastritis. (Clinical Trial)
Clinical Trial
AIM
to assess the safety and effectiveness of lansoprazole injection (Prosogan®) in patients with upper gastrointestinal bleeding due to peptic ulcers or erosive gastritis.
METHODS
this study was a multicenter observational postmarketing study of lansoprazole (Prosogan®) injection. Patients with upper gastrointestinal bleeding due to peptic ulcers or erosive gastritis were given intravenous lansoprazole for a maximum of 7 days or until the bleeding stopped and the patients were able to take oral doses of lansoprazole. Primary outcome of the study was cessation of bleeding. Some laboratory parameters were also measured.
RESULTS
among a total of 204 patients evaluable for safety, there was no adverse event reported during the study. A total of 200 patients were eligible for efficacy evaluation, 125 patients (62.5%) were males. Among these patients, upper GI bleeding stopped in 20 patients (10.0%) on day 1, in 71 patients (35.5%) on day 2, 75 patients (37.5%) on day 3, 24 patients (12.0%) on day 4, and 7 patients (3.5%) on day 5, making a cumulative of 197 patients (98.5%) on day 5. The hemostatic effect was rated as 'excellent' if the bleeding stopped within 3 days, and 'good' if the bleeding stopped within 5 days. Thus, the results were 'excellent' in 166 patients (83.0%) and 'good' in 31 patients (15.5%). These results were not different between males and females, between age below 60 years and 60 years and above, and between baseline Hb below 10 g/dL and 10 g/dL and above.
CONCLUSION
the results of this observational postmarketing study in 200 patients with upper gastrointestinal bleeding due to peptic ulcers or erosive gastritis demonstrated that intravenous lansoprazole twice a day was well tolerated and highly effective.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Administration, Oral; Adult; Aged; Anti-Ulcer Agents; Drug Administration Schedule; Female; Gastritis; Humans; Indonesia; Injections, Intravenous; Lansoprazole; Male; Middle Aged; Peptic Ulcer Hemorrhage; Product Surveillance, Postmarketing; Treatment Outcome
PubMed: 23770792
DOI: No ID Found -
The Journal of Toxicological Sciences 2023Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular...
In vivo analysis of acute eletropharmacological effects of proton pump inhibitors using halothane-anesthetized dogs: a translational study of cardiovascular adverse events.
Long-term use of proton pump inhibitors (PPIs) is known to clinically induce hypomagnesemia, increasing the risk toward QT-interval prolongation and lethal ventricular arrhythmias, whereas PPIs can directly modulate cardiac ionic currents in the in vitro experiments. In order to fill the gap between those information, we assessed acute cardiohemodynamic and electrophysiological effects of sub- to supra-therapeutic doses (0.05, 0.5 and 5 mg/kg/10 min) of typical PPIs omeprazole, lansoprazole and rabeprazole, using halothane-anesthetized dogs (n = 6 for each drug). The low and middle doses of omeprazole and lansoprazole increased or tended to increase the heart rate, cardiac output and ventricular contraction, whereas the high dose plateaued and decreased them. Meanwhile, the low and middle doses of omeprazole and lansoprazole decreased the total peripheral vascular resistance, whereas the high dose plateaued and increased it. Rabeprazole decreased the mean blood pressure in a dose-related manner; moreover, its high dose decreased the heart rate and tended to reduce the ventricular contractility. On the other hand, omeprazole prolonged the QRS width. Omeprazole and lansoprazole tended to prolong the QT interval and QTcV, and rabeprazole mildly but significantly prolonged them in a dose-related manner. High dose of each PPI prolonged the ventricular effective refractory period. Omeprazole shortened the terminal repolarization period, whereas lansoprazole and rabeprazole hardly altered it. In effects, PPIs can exert multifarious cardiohemodynamic and electrophysiological actions in vivo, including mild QT-interval prolongation; thus, PPIs should be given with caution to patients with reduced ventricular repolarization reserve.
Topics: Dogs; Animals; Proton Pump Inhibitors; Rabeprazole; Halothane; Omeprazole; Lansoprazole
PubMed: 37394651
DOI: 10.2131/jts.48.375 -
World Journal of Gastroenterology Jun 2016To compare the clinical efficacy of the second-generation H2RA lafutidine with that of lansoprazole in Japanese patients with mild gastroesophageal reflux disease (GERD). (Comparative Study)
Comparative Study Randomized Controlled Trial
AIM
To compare the clinical efficacy of the second-generation H2RA lafutidine with that of lansoprazole in Japanese patients with mild gastroesophageal reflux disease (GERD).
METHODS
Patients with symptoms of GERD and a diagnosis of grade A reflux esophagitis (according to the Los Angeles classification) were randomized to receive lafutidine (10 mg, twice daily) or lansoprazole (30 mg, once daily) for an initial 8 wk, followed by maintenance treatment comprising half-doses of the assigned drug for 24 wk. The primary endpoint was the frequency and severity of heartburn during initial and maintenance treatment. The secondary endpoints were the sum score of questions 2 and 3 in the Gastrointestinal Symptom Rating Scale (GSRS), and the satisfaction score.
RESULTS
Between April 2012 and March 2013, a total of 53 patients were enrolled, of whom 24 and 29 received lafutidine and lansoprazole, respectively. After 8 wk, the frequency and severity of heartburn was significantly reduced in both groups. However, lafutidine was significantly inferior to lansoprazole with regard to the severity of heartburn during initial and maintenance treatment (P = 0.016). The sum score of questions 2 and 3 in the GSRS, and satisfaction scores were also significantly worse in the lafutidine group than the lansoprazole group (P = 0.0068 and P = 0.0048, respectively).
CONCLUSION
The clinical efficacy of lafutidine was inferior to that of lansoprazole, even in Japanese patients with mild GERD.
Topics: Acetamides; Adult; Aged; Aged, 80 and over; Esophagitis, Peptic; Female; Gastroesophageal Reflux; Heartburn; Histamine H2 Antagonists; Humans; Japan; Lansoprazole; Male; Middle Aged; Piperidines; Proton Pump Inhibitors; Pyridines; Severity of Illness Index; Treatment Outcome
PubMed: 27340360
DOI: 10.3748/wjg.v22.i23.5430 -
PloS One 2013A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the...
A key event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of amyloid-β (Aβ) species in the brain, derived from the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Based on a systems biology study to repurpose drugs for AD, we explore the effect of lansoprazole, and other proton-pump inhibitors (PPIs), on Aβ production in AD cellular and animal models. We found that lansoprazole enhances Aβ37, Aβ40 and Aβ42 production and lowers Aβ38 levels on amyloid cell models. Interestingly, acute lansoprazole treatment in wild type and AD transgenic mice promoted higher Aβ40 levels in brain, indicating that lansoprazole may also exacerbate Aβ production in vivo. Overall, our data presents for the first time that PPIs can affect amyloid metabolism, both in vitro and in vivo.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Alzheimer Disease; Amyloid beta-Peptides; Animals; CHO Cells; Cricetinae; Cricetulus; Disease Models, Animal; Enzyme Inhibitors; Female; Humans; Lansoprazole; Mice; Mice, Knockout; Proton Pump Inhibitors
PubMed: 23520537
DOI: 10.1371/journal.pone.0058837 -
Circulation Journal : Official Journal... Jan 2023Low-dose aspirin (LDA) is used to prevent recurrent cardiovascular (CV) events, but is associated with upper gastrointestinal (GI) bleeding; concomitant use of a proton...
BACKGROUND
Low-dose aspirin (LDA) is used to prevent recurrent cardiovascular (CV) events, but is associated with upper gastrointestinal (GI) bleeding; concomitant use of a proton pump inhibitor (PPI) reduces this risk. This study aimed to assess the cost-effectiveness of vonoprazan compared with PPIs (lansoprazole and esomeprazole) in patients taking LDA for secondary prevention of CV events.Methods and Results: A Markov simulation model was developed to predict the number of GI bleeding and acute CV events using 3 strategies (vonoprazan+LDA, esomeprazole+LDA, and lansoprazole+LDA), which were translated into quality-adjusted life-years (QALYs) and costs. Transition probabilities and utilities were derived from the results of published literature, and medical costs were based on the Japanese National Health Insurance fee table and claims databases in 2020. Outcomes were projected over 30 years starting at age 65 years and discounted at 2% annually. Expected costs with esomeprazole 20 mg, lansoprazole 15 mg and vonoprazan 10 mg were JPY 1,225,657, JPY 943,930, and JPY 1,059,510, respectively. The QALY gain for vonoprazan vs. esomeprazole was 0.35, thus vonoprazan was dominant against esomeprazole. The QALY gain for vonoprazan vs. lansoprazole was 0.29 and the incremental cost-effectiveness ratio (ICER) was JPY 398,551, thus, vonoprazan was more cost-effective than lansoprazole.
CONCLUSIONS
Vonoprazan is dominant or cost-effective compared with esomeprazole and lansoprazole in patients taking LDA for secondary prevention of CV events.
Topics: Humans; Aged; Proton Pump Inhibitors; Esomeprazole; Cost-Benefit Analysis; Japan; Secondary Prevention; Aspirin; Pyrroles; Lansoprazole; Gastrointestinal Hemorrhage; Cardiovascular Diseases
PubMed: 36002313
DOI: 10.1253/circj.CJ-22-0127 -
Emerging Microbes & Infections Dec 2024has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive...
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, 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 LNP also potentiates the antifungal activity of AmB against other medically important species of and 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 ). 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 in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome inhibitor for combating drug-resistant infections.
Topics: Animals; Mice; Amphotericin B; Antifungal Agents; Candida auris; Lansoprazole; Respiration; Cytochromes; Candidiasis
PubMed: 38431850
DOI: 10.1080/22221751.2024.2322649 -
Cancer Science Oct 2015Cellular causes of resistance and limited drug distribution within solid tumors limit therapeutic efficacy of anticancer drugs. Acidic endosomes in cancer cells mediate...
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.
Topics: Animals; Antibiotics, Antineoplastic; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Resistance, Neoplasm; Female; Lansoprazole; MCF-7 Cells; Mammary Neoplasms, Animal; Mice; Mice, Nude; Proton Pump Inhibitors; Xenograft Model Antitumor Assays
PubMed: 26212113
DOI: 10.1111/cas.12756 -
Alimentary Pharmacology & Therapeutics Jul 1999Maintenance antisecretory therapy is often used to prevent duodenal ulcer recurrence and control symptoms. This study compared the efficacy and safety of lansoprazole 15... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
Double-blind comparison of lansoprazole 15 mg, lansoprazole 30 mg and placebo as maintenance therapy in patients with healed duodenal ulcers resistant to H2-receptor antagonists.
BACKGROUND
Maintenance antisecretory therapy is often used to prevent duodenal ulcer recurrence and control symptoms. This study compared the efficacy and safety of lansoprazole 15 mg and 30 mg daily with placebo in preventing ulcer recurrence in patients with a recent history of duodenal ulcer disease.
METHODS
Fifty-six patients were treated with either lansoprazole 15 mg, 30 mg or placebo o.m.
RESULTS
Within 1 month of study initiation, 27% (four out of 15) of placebo-treated patients experienced ulcer recurrence as compared to 13% (two out of 15) and 6% (one out of 18) of lansoprazole 15 mg and 30 mg treated patients, respectively. Median time to first ulcer recurrence was > 12 months in lansoprazole patients. At Month 12, significantly (P < 0.001) more lansoprazole 15 mg patients (70%) and lansoprazole 30 mg patients (85%) remained healed. Eighty-two per cent of lansoprazole 15 mg and 76% of lansoprazole 30 mg patients remained asymptomatic during the entire study period. All placebo patients became symptomatic, experienced ulcer recurrence, or withdrew from the study by month six. The incidence of adverse events was comparable among the three treatment groups.
CONCLUSIONS
Lansoprazole safely and effectively reduces duodenal ulcer recurrence and ulcer-related symptoms.
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Adult; Aged; Anti-Ulcer Agents; Double-Blind Method; Drug Resistance; Duodenal Ulcer; Female; Gastric Mucosa; Gastrins; Histamine H2 Antagonists; Humans; Lansoprazole; Male; Middle Aged; Omeprazole; Proton Pump Inhibitors; Recurrence; Treatment Outcome; United States
PubMed: 10383532
DOI: 10.1046/j.1365-2036.1999.00569.x -
CMAJ : Canadian Medical Association... Jul 2008
Topics: 2-Pyridinylmethylsulfinylbenzimidazoles; Aged; Follow-Up Studies; Gastric Antral Vascular Ectasia; Gastric Mucosa; Gastroesophageal Reflux; Gastrointestinal Hemorrhage; Gastroscopy; Humans; Lansoprazole; Laser Coagulation; Male; Scleroderma, Systemic; Severity of Illness Index; Treatment Outcome
PubMed: 18625989
DOI: 10.1503/cmaj.080461