RESUMO
Importance: Proton pump inhibitors (PPIs) are a widely prescribed class of drugs, potentially interacting with a large number of medicines, especially among older patients with multimorbidity and polypharmacy. Beyond summary of product characteristics (SPCs), interaction checkers (ICs) are routinely used tools to help clinicians in medication review interventions. Objective: To assess the consistency of information on drugs potentially interacting with PPIs as reported in their SPCs and different ICs. Design, Setting, and Participants: This cross-sectional study was conducted using data from SPCs for 5 PPIs (omeprazole, esomeprazole, lansoprazole, pantoprazole, and rabeprazole) and 5 ICs (ie, INTERCheck WEB, Micromedex, Lexicomp, Epocrates, and drugs.com). Information from the SPCs and the ICs were extracted between July 15 and 30, 2023. Main Outcomes and Measures: The main outcome was the level of agreement among SPCs and the 5 ICs in identifying drugs potentially interacting with PPIs and attributing drug-drug interaction (DDI) severity categories. The level of agreement was computed using Gwet AC1 statistic on the 5 ICs and by comparing 4-sets and 2-sets of ICs. As a sensitivity analysis, the level of agreement in listing PPI-related DDIs was evaluated using Cohen κ and Fleiss κ coefficients. Results: Considering SPCs and the 5 ICs, a total of 518 potentially interacting drugs with omeprazole were reported, 455 for esomeprazole, 433 for lansoprazole, 421 for pantoprazole, and 405 for rabeprazole. As compared with the ICs, the SPCs reported a much smaller number of drugs potentially interacting with PPIs, with proportions ranging from 2.7% (11 potentially interacting drugs) for rabeprazole to 7.6% (33 potentially interacting drugs) for lansoprazole of the total identified drugs at risk of interaction with a PPI. The overall level of agreement among the 5 ICs for identifying potential interactions was poor (from 0.23 [95% CI, 0.21-0.25] for omeprazole to 0.27 [95% CI, 0.24-0.29] for pantoprazole and 0.27 [95% CI, 0.25-0.29] for rabeprazole). Similarly, the level of agreement was low in 4-set and 2-set analyses as well as when restricting the analysis to the potential DDIs identified as severe (range, 0.30-0.32). Conclusions and Relevance: This cross-sectional study found significant disagreement among different ICs and SPCs, highlighting the need to focus on standardizing DDI databases. Therefore, to ensure evaluation and prevention of clinically relevant DDIs, it is recommended to revise multiple ICs and consult with specialists, such as clinical pharmacologists, particularly for patients with complex medical conditions.
Assuntos
Interações Medicamentosas , Inibidores da Bomba de Prótons , Humanos , Estudos Transversais , Rabeprazol/farmacologia , Lansoprazol , Omeprazol , Esomeprazol , PantoprazolRESUMO
Helicobacter pylori eradication is crucial in the treatment of peptic ulcers caused by H. pylori infection, a disease highly prevalent in Asia. We present a pooled analysis of two randomized, double-blind, double-dummy, phase 3 studies evaluating the efficacy and safety of vonoprazan-based bismuth-containing quadruple therapy for H. pylori eradication. Patients aged ≥18 years with endoscopically confirmed duodenal or gastric ulcers were randomized 1 : 1 to receive vonoprazan 20 mg or lansoprazole 30 mg once daily for up to 6 (duodenal ulcers) or 8 weeks (gastric ulcers). H. pylori-positive patients received vonoprazan- or lansoprazole-based bismuth-containing quadruple therapy for the first 2 weeks. H. pylori eradication was determined using the carbon-13 urea breath test at a follow-up visit 4 weeks post-treatment. The H. pylori eradication rate was 90.6% with vonoprazan vs. 85.2% with lansoprazole (difference: 5.4%; 95% confidence interval (CI): -0.1, 10.8). H. pylori eradication rates were 7.1% (95% CI: 1.4, 12.8) and 12.6% (95% CI: 3.9, 22.0) higher in patients aged <65 years and current smokers, respectively, with vonoprazan vs. lansoprazole. In the Chinese subpopulation, the H. pylori eradication rate was 92.0% with vonoprazan vs. 86.0% with lansoprazole (difference: 6.1%; 95% CI: 0.5, 11.7). Treatment-emergent adverse events occurred in 72.7 vs. 62.6% of H. pylori-positive patients at baseline in the vonoprazan vs. lansoprazole arm. H. pylori eradication with vonoprazan-based quadruple therapy was noninferior to lansoprazole-based quadruple therapy and exceeded 90%, a clinically relevant threshold for determining the efficacy of H. pylori eradication regimens (ClinicalTrials.gov identifier: NCT03050359; NCT03050307).
Assuntos
Antibacterianos , Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Lansoprazol , Úlcera Péptica , Inibidores da Bomba de Prótons , Pirróis , Sulfonamidas , Humanos , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Pirróis/administração & dosagem , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/administração & dosagem , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/efeitos dos fármacos , Pessoa de Meia-Idade , Masculino , Feminino , Método Duplo-Cego , Lansoprazol/uso terapêutico , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversos , Adulto , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Úlcera Péptica/tratamento farmacológico , Úlcera Péptica/microbiologia , Idoso , Antiulcerosos/uso terapêutico , Antiulcerosos/administração & dosagem , Antiulcerosos/efeitos adversos , Resultado do Tratamento , Testes RespiratóriosRESUMO
AIMS: Lansoprazole is one of the many proton pump inhibitors (PPIs) that acts more strongly with ABCB1 and ABCG2. The present study is to investigate the potential of lansoprazole on reversal of ABCB1/G2-mediated MDR in cancer, in vitro and in vivo. METHODS: Reversal studies and combination evaluation were conducted to determine the synergistic anti-MDR effects on lansoprazole. Lysosomal staining was used to determination of lansoprazole on ABCB1-mediated lysosomal sequestration. Substrate accumulation and efflux assays, ATPase activity, and molecular docking were conducted to evaluate lansoprazole on ABCB1/G2 functions. Western blot and immunofluorescence were used to detect lansoprazole on ABCB1/G2 expression and subcellular localization. MDR nude mice models were established to evaluate the effects of lansoprazole on MDR in vivo. RESULTS: Lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects with substrate drugs in MDR cells. In vivo experiments demonstrated that lansoprazole attenuated ABCB1/G2-mediated MDR and exhibited synergistic effects that augmented the sensitivity of substrate anticancer drugs in ABCB1/G2-mediated settings without obvious toxicity. Lansoprazole impeded lysosomal sequestration mediated by ABCB1, leading to a substantial increase in intracellular accumulation of substrate drugs. The effects of lansoprazole were not attributable to downregulation or alterations in subcellular localization of ABCB1/G2. Lansoprazole promoted the ATPase activity of ABCB1/G2 and competitively bound to the substrate-binding region of ABCB1/G2. CONCLUSIONS: These findings present novel therapeutic avenues whereby the combination of lansoprazole and chemotherapeutic agents mitigates MDR mediated by ABCB1/G2 overexpression.
Assuntos
Subfamília B de Transportador de Cassetes de Ligação de ATP , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Lansoprazol , Lisossomos , Inibidores da Bomba de Prótons , Animais , Humanos , Camundongos , Antineoplásicos/farmacologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Lansoprazol/farmacologia , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Camundongos Nus , Simulação de Acoplamento Molecular , Proteínas de Neoplasias , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Inibidores da Bomba de Prótons/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND AND AIMS: This study aimed to evaluate the efficacy and safety of vonoprazan and tetracycline (VT) dual therapy as first-line treatment for Helicobacter pylori infection in patients with penicillin allergy. METHODS: In this randomised controlled trial, treatment-naïve adults with H. pylori infection and penicillin allergy were randomised 1:1 to receive either open-label VT dual therapy (vonoprazan 20 mg two times per day+tetracycline 500 mg three times a day) or bismuth quadruple therapy (BQT; lansoprazole 30 mg two times per day+colloidal bismuth 150 mg three times a day+tetracycline 500 mg three times a day+metronidazole 400 mg three times a day) for 14 days. The primary outcome was non-inferiority in eradication rates in the VT dual group compared with the BQT group. Secondary outcomes included assessing adverse effects. RESULTS: 300 patients were randomised. The eradication rates in the VT group and the BQT group were: 92.0% (138/150, 95% CI 86.1% to 95.6%) and 89.3% (134/150, 95% CI 83.0% to 93.6%) in intention-to-treat analysis (difference 2.7%; 95% CI -4.6% to 10.0%; non-inferiority p=0.000); 94.5% (138/146, 95% CI 89.1% to 97.4%) and 93.1% (134/144, 95% CI 87.3% to 96.4%) in modiï¬ed intention-to-treat analysis (difference 1.5%; 95% CI -4.9% to 8.0%; non-inferiority p=0.001); 95.1% (135/142, 95% CI 89.7% to 97.8%) and 97.7% (128/131, 95% CI 92.9% to 99.4%) in per-protocol analysis (difference 2.6%; 95% CI -2.9% to 8.3%; non-inferiority p=0.000). The treatment-emergent adverse events (TEAEs) were significantly lower in the VT group (14.0% vs 48.0%, p=0.000), with fewer treatment discontinuations due to TEAEs (2.0% vs 8.7%, p=0.010). CONCLUSIONS: VT dual therapy demonstrated efficacy and safety as a first-line treatment for H. pylori infection in the penicillin-allergic population, with comparable efficacy and a lower incidence of TEAEs compared with traditional BQT. TRIAL REGISTRATION NUMBER: ChiCTR2300074693.
Assuntos
Antibacterianos , Hipersensibilidade a Drogas , Quimioterapia Combinada , Infecções por Helicobacter , Helicobacter pylori , Penicilinas , Pirróis , Sulfonamidas , Tetraciclina , Humanos , Sulfonamidas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Hipersensibilidade a Drogas/etiologia , Tetraciclina/uso terapêutico , Tetraciclina/efeitos adversos , Tetraciclina/administração & dosagem , Penicilinas/efeitos adversos , Penicilinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Pirróis/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Antibacterianos/administração & dosagem , Adulto , Bismuto/uso terapêutico , Bismuto/efeitos adversos , Bismuto/administração & dosagem , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Resultado do Tratamento , Idoso , Metronidazol/efeitos adversos , Metronidazol/uso terapêutico , Metronidazol/administração & dosagem , Lansoprazol/uso terapêutico , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversosRESUMO
OBJECTIVES: To determine whether concomitant use of ceftriaxone and oral or intravenous lansoprazole increases the risk of ventricular arrhythmia and cardiac arrest in the real-world setting in Japan. METHODS: The data analyzed were obtained from the JMDC hospital-based administrative claims database for the period April 2014 to August 2022. Patients who received a proton pump inhibitor (PPI) while receiving ceftriaxone or sulbactam/ampicillin were identified. The frequency of ventricular arrhythmia and cardiac arrest was analyzed according to whether oral or intravenous PPI was concomitant with ceftriaxone or sulbactam/ampicillin. Estimates of the incidence of ventricular arrhythmia and cardiac arrest were then compared among the groups, using the Fine-Gray competing risk regression model. RESULTS: The results showed that the risk of ventricular arrhythmia and cardiac arrest was significantly higher with concomitant ceftriaxone and oral lansoprazole (hazard ratio 2.92, 95% confidence interval 1.99-4.29, P < 0.01) or intravenous lansoprazole (hazard ratio 4.57, 95% confidence interval 1.24-16.80, P = 0.02) than with concomitant sulbactam/ampicillin and oral or intravenous lansoprazole. CONCLUSIONS: Oral and intravenous lansoprazole may increase the risk of ventricular arrhythmia and cardiac arrest in patients who are receiving ceftriaxone.
Assuntos
Arritmias Cardíacas , Ceftriaxona , Parada Cardíaca , Lansoprazol , Inibidores da Bomba de Prótons , Humanos , Lansoprazol/efeitos adversos , Lansoprazol/administração & dosagem , Ceftriaxona/efeitos adversos , Ceftriaxona/administração & dosagem , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/epidemiologia , Masculino , Japão/epidemiologia , Feminino , Idoso , Pessoa de Meia-Idade , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/epidemiologia , Antibacterianos/efeitos adversos , Antibacterianos/administração & dosagem , Bases de Dados Factuais , Idoso de 80 Anos ou mais , Adulto , Estudos Retrospectivos , Incidência , Administração Oral , Fatores de Risco , Quimioterapia Combinada/efeitos adversos , População do Leste AsiáticoRESUMO
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.
Assuntos
Anfotericina B , Antifúngicos , Candida auris , Farmacorresistência Fúngica Múltipla , Sinergismo Farmacológico , Lansoprazol , Testes de Sensibilidade Microbiana , Lansoprazol/farmacologia , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Humanos , Candida auris/efeitos dos fármacos , Candida auris/genética , Candidíase/tratamento farmacológico , Candidíase/microbiologia , Inibidores da Bomba de Prótons/farmacologiaRESUMO
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 IC50 value of lansoprazole against hOAT3-mediated transport of PNU-142586 was 0.59 ± 0.38⯵M. 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.
Assuntos
Linezolida , Trombocitopenia , Linezolida/efeitos adversos , Linezolida/farmacocinética , Humanos , Trombocitopenia/induzido quimicamente , Trombocitopenia/metabolismo , Células HEK293 , Animais , Masculino , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Ratos , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacologia , Lansoprazol/farmacologia , Transporte Biológico , Ratos Sprague-Dawley , Fatores de Risco , Adulto , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismoRESUMO
BACKGROUND: Erosive esophagitis (EE) is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus. Proton pump inhibitors are widely used as maintenance therapy for EE, but many patients still relapse. In this trial, we evaluated the noninferiority of vonoprazan vs. lansoprazole as maintenance therapy in patients with healed EE. METHODS: We performed a double-blind, double-dummy, multicenter, phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019. Patients from China, South Korea, and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks. The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10% using a two-sided 95% confidence interval (CI). Treatment-emergent adverse events (TEAEs) were recorded. RESULTS: Among 703 patients, EE recurrence was observed in 24/181 (13.3%) and 21/171 (12.3%) patients receiving vonoprazan 10 mg or 20 mg, respectively, and 47/184 (25.5%) patients receiving lansoprazole (differences: -12.3% [95% CI, -20.3% to -4.3%] and -13.3% [95% CI, -21.3% to -5.3%], respectively), meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks. Evidence of superiority (upper bound of 95% CI <0%) was also observed. At 12 weeks, endoscopically confirmed EE recurrence was observed in 5/18, 2/20, and 7/20 of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. TEAEs were experienced by 66.8% (157/235), 69.0% (156/226), and 65.3% (158/242) of patients receiving vonoprazan 10 mg, vonoprazan 20 mg, and lansoprazole, respectively. The most common TEAE was upper respiratory tract infection in 12.8% (30/235) and 12.8% (29/226) patients in vonoprazan 10 mg and 20 mg groups, respectively and 8.7% (21/242) patients in lansoprazole group. CONCLUSION: Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE. TRIAL REGISTRATION: https://clinicaltrials.gov; NCT02388737.
Assuntos
Lansoprazol , Inibidores da Bomba de Prótons , Pirróis , Sulfonamidas , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Povo Asiático , Método Duplo-Cego , Esofagite/tratamento farmacológico , Esofagite Péptica/tratamento farmacológico , Lansoprazol/uso terapêutico , Inibidores da Bomba de Prótons/uso terapêutico , Pirróis/uso terapêutico , Sulfonamidas/uso terapêutico , População do Leste Asiático , China , República da Coreia , MalásiaRESUMO
Current genotoxicity assessment methods are mainly employed to verify the genotoxic safety of drugs, but do not allow for rapid screening of specific genotoxic impurities (GTIs). In this study, a new approach for the recognition of GTIs has been proposed. It is to expose the complex samples to an in vitro nucleoside incubation model, and then draw complete DNA adduct profiles to infer the structures of potential genotoxic impurities (PGIs). Subsequently, the genotoxicity is confirmed in human by 3D bioprinted human liver organoids. To verify the feasibility of the approach, lansoprazole chloride compound (Lanchlor), a PGI during the synthesis of lansoprazole, was selected as the model drug. After confirming genotoxicity by Comet assay, it was exposed to different models to map and compare the DNA adduct profiles by LC-MS/MS. The results showed Lanchlor could generate diverse DNA adducts, revealing firstly its genotoxicity at molecular mechanism of action. Furthermore, the largest variety and content of DNA adducts were observed in the nucleoside incubation model, while the human liver organoids exhibited similar results with rats. The results showed that the combination of DNA adductomics and 3D bioprinted organoids were useful for the rapid screening of GTIs.
Assuntos
Adutos de DNA , Nucleosídeos , Humanos , Ratos , Animais , Nucleosídeos/toxicidade , Cromatografia Líquida , Espectrometria de Massas em Tandem , Dano ao DNA , Fígado , DNA , Organoides , LansoprazolRESUMO
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 bc1). 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 (â¼98%) 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.
Assuntos
Anfotericina B , Antifúngicos , Candidíase , Animais , Camundongos , Anfotericina B/farmacologia , Antifúngicos/farmacologia , Candida auris , Lansoprazol/farmacologia , Respiração , CitocromosRESUMO
BACKGROUND AND AIM: Healing rates of severe erosive esophagitis (EE; Los Angeles [LA] Grade C/D) in patients treated with a proton pump inhibitor (PPI) is suboptimal (~60-70%). Vonoprazan, a potassium-competitive acid blocker, is suggested to have better healing rates in patients with severe EE. This meta-analysis compares the efficacy and safety of vonoprazan 20 mg versus lansoprazole 30 mg daily in healing EE, specifically in those with LA Grade C/D. METHODS: We searched MEDLINE, Embase, and CENTRAL on May 24, 2023. Studies that randomized EE patients to vonoprazan 20 mg daily or lansoprazole 30 mg daily and compared healing rates were included. The risk of bias was assessed using Cochrane's Risk of Bias 2 tool. The fixed-effect model was used to obtain the pooled efficacy and safety outcomes. Subgroup analysis was done to compare healing rates in mild (LA Grade A/B) versus severe EE and based on study location. RESULTS: Four randomized controlled trials (RCTs) with low risks of bias comprising 2208 participants were included. Vonoprazan 20 mg was superior to lansoprazole 30 mg daily in healing severe EE at all weeks (Week 2 RR 1.294 [95% CI 1.169-1.433], Week 4 1.160 [1.059-1.270], and Week 8 1.175 [95% CI 1.107-1.247]), but was similar for mild EE at all weeks (P-interaction < 0.01). Vonoprazan 20 mg was more efficacious than lansoprazole 30 mg at Week 8 in Western versus Asian studies (P-interaction < 0.01). Any, serious, and drug-related treatment-emergent adverse events were comparable between groups. CONCLUSION: Vonoprazan 20 mg is superior to lansoprazole 30 mg for healing severe EE but not mild EE. Vonoprazan 20 mg daily has a similar safety profile to lansoprazole 30 mg daily.
Assuntos
Lansoprazol , Inibidores da Bomba de Prótons , Pirróis , Ensaios Clínicos Controlados Aleatórios como Assunto , Índice de Gravidade de Doença , Sulfonamidas , Lansoprazol/administração & dosagem , Lansoprazol/efeitos adversos , Humanos , Sulfonamidas/efeitos adversos , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/administração & dosagem , Pirróis/uso terapêutico , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/uso terapêutico , Resultado do Tratamento , Esofagite Péptica/tratamento farmacológico , Esofagite/tratamento farmacológicoRESUMO
Proton pump inhibitors (PPIs) have recently been reported to be linked with nephrotoxicity. PPIs are metabolized mainly or partly by cytochrome P450 2C19 (CYP2C19). However, the relationship between CYP2C19 genetic polymorphism and PPI-induced nephrotoxicity is unclear. In this study, we aimed to analyze the association between the time of occurrence of renal injury by PPIs, including lansoprazole, esomeprazole, rabeprazole, and vonoprazan, and CYP2C19 metabolizer status classified by CYP2C19 genotypes. Patients prescribed PPIs were reviewed in this retrospective cohort study. The primary outcome was the time to a 30% decrease in estimated glomerular filtration rate (eGFR) from baseline. In patients treated with lansoprazole, the time to a 30% decrease in eGFR for the CYP2C19 poor metabolizer (PM) group was significantly shorter than that for the non-PM group (hazard ratio for PM vs. non-PM, 2.43, 95% confidence interval, 1.21 to 4.87, P = 0.012). In contrast, in patients that received esomeprazole, rabeprazole, or vonoprazan, no significant differences were found in the time to a 30% decrease in eGFR between non-PM and PM groups. The adjusted hazard ratios for the time to a 30% eGFR decrease in patients treated with lansoprazole were significantly higher for CYP2C19 PM, hypertension, and a history of myocardial infarction. In conclusion, this retrospective study showed that CYP2C19 metabolizer status was associated with the time to a 30% eGFR decrease in patients treated with lansoprazole, but not with esomeprazole, rabeprazole, or vonoprazan.
Assuntos
Inibidores da Bomba de Prótons , Pirróis , Sulfonamidas , Humanos , Citocromo P-450 CYP2C19/genética , Esomeprazol/efeitos adversos , Genótipo , Rim/metabolismo , Lansoprazol , Inibidores da Bomba de Prótons/efeitos adversos , Rabeprazol/efeitos adversos , Estudos RetrospectivosRESUMO
INTRODUCTION: Proton pump inhibitors (PPIs) constitute a widely utilized pharmaceutical class, frequently associated with notable instances of therapeutic inappropriateness. Such patterns of misuse not only contribute to elevated healthcare expenditure, but may also exacerbate clinical conditions in certain patients. METHODS: A comprehensive analysis was conducted between 2019 and 2023 to assess all prescriptions dispensed using the Anatomical, Therapeutic and Chemical (ATC) classification system, which allowed trends among primary PPIs to be visualized. This was achieved by calculating the defined daily dose (DDD) and then defining the total expenditure incurred on these drugs. RESULTS: With regard to the prescription of PPIs, an upward trend in consumption was observed with a decreasing expenditure, due to the phenomena of drug generics and increased competition between pharmaceutical companies, ranging from 9,512,481.22 in the first six months of 2019 to 8,509,820.80 in the first six months of 2023. From 2019 to 2023, consumption increased by approximately 3 million DDDs for a total ranging from 18,483,167.59 DDDs to 21,480,871.00 DDDs. Pantoprazole and esomeprazole, the most expensive drugs compared to omeprazole, rabeprazole and lansoprazole, accounted for 61.4% of therapies in the first six months of 2023, up from 2019, where these two drugs were prescribed 54.9%. CONCLUSION: Within this analysis, we provide an illustrative representation of the prescribing trends for PPIs within a European context. Omeprazole, rabeprazole and lansoprazole appear to be the cheapest drugs compared to pantoprazole and esomeprazole. However, the results show that the most widely used PPIs, despite their therapeutic equivalence, are precisely the high-cost ones, thus generating higher expenditure for central governments.
Assuntos
Gastos em Saúde , Lansoprazol , Pantoprazol , Inibidores da Bomba de Prótons , Inibidores da Bomba de Prótons/economia , Inibidores da Bomba de Prótons/uso terapêutico , Humanos , Lansoprazol/economia , Lansoprazol/administração & dosagem , Gastos em Saúde/tendências , Gastos em Saúde/estatística & dados numéricos , Omeprazol/economia , Omeprazol/uso terapêutico , Esomeprazol/economia , Rabeprazol/economia , Rabeprazol/administração & dosagem , Custos de Medicamentos/tendências , Custos de Medicamentos/estatística & dados numéricos , Medicamentos Genéricos/economia , Uso de Medicamentos/tendências , Uso de Medicamentos/estatística & dados numéricosRESUMO
BACKGROUND AND AIM: The association between proton-pump inhibitors (PPIs) and rhabdomyolysis were unclear. The aim of this study was to explore and systematically analyze the potential link between five PPIs and the rhabdomyolysis events using the FDA Adverse Event Reporting System (FAERS) database. METHODS: Suspected rhabdomyolysis events associated with PPIs were identified by data mining with the reporting odds ratio (ROR), proportional reporting ratio (PRR), the information component (IC), and Empirical Bayes Geometric Mean (EBGM). Demographic information, drug administration, and outcomes of PPI-induced rhabdomyolysis events were also analyzed. RESULTS: There were 3311 reports associated with PPI-induced rhabdomyolysis that were identified. After removing duplicates, 1899 cases were determined to contain complete patient demographic data. The average age was 65 ± 18 year and 57% were male. Omeprazole and pantoprazole had the same largest percentage of reports. Lansoprazole had the highest ROR index of 12.67, followed by esomeprazole (11.18), omeprazole (10.27), rabeprazole (10.06), and pantoprazole (9.24). PRR, IC, and EBGM showed similar patterns. This suggested that lansoprazole exhibited the strongest correlation with rhabdomyolysis. In rhabdomyolysis events, PPIs were mainly "concomitant" (>60%), and only a few cases were "primary suspects" (<15%). Rabeprazole showed the lowest death rate while lansoprazole showed the highest. CONCLUSIONS: The study suggested that significant rhabdomyolysis signals were associated with PPIs. Further research should be performed in drug safety evaluation for a more comprehensive association.
Assuntos
Inibidores da Bomba de Prótons , Rabdomiólise , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Inibidores da Bomba de Prótons/efeitos adversos , Pantoprazol , Rabeprazol , Farmacovigilância , Teorema de Bayes , Omeprazol/efeitos adversos , Lansoprazol , Rabdomiólise/induzido quimicamente , Rabdomiólise/epidemiologiaRESUMO
The aims of this study were to analyze proton pump inhibitor (PPI) users in Germany, defining and classifying them in terms of treatment appropriateness, and to analyze the PPI prescription practices of healthcare providers. The updated DGVS (Deutsche Gesellschaft für Gastroenterologie, Verdauungs-und Stoffwechselkrankheiten) gastroesophageal reflux disease (GERD) treatment guideline (published March 2023) for mild heartburn symptoms recommends carrying out a probatory treatment of mild symptoms via other medication such as antacids, alginates, and H2 blockers before escalating to PPI treatments, if the patient profile allows. This retrospective cross-sectional study was based on data from the IQVIA™ Disease Analyzer database (DA) and included adult patients (18 years or older) in 1006 general and 39 gastroenterological practices in Germany who received at least 1 PPI prescription or alginate between September 2019 and September 2021 (hereinafter referred to as the index period). Analyses included indications associated with PPI prescription, co-diagnoses, co-therapies of PPI patients, duration of PPI therapy, dosages of PPI prescriptions, and proportions of practices prescribing PPIs and alginates. A total of 472 146 patients taking PPIs and 9101 patients taking alginates were available for analysis. Very few patients (4.5%) of the total cohort were treated in complete adherence to treatment guidelines. Conditions such as gastritis and duodenitis (47.2%) and reflux diseases (38.4%) were more frequently associated with PPI prescriptions. The average PPI treatment period lasted 141 days, and 36.6% of patients were treated for >6 months. High doses were prescribed relatively often (ie, 42.8% of esomeprazole prescriptions were 40 mg, 59.1% of lansoprazole prescriptions 30 mg, 28.6% of omeprazole prescriptions 40 mg). With each practice prescribing PPIs to at least 10% of their patients; 72% of general practitioners (GPs) and 8% of GENTS (Gastroenterologists) prescribed alginates. This study highlights that discrepancies exist between clinical guidelines and real-life prescribing practices of PPIs in Germany. Particular attention should be given to the incidence of patients being prescribed high-dose or long-duration PPI with mild indications. These findings are particularly apt considering the publication (March 2023) of new guidelines on the "management of gastroesophageal reflux disease and eosinophilic esophagitis," by the DGVS.
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Refluxo Gastroesofágico , Inibidores da Bomba de Prótons , Adulto , Humanos , Inibidores da Bomba de Prótons/uso terapêutico , Estudos Retrospectivos , Estudos Transversais , Omeprazol/uso terapêutico , Lansoprazol/uso terapêutico , Refluxo Gastroesofágico/tratamento farmacológico , Refluxo Gastroesofágico/complicações , Refluxo Gastroesofágico/diagnósticoRESUMO
In our preliminary experiment, peritoneal sclerosis likely induced by peritoneal dialysis was unexpectedly observed in the livers of rats given bleomycin and lansoprazole. We examined whether this peritoneal thickening around the liver was time-dependently induced by administration of both drugs. Male Wistar rats were injected with bleomycin and/or lansoprazole for 2 or 4 weeks. The 3YB-1 cell line derived from rat fibroblasts was treated by bleomycin and/or lansoprazole for 24 h. The administration of both drugs together, but not individually, thickened the peritoneal tissue around the liver. There was accumulation of collagen fibers, macrophages, and eosinophils under mesothelial cells. Expressions of Col1a1, Mcp1 and Mcp3 genes were increased in the peritoneal tissue around the liver and in 3YB-1 cells by the administration of both drugs together, and Opn genes had increased expressions in this tissue and 3YB-1 cells. Mesothelial cells indicated immunoreactivity against both cytokeratin, a mesothelial cell marker, and αSMA, a fibroblast marker, around the livers of rats given both drugs. Administration of both drugs induced the migration of macrophages and eosinophils and induced fibrosis associated with the possible activation of fibroblasts and the possible promotion of the mesothelial-mesenchymal transition. This might become a novel model of peritoneal sclerosis for peritoneal dialysis.
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Fibrose Peritoneal , Ratos , Masculino , Animais , Fibrose Peritoneal/induzido quimicamente , Fibrose Peritoneal/genética , Bleomicina/efeitos adversos , Ratos Wistar , Lansoprazol/efeitos adversos , Lansoprazol/metabolismo , Células Epiteliais/metabolismo , Peritônio/patologiaRESUMO
Baeyer-Villiger monooxygenases (BVMOs) are able to catalyse the asymmetric oxidation of sulfides. This property has made them attractive catalysts for the synthesis of chiral sulfoxide drugs. Here, we have designed and synthesised an exhaustive combinatorial mutant library of the previously identified lansoprazole sulfide monooxygenase CbBVMOV1. From this synthetic combinatorial mutant library, the best mutant, CbBVMOV3, was selected with a specific activity of approximately 1 U mg-1 for lansoprazole sulfoxides. We then optimised the reaction conditions of a two-phase system, achieving the enzymatic asymmetric synthesis of (R)-lansoprazole in a space-time yield of 213 g L-1 d-1 and an enantiomeric excess of >99% (R) with no detectable by-products. In addition, CbBVMOV3 showed higher activity towards other prazole sulfides. These results indicate the potential application of CbBVMO in the chiral sulfoxide drug industry.
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Oxigenases de Função Mista , Sulfóxidos , Oxigenases de Função Mista/metabolismo , Oxirredução , Sulfetos , LansoprazolRESUMO
Importance: The combination of ceftriaxone and lansoprazole has been shown to prolong the corrected QT interval on electrocardiogram. However, it is unknown whether this translates to clinically important patient outcomes. Objective: To compare lansoprazole with another proton pump inhibitor (PPI) during ceftriaxone treatment in terms of risk for ventricular arrhythmia, cardiac arrest, and in-hospital mortality. Design, Setting, and Participants: A retrospective cohort study including adult medical inpatients receiving ceftriaxone with lansoprazole or another PPI in 13 hospitals in Ontario, Canada, was conducted from January 1, 2015, to December 31, 2021. Exposure: Lansoprazole during ceftriaxone treatment vs other PPIs during ceftriaxone treatment. Main Outcomes and Measures: The primary outcome was a composite of ventricular arrhythmia or cardiac arrest that occurred after hospital admission. The secondary outcome was all-cause in-hospital mortality. Propensity-score weighting was used to adjust for covariates including hospital site, demographic characteristics, comorbidities, risk factors for ventricular arrhythmia, illness severity, admitting diagnoses, and concomitant medications. Results: Of the 31â¯152 patients hospitalized on internal medicine wards who were treated with ceftriaxone while receiving a PPI, 16â¯135 patients (51.8%) were male, and the mean (SD) age was 71.7 (16.0) years. The study included 3747 patients in the lansoprazole group and 27â¯405 patients in the other PPI group. Ventricular arrhythmia or cardiac arrest occurred in 126 patients (3.4%) within the lansoprazole group and 319 patients (1.2%) within the other PPI group. In-hospital mortality occurred in 746 patients (19.9%) within the lansoprazole group and 2762 patients (10.1%) in the other PPI group. After weighting using propensity scores, the adjusted risk difference for the lansoprazole group minus other PPI group was 1.7% (95% CI, 1.1%-2.3%) for ventricular arrhythmia or cardiac arrest and 7.4% (95% CI, 6.1%-8.8%) for in-hospital mortality. Conclusions and Relevance: The findings of this cohort study suggest that combination therapy with lansoprazole and ceftriaxone should be avoided. More studies are needed to determine whether these findings could be replicated in other populations and settings.
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Ceftriaxona , Parada Cardíaca , Adulto , Humanos , Masculino , Idoso , Feminino , Lansoprazol/uso terapêutico , Ceftriaxona/efeitos adversos , Estudos de Coortes , Estudos Retrospectivos , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/epidemiologia , Parada Cardíaca/induzido quimicamente , Parada Cardíaca/epidemiologia , Inibidores da Bomba de Prótons/efeitos adversos , Pacientes Internados , Ontário/epidemiologiaRESUMO
Nebivolol is a beta-1 receptor blocker used to treat hypertension, heart failure, erectile dysfunction, vascular disease, and diabetes mellitus. This review investigated the data regarding pharmacokinetic (PK) parameters, drug-drug interactions, dextrorotatory (D), and levorotatory (L) stereoisomers of nebivolol. The articles related to the PK of nebivolol were retrieved by searching the five databases; Google Scholar, PubMed, Cochrane Library, ScienceDirect, and EBSCO. A total of 20 studies comprising plasma concentration-time profile data following the nebivolol's oral and intravenous (IV) administration were included. The area under the concentration-time curve from zero to infinity (AUC0-∞) was 15 times greater in poor metabolizers (PMs) than in extensive metabolizers (EMs). In hypertensive patients, L-nebivolol expressed a higher maximum plasma concentration (Cmax) than D-nebivolol, i.e. 2.5 ng/ml vs 1.2 ng/ml. The AUC0-∞ of nebivolol was 3-fold greater in chronic kidney disease (CKD). The clearance (CL) was increased in obese than in controls from 51.6 ± 11.6 L/h to 71.6 ± 17.4 L/h when 0.5 mg/ml IV solution was infused. Nebivolol showed higher Cmax, AUC0-∞ and half-life (t1/2) when co-administered with bupropion, duloxetine, fluvoxamine, paroxetine, lansoprazole, and fluoxetine. This concise review of nebivolol would be advantageous in assessing all PK parameters, which may be crucial for clinicians to avoid drug-drug interactions, prevent adverse drug events and optimize the dosage regimen in diseased patients diagnosed with hypertension and cardiovascular disorders.
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Hipertensão , Masculino , Humanos , Nebivolol/farmacocinética , Nebivolol/uso terapêutico , Hipertensão/tratamento farmacológico , Fluvoxamina/uso terapêutico , Lansoprazol/uso terapêutico , Interações MedicamentosasRESUMO
Background: Proton-pump inhibitors (PPI) are among the most widely used drugs worldwide. However, the association between PPI use and the risk of asthma remains unclear. Objective: To investigate the association between PPI use and subsequent asthma risk. Methods: We included participants from the Taiwan National Health Insurance Research Database between 1999 and 2013. Patients who used PPIs and experienced new-onset asthma (n = 20,344) were assigned to the case cohort and matched in a 1:1 ratio with controls who did not subsequently develop asthma. PPI use was defined as > 30 cumulative defined daily doses (cDDD); non-PPI use was defined as ≤ 30 cDDDs. The Charlson Comorbidity Index (CCI) score was used for clinical prognosis and comorbidity adjustment. Multivariate Cox regression models were used for the calculation of adjusted odds ratios (OR). Results: There was a significant and dose-dependent association between PPI use and the risk of developing asthma. The adjusted ORs were 1.24 (95% confidence interval [CI], 1.15-1.33), 1.39 (95% CI, 1.28-1.50), and 1.61 (95% CI, 1.43-1.81) for the male subject with 31-120 cDDDs, 120-365 cDDDs, and >365 cDDDs, respectively, compared with PPI nonusers. Men were at higher risk of developing asthma with longer PPI use compared with women. Stratified analyses based on the PPI type showed that exposure to lansoprazole, pantoprazole, omeprazole, and esomeprazole was associated with subsequent asthma risk. Conclusion: Extended use of PPIs was found to be linked to an increased risk of asthma development. This association remained consistent across different age groups, sexes, demographic factors, indications for PPI use, CCI scores, and other atopic diseases. However, further prospective studies are required to elucidate the causal mechanisms involved.