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Menichelli D, Gazzaniga G, Del Sole F, Pani A, Pignatelli P, Pastori D. Acute upper and lower gastrointestinal bleeding management in older people taking or not taking anticoagulants: a literature review. Front Med (Lausanne) 2024; 11:1399429. [PMID: 38765253 PMCID: PMC11099229 DOI: 10.3389/fmed.2024.1399429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Accepted: 04/11/2024] [Indexed: 05/21/2024] Open
Abstract
Acute upper and lower gastrointestinal (GI) bleeding may be a potentially life-threatening event that requires prompt recognition and an early effective management, being responsible for a considerable number of hospital admissions. Methods. We perform a clinical review to summarize the recent international guidelines, helping the physician in clinical practice. Older people are a vulnerable subgroup of patients more prone to developing GI bleeding because of several comorbidities and polypharmacy, especially related to an increased use of antiplatelet and anticoagulant drugs. In addition, older patients may have higher peri-procedural risk that should be evaluated. The recent introduction of reversal strategies may help the management of GI bleeding in this subgroup of patients. In this review, we aimed to (1) summarize the epidemiology and risk factors for upper and lower GI bleeding, (2) describe treatment options with a focus on pharmacodynamics and pharmacokinetics of different proton pump inhibitors, and (3) provide an overview of the clinical management with flowcharts for risk stratification and treatment. In conclusion, GI is common in older patients and an early effective management may be helpful in the reduction of several complications.
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Affiliation(s)
- Danilo Menichelli
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
- Department of General Surgery and Surgical Specialty Paride Stefanini, Sapienza University of Rome, Rome, Italy
| | - Gianluca Gazzaniga
- Department of Medical Biotechnology and Translational Medicine, Postgraduate School of Clinical Pharmacology and Toxicology, Università degli Studi di Milano, Milan, Italy
| | - Francesco Del Sole
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Arianna Pani
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Pasquale Pignatelli
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
| | - Daniele Pastori
- Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy
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2
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Li S, Xie L, Yang L, Jiang L, Yang Y, Zhi H, Liu X, Yang H, Liu L. Prediction of Omeprazole Pharmacokinetics and its Inhibition on Gastric Acid Secretion in Humans Using Physiologically Based Pharmacokinetic-Pharmacodynamic Model Characterizing CYP2C19 Polymorphisms. Pharm Res 2023; 40:1735-1750. [PMID: 37226024 DOI: 10.1007/s11095-023-03531-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Accepted: 05/02/2023] [Indexed: 05/26/2023]
Abstract
PURPOSE To develop a whole physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model to describe the pharmacokinetics and anti-gastric acid secretion of omeprazole in CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs) and ultrarapid metabolizers (UMs) following oral or intravenous administration. METHODS A PBPK/PD model was built using Phoenix WinNolin software. Omeprazole was mainly metabolized by CYP2C19 and CYP3A4 and the CYP2C19 polymorphism was incorporated using in vitro data. We described the PD by using a turn-over model with parameter estimates from dogs and the effect of a meal on the acid secretion was also implemented. The model predictions were compared to 53 sets of clinical data. RESULTS Predictions of omeprazole plasma concentration (72.2%) and 24 h stomach pH after administration (85%) were within 0.5-2.0-fold of the observed values, indicating that the PBPK-PD model was successfully developed. Sensitivity analysis demonstrated that the contributions of the tested factors to the plasma concentration of omeprazole were Vmax,2C19 ≈ Papp > Vmax,3A4 > Kti, and contributions to its pharmacodynamic were Vmax,2C19 > kome > kms > Papp > Vmax,3A4. The simulations showed that while the initial omeprazole dose in UMs, EMs, and IMs increased 7.5-, 3- and 1.25-fold compared to those of PMs, the therapeutic effect was similar. CONCLUSIONS The successful establishment of this PBPK-PD model highlights that pharmacokinetic and pharmacodynamic profiles of drugs can be predicted using preclinical data. The PBPK-PD model also provided a feasible alternative to empirical guidance for the recommended doses of omeprazole.
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Affiliation(s)
- Shuai Li
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Xie
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lu Yang
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ling Jiang
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yiting Yang
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Hao Zhi
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaodong Liu
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Hanyu Yang
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
| | - Li Liu
- Center of Pharmacokinetics and Metabolism, School of Pharmacy, China Pharmaceutical University, Nanjing, China.
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Bořilová Linhartová P, Zendulka O, Janošek J, Mlčůchová N, Cvanová M, Daněk Z, Kroupa R, Bartošová L, Lipový B. CYP2C19 Gene Profiling as a Tool for Personalized Stress Ulcer Prophylaxis With Proton Pump Inhibitors in Critically Ill Patients - Recommendations Proposal. Front Med (Lausanne) 2022; 9:854280. [PMID: 35899207 PMCID: PMC9309431 DOI: 10.3389/fmed.2022.854280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 06/03/2022] [Indexed: 11/13/2022] Open
Abstract
To this date, there are no recommendations for personalized stress ulcer prophylaxis (SUP) in critical care that would take the patient's individual genetic predispositions into account. Of drugs used for this purpose, proton pump inhibitors (PPIs) are the first-choice drugs in intensive care unit patients. The degradation of proton pump inhibitors is mediated by cytochrome P450 (CYP) enzymes; in particular, CYP2C19 and, to a lesser extent, CYP3A4 are involved. Expression and metabolic activity of, namely in, CYP2C19 is significantly affected by single nucleotide polymorphisms, the drug metabolization rate varies greatly from ultrarapid to poor and likely influences the optimal dosage. As these CYP2C19 predictive phenotypes via CYP2C19 haplogenotypes (rs12248560/rs4244285) can be relatively easily determined using the current standard equipment of hospital laboratories, we prepared a set of recommendations for personalized PPI-based stress ulcer prophylaxis taking into account the patient's CYP2C19 predictive phenotype determined in this way. These recommendations are valid, in particular, for European, American and African populations, because these populations have the high representations of the CYP2C19*17 allele associated with the overexpression of the CYP2C19 gene and ultrarapid degradation of PPIs. We propose the CYP2C19 gene profiling as a tool for personalized SUP with PPI in critically ill patients.
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Affiliation(s)
- Petra Bořilová Linhartová
- RECETOX, Faculty of Science, Masaryk University, Brno, Czechia
- Clinic of Maxillofacial Surgery, Faculty of Medicine, Institution Shared With University Hospital Brno, Masaryk University, Brno, Czechia
| | - Ondřej Zendulka
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Jaroslav Janošek
- Faculty of Medicine, Center for Health Research, University of Ostrava, Ostrava, Czechia
| | | | - Michaela Cvanová
- Faculty of Medicine, Institute of Biostatistics and Analyses, Masaryk University, Brno, Czechia
| | - Zdeněk Daněk
- RECETOX, Faculty of Science, Masaryk University, Brno, Czechia
- Clinic of Maxillofacial Surgery, Faculty of Medicine, Institution Shared With University Hospital Brno, Masaryk University, Brno, Czechia
| | - Radek Kroupa
- Department of Internal Medicine and Gastroenterology, Faculty of Medicine, Institution Shared With University Hospital Brno, Masaryk University, Brno, Czechia
| | - Ladislava Bartošová
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Břetislav Lipový
- Department of Burns and Plastic Surgery, Faculty of Medicine, Institution Shared With University Hospital BrnoMasaryk University, Brno, Czechia
- *Correspondence: Břetislav Lipový
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4
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Lucendo AJ, Molina-Infante J. Current treatment options and long-term outcomes in patients with eosinophilic esophagitis. Expert Rev Clin Immunol 2022; 18:859-872. [PMID: 35770955 DOI: 10.1080/1744666x.2022.2096591] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Dietary and pharmacological (proton pump inhibitors, swallowed topical corticosteroids) therapies are effective for induction of clinical and histological remission of eosinophilic esophagitis. However, data evaluating their long-term efficacy and safety is limited. AREAS COVERED Since eosinophilic esophagitis is chronic, clinical, endoscopic, and histological features usually recur when successful treatments are stopped. In untreated patients, persistent esophageal eosinophilic inflammation may progress to fibrostenosis over time, giving place to strictures and narrow-caliber esophagi. This article comprehensively reviews available data on long-term maintenance of eosinophilic esophagitis with pharmacological and dietary treatment. It also discusses limitations re: available literature and outlines data gaps on adherence to therapy and monitoring disease activity in the long-term. EXPERT OPINION Evidence indicates that long-term maintenance therapy may decrease the risk of esophageal stricture, food bolus impaction, and need for dilation in patients with eosinophilic esophagitis. Further knowledge on eosinophilic esophagitis phenotypes is needed to ascertain who will benefit best from sustained therapy. Unanswered questions include an adequate definition for sustained remission, best strategies for maintenance drugs and diets, enhancement of treatment adherence, and proper monitoring for long-term surveillance.
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Affiliation(s)
- Alfredo J Lucendo
- Department of Gastroenterology, Hospital General de Tomelloso, Tomelloso, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Instituto de Investigación Sanitaria de Castilla-La Mancha (IDISCAM), Spain.,Instituto de Investigación Sanitaria La Princesa, Madrid, Spain
| | - Javier Molina-Infante
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.,Department of Gastroenterology, Hospital Universitario de Caceres, Caceres, Spain
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Gebreyesus MS, Decloedt EH, Cluver CA, Hunfeld NGM, Helgadóttir H, Björnsson ES, Wasmann RE, Denti P. Population pharmacokinetics of esomeprazole in patients with preterm preeclampsia. Br J Clin Pharmacol 2022; 88:4639-4645. [PMID: 35599445 DOI: 10.1111/bcp.15416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/19/2022] [Accepted: 05/05/2022] [Indexed: 11/30/2022] Open
Abstract
Esomeprazole is a proton pump inhibitor being investigated for treatment of preeclampsia. Esomeprazole pharmacokinetics during pregnancy are unknown. We used data from 10 pregnant participants with preterm preeclampsia, and 49 non-pregnant participants to develop a population pharmacokinetic model of esomeprazole. A two-compartment model described the data well. In pregnant participants after single dose, clearance was 42.2% (14.9% - 61.6%) lower compared to non-pregnant, most likely due to inhibition of CYP2C19. In non-pregnant after repeated dosing, clearance was 54.9% (48.2% - 63.5%) lower in extensive metabolizers and bioavailability was 33% (10.0% - 52.0%) higher compared to single dosing, which could be due to autoinhibition of CYP2C19. During pregnancy, the CYP2C19 autoinhibition effect with repeated dosing is expected to lead to much lower increase in exposure compared to non-pregnant, since CYP2C19 is already inhibited due to pregnancy.
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Affiliation(s)
- Manna Semere Gebreyesus
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Eric H Decloedt
- Division of Clinical Pharmacology, Department of Medicine, Stellenbosch University and Tygerberg Hospital, Stellenbosch, South Africa
| | - Catherine A Cluver
- Department of Obstetrics and Gynaecology, Stellenbosch University and Tygerberg Hospital, Stellenbosch, South Africa
| | - Nicole G M Hunfeld
- Department of Pharmacy and Intensive Care, Erasmus University Rotterdam, Rotterdam, Netherlands
| | - Hólmfríður Helgadóttir
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Einar S Björnsson
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
| | - Roeland E Wasmann
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
| | - Paolo Denti
- Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa
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6
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Ghazvini K, Kamali H, Hosseininasab-nodoushan SA, Keikha M. The CYP2C19 polymorphisms effects on H. pylori cure rate in proton pump inhibitor-based therapeutic regimens: An updated meta-analysis. GENE REPORTS 2021; 25:101340. [DOI: 10.1016/j.genrep.2021.101340] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Ochiai Y, Iizuka T, Hoshihara Y, Suzuki Y, Hayasaka J, Nomura K, Tanaka M, Odagiri H, Yamashita S, Matsui A, Kikuchi D, Ueno M, Udagawa H, Hoteya S. Efficacy of Vonoprazan for Refractory Reflux Esophagitis after Esophagectomy. Dig Dis 2021; 39:569-576. [PMID: 33567428 PMCID: PMC8686710 DOI: 10.1159/000515146] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 01/27/2021] [Indexed: 02/02/2023]
Abstract
BACKGROUND Refractory reflux esophagitis (RRE), unresponsive to conventional proton-pump inhibitors (PPIs), is a complication in esophagectomy with gastric pull-up. Vonoprazan (VPZ), a novel potassium-competitive acid blocker, has been available in Japan since 2015. Here, we investigated the efficacy of VPZ on PPI-resistant RRE after esophagectomy with gastric pull-up. METHODS This was a single-center retrospective study. We used the revised Los Angeles (r-LA) classification based on the Los Angeles classification and the modified Los Angeles classification to evaluate abnormal forms of mucosal breaks such as lateral spreading consistently. Patients who underwent esophagectomy with gastric pull-up and had RRE grade B-D as per the r-LA classification, despite using standard-dose PPIs or double dose of rabeprazole, were included. Sixteen patients who switched to VPZ (20 mg/day) and 14 patients who continued PPIs were assigned to the VPZ and PPI groups, respectively. Endoscopic observations were reviewed by 3 endoscopists using the r-LA classification to ensure consistent diagnosis, while the treatment arm and patient information were blinded to evaluators. We defined mucosal breaks that improved by at least one grade after treatment as improved mucosa and recovery to grade M or N as mucosal healing. RESULTS The percentage of patients with improved mucosa in the VPZ and PPI groups was 81.3 and 14.3%, respectively (p < 0.001). The rate of mucosal healing was 68.8 and 7.1%, respectively (p = 0.001). CONCLUSION VPZ significantly improved PPI-resistant RRE after esophagectomy with gastric pull-up.
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Affiliation(s)
- Yorinari Ochiai
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan,*Yorinari Ochiai,
| | - Toshiro Iizuka
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Yoshio Hoshihara
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan,Department of Gastroenterology, Nippon Medical School, Tokyo, Japan
| | - Yugo Suzuki
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | | | - Kosuke Nomura
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Masami Tanaka
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Hiroyuki Odagiri
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | | | - Akira Matsui
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Daisuke Kikuchi
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
| | - Masaki Ueno
- Department of Gastrointestinal Surgery, Toranomon Hospital, Tokyo, Japan
| | - Harushi Udagawa
- Department of Gastrointestinal Surgery, Toranomon Hospital, Tokyo, Japan
| | - Shu Hoteya
- Department of Gastroenterology, Toranomon Hospital, Tokyo, Japan
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8
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Carvalho Henriques B, Yang EH, Lapetina D, Carr MS, Yavorskyy V, Hague J, Aitchison KJ. How Can Drug Metabolism and Transporter Genetics Inform Psychotropic Prescribing? Front Genet 2020; 11:491895. [PMID: 33363564 PMCID: PMC7753050 DOI: 10.3389/fgene.2020.491895] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 09/25/2020] [Indexed: 12/11/2022] Open
Abstract
Many genetic variants in drug metabolizing enzymes and transporters have been shown to be relevant for treating psychiatric disorders. Associations are strong enough to feature on drug labels and for prescribing guidelines based on such data. A range of commercial tests are available; however, there is variability in included genetic variants, methodology, and interpretation. We herein provide relevant background for understanding clinical associations with specific variants, other factors that are relevant to consider when interpreting such data (such as age, gender, drug-drug interactions), and summarize the data relevant to clinical utility of pharmacogenetic testing in psychiatry and the available prescribing guidelines. We also highlight areas for future research focus in this field.
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Affiliation(s)
| | - Esther H. Yang
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Diego Lapetina
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Michael S. Carr
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Vasyl Yavorskyy
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
| | - Joshua Hague
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | - Katherine J. Aitchison
- Department of Psychiatry, University of Alberta, Edmonton, AB, Canada
- Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada
- Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada
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9
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Lapetina DL, Yang EH, Henriques BC, Aitchison KJ. Pharmacogenomics and Psychopharmacology. SEMINARS IN CLINICAL PSYCHOPHARMACOLOGY 2020:151-202. [DOI: 10.1017/9781911623465.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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10
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Helicobacter pylori treatment in Turkey: Current status and rational treatment options. North Clin Istanb 2019; 7:87-94. [PMID: 32232212 PMCID: PMC7103748 DOI: 10.14744/nci.2019.62558] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2019] [Accepted: 05/14/2019] [Indexed: 02/07/2023] Open
Abstract
According to the TURHEP study, the prevalence of Helicobacter pylori in Turkey is 82.5%. After FDA approval in 1995, many countries have used standard triple therapy (proton pump inhibitor 40 mg b.i.d clarithromycin 500 mg b.i.d and amoxicillin 1 gr b.i.d) for Helicobacter pylori treatment. In the beginning, eradication rates were above 90% in many countries; however, current studies have demonstrated a prominent decrease in successful treatment rates, even down to 60%. This unfavorable reduction stimulated searches for new treatment protocols. Treatment protocols differ according to country, prevalence, cost-effectiveness, antibiotic resistance, CYP2C19 polymorphism and eradication rates. Thus, each country/region needs to revise its own therapeutic results and the efficacy of various eradication regimens in the treatment of Helicobacter pylori. This report aims to review the current status of Helicobacter pylori treatment in Turkey and to provide recommendations for rational therapeutic considerations for the eradication of the bacterium.
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11
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Key Pharmacokinetic Essentials of Fixed-Dosed Combination Products: Case Studies and Perspectives. Clin Pharmacokinet 2019; 57:419-426. [PMID: 28791593 DOI: 10.1007/s40262-017-0589-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Fixed-dose combinations are gaining popularity because they provide convenience while enhancing patient compliance. Literature examples suggest that many fixed-dose combinations are being rationalized and investigated for their potential utility in therapy. This article provides an introspection into the pharmacokinetic essentials that need to be considered prior to implementing a fixed-dose combination strategy. While the drug-drug interaction potential is an important question for the two drugs in a fixed-dose combination, the occurrence of a drug-drug interaction in itself is not a negative outcome for the proposed fixed-dose combination. However, the magnitude of a drug-drug interaction may require a re-assessment of the doses of the two drugs in a fixed-dose combination. Several case studies are provided and discussed to provide a broad perspective on the topic along with a representative framework and strategy on the development of fixed-dose combinations using key pharmacokinetic parameters.
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12
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Tran-Duy A, Connell NJ, Vanmolkot FH, Souverein PC, de Wit NJ, Stehouwer CDA, Hoes AW, de Vries F, de Boer A. Use of proton pump inhibitors and risk of iron deficiency: a population-based case-control study. J Intern Med 2019; 285:205-214. [PMID: 30141278 DOI: 10.1111/joim.12826] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Hypochlorhydric states are an important cause of iron deficiency (ID). Nevertheless, the association between therapy with proton pump inhibitors (PPIs) and ID has long been a subject of debate. This case-control study aimed to investigate the risk of ID associated with the use of PPIs using the UK Clinical Practice Research Datalink (CPRD) database. METHODS Cases were patients aged 19 years or older with first-time diagnosis of ID between 2005 and 2016 (n = 26 806). The dates of first diagnosis of ID in cases defined the index dates. For each case, one control was matched by age, gender and general practice. A PPI "full" user (PFU) was defined as a subject who had received PPIs for a continuous duration of at least 1 year prior to the index date. A PPI "limited" users (PLU) was a subject who intermittently received PPI therapy. A PPI non-user (PNU) was a subject who received no PPI prescriptions prior to the index date. The odds ratio of ID in PFU and PLU compared to PNU was estimated using conditional logistic regression. RESULTS Among cases, 2960 were PFU, 6607 PLU and 17 239 PNU. Among controls, 1091 were PFU, 5058 PLU and 20 657 PNU. Adjusted odds ratio of ID in PFU and PLU compared to PNU was 3.60 (95%CI, [3.32-3.91]) and 1.51 (95% CI, [1.44-1.58]). Positive dose-response and time-response relationships were observed. CONCLUSIONS Chronic PPI use increases the risk of ID. Physicians should consider this when balancing the risks and benefits of chronic PPI prescription.
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Affiliation(s)
- A Tran-Duy
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.,Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia
| | - N J Connell
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.,Department of Nutrition and Movement Sciences, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands
| | - F H Vanmolkot
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - P C Souverein
- Department of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
| | - N J de Wit
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - C D A Stehouwer
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - A W Hoes
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | - F de Vries
- CAPHRI Care and Public Health Research Institute, Maastricht University Medical Center, Maastricht, The Netherlands
| | - A de Boer
- Department of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands
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13
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Pu J, Wang F, Tang W, Zhu M. Biotransformation of Ilaprazole in Human Liver Microsomes and Human: Role of CYP3A4 in Ilaprazole Clearance and Drug-Drug Interaction. Drug Metab Dispos 2018; 46:1453-1461. [PMID: 30002078 DOI: 10.1124/dmd.118.081570] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 07/09/2018] [Indexed: 01/02/2023] Open
Abstract
Ilaprazole is a new proton pump inhibitor and is currently marketed in China and South Korea for the treatment of gastric and duodenal ulcer. Ilaprazole has a favorable long half-life and minimal pharmacokinetic variability associated with CYP2C19 polymorphism. Sulfoxide oxidation of ilaprazole is catalyzed mainly by CYP3A4. Thus, it has been widely accepted that CYP3A4 plays a major role in the clearance of ilaprazole in humans. However, absorption, distribution, metabolism, and excretion data of radiolabeled ilaprazole in humans are not available. The primary goal of this study was to determine if sulfoxide oxidation is a major metabolic pathway of ilaprazole in humans. Metabolite profiles of ilaprazole, ilaprazole sulfide, and ilaprazole sulfone in human liver microsomes (HLMs) were characterized and quantitively analyzed by liquid chromatography (LC)/UV/high-resolution mass spectrometry (HRMS). Moreover, metabolites of ilaprazole in human urine and feces were detected and identified by LC-HRMS. The results revealed that sulfoxide reduction to ilaprazole sulfide rather than sulfoxide oxidation was the major biotransformation pathway in HLMs. Sulfoxide reduction also occurred in HLMs without NADPH or in deactivated HLMs. Ilaprazole sulfide and its multiple oxidative metabolites were major drug-related components in human urine and feces, where there were no ilaprazole sulfone and its metabolites. A small amount of the parent drug was found in feces. Thus, we propose that nonenzymatic sulfoxide reduction rather than CYP3A4-medidated sulfoxide oxidation is the major metabolic clearance pathway of ilaprazole in humans. Consequently, it is predicted that ilaprazole has no significant drug-drug interaction via CYP3A4 inhibition or induction by a coadministered drug.
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Affiliation(s)
- Jie Pu
- DMPK Department ChemPartner, Shanghai, China (J.P., F.W., W.T.); School of Pharmacy, East China University of Science and Technology, Shanghai, China (J.P.); and MassDefect Technologies, Princeton, New Jersey (M.Z.)
| | - Fen Wang
- DMPK Department ChemPartner, Shanghai, China (J.P., F.W., W.T.); School of Pharmacy, East China University of Science and Technology, Shanghai, China (J.P.); and MassDefect Technologies, Princeton, New Jersey (M.Z.)
| | - Wei Tang
- DMPK Department ChemPartner, Shanghai, China (J.P., F.W., W.T.); School of Pharmacy, East China University of Science and Technology, Shanghai, China (J.P.); and MassDefect Technologies, Princeton, New Jersey (M.Z.)
| | - Mingshe Zhu
- DMPK Department ChemPartner, Shanghai, China (J.P., F.W., W.T.); School of Pharmacy, East China University of Science and Technology, Shanghai, China (J.P.); and MassDefect Technologies, Princeton, New Jersey (M.Z.)
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14
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Fedorinov DS, Mirzaev KB, Ivashchenko DV, Temirbulatov II, Sychev DA, Maksimova NR, Chertovskih JV, Popova NV, Tayurskaya KS, Rudykh ZA. Pharmacogenetic testing by polymorphic markers 681G>A and 636G>A CYP2C19 gene in patients with acute coronary syndrome and gastric ulcer in the Republic of Sakha (Yakutia). Drug Metab Pers Ther 2018; 33:91-98. [PMID: 29738309 DOI: 10.1515/dmpt-2018-0004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 04/10/2018] [Indexed: 11/15/2022]
Abstract
BACKGROUND The focus of the study is to determine the prevalence of CYP2C19 alleles, associated with the risk of changes in the pharmacological response to clopidogrel and proton pump inhibitors in patients with acute coronary syndrome (ACS) and gastric ulcer from Russian and Yakut ethnic groups. METHODS The research included 411 patients with ACS (143 Russians and 268 Yakuts) and 204 patients with histologically confirmed gastric ulcer (63 Russians and 141 Yakuts). Genotyping of 681G>A and 636G>A polymorphisms was performed by using polymerase real-time chain reaction. RESULTS In both ethnic groups, Hardy-Weinberg equilibrium was followed in a distribution of alleles and genotypes in the population (p>0.05). The 681A allele frequency in the Yakut ethnic group was higher than in the Russian group: 17.53% vs. 8.39% (p=0.001). No statistically significant difference was found in the frequency of 636A in Yakuts and Russians with ACS: 3.92% vs. 3.50% (p=0.840). While comparing the frequency distribution of alleles 681A (13.49% vs. 14.54%, p=0.878) and 636A (7.94% vs. 7.80%, p=1) in patients with a gastric ulcer from Russian and Yakut ethnic groups, no significant difference was found in carrier frequency. CONCLUSIONS The results of the present study may be helpful for developing guidelines for CYPC19 genotype-directed antiplatelet therapy for Yakut and Russian patients.
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Affiliation(s)
- Denis S Fedorinov
- Department of Clinical Pharmacology and Pharmacotherapy, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya str., Moscow 119991, Russian Federation.,Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation, Phone: +79169553950
| | - Karin B Mirzaev
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation
| | - Dmitriy V Ivashchenko
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation
| | - Ilyas I Temirbulatov
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation.,I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Dmitriy A Sychev
- Russian Medical Academy of Continuous Professional Education of the Ministry of Healthcare, Moscow, Russian Federation
| | | | | | | | | | - Zoya A Rudykh
- Republican Hospital No. 3, Yakutsk, Russian Federation
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15
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Kawara F, Fujita T, Morita Y, Uda A, Masuda A, Saito M, Ooi M, Ishida T, Kondo Y, Yoshida S, Okuno T, Yano Y, Yoshida M, Kutsumi H, Hayakumo T, Yamashita K, Hirano T, Hirai M, Azuma T. Factors associated with residual gastroesophageal reflux disease symptoms in patients receiving proton pump inhibitor maintenance therapy. World J Gastroenterol 2017; 23:2060-2067. [PMID: 28373773 PMCID: PMC5360648 DOI: 10.3748/wjg.v23.i11.2060] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 01/24/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice.
METHODS The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed.
RESULTS The FSSG scores ranged from 1 to 28 points (median score: 7.5 points), and 19 patients (48.7%) had a score of 8 points or more. The patients’ GSRS scores were significantly correlated with their FSSG scores (correlation coefficient = 0.47, P < 0.005). In erosive esophagitis patients, the FSSG scores of the CYP2C19 rapid metabolizers (RMs) were significantly higher than the scores of the poor metabolizers and intermediate metabolizers (total scores: 16.7 ± 8.6 vs 7.8 ± 5.4, P < 0.05; acid reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P < 0.005). In contrast, the FSSG scores of the CYP2C19 RMs in the non-erosive reflux disease patients were significantly lower than those of the other patients (total scores: 5.5 ± 1.0 vs 11.8 ± 6.3, P < 0.05; dysmotility symptom-related scores: 1.0 ± 0.4 vs 6.0 ± 0.8, P < 0.01).
CONCLUSION Approximately half of the GERD patients receiving maintenance PPI therapy had residual symptoms associated with a lower quality of life, and the CYP2C19 genotype appeared to be associated with these residual symptoms.
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16
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Hu ZH, Shi AM, Hu DM, Bao JJ. Efficacy of proton pump inhibitors for patients with duodenal ulcers: A pairwise and network meta-analysis of randomized controlled trials. Saudi J Gastroenterol 2017; 23:11-19. [PMID: 28139495 PMCID: PMC5329971 DOI: 10.4103/1319-3767.199117] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND/AIM To compare the efficacy and tolerance of different proton pump inhibitors (PPIs) in different doses for patients with duodenal ulcers. MATERIALS AND METHODS An electronic database was searched to collect all randomized clinical trials (RCTs), and a pairwise and network meta-analysis were performed. RESULTS A total of 24 RCTs involving 6188 patients were included. The network meta-analysis showed that there were no significant differences for the 4-week healing rate of duodenal ulcer treated with different PPI regimens except pantoprazle 40 mg/d versus lansoprazole 15 mg/d [Relative risk (RR) = 3.57; 95% confidence interval (CI) = 1.36-10.31)] and lansoprazole 30 mg/d versus lansoprazole 15 mg/d (RR = 2.45; 95% CI = 1.01-6.14). In comparison with H2receptor antagonists (H2RA), pantoprazole 40 mg/d and lansoprazole 30 mg/d significantly increase the healing rate (RR = 2.96; 95% CI = 1.78-5.14 and RR = 2.04; 95% CI = 1.13-3.53, respectively). There was no significant difference for the rate of adverse events between different regimens, including H2RA for a duration of 4-week of follow up. CONCLUSION There was no significant difference for the efficacy and tolerance between the ordinary doses of different PPIs with the exception of lansoprazle 15 mg/d.
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Affiliation(s)
- Zhan-Hong Hu
- Department of Pharmacy, The Second Hospital Affiliated to Soochow University, Suzhou, People's Republic of China
| | - Ai-Ming Shi
- Department of Pharmacy, The Second Hospital Affiliated to Soochow University, Suzhou, People's Republic of China
| | - Duan-Min Hu
- Digestive Department, The Second Hospital Affiliated to Soochow University, Suzhou, People's Republic of China
| | - Jun-Jie Bao
- Department of Pharmacy, The Second Hospital Affiliated to Soochow University, Suzhou, People's Republic of China,Address for correspondence: Dr. Jun-Jie Bao, Department of Pharmacy, The Second Hospital Affiliated to Soochow University, Suzhou, Jiang Su Province - 215004, People's Republic of China. E-mail:
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17
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Fock KM, Talley N, Goh KL, Sugano K, Katelaris P, Holtmann G, Pandolfino JE, Sharma P, Ang TL, Hongo M, Wu J, Chen M, Choi MG, Law NM, Sheu BS, Zhang J, Ho KY, Sollano J, Rani AA, Kositchaiwat C, Bhatia S. Asia-Pacific consensus on the management of gastro-oesophageal reflux disease: an update focusing on refractory reflux disease and Barrett's oesophagus. Gut 2016; 65:1402-15. [PMID: 27261337 DOI: 10.1136/gutjnl-2016-311715] [Citation(s) in RCA: 146] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Accepted: 05/15/2016] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Since the publication of the Asia-Pacific consensus on gastro-oesophageal reflux disease in 2008, there has been further scientific advancement in this field. This updated consensus focuses on proton pump inhibitor-refractory reflux disease and Barrett's oesophagus. METHODS A steering committee identified three areas to address: (1) burden of disease and diagnosis of reflux disease; (2) proton pump inhibitor-refractory reflux disease; (3) Barrett's oesophagus. Three working groups formulated draft statements with supporting evidence. Discussions were done via email before a final face-to-face discussion. We used a Delphi consensus process, with a 70% agreement threshold, using Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria to categorise the quality of evidence and strength of recommendations. RESULTS A total of 32 statements were proposed and 31 were accepted by consensus. A rise in the prevalence rates of gastro-oesophageal reflux disease in Asia was noted, with the majority being non-erosive reflux disease. Overweight and obesity contributed to the rise. Proton pump inhibitor-refractory reflux disease was recognised to be common. A distinction was made between refractory symptoms and refractory reflux disease, with clarification of the roles of endoscopy and functional testing summarised in two algorithms. The definition of Barrett's oesophagus was revised such that a minimum length of 1 cm was required and the presence of intestinal metaplasia no longer necessary. We recommended the use of standardised endoscopic reporting and advocated endoscopic therapy for confirmed dysplasia and early cancer. CONCLUSIONS These guidelines standardise the management of patients with refractory gastro-oesophageal reflux disease and Barrett's oesophagus in the Asia-Pacific region.
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Affiliation(s)
- Kwong Ming Fock
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore
| | - Nicholas Talley
- Faculty of Health and Medicine, University of Newcastle, Callaghan, New South Wales, Australia
| | - Khean Lee Goh
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Kentaro Sugano
- Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Peter Katelaris
- Gastroenterology Department, Concord Hospital, University of Sydney, Sydney, New South Wales, Australia
| | - Gerald Holtmann
- Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
| | - John E Pandolfino
- Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA
| | - Prateek Sharma
- University of Kansas and VA Medical Center, Kansas City, Kansas, USA
| | - Tiing Leong Ang
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore
| | - Michio Hongo
- Department of Comprehensive Medicine, Tohoku University, Sendai, Japan
| | - Justin Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Shatin, China
| | - Minhu Chen
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Myung-Gyu Choi
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ngai Moh Law
- Department of Gastroenterology and Hepatology, Changi General Hospital, Singapore, Singapore
| | - Bor-Shyang Sheu
- Department of Internal Medicine, National Cheng Kung University Hospital, Medical College, National Cheng Kung University, Tainan, Taiwan
| | - Jun Zhang
- The Second Affiliated Hospital, Xian Jiaotong University, Xian, China
| | - Khek Yu Ho
- Division of Gastroenterology and Hepatology, National University Hospital, Singapore, Singapore
| | - Jose Sollano
- Department of Medicine, University of Sano Tomas, Manila, Philippines
| | - Abdul Aziz Rani
- Faculty of Medicine, University of Indonesia, Jakarta, Indonesia
| | - Chomsri Kositchaiwat
- Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Shobna Bhatia
- Department of Gastroenterology, Seth GS Medical College and King Edward Memorial Hospital, Mumbai, India
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18
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Goh KL, Choi MG, Hsu PI, Chun HJ, Mahachai V, Kachintorn U, Leelakusolvong S, Kim N, Rani AA, Wong BCY, Wu J, Chiu CT, Shetty V, Bocobo JC, Chan MM, Lin JT. Pharmacological and Safety Profile of Dexlansoprazole: A New Proton Pump Inhibitor - Implications for Treatment of Gastroesophageal Reflux Disease in the Asia Pacific Region. J Neurogastroenterol Motil 2016; 22:355-366. [PMID: 26932927 PMCID: PMC4930293 DOI: 10.5056/jnm15150] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2015] [Revised: 01/27/2016] [Accepted: 01/30/2016] [Indexed: 12/13/2022] Open
Abstract
Although gastroesophageal reflux disease is not as common in Asia as in western countries, the prevalence has increased substantially during the past decade. Gastroesophageal reflux disease is associated with considerable reductions in subjective well-being and work productivity, as well as increased healthcare use. Proton pump inhibitors (PPIs) are currently the most effective treatment for gastroesophageal reflux disease. However, there are limitations associated with these drugs in terms of partial and non-response. Dexlansoprazole is the first PPI with a dual delayed release formulation designed to provide 2 separate releases of medication to extend the duration of effective plasma drug concentration. Dexlansoprazole has been shown to be effective for healing of erosive esophagitis, and to improve subjective well-being by controlling 24-hour symptoms. Dexlansoprazole has also been shown to achieve good plasma concentration regardless of administration with food, providing flexible dosing. Studies in healthy volunteers showed no clinically important effects on exposure to the active metabolite of clopidogrel or clopidogrel-induced platelet inhibition, with no dose adjustment of clopidogrel necessary when coprescribed. This review discusses the role of the new generation PPI, dexlansoprazole, in the treatment of gastroesophageal reflux disease in Asia.
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Affiliation(s)
- Khean Lee Goh
- Department of Medicine, University of Malaya, Kuala Lumpur,
Malaysia
| | - Myung Gyu Choi
- Department of Internal Medicine, Catholic University of Korea, Seoul,
Korea
| | - Ping I Hsu
- Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung,
Taiwan ROC
| | - Hoon Jai Chun
- Department of Internal Medicine, Korea University College of Medicine, Seoul,
Korea
| | - Varocha Mahachai
- Division of Gastroenterology, Chulalongkorn University, Bangkok,
Thailand
| | - Udom Kachintorn
- Division of Gastroenterology, Department of Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok,
Thailand
| | - Somchai Leelakusolvong
- Division of Gastroenterology, Department of Internal Medicine, Siriraj Hospital, Mahidol University, Bangkok,
Thailand
| | - Nayoung Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do,
Korea
| | - Abdul Aziz Rani
- Department of Internal Medicine, University of Indonesia, Depok,
Indonesia
| | - Benjamin C Y Wong
- Department of Medicine, The University of Hong Kong, Hong Kong SAR,
China
| | - Justin Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR,
China
| | - Cheng Tang Chiu
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital & Chang Gung University, Taoyuan,
Taiwan ROC
| | - Vikram Shetty
- Medical Affairs, Takeda Pharmaceuticals (Asia Pacific) Pte Ltd,
Singapore
| | - Joseph C Bocobo
- St. Luke’s College of Medicine-William H. Quasha Memorial, Quezon City,
Philippines
| | - Melchor M Chan
- Faculty of Medicine and Surgery, University of Santo Tomas Hospital, Manila,
Philippines
| | - Jaw-Town Lin
- Department of Medicine, Fu Jen Catholic University, New Taipei City,
Taiwan ROC
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19
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Deshpande N, V S, V V RK, H V V M, M S, Banerjee R, Tandan M, D NR. Rapid and ultra-rapid metabolizers with CYP2C19*17 polymorphism do not respond to standard therapy with proton pump inhibitors. Meta Gene 2016; 9:159-64. [PMID: 27419077 PMCID: PMC4932617 DOI: 10.1016/j.mgene.2016.06.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Revised: 06/03/2016] [Accepted: 06/17/2016] [Indexed: 02/08/2023] Open
Abstract
Introduction and objective Polymorphisms in genes encoding drug metabolizing enzymes may lead to varied enzyme activity and inter-individual variability in drug efficacy and/or toxicity. Since CYP2C19 and CYP3A4 genes code for enzymes involved in metabolizing wide variety of drugs including proton pump inhibitors, we sought to identify polymorphisms in these genes in order to study their impact on drug metabolism in subjects. Methods DNA was isolated from healthy individuals including tribals and genotyped for 11 single nucleotide polymorphisms in CYP2C19 and 6 polymorphisms in CYP3A4. Individuals were categorized into different phenotypes based on their drug metabolizing genotype. Volunteers from each group were administered proton pump inhibitors (Esomeprazole, Pantoprazole; 40 mg/day) for 5 days followed by pharmacokinetic studies and measurement of intra-gastric pH. Results Of the 17 polymorphisms studied, only CYP2C19*2,*3,*17 and CYP3A4*1B polymorphisms were observed. In comparison to urban individuals, a significantly (p = 0.0003) higher number of poor metabolizers were noted in the tribal individuals. Pantoprazole was found to be most effective in poor metabolizers in terms of area under the curve and Tmax. No significant difference was observed in the intra-gastric pH at baseline and day 6 in rapid and ultra-rapid metabolizers. Conclusion Our study has demonstrated that 19.7% of our subjects are carriers of the CYP2C19*17 allele who did not respond to the standard dose of proton pump inhibitors. Genetic screening to identify subjects with variant alleles would thus be useful for personalization of therapy with proton pump inhibitors.
Frequency of poor metabolizers varies significantly in two distinct ethnic groups studied. Subjects with CYP2C19*17 polymorphism are not responsive to standard PPI dose. Identifying individuals with these variants may aid in tailoring drug dose for hyper acidic conditions.
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Affiliation(s)
- Neha Deshpande
- Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
| | - Sharanya V
- Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
| | - Ravi Kanth V V
- Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
| | - Murthy H V V
- Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
| | - Sasikala M
- Asian Healthcare Foundation, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
| | - Rupa Banerjee
- Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
| | - Manu Tandan
- Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
| | - Nageshwar Reddy D
- Asian Institute of Gastroenterology, 6-3-661, Somajiguda, Hyderabad 500082, Telangana, India
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20
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Otake K, Sakurai Y, Nishida H, Fukui H, Tagawa Y, Yamasaki H, Karashima M, Otsuka K, Inatomi N. Characteristics of the Novel Potassium-Competitive Acid Blocker Vonoprazan Fumarate (TAK-438). Adv Ther 2016; 33:1140-57. [PMID: 27287852 DOI: 10.1007/s12325-016-0345-2] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Indexed: 12/18/2022]
Affiliation(s)
- Kazuyoshi Otake
- Global Medical Affairs Japan Department, Takeda Pharmaceutical Co., Ltd., Tokyo, Japan.
| | - Yuuichi Sakurai
- Clinical Science, Takeda Development Center Japan, Takeda Pharmaceutical Co., Ltd., Osaka, Japan
| | - Haruyuki Nishida
- Medicinal Chemistry Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
| | - Hideo Fukui
- Drug Safety Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
| | - Yoshihiko Tagawa
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
| | - Hitomi Yamasaki
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
| | - Masatoshi Karashima
- Analytical Development Laboratories, CMC Center, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
| | - Keiichi Otsuka
- Analytical Development Laboratories, CMC Center, Takeda Pharmaceutical Co., Ltd., Osaka, Japan
| | - Nobuhiro Inatomi
- Extra Value Generation Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Co., Ltd., Kanagawa, Japan
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21
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Abstract
Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.
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22
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Pramanik MMD, Rastogi N. Visible light catalyzed methylsulfoxidation of (het)aryl diazonium salts using DMSO. Chem Commun (Camb) 2016; 52:8557-60. [DOI: 10.1039/c6cc04142f] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The visible light catalyzed methylsulfoxidation of (het)aryl diazonium salts using DMSO is illustrated.
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Affiliation(s)
- Mukund M. D. Pramanik
- Medicinal & Process Chemistry Division
- CSIR-Central Drug Research Institute
- Sector 10
- Jankipuram Extension
- Lucknow 226031
| | - Namrata Rastogi
- Medicinal & Process Chemistry Division
- CSIR-Central Drug Research Institute
- Sector 10
- Jankipuram Extension
- Lucknow 226031
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23
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Takeshima F, Hashiguchi K, Onitsuka Y, Tanigawa K, Minami H, Matsushima K, Akazawa Y, Shiozawa K, Yamaguchi N, Taura N, Ohnita K, Ichikawa T, Isomoto H, Nakao K. Clinical Characteristics of Patients with Gastroesophageal Reflux Disease Refractory to Proton Pump Inhibitors and the Effects of Switching to 20 mg Esomeprazole on Reflux Symptoms and Quality of Life. Med Sci Monit 2015; 21:4111-21. [PMID: 26719012 PMCID: PMC4700865 DOI: 10.12659/msm.895346] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Refractory gastroesophageal reflux disease (GERD) may deteriorate patient quality of life (QOL) despite proton pump inhibitor (PPI) therapy. MATERIAL AND METHODS Nineteen Japanese institutions were surveyed to determine the clinical characteristics and QOL of patients with refractory GERD. Those patients treated with a conventional PPI were switched to 20 mg esomeprazole for 4 weeks. Symptoms and QOL were assessed using Global Overall Symptom and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires at baseline and at 2 and/or 4 weeks of esomeprazole treatment. RESULTS Of 120 patients who completed the survey, 58 (48.3%) had refractory GERD. Of these, 69.0% were aged ≥ 65 years, 79.3% were prescribed a PPI at a standard or high dose, and 22.4% were prescribed a PPI together with another drug. After switching to esomeprazole, patients reported significant improvements in heartburn, acid regurgitation, and excessive belching at 2 weeks using a symptom diary, as well as the total score, reflux, abdominal pain, and indigestion, which were assessed using the GSRS at 4 weeks. CONCLUSIONS About half of Japanese patients with GERD may be refractory to conventional PPIs. Their reflux-related symptoms are often severe and may impair QOL. Switching to esomeprazole could be used to improve their symptoms and QOL.
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Affiliation(s)
- Fuminao Takeshima
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | - Keiichi Hashiguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | - Yasunori Onitsuka
- Department of Internal Medicine, Onitsuka Clinic of Internal Medicine, Nagasaki, Japan
| | - Ken Tanigawa
- Department of Gastroenterology and Hepatology, Tanigawa Clinic of Radiology and Gastroenterology, Nagasaki, Japan
| | | | - Kayoko Matsushima
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | - Yuko Akazawa
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | | | - Naoyuki Yamaguchi
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | - Naota Taura
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | - Ken Ohnita
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | | | - Hajime Isomoto
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
| | - Kazuhiko Nakao
- Department of Gastroenterology and Hepatology, Nagasaki University Hospital, Nagasaki, Japan
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24
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Interethnic variation of CYP2C19 alleles, 'predicted' phenotypes and 'measured' metabolic phenotypes across world populations. THE PHARMACOGENOMICS JOURNAL 2015; 16:113-23. [PMID: 26503820 DOI: 10.1038/tpj.2015.70] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 07/15/2015] [Accepted: 08/19/2015] [Indexed: 02/08/2023]
Abstract
The present study evaluates the worldwide frequency distribution of CYP2C19 alleles and CYP2C19 metabolic phenotypes ('predicted' from genotypes and 'measured' with a probe drug) among healthy volunteers from different ethnic groups and geographic regions, as well as the relationship between the 'predicted' and 'measured' CYP2C19 metabolic phenotypes. A total of 52 181 healthy volunteers were studied within 138 selected original research papers. CYP2C19*17 was 42- and 24-fold more frequent in Mediterranean-South Europeans and Middle Easterns than in East Asians (P<0.001, in both cases). Contrarily, CYP2C19*2 and CYP2C19*3 alleles were more frequent in East Asians (30.26% and 6.89%, respectively), and even a twofold higher frequency of these alleles was found in Native populations from Oceania (61.30% and 14.42%, respectively; P<0.001, in all cases), which may be a consequence of genetic drift process in the Pacific Islands. Regarding CYP2C19 metabolic phenotype, poor metabolizers (PMs) were more frequent among Asians than in Europeans, contrarily to the phenomenon reported for CYP2D6. A correlation has been found between the frequencies of CYP2C19 poor metabolism 'predicted' from CYP2C19 genotypes (gPMs) and the poor metabolic phenotype 'measured' with a probe drug (mPMs) when subjects are either classified by ethnicity (r=0.94, P<0.001) or geographic region (r=0.99, P=0.002). Nevertheless, further research is needed in African and Asian populations, which are under-represented, and additional CYP2C19 variants and the 'measured' phenotype should be studied.
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Interindividual variability of CYP2C19-catalyzed drug metabolism due to differences in gene diplotypes and cytochrome P450 oxidoreductase content. THE PHARMACOGENOMICS JOURNAL 2015; 16:375-87. [PMID: 26323597 PMCID: PMC4775436 DOI: 10.1038/tpj.2015.58] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 05/19/2015] [Accepted: 06/23/2015] [Indexed: 02/01/2023]
Abstract
Large interindividual variability has been observed in the metabolism of CYP2C19 substrates in vivo. The study aimed to evaluate sources of this variability in CYP2C19 activity, focusing on CYP2C19 diplotypes and the cytochrome P450 oxidoreductase (POR). CYP2C19 gene analysis was carried out on 347 human liver samples. CYP2C19 activity assayed using human liver microsomes confirmed a significant a priori predicted rank order for (S)-mephenytoin hydroxylase activity of CYP2C19*17/*17 > *1B/*17 > *1B/*1B > *2A/*17 > *1B/*2A > *2A/*2A diplotypes. In a multivariate analysis, the CYP2C19*2A allele and POR protein content were associated with CYP2C19 activity. Further analysis indicated a strong effect of the CYP2C19*2A, but not the *17, allele on both metabolic steps in the conversion of clopidogrel to its active metabolite. The present study demonstrates that interindividual variability in CYP2C19 activity is due to differences in both CYP2C19 protein content associated with gene diplotypes and the POR concentration.
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Román M, Ochoa D, Sánchez-Rojas SD, Talegón M, Prieto-Pérez R, Rivas Â, Abad-Santos F, Cabaleiro T. Evaluation of the relationship between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, pantoprazole and rabeprazole. Pharmacogenomics 2015; 15:1893-901. [PMID: 25495411 DOI: 10.2217/pgs.14.141] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
AIM To evaluate the possible association between polymorphisms in CYP2C19 and the pharmacokinetics of omeprazole, rabeprazole and pantoprazole. MATERIALS & METHODS 151 healthy volunteers were evaluated for polymorphisms in the CYP2C19 gene using real-time polymerase chain reaction. Plasma concentrations were measured using high-performance liquid chromatography coupled to mass spectrometry. RESULTS Carriers of the *2 allele displayed poor metabolism for all the PPIs studied (around 50% decrease in clearance). Subjects with the *17 allele showed a light increase in clearance compared with *1/*1 (not significant). CONCLUSION CYP2C19*2 is associated with decreased clearance of all the PPIs, that could be associated with higher drug efficacy. CYP2C19*17 could increase clearance of these drugs, although the effect seems small.
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Affiliation(s)
- Manuel Román
- Service of Clinical Pharmacology, Hospital Universitario de la Princesa, Instituto Teófilo Hernando, Instituto de Investigación Sanitaria Princesa (IP), Diego de León 62, 28006 Madrid, Spain
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Šutalo S, Ruetten M, Hartnack S, Reusch CE, Kook PH. The effect of orally administered ranitidine and once-daily or twice-daily orally administered omeprazole on intragastric pH in cats. J Vet Intern Med 2015; 29:840-6. [PMID: 25966746 PMCID: PMC4895399 DOI: 10.1111/jvim.12580] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2014] [Revised: 02/12/2015] [Accepted: 02/26/2015] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Gastric acid suppressants frequently are used in cats with acid-related gastric disorders. However, it is not known if these drugs effectively increase intragastric pH in cats. OBJECTIVES To examine the effects of PO administered ranitidine and omeprazole on intragastric pH in cats and to compare the efficacy of once-daily versus twice-daily dosage regimens for omeprazole. ANIMALS Eight domestic shorthair cats. METHODS Using a randomized 4-way cross-over design, cats were given enteric-coated omeprazole granules (1.1-1.3 mg/kg q24h and q12h), ranitidine (1.5-2.3 mg/kg q12h), and placebo. Intragastric pH was monitored continuously for 96 hours using the Bravo(™) system, starting on day 4 of treatment, followed by a median washout period of 12 days. Mean percentage of time pH was ≥3 and ≥4 was compared among groups using repeated measures ANOVA. RESULTS Mean ± SD percentage of time intragastric pH was ≥3 and ≥4 was 67.0 ± 24.0% and 54.6 ± 26.4% for twice-daily omeprazole, 24.4 ± 22.8% and 16.8 ± 19.3% for once-daily omeprazole, 16.5 ± 9.0% and 9.6 ± 5.9% for ranitidine, and 9.4 ± 8.0% and 7.0 ± 6.6% for placebo administration. Twice-daily omeprazole treatment significantly increased intragastric pH, whereas pH after once-daily omeprazole and ranitidine treatments did not differ from that of placebo-treated cats. CONCLUSION AND CLINICAL IMPORTANCE Only twice-daily PO administered omeprazole significantly suppressed gastric acidity in healthy cats, whereas once-daily omeprazole and standard dosages of ranitidine were not effective acid suppressants in cats.
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Affiliation(s)
- S Šutalo
- Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - M Ruetten
- Institute of Veterinary Pathology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - S Hartnack
- Section of Epidemiology, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - C E Reusch
- Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
| | - P H Kook
- Clinic for Small Animal Internal Medicine, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
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Kuo CH, Lu CY, Shih HY, Liu CJ, Wu MC, Hu HM, Hsu WH, Yu FJ, Wu DC, Kuo FC. CYP2C19 polymorphism influences Helicobacter pylori eradication. World J Gastroenterol 2014; 20:16029-16036. [PMID: 25473155 PMCID: PMC4239489 DOI: 10.3748/wjg.v20.i43.16029] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 07/04/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.
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Vicente J, González-Andrade F, Soriano A, Fanlo A, Martínez-Jarreta B, Sinués B. Genetic polymorphisms of CYP2C8, CYP2C9 and CYP2C19 in Ecuadorian Mestizo and Spaniard populations: a comparative study. Mol Biol Rep 2014; 41:1267-72. [PMID: 24430292 DOI: 10.1007/s11033-013-2971-y] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 12/23/2013] [Indexed: 11/28/2022]
Abstract
This study was designed to investigate the potential differences between Spaniards and Ecuadorian Mestizo people regarding CYP2C8, CYP2C9, and CYP2C19 genetic polymorphisms. DNA from 282 Spaniard and 297 Ecuadorian subjects were analyzed by either a previously reported pyrosequencing method (CY2C8*3, CYP2C9*2, CYP2C9*3, CYP2C19*2 and CYP2C19*3) or a nested PCR technique (CYP2C19*17). Whereas CYP2C19*17 allele distribution was higher in Ecuadorians than in Spaniards (P < 0.001) and the frequency of CYP2C19*3 was similar in these two populations (P > 0.05), the other allelic variants were detected at significantly lower frequencies in Ecuadorians than in Spaniards (P < 0.05). According to the diplotype distributions, the prevalence of the presumed CYP2C9 and CYP2C8 extensive metabolizers was higher in Ecuadorians than in Spaniards (P < 0.05). Individuals genotyped CYP2C19*1/*17 and *17/*17 who were considered as ultrarapid metabolizers were overrepresented in Ecuadorians in relation to Spaniards (P < 0.001). By contrast, among Ecuadorians no poor metabolizers (PMs) of either CYP2C8 or CYP2C9 were found and only two individuals were CYP2C19 PMs. These data are compatible with a higher CYP2C8, CYP2C9, and CYP2C19 activity in Mestizo Ecuadorians as opposed to Spaniards, which could imply differences in dosage requirements for drugs metabolized by these cytochromes and should also be considered in allele-disease association studies.
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Affiliation(s)
- Jorge Vicente
- Department of Pharmacology, University of Zaragoza, 50009, Saragossa, Spain,
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Mejia A, Kraft WK. Acid peptic diseases: pharmacological approach to treatment. Expert Rev Clin Pharmacol 2014; 2:295-314. [PMID: 21822447 DOI: 10.1586/ecp.09.8] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Acid peptic disorders are the result of distinctive, but overlapping pathogenic mechanisms leading to either excessive acid secretion or diminished mucosal defense. They are common entities present in daily clinical practice that, owing to their chronicity, represent a significant cost to healthcare. Key elements in the success of controlling these entities have been the development of potent and safe drugs based on physiological targets. The histamine-2 receptor antagonists revolutionized the treatment of acid peptic disorders owing to their safety and efficacy profile. The proton-pump inhibitors (PPIs) represent a further therapeutic advance due to more potent inhibition of acid secretion. Ample data from clinical trials and observational experience have confirmed the utility of these agents in the treatment of acid peptic diseases, with differential efficacy and safety characteristics between and within drug classes. Paradigms in their speed and duration of action have underscored the need for new chemical entities that, from a single dose, would provide reliable duration of acid control, particularly at night. Moreover, PPIs reduce, but do not eliminate, the risk of ulcers in patients taking NSAIDs, reflecting untargeted physiopathologic pathways and a breach in the ability to sustain an intragastric pH of more than 4. This review provides an assessment of the current understanding of the physiology of acid production, a discussion of medications targeting gastric acid production and a review of efficacy in specific acid peptic diseases, as well as current challenges and future directions in the treatment of acid-mediated diseases.
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Affiliation(s)
- Alex Mejia
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1170 Main Building, 132 South 10th Street, Philadelphia, PA 19107-5244, USA, Tel.: +1 203 243 7501
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Yang H, Li J, Zhao Q, Li J, Shen K, Yang X, Jiang J, Hu P, Qian J. Pharmacokinetics, pharmacodynamics, and safety of esomeprazole injection/infusion in healthy Chinese volunteers: a five-way crossover study. J Gastroenterol Hepatol 2013; 28:1823-8. [PMID: 23800161 DOI: 10.1111/jgh.12305] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/14/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Esomeprazole provides effective and long lasting inhibition of gastric acid secretion. However, the pharmacokinetics and pharmacodynamics of intravenous esomeprazole in the Chinese population remain unclear. AIM To compare the pharmacokinetics and pharmacodynamics of intravenous esomeprazole (injection and infusion) and their clinical safety and tolerability in healthy Chinese subjects. METHODS A randomized, single-center, open-label, five-way crossover study was conducted in 20 healthy volunteers. CYP2C19 metabolizer genotype and Helicobacter pylori status were examined. Five dosing regimens were used: single 40 mg injection, 40 mg infusion every 12 h, 40 mg infusion followed by continuous infusion at 8 mg/h, 80 mg infusion followed by continuous infusion at 4 or 8 mg/h. Intragastric pH was recorded within 24 h. Plasma concentration-time curve, maximum plasma concentration (Cmax ), steady state concentration, and total plasma clearance were determined. Adverse events were also recorded. RESULTS Continuous infusion resulted in a higher mean area under the curve and Cmax than injection. There were no significant differences among the four infusion groups in terms of percentages of time at pH > 4, > 5, > 6, > 7 within 24 h and pH > 6 within the first 3 h. There were no significant differences in pharmacokinetic or pH values among variants of CYP2C19 genotype. The pH value within 24 h was unaffected by H. pylori infection in subjects with continuous infusion. CONCLUSIONS Esomeprazole administrated by infusion produces better pharmacokinetic and intragastric pH profiles compared with those by injection. The optimal administration schedule for esomeprazole in Chinese subjects is infusion with 40 mg/12 h.
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Affiliation(s)
- Hong Yang
- Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Science, Beijing, China
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Cardelli M, Marchegiani F, Corsonello A, Lattanzio F, Provinciali M. A review of pharmacogenetics of adverse drug reactions in elderly people. Drug Saf 2013; 35 Suppl 1:3-20. [PMID: 23446782 DOI: 10.1007/bf03319099] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Older adults are more susceptible to the prevalence of therapeutic failure and adverse drug reactions (ADRs). Recent advances in genomic research have shed light on the crucial role of genetic variants, mainly involving genes encoding drug-metabolizing enzymes, drug transporters and genes responsible for a compound's mechanism of action, in driving different treatment responses among individuals, in terms of therapeutic efficacy and safety. The interindividual variations of these genes may account for the differences observed in drug efficacy and the appearance of ADRs in elderly people. The advent of whole genome mapping techniques has allowed researchers to begin to characterize the genetic components underlying serious ADRs. The identification and validation of these genetic markers will enable the screening of patients at risk of serious ADRs and to establish personalized treatment regimens.The aim of this review was to provide an update on the recent developments in geriatric pharmacogenetics in clinical practice by reviewing the available evidence in the PubMed database to September 2012. A Pubmed search was performed (years 1999-2012) using the following two search strategies: ('pharmacogenomic' OR 'pharmacogenetic ') AND ('geriatric' or 'elderly ') AND 'adverse drug reactions'; [gene name] AND ('geriatric' or 'elderly ') AND 'adverse drug reactions', in which the gene names were those contained in the Table of Pharmacogenomic Biomarkers in Drug Labels published online by the US Food and Drug Administration ( http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm ). Reference lists of included original articles and relevant review articles were also screened. The search was limited to studies published in the English language.
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Affiliation(s)
- Maurizio Cardelli
- Advanced Technology Center for Aging Research, Scientific Technological Area, IRCCS-INRCA, Via Birarelli 8, 60121, Ancona, Italy
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Koch KM, Im YH, Kim SB, Urruticoechea Ribate A, Stephenson J, Botbyl J, Cartee L, Holshouser J, Ridgway D. Effects of Esomeprazole on the Pharmacokinetics of Lapatinib in Breast Cancer Patients. Clin Pharmacol Drug Dev 2013; 2:336-41. [PMID: 27121938 DOI: 10.1002/cpdd.45] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2012] [Accepted: 05/31/2013] [Indexed: 11/05/2022]
Abstract
The aqueous solubility of lapatinib declines significantly at pH >4, suggesting that its bioavailability might be lowered by acid-reducing drugs. A study was therefore conducted to assess the effects of esomeprazole on lapatinib pharmacokinetics (PK). Women with metastatic human epidermal growth factor receptor 2 positive (HER2(+) ) breast cancer were enrolled. Patients received 1,250 mg lapatinib once daily (QD) in the morning on Days 1-7 (Period 1) and Days 8-14 (Period 2) with 40 mg esomeprazole QD at bedtime 3 hours after dinner on Days 8-14. Lapatinib PK sampling occurred during the 24-hour steady-state dosing intervals on Day 7 (lapatinib alone) and Day 14 (lapatinib with esomeprazole). Esomeprazole treatment resulted in decreased lapatinib bioavailability (mean 26%, range 6-49%) that was inversely associated with patient age as a significant covariate.
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Affiliation(s)
- Kevin M Koch
- GlaxoSmithKline Pharmaceuticals, Clinical Pharmacology Modeling and Simulation, Research Triangle Park, NC, USA
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Kearns GL, Blumer J, Schexnayder S, James LP, Adcock KG, Reed MD, Daniel JF, Gaedigk A, Paul J. Single-Dose Pharmacokinetics of Oral and Intravenous Pantoprazole in Children and Adolescents. J Clin Pharmacol 2013; 48:1356-65. [DOI: 10.1177/0091270008321811] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
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Yamamoto N, Murakami H, Nishina T, Hirashima T, Sugio K, Muro K, Takahashi T, Naito T, Yasui H, Akinaga S, Koh Y, Boku N. The effect of CYP2C19 polymorphism on the safety, tolerability, and pharmacokinetics of tivantinib (ARQ 197): results from a phase I trial in advanced solid tumors. Ann Oncol 2013; 24:1653-9. [PMID: 23413279 DOI: 10.1093/annonc/mdt014] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ~20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). PATIENTS AND METHODS Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. RESULTS Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC(0-12) compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. CONCLUSION Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.
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Affiliation(s)
- N Yamamoto
- Division of Thoracic Oncology, Shizuoka Cancer Center, Naga-izumi, Japan.
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Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013; 138:103-41. [PMID: 23333322 DOI: 10.1016/j.pharmthera.2012.12.007] [Citation(s) in RCA: 2716] [Impact Index Per Article: 226.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 12/27/2012] [Indexed: 02/06/2023]
Abstract
Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH:cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s.
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Shin JM, Kim N. Pharmacokinetics and pharmacodynamics of the proton pump inhibitors. J Neurogastroenterol Motil 2013; 19:25-35. [PMID: 23350044 PMCID: PMC3548122 DOI: 10.5056/jnm.2013.19.1.25] [Citation(s) in RCA: 270] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 12/20/2012] [Accepted: 12/21/2012] [Indexed: 12/13/2022] Open
Abstract
Proton pump inhibitor (PPI) is a prodrug which is activated by acid. Activated PPI binds covalently to the gastric H+, K+-ATPase via disulfide bond. Cys813 is the primary site responsible for the inhibition of acid pump enzyme, where PPIs bind. Omeprazole was the first PPI introduced in market, followed by pantoprazole, lansoprazole and rabeprazole. Though these PPIs share the core structures benzimidazole and pyridine, their pharmacokinetics and pharmacodynamics are a little different. Several factors must be considered in understanding the pharmacodynamics of PPIs, including: accumulation of PPI in the parietal cell, the proportion of the pump enzyme located at the canaliculus, de novo synthesis of new pump enzyme, metabolism of PPI, amounts of covalent binding of PPI in the parietal cell, and the stability of PPI binding. PPIs have about 1hour of elimination half-life. Area under the plasmic concentration curve and the intragastric pH profile are very good indicators for evaluating PPI efficacy. Though CYP2C19 and CYP3A4 polymorphism are major components of PPI metabolism, the pharmacokinetics and pharmacodynamics of racemic mixture of PPIs depend on the CYP2C19 genotype status. S-omeprazole is relatively insensitive to CYP2C19, so better control of the intragastric pH is achieved. Similarly, R-lansoprazole was developed in order to increase the drug activity. Delayed-release formulation resulted in a longer duration of effective concentration of R-lansoprazole in blood, in addition to metabolic advantage. Thus, dexlansoprazole showed best control of the intragastric pH among the present PPIs. Overall, PPIs made significant progress in the management of acid-related diseases and improved health-related quality of life.
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Topinková E, Baeyens JP, Michel JP, Lang PO. Evidence-based strategies for the optimization of pharmacotherapy in older people. Drugs Aging 2012; 29:477-94. [PMID: 22642782 DOI: 10.2165/11632400-000000000-00000] [Citation(s) in RCA: 99] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022]
Abstract
Geriatric pharmacotherapy represents one of the biggest achievements of modern medical interventions. However, geriatric pharmacotherapy is a complex process that encompasses not only drug prescribing but also age-appropriate drug development and manufacturing, appropriate drug testing in clinical trials, rational and safe prescribing, reliable administration and assessment of drug effects, including adherence measurement and age-appropriate outcomes monitoring. During this complex process, errors can occur at any stage, and intervention strategies to improve geriatric pharmacotherapy are targeted at improving the regulatory processes of drug testing, reducing inappropriate prescribing, preventing beneficial drug underuse and use of potentially harmful drugs, and preventing adverse drug interactions. The aim of this review is to provide an update on selected recent developments in geriatric pharmacotherapy, including age discrimination in drug trials, a new healthcare professional qualification and shared competence in geriatric drug therapy, the usefulness of information and communication technologies, and pharmacogenetics. We also review optimizing strategies aimed at medication adherence focusing on complex elderly patients. Among the current information technologies, there is sufficient evidence that computerized decision-making support systems are modestly but significantly effective in reducing inappropriate prescribing and adverse drug events across healthcare settings. The majority of interventions target physicians, for whom the scientific concept of appropriate prescribing and the acceptability of the alert system used play crucial roles in the intervention's success. For prescribing optimization, results of educational intervention strategies were inconsistent. The more promising strategies involved pharmacists or multidisciplinary teams including geriatric medicine services. However, methodological weaknesses including population and intervention heterogeneity do not allow for comprehensive meta-analyses to determine the clinical value of individual approaches. In relation to drug adherence, a recent meta-analysis of 33 randomized clinical trials in older patients found behavioural interventions had significant effects, and these interventions were more effective than educational interventions. For patients with multiple conditions and polypharmacy, successful interventions included structured medication review, medication regimen simplification, administration aids and medication reminders, but no firm conclusion in favour of any particular intervention could be made. Interventions to optimize geriatric pharmacotherapy focused most commonly on pharmacological outcomes (drug appropriateness, adverse drug events, adherence), providing only limited information about clinical outcomes in terms of health status, morbidity, functionality and overall healthcare costs. Little attention was given to psychosocial and behavioural aspects of pharmacotherapy. There is sufficient potential for improvements in geriatric pharmacotherapy in terms of drug safety and effectiveness. However, just as we require evidence-based, age-specific, pharmacological information for efficient clinical decision making, we need solid evidence for strategies that consistently improve the quality of pharmacological treatments at the health system level to shape 'age-attuned' health and drug policy.
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Affiliation(s)
- Eva Topinková
- Department of Geriatric Medicine, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
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Furuta T, Sugimoto M, Shirai N. Individualized therapy for gastroesophageal reflux disease: potential impact of pharmacogenetic testing based on CYP2C19. Mol Diagn Ther 2012. [PMID: 22873740 DOI: 10.2165/11634960-000000000-00000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
The main therapeutic agent for gastroesophageal reflux disease (GERD) is a proton pump inhibitor (PPI). Plasma levels and the acid inhibitory effect of PPIs depend on the activity of cytochrome P450 (CYP) 2C19, which is polymorphic. Genotypes of CYP2C19 are classified into three groups: rapid metabolizers (RMs: *1/*1), intermediate metabolizers (IMs: *1/*X), and poor metabolizers (PMs: *X/*X), where *1 and X represent the wild type and the mutant allele, respectively. RMs include ultra-rapid metabolizers, who possess the CYP2C19*17 allele. The pharmacokinetics and pharmacodynamics of PPIs differ among different CYP2C19 genotype groups. Plasma PPI levels and intragastric pH values during PPI treatment are lowest in the RM group, intermediate in the IM group, and highest in the PM group. These CYP2C19-genotype-dependent differences in the pharmacokinetics and pharmacodynamics of PPIs influence the healing and recurrence of GERD during PPI treatment, suggesting the need for CYP2C19 genotype-based tailored therapy for GERD. CYP2C19 pharmacogenetics should be taken into consideration for the personalization of PPI-based therapy. However, the clinical usefulness of CYP2C19 genotype testing in GERD therapy should be verified in clinical studies.
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Affiliation(s)
- Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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McNicholl AG, Linares PM, Nyssen OP, Calvet X, Gisbert JP. Meta-analysis: esomeprazole or rabeprazole vs. first-generation pump inhibitors in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 2012; 36:414-25. [PMID: 22803691 DOI: 10.1111/j.1365-2036.2012.05211.x] [Citation(s) in RCA: 132] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 04/05/2012] [Accepted: 06/20/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND The decreasing efficacy of H. pylori eradication treatments over time makes the search for better regimens and adjuvant medications a priority. AIM To conduct a meta-analysis of studies comparing rabeprazole or esomeprazole with other proton pump inhibitors (PPI) or with each other in H. pylori eradication treatment. SELECTION OF STUDIES Randomised clinical trials comparing esomeprazole or rabeprazole with first-generation PPIs (omeprazole-lansoprazole-pantoprazole) or with each other. RESULTS The meta-analysis (35 studies, 5998 patients) showed higher eradication rates for esomeprazole than for first-generation PPIs: 82.3% vs. 77.6%; OR = 1.32(1.01-1.73); NNT = 21. Rabeprazole also showed better results than first-generation PPIs: 80.5% vs. 76.2%; OR = 1.21(1.02-1.42); NNT = 23. PPI dosage sub-analysis: only esomeprazole 40 mg b.d. improved results [83.5% esomeprazole vs. 72.4% first generation; OR = 2.27(1.07-4.82); NNT = 9]. Whereas rabeprazole 10 and 20 mg b.d. maintained results, esomeprazole 20 mg b.d. obtained lower efficacy. Esomeprazole vs. rabeprazole sub-analysis (five studies): no significant differences were found: 78.7% vs. 76.7%; OR = 0.90(0.70-1.17). CYP2C19 sub-analysis: Genotype did not significantly affect eradication either in first [OR = 1.76(0.99-3.12)] or new generation [OR = 1.19(0.73-1.95)] PPIs. However, sub-analysis considering only extensive metaboliser patients showed higher eradication with new-generation PPIs [OR = 1.37(1.02-1.84)]. CONCLUSIONS Esomeprazole and rabeprazole show better overall H. pylori eradication rates than first-generation PPIs. This clinical benefit is more pronounced in esomeprazole 40 mg b.d. regimens. In CYP2C19 extensive metabolisers, new-generation PPIs are more effective than first-generation PPIs for H. pylori eradication. However, a general recommendation of using new-generation PPIs in all scenarios remains unclear.
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Affiliation(s)
- A G McNicholl
- Gastroenterology Unit, Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
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PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19. Pharmacogenet Genomics 2012; 22:159-65. [PMID: 22027650 DOI: 10.1097/fpc.0b013e32834d4962] [Citation(s) in RCA: 127] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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López M, Dorado P, Monroy N, Alonso ME, Jung-Cook H, Machín E, Peñas-Lledó E, Llerena A. Pharmacogenetics of the antiepileptic drugs phenytoin and lamotrigine. ACTA ACUST UNITED AC 2012; 26:5-12. [PMID: 21557672 DOI: 10.1515/dmdi.2011.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Patients treated with antiepileptic drugs can exhibit large interindividual variability in clinical efficacy or adverse effects. This could be partially due to genetic variants in genes coding for proteins that function as drug metabolizing enzymes, drug transporters or drug targets. The purpose of this article is to provide an overview of the current knowledge on the pharmacogenetics of two commonly prescribed antiepileptic drugs with similar mechanisms of action; phenytoin (PHT) and lamotrigine (LTG). These two drugs have been selected in order to model the pharmacogenetics of Phase I and Phase II metabolism for PHT and LTG, respectively. In light of the present evidence, patients treated with PHT could benefit from CYP2C9 and CYP2C19 genotyping/phenotyping. For those under treatment with LTG, UGT1A4 and UGT2B7 genotyping might be of clinical use and could contribute to the interindividual variability in LTG concentration to dose ratio in epileptic patients.
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Affiliation(s)
- Marisol López
- Department of Biological Systems, Universidad Autónoma Metropolitana-Xochimilco, Mexico City, Mexico
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Abstract
Proton pump inhibitors are widely used for the treatment of acid-related disorders. Rabeprazole is a potent and irreversible inhibitor of H(+)/K(+)-ATPase gastric pump, and it is indicated for the treatment of gastroesophageal reflux disease, Zollinger Ellison syndrome, duodenal and gastric ulcers and for the eradication of Helicobacter pylori in combination with antibiotics. Pharmacokinetic and pharmacodynamic data show that rabeprazole achieves a pronounced acid suppression from the first administration that is maintained with repeated use; this may translate into faster onset of symptom relief for patients, particularly suitable when the indication is for the on-demand long-term maintenance of gastroesophageal reflux disease. Due to its predominantly nonenzymatic metabolism, rabeprazole has a lower potential for drug-drug interactions. The objective of this article is to update efficacy and safety data of rabeprazole in the treatment of acid-related disorders, following a previous review dated 2008.
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Affiliation(s)
- Silvia Marelli
- Janssen-Cilag SpA, Via Buonarroti, 23, 20093 Cologno Monzese, Milan, Italy.
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Furuta T, Sugimoto M, Shirai N. Individualized therapy for gastroesophageal reflux disease: potential impact of pharmacogenetic testing based on CYP2C19. Mol Diagn Ther 2012; 16:223-234. [PMID: 22873740 DOI: 10.1007/bf03262211] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The main therapeutic agent for gastroesophageal reflux disease (GERD) is a proton pump inhibitor (PPI). Plasma levels and the acid inhibitory effect of PPIs depend on the activity of cytochrome P450 (CYP) 2C19, which is polymorphic. Genotypes of CYP2C19 are classified into three groups: rapid metabolizers (RMs: *1/*1), intermediate metabolizers (IMs: *1/*X), and poor metabolizers (PMs: *X/*X), where *1 and X represent the wild type and the mutant allele, respectively. RMs include ultra-rapid metabolizers, who possess the CYP2C19*17 allele. The pharmacokinetics and pharmacodynamics of PPIs differ among different CYP2C19 genotype groups. Plasma PPI levels and intragastric pH values during PPI treatment are lowest in the RM group, intermediate in the IM group, and highest in the PM group. These CYP2C19-genotype-dependent differences in the pharmacokinetics and pharmacodynamics of PPIs influence the healing and recurrence of GERD during PPI treatment, suggesting the need for CYP2C19 genotype-based tailored therapy for GERD. CYP2C19 pharmacogenetics should be taken into consideration for the personalization of PPI-based therapy. However, the clinical usefulness of CYP2C19 genotype testing in GERD therapy should be verified in clinical studies.
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Affiliation(s)
- Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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Budha NR, Frymoyer A, Smelick GS, Jin JY, Yago MR, Dresser MJ, Holden SN, Benet LZ, Ware JA. Drug absorption interactions between oral targeted anticancer agents and PPIs: is pH-dependent solubility the Achilles heel of targeted therapy? Clin Pharmacol Ther 2012; 92:203-13. [PMID: 22739140 DOI: 10.1038/clpt.2012.73] [Citation(s) in RCA: 241] [Impact Index Per Article: 18.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
A majority of the novel orally administered, molecularly targeted anticancer therapies are weak bases that exhibit pH-dependent solubility, and suppression of gastric acidity with acid-reducing agents could impair their absorption. In addition, a majority of cancer patients frequently take acid-reducing agents to alleviate symptoms of gastroesophageal reflux disease, thereby raising the potential for a common but underappreciated drug-drug interaction (DDI) that could decrease the exposure of anticancer medication and result in subsequent failure of therapy. This article is a review of the available clinical literature describing the extent of the interaction between 15 orally administered, small-molecule targeted anticancer therapies and acid-reducing agents. The currently available clinical data suggest that the magnitude of this DDI is largest for compounds whose in vitro solubility varies over the pH range 1-4. This range represents the normal physiological gastric acidity (pH ~1) and gastric acidity while on an acid-reducing agent (pH ~4).
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Affiliation(s)
- N R Budha
- Department of Clinical Pharmacology, Genentech, South San Francisco, California, USA
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Yousef AM, Bulatova NR, Newman W, Hakooz N, Ismail S, Qusa H, Zahran F, Anwar Ababneh N, Hasan F, Zaloom I, Khayat G, Al-Zmili R, Naffa R, Al-Diab O. Allele and genotype frequencies of the polymorphic cytochrome P450 genes (CYP1A1, CYP3A4, CYP3A5, CYP2C9 and CYP2C19) in the Jordanian population. Mol Biol Rep 2012; 39:9423-33. [DOI: 10.1007/s11033-012-1807-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2011] [Accepted: 06/09/2012] [Indexed: 12/20/2022]
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Hayato S, Hasegawa S, Hojo S, Okawa H, Abe H, Sugisaki N, Munesue M, Horai Y, Ohnishi A. Dose-response relationships of rabeprazole 5, 10, 20, and 40 mg once daily on suppression of gastric acid secretion through the night in healthy Japanese individuals with different CYP2C19 genotypes. Eur J Clin Pharmacol 2012; 68:579-88. [PMID: 22108775 DOI: 10.1007/s00228-011-1164-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2011] [Accepted: 10/31/2011] [Indexed: 12/22/2022]
Abstract
PURPOSE This study was designed to investigate the antisecretory activity of rabeprazole administered once daily in doses of 5, 10, 20, and 40 mg and different cytochrome P450 2C19 (CYP2C19) genotypes on gastric pH in healthy individuals. Additional objectives were delineating the nighttime from the daytime effect and determining the relationships between the pharmacokinetics and pharmacodynamics of rabeprazole. METHODS Eight individuals of each of the three genotypes of CYP2C19-homozygous extensive metabolizers (homo-EMs), heterozygous EMs (hetero-EMs), and poor metabolizers (PMs)-were recruited. Twenty-four individuals received a once-daily dose, with dosing interval 24 h of 5, 10, 20, or 40 mg rabeprazole for 5 days in a 4-period crossover fashion. Twenty-four-hour intragastric pH and plasma rabeprazole concentrations were determined on day 5. RESULTS A dose-dependent increase in median pH and in pH 4 holding time was observed across all CYP2C19 genotypes. When rabeprazole was increased from 20 mg to 40 mg, the differences and 95% confidence intervals (CIs) of nighttime pH 4 holding time between 40 mg and 20 mg in homo-EMs, hetero-EMs, and PMs were 8.0% (-5.0% -21.0%), 28.7% (15.7% -41.6%), and 16.9% (3.9% -29.9%), respectively. The relationship between the area under the plasma concentration-time curve up to the last time point at which rabeprazole was quantifiable (AUC(0-t)) and the pH 4 holding time could be described using a sigmoid maximum effect (E(max)) model. CONCLUSIONS Our data demonstrate that increasing rabeprazole dose up to 40 mg once daily results in an increasing pharmacodynamic effect, which is most apparent for the control of nocturnal gastric acid secretion.
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Affiliation(s)
- Seiichi Hayato
- Eisai Product Creation Systems, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo 112-8088, Japan
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Huang B, Huang Y, Li Y, Yao H, Jing X, Huang H, Li J. Adverse Cardiovascular Effects of Concomitant Use of Proton Pump Inhibitors and Clopidogrel in Patients with Coronary Artery Disease: A Systematic Review and Meta-Analysis. Arch Med Res 2012; 43:212-24. [DOI: 10.1016/j.arcmed.2012.04.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2011] [Accepted: 04/14/2012] [Indexed: 02/06/2023]
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Zhan XB, Guo XR, Li ZS, Gong YF, Gao J, Liao Z, Li Z, Gao S, Huang L, Liu P. Inhibitory effects of intravenous lansoprazole 30 mg and pantoprazole 40 mg twice daily on intragastric acidity in healthy Chinese volunteers: a randomized, open-labeled, two-way crossover study. Med Sci Monit 2012; 18:CR125-130. [PMID: 22293876 PMCID: PMC3560577 DOI: 10.12659/msm.882468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2010] [Accepted: 06/24/2011] [Indexed: 12/02/2022] Open
Abstract
BACKGROUND Until now there has been no study that directly compares the effect of lansoprazole and pantoprazole administered intravenously on intragastric acidity. The aim of this study is to compare the effect of lansoprazole (30 mg) and pantoprazole (40 mg) administered intravenously on gastric acidity. MATERIAL/METHODS Helicobacter pylori-negative healthy volunteers were recruited in this open-label, randomized, two-way crossover, single centre study. Lansoprazole at 30 mg or pantoprazole at 40 mg was intravenously administered twice daily for 5 consecutive days with at least a 14-day washout interval. Twenty-four-hour intragastric pH was continuously monitored on days 1 and 5 of each dosing period. RESULTS Twenty-five volunteers completed the 2 dosing periods. The mean intragastric pH values were higher in subjects treated with lansoprazole than those with pantoprazole on both day 1 (6.41 ± 0.14 vs. 5.49 ± 0.13, P=0.0003) and day 5 (7.09 ± 0.07 vs. 6.64 ± 0.07, P=0.0002). Significantly higher percentages of time with intragastric pH >4 and pH >6 were found in the subjects treated with lansoprazole than those with pantoprazole on day 1 (pH >4, 87.12 ± 4.55% vs. 62.28 ± 4.15%, P=0.0012; pH >6, 62.12 ± 4.12% vs. 47.25 ± 3.76%, P=0.0216) and pH >6 on day 5 (76.79 ± 3.77% vs. 58.20 ± 3.77%, P=0.0025). CONCLUSIONS Intravenous lansoprazole produces a longer and more potent inhibitory effect on intragastric acidity than does intravenous pantoprazole.
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Affiliation(s)
- Xian-Bao Zhan
- Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Xiao-Rong Guo
- Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, China
- Zhao-Shen Li, Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, 200433, China, e-mail:
| | - Yan-Fang Gong
- Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Jun Gao
- Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Zhuan Liao
- Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Zhen Li
- Department of Pharmacology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Shen Gao
- Department of Pharmacology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Ling Huang
- Department of Gastroenterology, Changhai Hospital, 2 Military Medical University, Shanghai, China
| | - Pei Liu
- Department of Medical Statistics, Southeast University, Nanjing, China
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