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Liao Y, Chen Y, Hsiao T, Lin C, Wu M, Hsu C, Chen Y, Hsu C. CYP2C19 genotypes and osteoporotic fractures in long-term users of proton pump inhibitors: A hospital-based study. Clin Transl Sci 2023; 16:2198-2208. [PMID: 37641483 PMCID: PMC10651637 DOI: 10.1111/cts.13620] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2023] [Revised: 07/25/2023] [Accepted: 08/11/2023] [Indexed: 08/31/2023] Open
Abstract
Proton pump inhibitors (PPIs) are commonly prescribed medications. The existing data suggest that individuals at a high risk of fractures have been exposed to high doses of PPIs for prolonged durations. CYP2C19 plays a pivotal role in metabolism of PPIs and thereby influences their pharmacokinetic profile. Hence, we hypothesize that CYP2C19 genotypes may be associated with fragility fracture among PPIs users due to PPI exposure. This study aimed to investigate the association between CYP2C19 genotypes, bone mineral density (BMD), and osteoporotic fracture in a hospital-based population. This retrospective cohort study enrolled patients who were prescribed long-term PPIs at Taichung Veterans General Hospital using data extracted from the Taiwan Precision Medicine Initiative between January 2010 and April 2021. Associations between CYP2C19 phenotypes, comorbidities, and fractures in PPI users were analyzed. We enrolled 1518 long-term PPI users; 571 (38%), 727 (48%), and 220 (14%) CYP2C19 normal metabolizers (NMs), intermediate metabolizers (IMs), and poor metabolizers (PMs), respectively. Among them, 49 (3.2%) patients developed fractures within the 1-year follow-up period; 20 (3.5%) fractures in NMs, 24 (3.3%) in IMs, and 5 (2.3%) in PMs, respectively. No significant difference was observed among CYP2C19 genotypes and fracture. Additionally, BMD measurements during the 1-year follow-up period were made available among 75 participants. No significant difference in BMD between CYP2C19 PMs and non-PMs was found. This real-world, hospital-based study concludes that CYP2C19 PMs/IMs are not associated with an increased risk for fractures or reduced BMD in individuals on long-term PPI therapy.
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Affiliation(s)
- Yi‐Ju Liao
- Department of PharmacyTaichung Veterans General HospitalTaichungTaiwan
- Department of PharmacyNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Yu‐Ting Chen
- Department of PharmacyTaichung Veterans General HospitalTaichungTaiwan
| | - Tzu‐Hung Hsiao
- Department of Medical ResearchTaichung Veterans General HospitalTaichungTaiwan
- Department of Public HealthFu Jen Catholic UniversityNew TaipeiTaiwan
- Institute of Public Health and Community Medicine Research CenterNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Ching‐Heng Lin
- Department of Medical ResearchTaichung Veterans General HospitalTaichungTaiwan
- Department of Public HealthFu Jen Catholic UniversityNew TaipeiTaiwan
- Institute of Public Health and Community Medicine Research CenterNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Department of Industrial Engineering and Enterprise InformationTunghai UniversityTaichungTaiwan
| | - Ming‐Fen Wu
- Department of PharmacyTaichung Veterans General HospitalTaichungTaiwan
| | - Chiann‐Yi Hsu
- Department of Medical ResearchTaichung Veterans General HospitalTaichungTaiwan
- Biostatistics Task Force of Taichung Veterans General HospitalTaichungTaiwan
| | - Yi‐Ming Chen
- Department of Medical ResearchTaichung Veterans General HospitalTaichungTaiwan
- Division of Allergy, Immunology and Rheumatology, Department of Internal MedicineTaichung Veterans General HospitalTaichungTaiwan
- Department of Post‐Baccalaureate Medicine, College of MedicineNational Chung Hsing UniversityTaichungTaiwan
- School of MedicineNational Yang‐Ming Chiao Tung UniversityTaipeiTaiwan
- Rong Hsing Research Center for Translational Medicine & Ph.D. Program in Translational MedicineNational Chung Hsing UniversityTaichungTaiwan
- Precision Medicine Research Center, College of MedicineNational Chung Hsing UniversityTaichungTaiwan
| | - Chun‐Sheng Hsu
- Department of Post‐Baccalaureate Medicine, College of MedicineNational Chung Hsing UniversityTaichungTaiwan
- Department of Physical Medicine and RehabilitationTaichung Veterans General HospitalTaichungTaiwan
- School of MedicineNational Defense Medical CenterTaipeiTaiwan
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Eken E, Estores DS, Cicali EJ, Wiisanen KK, Johnson JA. A Pharmacogenetics-Based Approach to Managing Gastroesophageal Reflux Disease: Current Perspectives and Future Steps. Pharmgenomics Pers Med 2023; 16:645-664. [PMID: 37383676 PMCID: PMC10296543 DOI: 10.2147/pgpm.s371994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Accepted: 05/18/2023] [Indexed: 06/30/2023] Open
Abstract
Proton pump inhibitors (PPIs) are commonly used medications to treat acid-related conditions, including gastro-esophageal reflux disease (GERD). Gastroenterology guidelines mention the importance of CYP2C19 in PPI metabolism and the influence of CYP2C19 genetic variations on variable responses to PPIs, but do not currently recommend the genotyping of CYP2C19 prior to prescribing PPIs. There are strong data to support the influence of CYP2C19 genetic variations on the pharmacokinetics of PPIs and clinical outcomes. Existing pharmacogenetic guideline recommendations for dose increases focus on H. pylori and erosive esophagitis indications, but PPIs are also the main therapy for treating GERD. Recent data suggest GERD patients being treated with a PPI may also benefit from genotype-guided dosing. We summarize the literature supporting this contention and highlight future directions for improved management of patients with GERD through precision medicine approaches.
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Affiliation(s)
- Eda Eken
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
- Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL, USA
| | - David S Estores
- Division of Gastroenterology, Hepatology, and Nutrition, College of Medicine, University of Florida, Gainesville, FL, USA
| | - Emily J Cicali
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
- Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL, USA
| | - Kristin K Wiisanen
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
- Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL, USA
| | - Julie A Johnson
- Department of Pharmacotherapy and Translational Research, College of Pharmacy, University of Florida, Gainesville, FL, USA
- Center for Pharmacogenomics and Precision Medicine, University of Florida, Gainesville, FL, USA
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Zhang Z, Bao Y, Cai L, Gu Y, Yang T, Li X. Cost-Utility Analysis of CYP2C19 Genotype Detection for Selection of Acid-Suppressive Therapy with Lansoprazole or Vonoprazan for Patients with Reflux Esophagitis in China. Clin Drug Investig 2022; 42:839-851. [PMID: 35994227 DOI: 10.1007/s40261-022-01188-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/01/2022] [Indexed: 11/25/2022]
Abstract
BACKGROUND The cytochrome P450 (CYP) 2C19 genotype has a profound effect on the efficacy of lansoprazole, with less of an influence on vonoprazan. Both are first-choice drugs for the treatment of reflux esophagitis in China. OBJECTIVE We aimed to estimate the cost-effectiveness of acid-suppressive treatments in Chinese patients with reflux esophagitis over 1 year from the societal perspective. METHODS We developed a decision-based Markov model with a 4-week cycle to simulate the economic benefits and quality-adjusted life-years between different treatment strategies for patients with reflux esophagitis: universal lansoprazole, universal vonoprazan, and CYP2C19 genotype-guided strategies. The primary outcome was the incremental cost-effectiveness ratio. Data sources were the published literature, clinical trials, documents, and local charges. We used sensitivity analyses to detect the robustness of the findings and explored subgroup analyses and scenario analyses to make further evaluations. RESULTS Compared to lansoprazole, vonoprazan and the CYP2C19 genotype-guided strategy were not preferable for Chinese patients with reflux esophagitis, with an incremental cost-effectiveness ratio of 222,387.1316 yuan/quality-adjusted life-year and 349,627.5000 yuan/quality-adjusted life-year, respectively. Sensitivity analyses showed the impact factors were the utility scores and the expenditures for the maintenance stage with lansoprazole and vonoprazan. When the willingness-to-pay threshold was 215,484 yuan/quality-adjusted life-year, 46.20% of the reflux esophagitis population was willing to pay for vonoprazan, compared with 8.30% for the CYP2C19 genotype-guided strategies. Vonoprazan and the CYP2C19 genotype-guided strategy were cost effective in the severe reflux esophagitis population, and in the reduction of the price of vonoprazan. CONCLUSIONS The health economic evaluations revealed that for Chinese patients with reflux esophagitis, vonoprazan and the CYP2C19 genotype-guided strategy were not cost-effective regimens compared with lansoprazole. However, we found that in certain conditions like a reduction in the price of vonoprazan and in patients with severe reflux esophagitis these could be cost-effective.
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Affiliation(s)
- Zhuolin Zhang
- School of Pharmacy, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yuwen Bao
- School of Health Policy and Management, Nanjing Medical University, Nanjing, People's Republic of China
| | - Lele Cai
- School of Pharmacy, Nanjing Medical University, Nanjing, People's Republic of China
| | - Yajie Gu
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, People's Republic of China
| | - Ting Yang
- Department of Pharmacy, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, People's Republic of China
| | - Xin Li
- School of Pharmacy, Nanjing Medical University, Nanjing, People's Republic of China. .,Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
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Gronich N, lavi I, Lejbkowicz F, Pinchev M, Rennert G. Association of CYP2C19 polymorphism with proton pump inhibitors effectiveness and with fractures in real‐life: retrospective cohort study. Clin Pharmacol Ther 2022; 111:1084-1092. [PMID: 35124810 PMCID: PMC9311419 DOI: 10.1002/cpt.2552] [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: 12/04/2021] [Accepted: 02/01/2022] [Indexed: 11/08/2022]
Abstract
Symptom refractoriness of patients treated with proton pump inhibitors (PPIs) might be explained by polymorphism in CYP2C19. This is a retrospective cohort study in which we used the computerized database of Clalit Health Services to compose a cohort from cancer case‐control studies’ participants that had been genotyped, and that have been dispensed PPI (January 1, 2002 to November 10, 2020). We retrieved demographic and clinical variables on date of PPI initiation (cohort entry), and studies’ questionnaires‐reported consumption of foods/beverages known to increase peptic‐related symptoms. Primary outcome was an abdominal pain diagnosis; secondary outcome was a composite of abdominal pain, visit to a gastroenterology clinic, change to another PPI, PPI dose increase, or metoclopramide prescription, reflecting symptoms persistence/recurrence; in a 2‐year follow‐up. We also evaluated the association between genetic groups and hip/wrist/spine fractures, in a long‐term follow‐up. Of 3,326 PPI initiators, there were 66 (2.0%), 739 (22.2%), 1394 (41.9%), 947 (28.5%), and 180 (5.4%) CYP2C19 poor, intermediate, normal, rapid, and ultra‐rapid metabolizers, respectively. Being a poor metabolizer was associated with lower risk for the primary outcome, hazard ratio (HR) = 0.50 (95% confidence interval (CI) 0.27–0.91), HR = 0.52 (95% CI 0.28–0.94); and for the secondary outcome, HR = 0.57 (95% CI 0.38–0.86), HR = 0.58 (95% CI 0.39–0.87), in univariate and multivariable cox regression analyses, respectively. In long‐term follow‐up with 20,142 person‐years of follow‐up: 7.6% (5 cases) within the poor metabolizers group, and 11.6%, 12.9%, 12.8%, and 11.1% in the normal, intermediate, rapid, and ultra‐rapid metabolizers groups, respectively, had a new fracture (nonsignificant). We conclude that CYP2C19 poor metabolizer status is associated with higher effectiveness of PPIs, and is not associated with higher risk for fractures.
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Affiliation(s)
- Naomi Gronich
- Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
- Ruth and Bruce Rappaport Faculty of Medicine Technion–Israel Institute of Technology Haifa Israel
| | - Idit lavi
- Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
| | - Flavio Lejbkowicz
- Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
| | - Mila Pinchev
- Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
| | - Gad Rennert
- Department of Community Medicine and Epidemiology Lady Davis Carmel Medical Center Haifa Israel
- Ruth and Bruce Rappaport Faculty of Medicine Technion–Israel Institute of Technology Haifa Israel
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Suzuki T, Higuchi T, Kagami T, Uotani T, Yamade M, Tani S, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Miyajima H, Furuta T. Effects of pirenzepine on vonoprazan-induced gastric acid inhibition and hypergastrinemia. Eur J Clin Pharmacol 2021; 77:971-978. [PMID: 34059932 DOI: 10.1007/s00228-021-03162-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Accepted: 05/14/2021] [Indexed: 10/21/2022]
Abstract
BACKGROUND Compared to proton pump inhibitors, vonoprazan exerts a greater inhibitory effect on gastric acid secretion and is useful for treating acid-related diseases, such as gastro-esophageal reflux disease. However, there is a problem that vonoprazan causes hypergastrinemia, which confers a risk of carcinoid tumor. A previous report demonstrated that pirenzepine, an M1 muscarinic receptor antagonist, enhances the acid inhibitory effects while suppressing hypergastrinemia induced by omeprazole. Here, we examined whether pirenzepine enhances the gastric acid inhibitory effects of vonoprazan without further increasing serum gastrin levels. METHODS Eleven healthy volunteers were subjected to 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: pirenzepine 75 mg alone, vonoprazan 10 mg alone, and vonoprazan 10 mg plus pirenzepine 75 mg administered in a randomized crossover fashion. RESULTS Median pH 4 holding time ratios (range) achieved with pirenzepine 75 mg, vonoprazan 10 mg, and vonoprazan 10 mg plus pirenzepine 75 mg were 6.9% (2.4-32.8%), 88.4% (54.6-100%), and 84.2% (40.3-100%), respectively. Respective serum gastrin levels were 79 (75-210) pg/ml, 310 (110-870) pg/ml, and 170 (140-930) pg/ml. In cases with hypergastrinemia (gastrin ≥ 200 pg/ml) induced by vonoprazan 10 mg alone, concomitant treatment with pirenzepine significantly reduced serum gastrin levels from 370 to 180 pg/ml (P = 0.028). CONCLUSION Although pirenzepine does not enhance acid inhibition, it does improve hypergastrinemia induced by vonoprazan to some extent.
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Affiliation(s)
- Takahiro Suzuki
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Tomohiro Higuchi
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takuma Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Shinya Tani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan.
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Perbtani YB, Westerveld DR, Yang DJ, Draganov PV. CYP2C19 genotype variability in patients with refractory gastroesophageal reflux after per-oral endoscopic myotomy (POEM). Endosc Int Open 2021; 9:E843-E847. [PMID: 34079865 PMCID: PMC8159581 DOI: 10.1055/a-1401-9853] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 02/15/2021] [Indexed: 12/30/2022] Open
Abstract
Background and study aims Symptomatic gastroesophageal reflux is a recognized potential adverse event following peroral endoscopic myotomy (POEM). Proton pump inhibitors (PPIs) are an effective first-line therapy; although their efficacy can be affected by genotype cytochrome P450 2C19 (CYP2C19) variability leading to enhanced clearance of PPIs. The aim of our study was to evaluate the incidence of CYP2C19 genotype variability in POEM patients with refractory gastroesophageal reflux symptoms. Patients and methods This was a single-center, prospective, cohort study of consecutive POEM cases during a 7-year study period (2013-2020). Reflux symptoms were assessed with the validated gastroesophageal reflux disease questionnaire (GerdQ) and objective pH testing after POEM. CYP2C19 genotype testing was obtained in all patients with refractory gastroesophageal reflux disease (GERD) symptoms, defined as an abnormal pH study and GerdQ score ≥ 8 while on PPIs twice daily. Results POEM was performed in 325 consecutive patients (48.3 % female; mean age 57 years) during the study period. Twenty patients (6.8 %) had PPI-refractory, post-POEM gastroesophageal reflux based on their GerdQ score (median 9, range 8-11) and abnormal pH studies. CYP2C19 genotype testing identified 55 % (11/20) of these patients as being rapid metabolizers. Out of these, 9 (82 %) had improvement in clinical GERD symptoms after changing to a PPI less affected by CYP2C19 pharmacogenetics. Conclusions Post-POEM, PPI-refractory GERD is rare. As shown in this study, rapid metabolizers commonly respond by changing to a PPI less affected by CYP2C19 pharmacogenetics, thereby reducing the risk of long-term consequences from GERD and unnecessary anti-reflux surgery.
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Affiliation(s)
- Yaseen B. Perbtani
- Department of Internal Medicine, University of Florida, Gainesville, Florida, United States
| | - Donevan R. Westerveld
- Division of Gastroenterology and Hepatology, University of Florida, Gainesville, Florida, United States
| | - Dennis J. Yang
- Department of Internal Medicine, University of Florida, Gainesville, Florida, United States
| | - Peter V. Draganov
- Department of Internal Medicine, University of Florida, Gainesville, Florida, United States
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Isshi K, Matsuhashi N, Joh T, Higuchi K, Iwakiri K, Kamiya T, Manabe N, Nakada T, Ogawa M, Arihiro S, Haruma K, Nakada K. Clinical features and therapeutic responses to proton pump inhibitor in patients with severe reflux esophagitis: A multicenter prospective observational study. JGH Open 2021; 5:99-106. [PMID: 33490619 PMCID: PMC7812480 DOI: 10.1002/jgh3.12455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 11/02/2020] [Accepted: 11/03/2020] [Indexed: 11/28/2022]
Abstract
BACKGROUND AND AIM In patients with severe erosive reflux disease (ERD; Los Angeles classification grade C/D) who do not undergo endoscopic examination, insufficient strength and duration of proton pump inhibitor (PPI) therapy may lead to complications such as esophageal bleeding and stenosis. Therefore, to provide a safe and effective treatment for gastroesophageal reflux disease (GERD), we investigated the clinical features of patients with severe ERD and their responses to PPI therapy. METHODS Patients with GERD symptoms received PPI therapy for 4 weeks after endoscopic examination. The patients completed the Gastroesophageal reflux and dyspepsia therapeutic efficacy and satisfaction test questionnaire before and 2 or 4 weeks after PPI treatment. Patient characteristics, presence/absence of coexisting atrophic gastritis (AG) and hiatus hernia (HH), and responses to PPI therapy were compared in patients with GERD among three groups (nonerosive reflux disease, mild ERD [grade A/B], and severe ERD). RESULTS The severe ERD group had a significantly higher proportion of males, higher body mass index, and longer duration of GERD morbidity. Furthermore, the severe ERD group also had a significantly lower incidence of coexisting AG and higher incidence of HH. There was no difference in the severity of GERD before PPI treatment among the three groups. Unexpectedly, the response to PPI therapy was the best in the severe ERD group. CONCLUSION Sufficient strength and period of PPI therapy are required, even if the symptoms show early improvement, when treating GERD patients without performing endoscopy, considering the possibility of severe ERD.
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Affiliation(s)
- Kimio Isshi
- Department of GastroenterologyIsshi Gastro‐Intestinal Clinic2‐15‐21, Shinozaki‐choEdogawa‐Ku133‐0061TokyoJapan
- Department of EndoscopyThe Jikei University School of Medicine3‐15‐8, NishishinbashiMinato‐Ku105‐8461TokyoJapan
| | - Nobuyuki Matsuhashi
- Department of GastroenterologyNTT Medical Center Tokyo5‐9‐22, Higashi‐GotandaShinagawa‐Ku144‐8625TokyoJapan
| | - Takashi Joh
- Department of GastroenterologyGamagori City Hospital1‐1, Mukaida Hirata‐choGamagori443‐8501AichiJapan
| | - Kazuhide Higuchi
- Second Department of Internal MedicineOsaka Medical College2‐7, DaigakumachiTakatsuki569‐8686OsakaJapan
| | - Katsuhiko Iwakiri
- Department of GastroenterologyNippon Medical School Graduate School of Medicine1‐1‐5, SendagiBunkyo‐Ku133‐8603TokyoJapan
| | - Takeshi Kamiya
- Department of Medical InnovationNagoya City University Graduate School Medical Sciences1, Kwasumi Mizuhocho, Mizuho‐KuNagoya467‐8601AichiJapan
| | - Noriaki Manabe
- Division of Endoscopy and Ultrasonography, Department of Laboratory MedicineKawasaki Medical School2‐6‐1, Nakasange, Kita‐KuOkayama700‐8505OkayamaJapan
| | - Tatsuya Nakada
- Division of Gastroenterology and Hepatology, Department of Internal MedicineKatsushika Medical Center, The Jikei University School of Medicine6‐41‐2, AotoKatsushika‐Ku125‐8506TokyoJapan
| | - Maiko Ogawa
- Division of Gastroenterology and Hepatology, Department of Internal MedicineKatsushika Medical Center, The Jikei University School of Medicine6‐41‐2, AotoKatsushika‐Ku125‐8506TokyoJapan
| | - Seiji Arihiro
- Division of Gastroenterology and Hepatology, Department of Internal MedicineKatsushika Medical Center, The Jikei University School of Medicine6‐41‐2, AotoKatsushika‐Ku125‐8506TokyoJapan
| | - Ken Haruma
- Department of General Internal Medicine 2Kawasaki Medical School Kawasaki Hospital577, MatsushimaKurashiki701‐0192OkayamaJapan
| | - Koji Nakada
- Department of Laboratory MedicineThe Jikei University School of Medicine3‐25‐8, NishishinbashiMinato‐Ku105‐8461TokyoJapan
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Murata M, Sugimoto M. Effect of a rabeprazole half-dose twice daily on acid inhibition in patients with different CYP2C19 alleles. Eur J Clin Pharmacol 2020; 76:1253-1261. [PMID: 32488332 DOI: 10.1007/s00228-020-02917-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 05/25/2020] [Indexed: 10/24/2022]
Abstract
PURPOSE Fractional doses of proton pump inhibitors (PPIs) more often than once daily (qd) inhibit 24-h acid secretion more effectively than an increase in the standard single daily dose. Although rabeprazole 5 mg qd is covered for prevention of aspirin-induced gastric injury under the Japanese insurance system, it is unclear whether rabeprazole 5 mg twice daily (bid) would more effectively inhibit acid secretion. We compared acid inhibition between rabeprazole 10 mg qd and 5 mg bid in healthy volunteers with different alleles of CYP2C19. METHODS Twelve Helicobacter pylori-negative healthy volunteers (CYP2C19 genotypes: extensive metabolizer (EM) (n = 6) and poor metabolizer (PM) (n = 6)) received three kinds of regimen for 7 days under a randomized crossover design: rabeprazole 5 mg qd (5 mg QD), 10 mg qd (10 mg QD), and 5 mg bid (5 mg BID). A 24-hour pH monitoring was conducted before the trial and on day 7 of each regimen. RESULTS No significant differences in median pH values (4.0 (1.9-5.9)) and (4.4 (2.1-6.5)) or percent time of pH ≥ 4 (50.7% (11.9-86.8%) and 56.8% (19.3-83.9%)) were seen between the 10 mg QD and 5 mg BID regimens. Median pHs and percent time of pH ≥ 4 in CYP2C19 PMs were significantly higher than those in EMs. With 5 mg BID, there was no significant difference in percent-time with pH ≥ 4 between daytime and nighttime, but the 10 mg QD showed a significant difference. CONCLUSION Rabeprazole 5 mg bid provided no therapeutic advantage for acid inhibition compared with rabeprazole 10 mg qd, regardless of CYP2C19 genotype status.
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Affiliation(s)
- Masaki Murata
- Department of Gastroenterology, National Hospital Organization, Kyoto Medical Center, Kyoto, 612-8555, Japan
| | - Mitsushige Sugimoto
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, 6-7-1, Nishishinjuku, Shinjuku-ku, Tokyo, 160-0023, Japan.
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Risk of hemorrhage and stricture significantly increases in elderly patients with proton pump inhibitor (PPI)-resistant reflux esophagitis. Esophagus 2020; 17:87-91. [PMID: 31679094 DOI: 10.1007/s10388-019-00702-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2019] [Accepted: 10/27/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND To examine the clinical characteristics, including complications, of patients older than 75 years of age with proton pump inhibitor-resistant reflux esophagitis. METHODS Patients who were resistant to standard-dose proton pump inhibitors were enrolled in the present study. Eligible patients (n = 26) were divided into those who were older (n = 11) and younger (n = 15) than 75 years of age. Clinical characteristics including complications (hemorrhage and stricture), body mass index, the severity of reflux esophagitis, Helicobactor pylori infection, gastric mucosal atrophy, hiatal hernia, kyphosis, and the use of antithrombotic agents were examined. The efficacy of 20 mg vonoprazan for proton pump inhibitor-resistant reflux esophagitis was also investigated. RESULTS The severity of reflux esophagitis was significantly higher in the elderly group than in the non-elderly group. No other significant differences were observed between the groups. The proportion of patients with hemorrhage was significantly larger in the elderly group than in the non-elderly group. Similarly, the proportion of patients with stricture was significantly larger in the elderly group than in the non-elderly group. Nine out of 10 patients in the elderly group and all patients in the non-elderly group achieved healing after the 4-week administration of 20 mg vonoprazan. No significant differences were observed in healing rates between the groups. CONCLUSION Among patients with proton pump inhibitor-resistant reflux esophagitis, the rates of severe reflux esophagitis and complications (hemorrhage and/or stricture) were significantly higher in elderly patients than in non-elderly patients. Regardless of age, 20 mg vonoprazan was effective for proton pump inhibitor-resistant reflux esophagitis.
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Efficacy of long-term maintenance therapy with 10-mg vonoprazan for proton pump inhibitor-resistant reflux esophagitis. Esophagus 2019; 16:377-381. [PMID: 31119492 DOI: 10.1007/s10388-019-00676-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2019] [Accepted: 05/14/2019] [Indexed: 02/03/2023]
Abstract
BACKGROUND To investigate the efficacy of long-term (52 weeks) maintenance therapy by 10-mg vonoprazan administration for proton pump inhibitor-resistant reflux esophagitis continued from the preceding study. METHODS Sixteen patients with proton pump inhibitor-resistant reflux esophagitis (mean age 70.9 years, eight males) in whom endoscopic healing was achieved by 20-mg vonoprazan administration for 4 weeks and maintenance of remission was maintained by 10-mg vonoprazan administration for 8 weeks were enrolled. Endoscopy was performed at 52 weeks after the initiation of maintenance therapy with 10-mg vonoprazan to evaluate whether there was any recurrence of reflux esophagitis. Changes in the gastric mucosa were investigated at 52 weeks. Symptoms were assessed using the frequency scale for the symptoms of gastroesophageal reflux disease and the fast gastrin level at 8 and 52 weeks following the maintenance therapy. RESULTS Endoscopic remission was maintained at 52 weeks in 15 (93.8%) of the 16 patients with proton pump inhibitor-resistant reflux esophagitis. One patient relapsed with grade C of reflux esophagitis. There were no significant differences in the symptom score at 8 and 52 weeks, nor the gastrin level at 8 and 52 weeks. There was no change in the stomach on endoscopy at 52 weeks. CONCLUSION Long-term maintenance therapy by 10-mg vonoprazan administration is very effective for proton pump inhibitor-resistant reflux esophagitis patients in whom endoscopic healing was maintained by 8 weeks maintenance therapy with 10-mg vonoprazan administration.
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Jhun EH, Apfelbaum JL, Dickerson DM, Shahul S, Knoebel R, Danahey K, Ratain MJ, O’Donnell PH. Pharmacogenomic considerations for medications in the perioperative setting. Pharmacogenomics 2019; 20:813-827. [PMID: 31411557 PMCID: PMC6949515 DOI: 10.2217/pgs-2019-0040] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 05/08/2019] [Indexed: 11/21/2022] Open
Abstract
Several high-profile examples of adverse outcomes from medications used in the perioperative setting are well known (e.g., malignant hyperthermia, prolonged apnea, respiratory depression, inadequate analgesia), leading to an increased understanding of genetic susceptibilities underlying these risks. Pharmacogenomic information is increasingly being utilized in certain areas of medicine. Despite this, routine preoperative genetic screening to inform medication risk is not yet standard practice. In this review, we assess the current readiness of pharmacogenomic information for clinical consideration for several common perioperative medications, including description of key pharmacogenes, pharmacokinetic implications and potential clinical outcomes. The goal is to highlight medications for which emerging or considerable pharmacogenomic information exists and identify areas for future potential research.
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Affiliation(s)
- Ellie H Jhun
- Committee on Clinical Pharmacology & Pharmacogenomics, University of Chicago, Chicago, IL, 60637, USA
- Current affiliation: Department of Pharmacogenetics, Base10 Genetics, Chicago, IL 60603, USA
| | - Jeffrey L Apfelbaum
- Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL 60637, USA
| | - David M Dickerson
- Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL 60637, USA
- Current affiliation: Northshore University Health System, Evanston, IL 60201, USA
| | - Sajid Shahul
- Department of Anesthesia & Critical Care, University of Chicago, Chicago, IL 60637, USA
| | - Randall Knoebel
- Department of Pharmacy, University of Chicago Medicine, Chicago, IL 60637, USA
| | - Keith Danahey
- Center for Personalized Therapeutics, University of Chicago, Chicago, IL 60637, USA
- Center for Research Informatics, University of Chicago, Chicago, IL 60637, USA
| | - Mark J Ratain
- Committee on Clinical Pharmacology & Pharmacogenomics, University of Chicago, Chicago, IL, 60637, USA
- Center for Personalized Therapeutics, University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
| | - Peter H O’Donnell
- Committee on Clinical Pharmacology & Pharmacogenomics, University of Chicago, Chicago, IL, 60637, USA
- Center for Personalized Therapeutics, University of Chicago, Chicago, IL 60637, USA
- Department of Medicine, University of Chicago, Chicago, IL 60637, USA
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12
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Suzuki T, Kagami T, Uotani T, Yamade M, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Miyajima H, Furuta T. Comparison of effect of an increased dosage of vonoprazan versus vonoprazan plus lafutidine on gastric acid inhibition and serum gastrin. Eur J Clin Pharmacol 2018; 74:45-52. [PMID: 28986609 DOI: 10.1007/s00228-017-2324-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Accepted: 08/21/2017] [Indexed: 12/16/2022]
Abstract
BACKGROUND Vonoprazan, a novel potassium-competitive acid blocker, elicits potent acid inhibition and hypergastrinemia at a dose of 20 mg. Its recommended maintenance dose for gastro-esophageal reflux disease is 10 mg, which is sometimes insufficient for preventing nocturnal acid breakthrough (NAB). Concomitant use of a histamine 2 receptor antagonist (H2RA) is effective for NAB. However, further acid inhibition by addition of H2RA has concern of hypergastrinemia again. Lafutidine (H2RA) is known to stimulate somatostatin release. AIMS The aim of this study is to compare the levels of acid inhibition and serum gastrin attained by addition of lafutidine to vonoprazan 10 mg with levels after a dose increase of vonoprazan from 10 to 20 mg. METHODS Thirteen healthy volunteers underwent 24-h intragastric pH monitoring and serum gastrin measurements on day 7 of three different regimens: vonoprazan 10 mg, vonoprazan 10 mg plus lafutidine 10 mg, and vonoprazan 20 mg. RESULTS Median pH 4 holding time ratios (range) by vonoprazan 10 mg, vonoprazan 10 mg plus lafutidine 10 mg, and vonoprazan 20 mg were 82% (47-88%), 88% (76-93%), and 99% (95-100%) while those at nighttime from 10 p.m. to 8 a.m. were 94% (29-100%), 100% (95-100%), and 100%, respectively. The incidences of NAB with vonoprazan 10 mg, vonoprazan plus lafutidine, and vonoprazan 20 mg were 38, 8, and 0%, respectively. Respective serum gastrin levels were 420 (173-508), 323 (196-521), and 504 (400-812) pg/ml. CONCLUSION Addition of lafutidine 10 mg to vonoprazan 10 mg achieved sufficient acid inhibition, especially at nighttime, without further increase of serum gastrin levels.
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Affiliation(s)
- Takahiro Suzuki
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takuma Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Uotani
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Department of Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
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13
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Toda R, Miyagawa T, Masuda Y, Hoshino Y, Yoshii K, Hirayama M, Shibuya M, Kawabata Y. Mass balance and metabolism of Z-215, a novel proton pump inhibitor, in healthy volunteers. Xenobiotica 2017; 48:1006-1020. [PMID: 29092680 DOI: 10.1080/00498254.2017.1390625] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
The human mass balance of [14 C]Z-215, a novel proton pump inhibitor, was characterised in six healthy male volunteers following single oral administration of [14 C]Z-215 (20 mg, 3.7 MBq) to determine the elimination pathway of Z-215 and the distribution of its metabolites in plasma, urine, and faeces (NCT02618629). [14 C]Z-215 was rapidly absorbed, with a Cmax of 434 ng/mL at 0.38 h for Z-215 and 732 ng eq./mL at 0.5 h for total radioactivity. Means of 59.61% and 31.36% of the administered radioactive dose were excreted in urine and faeces, respectively, within 168 h post-dose. The majority of the dose was recovered within 24 h in urine and 96 h in faeces. Unchanged Z-215 was excreted in urine at trace levels but was not detected in faeces. The main components in plasma were Z-215 and Z-215 sulphone, accounting for 29.8% and 13.3% of the total circulating radioactivity, respectively. Additionally, Z-215 was metabolised through oxidation, reduction and conjugation. Our in vitro Z-215 metabolism study showed that the major isozyme contributing to the oxidation of Z-215, including the formation of Z-215 sulphone, was CYP3A4. In conclusion, Z-215 is well absorbed in humans and primarily eliminated via metabolism, where CYP3A4 plays an important role.
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Affiliation(s)
- Ryoko Toda
- a Central Research Laboratories, Zeria Pharmaceutical Co., Ltd , Kumagaya , Saitama , Japan and
| | - Tomoharu Miyagawa
- b Clinical Research, Research & Development, Zeria Pharmaceutical Co., Ltd , Chuo-ku , Tokyo , Japan
| | - Yuka Masuda
- b Clinical Research, Research & Development, Zeria Pharmaceutical Co., Ltd , Chuo-ku , Tokyo , Japan
| | - Yusuke Hoshino
- a Central Research Laboratories, Zeria Pharmaceutical Co., Ltd , Kumagaya , Saitama , Japan and
| | - Kazuyoshi Yoshii
- a Central Research Laboratories, Zeria Pharmaceutical Co., Ltd , Kumagaya , Saitama , Japan and
| | - Masamichi Hirayama
- a Central Research Laboratories, Zeria Pharmaceutical Co., Ltd , Kumagaya , Saitama , Japan and
| | - Minaka Shibuya
- a Central Research Laboratories, Zeria Pharmaceutical Co., Ltd , Kumagaya , Saitama , Japan and
| | - Yoshihiro Kawabata
- a Central Research Laboratories, Zeria Pharmaceutical Co., Ltd , Kumagaya , Saitama , Japan and
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14
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Nuki Y, Umeno J, Washio E, Maehata Y, Hirano A, Miyazaki M, Kobayashi H, Kitazono T, Matsumoto T, Esaki M. The influence of CYP2C19 polymorphisms on exacerbating effect of rabeprazole in celecoxib-induced small bowel injury. Aliment Pharmacol Ther 2017; 46:331-336. [PMID: 28481007 DOI: 10.1111/apt.14134] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2016] [Revised: 01/20/2017] [Accepted: 04/14/2017] [Indexed: 12/12/2022]
Abstract
BACKGROUND Simultaneous use of proton pump inhibitors (PPIs) has been shown to increase the risk of nonsteroidal anti-inflammatory drug (NSAID)-induced small bowel injury. AIM To investigate whether polymorphisms of the cytochrome P450 2C19 gene (CYP2C19), encoding a key metabolising enzyme for PPIs, are associated with small bowel injury induced by celecoxib in combination with the PPI rabeprazole. METHODS Study participants included 55 healthy Japanese volunteers, who participated in the PPI-NSAID Kyushu University Study using video capsule endoscopy. For 2 weeks, 26 subjects were treated with celecoxib plus rabeprazole (rabeprazole group), and 29 subjects received celecoxib plus placebo (placebo group). All subjects were genotyped for CYP2C19 using real-time fluorescent polymerase chain reaction. Subjects were sub-classified as poor metabolizers or extensive metabolizers. The incidence and number of small bowel injuries were compared between poor metabolizers and extensive metabolizers in each group. RESULTS In the rabeprazole group, the incidence of small bowel injuries was significantly higher in poor metabolizers than in extensive metabolizers (85.7% vs 31.6%, P=.026). The number of mucosal injuries in the rabeprazole group was also significantly higher in poor metabolizers compared with extensive metabolizers (median [range] 3 [0-31] vs 0 [0-7], P=.01). In addition, we found a significant interaction between CYP2C19 genotype and concomitant use of rabeprazole in subjects at risk for celecoxib-induced small bowel injury. CONCLUSIONS The CYP2C19 genotype might be associated with the risk of small bowel injury when celecoxib is combined with rabeprazole.
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Affiliation(s)
- Y Nuki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - J Umeno
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - E Washio
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Y Maehata
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - A Hirano
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - M Miyazaki
- Division of Gastroenterology, International University of Health and Welfare Fukuoka Sanno Hospital, Fukuoka, Japan
| | - H Kobayashi
- Division of Gastroenterology, International University of Health and Welfare Fukuoka Sanno Hospital, Fukuoka, Japan
| | - T Kitazono
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - T Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - M Esaki
- Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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15
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Kawami N, Takenouchi N, Umezawa M, Hoshino S, Hanada Y, Hoshikawa Y, Sano H, Hoshihara Y, Nomura T, Uchida E, Iwakiri K. Pathogenesis of Double-Dose Proton Pump Inhibitor-Resistant Non-Erosive Reflux Disease, and Mechanism of Reflux Symptoms and Gastric Acid Secretion-Suppressive Effect in the Presence or Absence of Helicobacter pylori Infection. Digestion 2017; 95:140-145. [PMID: 28161707 DOI: 10.1159/000455834] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 01/05/2017] [Indexed: 02/04/2023]
Abstract
BACKGROUND Various mechanisms have been suggested to be responsible for contributing to the occurrence of proton pump inhibitor (PPI)-resistant non-erosive reflux disease (NERD). The aims of this study were to clarify the pathogenesis of PPI-resistant NERD. METHODS Fifty-three patients with NERD, who had persistent reflux symptoms despite taking double-dose PPI, were included in this study. After excluding eosinophilic esophagitis (EoE) and primary esophageal motility disorder, esophageal impedance-pH monitoring was carried out. In symptom index (SI)-positive patients, the mechanism of SI positivity and the percent time with intragastric pH >4 were investigated according to the presence or absence of Helicobacter pylori infection. RESULTS One of the 53 patients had EoE, and 4 had primary esophageal motility disorder. Twenty-three and 2 patients were SI-positive for liquid and gas-only reflux respectively. Of 17 SI-positive, H. pylori-negative patients, 5 were SI-positive for acid reflux, whereas all of the H. pylori-positive patients were SI-positive for non-acid reflux. The percent time with intragastric pH >4 was significantly lower in the H. pylori-negative patients than in the H. pylori-positive patients. CONCLUSIONS The pathogenesis of double-dose PPI-resistant NERD was identified in 57%. In some of H. pylori-negative patients, acid-related symptoms were observed. However, in H. pylori-positive patients, these symptoms were excluded by taking double-dose PPI.
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Affiliation(s)
- Noriyuki Kawami
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Tokyo, Japan
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16
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Kawai T, Hirayama Y, Oguchi A, Ishii F, Matushita M, Kitayama N, Morishita S, Hiratsuka N, Ohata K, Konishi H, Kishino M, Nakamura S. Effects of rikkunshito on quality of life in patients with gastroesophageal reflux disease refractory to proton pump inhibitor therapy. J Clin Biochem Nutr 2017. [PMID: 28366995 DOI: 10.3164/jcbn.16.77] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
We investigated the effects of rikkunshito, in combination with a proton pump inhibitor, on symptoms and quality of life in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. The subjects were 47 patients with gastroesophageal reflux disease with residual symptoms such as heartburn following 8 weeks of proton pump inhibitor therapy. We administered these subjects rikkunshito in combination with a proton pump inhibitor for 6-8 weeks. We scored their symptoms of heartburn, fullness, abdominal discomfort, and abdominal pain, and surveyed their quality of life using the Reflux Esophagitis Symptom Questionnaire, comprising questions concerning daily activities, meals (changes in amount and favorite foods), and sleep (getting to sleep and early morning waking). Improvement was seen in all symptoms, and quality of life scores for meals and sleep also improved. These results indicate that combination therapy with rikkunshito and a proton pump inhibitor improves quality of life related to eating and sleep in patients with patients with proton pump inhibitor-refractory gastroesophageal reflux disease.
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Affiliation(s)
- Takashi Kawai
- Gastroenterological Endoscopy, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Yoji Hirayama
- Department of General Medicine and Primary Care, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Aiko Oguchi
- Shinjuku NS Building Clinic, 2-4-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0820, Japan
| | - Fumi Ishii
- Shinjuku Mitsui Building Clinic, 2-1-1 Nishishinjuku, Shinjuku-ku, Tokyo 183-0410, Japan
| | - Masanao Matushita
- Department of Internal Medicine, International Catholic Hospital, 2-5-1 Nakaochiai, Shinjuku-ku, Tokyo 161-8521, Japan
| | - Naoya Kitayama
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Shinji Morishita
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Noboru Hiratsuka
- Hiratsuka Gastroenterological Hospital Shinjuku Center Clinic, 1-25-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0690, Japan
| | - Ken Ohata
- Department of Gastroenterology, NTT Medical Center Tokyo, 5-9-22 Higashi-gotanda, Shinagawa-ku, Tokyo 141-8625, Japan
| | - Hiroyuki Konishi
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Maiko Kishino
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Shinichi Nakamura
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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17
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Kawai T, Hirayama Y, Oguchi A, Ishii F, Matushita M, Kitayama N, Morishita S, Hiratsuka N, Ohata K, Konishi H, Kishino M, Nakamura S. Effects of rikkunshito on quality of life in patients with gastroesophageal reflux disease refractory to proton pump inhibitor therapy. J Clin Biochem Nutr 2017; 60:143-145. [PMID: 28366995 PMCID: PMC5370532 DOI: 10.3164/jcbn.16-77] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2016] [Accepted: 09/14/2016] [Indexed: 12/24/2022] Open
Abstract
We investigated the effects of rikkunshito, in combination with a proton pump inhibitor, on symptoms and quality of life in patients with proton pump inhibitor-refractory gastroesophageal reflux disease. The subjects were 47 patients with gastroesophageal reflux disease with residual symptoms such as heartburn following 8 weeks of proton pump inhibitor therapy. We administered these subjects rikkunshito in combination with a proton pump inhibitor for 6–8 weeks. We scored their symptoms of heartburn, fullness, abdominal discomfort, and abdominal pain, and surveyed their quality of life using the Reflux Esophagitis Symptom Questionnaire, comprising questions concerning daily activities, meals (changes in amount and favorite foods), and sleep (getting to sleep and early morning waking). Improvement was seen in all symptoms, and quality of life scores for meals and sleep also improved. These results indicate that combination therapy with rikkunshito and a proton pump inhibitor improves quality of life related to eating and sleep in patients with patients with proton pump inhibitor-refractory gastroesophageal reflux disease.
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Affiliation(s)
- Takashi Kawai
- Gastroenterological Endoscopy, Tokyo Medical University, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Yoji Hirayama
- Department of General Medicine and Primary Care, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
| | - Aiko Oguchi
- Shinjuku NS Building Clinic, 2-4-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0820, Japan
| | - Fumi Ishii
- Shinjuku Mitsui Building Clinic, 2-1-1 Nishishinjuku, Shinjuku-ku, Tokyo 183-0410, Japan
| | - Masanao Matushita
- Department of Internal Medicine, International Catholic Hospital, 2-5-1 Nakaochiai, Shinjuku-ku, Tokyo 161-8521, Japan
| | - Naoya Kitayama
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Shinji Morishita
- Department of Gastroenterology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-0821, Japan
| | - Noboru Hiratsuka
- Hiratsuka Gastroenterological Hospital Shinjuku Center Clinic, 1-25-1 Nishishinjuku, Shinjuku-ku, Tokyo 163-0690, Japan
| | - Ken Ohata
- Department of Gastroenterology, NTT Medical Center Tokyo, 5-9-22 Higashi-gotanda, Shinagawa-ku, Tokyo 141-8625, Japan
| | - Hiroyuki Konishi
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Maiko Kishino
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
| | - Shinichi Nakamura
- Department of Gastroenterology, Tokyo Women's Medical University Hospital, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan
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18
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Agrawal M, Kumar A, Gupta A. Conformational stability, spectroscopic signatures and biological interactions of proton pump inhibitor drug lansoprazole based on structural motifs. RSC Adv 2017. [DOI: 10.1039/c7ra00130d] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Structure based biological and chemical properties of lansoprazole (LSP) have been studied by spectroscopic and quantum chemical methods.
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Affiliation(s)
- Megha Agrawal
- Department of Applied Physics
- Faculty of Engineering & Technology
- M. J. P. Rohilkhand University
- Bareilly
- India
| | - Amit Kumar
- Department of Applied Physics
- Faculty of Engineering & Technology
- M. J. P. Rohilkhand University
- Bareilly
- India
| | - Archana Gupta
- Department of Applied Physics
- Faculty of Engineering & Technology
- M. J. P. Rohilkhand University
- Bareilly
- India
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19
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Stingl JC, Just KS, Kaumanns K, Schurig-Urbaniak M, Scholl C, von Mallek D, Brockmöller J. [Personalized drug therapy based on genetics. Possibilities and examples from clinical practice]. Internist (Berl) 2016; 57:289-97. [PMID: 26830424 DOI: 10.1007/s00108-015-0013-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
BACKGROUND Pharmacogenetics are an important component in the individualization of treatment; however, pharmacogenetic diagnostics have so far not been used to any great extent in clinical practice. A consistent consideration of individual patient factors, such as pharmacogenetics may help to improve drug therapy and increase individual safety and efficacy aspects. OBJECTIVE A brief summary of structures and effects of genetic variations on drug efficacy is presented. Some frequently prescribed pharmaceuticals are specified. Furthermore, the feasibility of pharmacogenetic diagnostics and dose recommendations in the clinical practice are described. CURRENT DATA The European Medicines Agency (EMA) as the European approval authority has already extended the drug labels of more than 70 pharmaceuticals by information on pharmacogenetic biomarkers and the U.S. Food and Drug Administration (FDA) more than 150. This is a crucial step towards targeted medicine. Guidelines on dose and therapy adjustments are provided by the Clinical Pharmacogenetics Implementation Consortium of the Pharmacogenomics Research Network. CONCLUSION It is fundamental to consider individual patient factors for successful drug therapy. Dose and therapy recommendations based on pharmacogenetic diagnostics are highly important for individualization as well as improvement of safety and efficiency of drug therapy.
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Affiliation(s)
- J C Stingl
- Abteilung Forschung, Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Deutschland.
- Zentrum für Translationale Medizin, Medizinische Fakultät, Universität Bonn, Bonn, Deutschland.
| | - K S Just
- Abteilung Forschung, Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Deutschland
- Zentrum für Translationale Medizin, Medizinische Fakultät, Universität Bonn, Bonn, Deutschland
| | - K Kaumanns
- Abteilung Forschung, Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Deutschland
- Zentrum für Translationale Medizin, Medizinische Fakultät, Universität Bonn, Bonn, Deutschland
| | - M Schurig-Urbaniak
- Abteilung Forschung, Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Deutschland
- Zentrum für Translationale Medizin, Medizinische Fakultät, Universität Bonn, Bonn, Deutschland
| | - C Scholl
- Abteilung Forschung, Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Deutschland
- Zentrum für Translationale Medizin, Medizinische Fakultät, Universität Bonn, Bonn, Deutschland
| | - D von Mallek
- Abteilung Forschung, Bundesinstitut für Arzneimittel und Medizinprodukte, Kurt-Georg-Kiesinger-Allee 3, 53175, Bonn, Deutschland
- Zentrum für Translationale Medizin, Medizinische Fakultät, Universität Bonn, Bonn, Deutschland
| | - J Brockmöller
- Institut für Klinische Pharmakologie, Universität Göttingen, Göttingen, Deutschland
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Chueca E, Apostolova N, Esplugues JV, García-González MA, Lanas Á, Piazuelo E. Proton Pump Inhibitors Display Antitumor Effects in Barrett's Adenocarcinoma Cells. Front Pharmacol 2016; 7:452. [PMID: 27932981 PMCID: PMC5122752 DOI: 10.3389/fphar.2016.00452] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 11/11/2016] [Indexed: 12/14/2022] Open
Abstract
Recent evidence has reported that proton pump inhibitors (PPIs) can exert antineoplastic effects through the disruption of pH homeostasis by inhibiting vacuolar ATPase (H+-VATPase), a proton pump overexpressed in several tumor cells, but this aspect has not been deeply investigated in EAC yet. In the present study, the expression of H+-VATPase was assessed through the metaplasia-dysplasia-adenocarcinoma sequence in Barrett's esophagus (BE) and the antineoplastic effects of PPIs and cellular mechanisms involved were evaluated in vitro. H+-VATPase expression was assessed by immunohistochemistry in paraffined-embedded samples or by immunofluorescence in cultured BE and EAC cell lines. Cells were treated with different concentrations of PPIs and parameters of citotoxicity, oxidative stress, and autophagy were evaluated. H+-VATPase expression was found in all biopsies and cell lines evaluated, showing differences in the location of the pump between the cell lines. Esomeprazole inhibited proliferation and cell invasion and induced apoptosis of EAC cells. Production of reactive oxygen species (ROS) seemed to be involved in the cytotoxic effects observed since the addition of N-acetylcysteine significantly reduced esomeprazole-induced apoptosis in EAC cells. Esomeprazole also reduced intracellular pH of tumor cells, whereas only disturbed the mitochondrial membrane potential in OE33 cells. Esomeprazole induced autophagy in both EAC cells, but also triggered a blockade in autophagic flux in the metastatic cell line. These data provide in vitro evidence supporting the potential use of PPIs as novel antineoplastic drugs for EAC and also shed some light on the mechanisms that trigger PPIs cytotoxic effects, which differ upon the cell line evaluated.
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Affiliation(s)
- Eduardo Chueca
- CIBERehdMadrid, Spain; Instituto de Investigación Sanitaria AragónZaragoza, Spain
| | - Nadezda Apostolova
- CIBERehdMadrid, Spain; Department of Pharmacology, University of ValenciaValencia, Spain
| | - Juan V Esplugues
- CIBERehdMadrid, Spain; Department of Pharmacology, University of ValenciaValencia, Spain
| | - María A García-González
- CIBERehdMadrid, Spain; Instituto de Investigación Sanitaria AragónZaragoza, Spain; CIBA, Instituto Aragonés de Ciencias de la SaludZaragoza, Spain
| | - Ángel Lanas
- CIBERehdMadrid, Spain; Instituto de Investigación Sanitaria AragónZaragoza, Spain; Department of Medicine, Psychiatry and Dermatology, University of ZaragozaZaragoza, Spain
| | - Elena Piazuelo
- CIBERehdMadrid, Spain; Instituto de Investigación Sanitaria AragónZaragoza, Spain; CIBA, Instituto Aragonés de Ciencias de la SaludZaragoza, Spain
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21
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Iwakiri K, Kinoshita Y, Habu Y, Oshima T, Manabe N, Fujiwara Y, Nagahara A, Kawamura O, Iwakiri R, Ozawa S, Ashida K, Ohara S, Kashiwagi H, Adachi K, Higuchi K, Miwa H, Fujimoto K, Kusano M, Hoshihara Y, Kawano T, Haruma K, Hongo M, Sugano K, Watanabe M, Shimosegawa T. Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015. J Gastroenterol 2016; 51:751-767. [PMID: 27325300 DOI: 10.1007/s00535-016-1227-8] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2016] [Accepted: 05/17/2016] [Indexed: 02/04/2023]
Abstract
As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8 weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.
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Affiliation(s)
- Katsuhiko Iwakiri
- Department of Gastroenterology, Nippon Medical School Graduate School of Medicine, Sendagi 1-1-5, Bunkyo-ku, Tokyo, 113-8603, Japan.
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan.
| | - Yoshikazu Kinoshita
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yasuki Habu
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Tadayuki Oshima
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Noriaki Manabe
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yasuhiro Fujiwara
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Akihito Nagahara
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Osamu Kawamura
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Ryuichi Iwakiri
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Soji Ozawa
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Kiyoshi Ashida
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Shuichi Ohara
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Hideyuki Kashiwagi
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Kyoichi Adachi
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Kazuhide Higuchi
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Hiroto Miwa
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Kazuma Fujimoto
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Motoyasu Kusano
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Yoshio Hoshihara
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Tatsuyuki Kawano
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Ken Haruma
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Michio Hongo
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Kentaro Sugano
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Mamoru Watanabe
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
| | - Tooru Shimosegawa
- Guidelines Committee for Creating and Evaluating the "Evidence-based Clinical Practice Guidelines for Gastroesophageal Reflux Disease", the Japanese Society of Gastroenterology (JSGE), K-18 Building 8F, 8-9-13, Ginza, Chuo, Tokyo, 104-0061, Japan
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22
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Yamasaki H, Kawaguchi N, Nonaka M, Takahashi J, Morohashi A, Hirabayashi H, Moriwaki T, Asahi S. In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker. Xenobiotica 2016; 47:1027-1034. [DOI: 10.1080/00498254.2016.1203505] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Hitomi Yamasaki
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Naohiro Kawaguchi
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Masami Nonaka
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Junzo Takahashi
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Akio Morohashi
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Hideki Hirabayashi
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Toshiya Moriwaki
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Satoru Asahi
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
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23
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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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24
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Kagami T, Sahara S, Ichikawa H, Uotani T, Yamade M, Sugimoto M, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Miyajima H, Furuta T. Potent acid inhibition by vonoprazan in comparison with esomeprazole, with reference to CYP2C19 genotype. Aliment Pharmacol Ther 2016; 43:1048-1059. [PMID: 26991399 DOI: 10.1111/apt.13588] [Citation(s) in RCA: 169] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 01/08/2016] [Accepted: 02/26/2016] [Indexed: 12/18/2022]
Abstract
BACKGROUND Acid inhibitory effects of proton pump inhibitors (PPIs) are influenced by CYP2C19 genotype. In contrast, the potent acid inhibition of vonoprazan is not influenced by CYP2C19 genotype. AIM To compare the acid inhibitory effects of vonoprazan and esomeprazole in relation to CYP2C19 genotype. METHODS Twenty-eight healthy Japanese volunteers [7 CYP2C19 poor metabolisers (PMs), 11 intermediate metabolisers (IMs) and 10 rapid metabolisers (RMs)] received four different regimens in a randomised crossover manner: (i) vonoprazan 20 mg twice daily (b.d.), (ii) vonoprazan 20 mg daily, (iii) esomeprazole 20 mg b.d. and (iv) esomeprazole 20 mg daily. The timing of each dosing was 1 h before a meal. Twenty-four-hour intragastric pH monitoring was performed on day 7 on each regimen. RESULTS In the overall genotype group, pH ≥4 holding time ratios (pH 4 HTRs) with vonoprazan b.d., vonoprazan daily, esomeprazole b.d. and esomeprazole daily were 100%, 95%, 91%, and 68% respectively. pH 5 HTRs were 99%, 91%, 84% and 54% respectively. Vonoprazan b.d. potently suppressed acid for 24 h, and was significantly superior to other regimens irrespective of CYP2C19 genotype. Vonoprazan daily was equivalent to esomeprazole b.d. in IMs and PMs, but superior in RMs. CYP2C19 genotype-dependent differences were observed in esomeprazole daily but not in vonoprazan b.d. or daily. CONCLUSION Vonoprazan 20 mg b.d. inhibits acid irrespective of CYP2C19 genotype, more potently than esomeprazole 20 mg b.d., pH 4 and 5 holding time ratios reached 100% and 99%, respectively.
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Affiliation(s)
- T Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - S Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - H Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - T Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - M Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - M Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Y Hamaya
- Department of Clinical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - M Iwaizumi
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - S Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - K Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - H Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - T Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
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25
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Ichikawa H, Sugimoto M, Sugimoto K, Andoh A, Furuta T. Rapid metabolizer genotype of CYP2C19 is a risk factor of being refractory to proton pump inhibitor therapy for reflux esophagitis. J Gastroenterol Hepatol 2016; 31:716-726. [PMID: 26580676 DOI: 10.1111/jgh.13233] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Revised: 08/14/2015] [Accepted: 11/10/2015] [Indexed: 12/11/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are mainly metabolized by cytochrome P450 2C19 (CYP2C19) and used as the first-line therapy for gastroesophageal reflux disease (GERD). However, while several studies have examined the influence of CYP2C19 polymorphism on GERD treatment with PPIs, most have had small sample sizes and were conducted in a single center. Here, we used meta-analysis to investigate whether or not the CYP2C19 rapid metabolizer (RM) genotype is a risk factor for GERD patients being refractory to PPI therapy. METHODS PubMed and other electronic databases were systematically searched up to August 2014 using the following terms: "GERD and CYP2C19", "esophagitis and CYP2C19", and "non-erosive reflux disease and CYP2C19." Searches were limited to publications in English, and two investigators evaluated eligible studies and extracted data. RESULTS The total efficacy rate of PPIs for GERD, including reflux esophagitis (RE) and non-erosive reflux disease, was 56.4% (95% confidence interval [CI]; 53.9-58.9%, 870/1543) in intention-to-treat analysis and 63.8% (95%CI; 61.3-66.2%, 950/1489) in per-protocol analysis. Efficacy rates varied significantly between CYP2C19 genotypes (intention-to-treat analysis: RMs, 52.2% [315/604]; intermediate metabolizers, 56.7% [298/526]; poor metabolizers [PMs], 61.3% [138/225]; P = 0.047). Among RE patients, CYP2C19 RMs had an increased risk of being refractory to PPI therapy compared with PMs (odds ratio: 1.661, 95% CI: 1.023-2.659, P = 0.040). CONCLUSIONS The present meta-analysis demonstrates that CYP2C19 RMs with RE have an increased risk of being refractory to PPI therapy compared with PMs. Individualized dosing regimen with PPIs based on CYP2C19 genotype might be a valid therapeutic strategy for overcoming insufficient gastric acid inhibition.
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Affiliation(s)
- Hitomi Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
- Division of Digestive Endoscopy, Shiga University of Medical Science Hospital, Otsu, Shiga, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Akira Andoh
- Department of Gastroenterology, Shiga University of Medical Science, Otsu, Shiga, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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26
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Kagami T, Sugimoto M, Ichikawa H, Sahara S, Uotani T, Yamade M, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Miyajima H, Furuta T. One-day front-loading with four doses of rabeprazole followed by a standard twice-daily regimen provides sufficient acid inhibition in extensive metabolizers of CYP2C19. Eur J Clin Pharmacol 2015; 71:1467-1475. [PMID: 26427705 DOI: 10.1007/s00228-015-1941-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2015] [Accepted: 09/04/2015] [Indexed: 11/24/2022]
Abstract
BACKGROUND Four times daily dosing (qid) with a proton pump inhibitor can cause rapid increase in intragastric pH. We investigated the efficacy of the front-loading with rabeprazole 10 mg qid on a subsequent regimen with rabeprazole 10 mg twice daily (bid) for 7 days in extensive metabolizers (EMs) of CYP2C19. METHODS Five EMs received three different 1-week regimens in a crossover manner as follows: (1) rabeprazole 10 mg bid for 7 days; (2) a front-loading regimen of rabeprazole (rabeprazole 10 mg qid on day 0 and bid on days 1 to 7); and (3) rabeprazole 10 mg qid for 7 days. Five intermediate metabolizers (IMs) and four poor metabolizers (PMs) received rabeprazole 10 mg bid regimen only. Twenty-four-hour intragastric pH-monitorings were performed on days 1, 4, and 7. Area under the intragastric pH-time curves (AUCs) from days 1 to 7 was calculated using 24-h median intragastric pHs on days 1, 4, and 7. RESULTS Twenty-four-hour intragastric pHs in the front-loading group on days 1, 4, and 7 were 5.1, 4.9, and 5.1, respectively. The median AUC with front-loading in EMs (34.4, pH·day) was significantly higher than that in EMs with rabeprazole 10 mg bid (30.74, p = 0.043). No statistically significant differences in median AUCs were noted among front-loading in EMs, rabeprazole 10 mg qid in EMs (37.2), rabeprazole 10 mg bid in IMs (37.3), and PMs (39.4). CONCLUSIONS The one-day front-loading regimen of rabeprazole 10 mg qid provided sufficient acid inhibition for 7 days, even in CYP2C19 EMs.
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Affiliation(s)
- Takuma Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hitomi Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Shu Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Department of Clinical Oncology, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1, Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
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27
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Mizuno H, Matsuhashi N, Sakaguchi M, Inoue S, Nakada K, Higuchi K, Haruma K, Joh T. Recent effectiveness of proton pump inhibitors for severe reflux esophagitis: the first multicenter prospective study in Japan. J Clin Biochem Nutr 2015; 57:233-238. [PMID: 26566310 PMCID: PMC4639585 DOI: 10.3164/jcbn.14-144] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 02/08/2015] [Indexed: 02/06/2023] Open
Abstract
Proton pump inhibitors are the first-line treatment for reflux esophagitis. Because severe reflux esophagitis has very low prevalence in Japan, little is known about the effectiveness of proton pump inhibitors in these patients. This prospective multicenter study assessed the effectiveness of proton pump inhibitors for severe reflux esophagitis in Japan. Patients with modified Los Angeles grade C or D reflux esophagitis were treated with daily omeprazole (10 or 20 mg), lansoprazole (15 or 30 mg), or rabeprazole (10, 20, or 40 mg) for 8 weeks. Healing was assessed endoscopically, with questionnaires administered before and after treatment to measure the extent of reflux and dyspepsia symptoms. Factors affecting healing rates, including patient characteristics and endoscopic findings, were analyzed. Of the 115 patients enrolled, 64 with grade C and 19 with grade D reflux esophagitis completed the study. The healing rate was 67.5% (56/83), with 15 of the other 27 patients (55.6%) improving to grade A or B. No patient characteristic or endoscopic comorbidity was significantly associated with healing rate. Reflux and dyspepsia symptoms improved significantly with treatment. The low healing rate suggests the need of endoscopic examination to assess healing of reflux esophagitis at the end of therapy. (UMIN000005271).
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Affiliation(s)
- Hideki Mizuno
- Department of Gastroenterology, Toyama City Hospital, 2-1 Imaizumihokubo-machi, Toyama 939-8511, Japan
| | - Nobuyuki Matsuhashi
- Department of Gastroenterology, NTT Medical Center Tokyo, 5-9-22 Higasigotanda, Shinagawa-ku, Tokyo 141-8625, Japan
| | - Masahiro Sakaguchi
- Department of Internal Medicine, Moriguchi Keijinkai Hospital, 2-47-12 Yakumohigashi-machi, Moriguchi-shi, Osaka 570-0021, Japan
| | - Syuji Inoue
- Department of Gastroenterology, National Hospital Organization Kochi Hospital, 1-2-25 Asakuranishi, Kochi 780-8077, Japan
| | - Koji Nakada
- Department of Surgery, The Jikei University School of Medicine, 3-25-8 Nishisinbashi, Minato-ku, Tokyo 105-8461, Japan
- Study Committee, GERD Society, 12 Floor, Oasaka-Nakanosima-Bill, 2-2-2 Nakanoshima, Kita-ku, Osaka 530-0005, Japan
| | - Kazuhide Higuchi
- Study Committee, GERD Society, 12 Floor, Oasaka-Nakanosima-Bill, 2-2-2 Nakanoshima, Kita-ku, Osaka 530-0005, Japan
- Second Department of Internal Medicine, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki-shi, Osaka 569-8686, Japan
| | - Ken Haruma
- Study Committee, GERD Society, 12 Floor, Oasaka-Nakanosima-Bill, 2-2-2 Nakanoshima, Kita-ku, Osaka 530-0005, Japan
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki-shi, Okayama 701-0192, Japan
| | - Takashi Joh
- Study Committee, GERD Society, 12 Floor, Oasaka-Nakanosima-Bill, 2-2-2 Nakanoshima, Kita-ku, Osaka 530-0005, Japan
- Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601, Japan
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Stingl JC, Welker S, Hartmann G, Damann V, Gerzer R. Where Failure Is Not an Option -Personalized Medicine in Astronauts. PLoS One 2015; 10:e0140764. [PMID: 26489089 PMCID: PMC4619198 DOI: 10.1371/journal.pone.0140764] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 09/30/2015] [Indexed: 11/17/2022] Open
Abstract
Drug safety and efficacy are highly variable among patients. Most patients will experience the desired drug effect, but some may suffer from adverse drug reactions or gain no benefit. Pharmacogenetic testing serves as a pre-treatment diagnostic option in situations where failure or adverse events should be avoided at all costs. One such situation is human space flight. On the international space station (ISS), a list of drugs is available to cover typical emergency settings, as well as the long-term treatment of common conditions for the use in self-medicating common ailments developing over a definite period. Here, we scrutinized the list of the 78 drugs permanently available at the ISS (year 2014) to determine the extent to which their metabolism may be affected by genetic polymorphisms, potentially requiring genotype-specific dosing or choice of an alternative drug. The purpose of this analysis was to estimate the potential benefit of pharmacogenetic diagnostics in astronauts to prevent therapy failure or side effects.
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Affiliation(s)
- Julia C. Stingl
- Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany
- Centre for Translational Medicine, University Bonn Medical Faculty, Bonn, Germany
- * E-mail:
| | - Susanne Welker
- Research Division, Federal Institute for Drugs and Medical Devices, Bonn, Germany
| | - Gunther Hartmann
- Institute for clinical chemistry and clinical pharmacology, University of Bonn, Bonn, Germany
| | - Volker Damann
- Space Medicine Office, European Space Agency, Cologne, Germany
| | - Ruppert Gerzer
- Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany
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Sahara S, Sugimoto M, Uotani T, Ichikawa H, Yamade M, Kagami T, Hamaya Y, Iwaizumi M, Osawa S, Sugimoto K, Miyajima H, Furuta T. Potent Gastric Acid Inhibition Over 24 Hours by 4-Times Daily Dosing of Esomeprazole 20 mg. Digestion 2015; 91:277-285. [PMID: 25924819 DOI: 10.1159/000381419] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 03/04/2015] [Indexed: 02/04/2023]
Abstract
BACKGROUND When administered at a standard dose, proton pump inhibitors (PPIs) do not always provide sufficient acid inhibition for all subjects, particularly in extensive metabolizers (EMs) of CYP2C19. Whether esomeprazole at a dose of 20 mg four times daily dosing (q.i.d.) can attain sufficient acid inhibition throughout 24 h in EMs remains unclear. We therefore investigated the efficacy of esomeprazole q.i.d. for acid inhibition. METHODS In a randomized cross-over design, 30 Helicobacter pylori-negative healthy young Japanese volunteers received esomeprazole at a dose of 20 mg two times a day (b.i.d.) or q.i.d. for 7 days. A pH monitoring was conducted before the trial as a control and on day 7 of both regimens. RESULTS Median pH values in the q.i.d. regimen were significantly higher than those with the b.i.d. regimen in EMs (b.i.d.: 5.3, q.i.d.: 6.6, p = 0.022), intermediate metabolizer (IM) (b.i.d.: 5.5, q.i.d.: 6.8, p = 0.005) and poor metabolizer (PM) (b.i.d.: 6.2, q.i.d.: 7.0, p = 0.047), respectively. Median pH with the b.i.d. regimen differed significantly by CYP2C19 genotypes (p = 0.004), but not the q.i.d. regimen (p = 0.384). CONCLUSION Esomeprazole q.i.d. achieved potent acid inhibition in all Helicobacter pylori-negative subjects, irrespective of CYP2C19 genotype, which might be one of the rescue regimens for patients' refractory to PPI treatment.
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Affiliation(s)
- Shu Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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30
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Evsyutina YV, Trukhmanov AS. [Inadequate response to proton pump inhibitor therapy: causes and patient management tactics]. TERAPEVT ARKH 2015; 87:85-89. [PMID: 25864356 DOI: 10.17116/terarkh201587285-89] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
The past decade has been marked by a considerable increase in the number of patients with gastroesophageal reflux disease and gastroduodenal ulcer who show an inadequate response to proton pump inhibitor (PPI) therapy. At the present time, most of the causes diminishing the response have been elucidated. Unfortunately, they cannot always be eliminated by drug therapy; nonetheless, rabeprazole has a number of advantages over other PPIs. The major causes of an inadequate response to PPI therapy are low treatment motivation; nocturnal gastric acid breakthroughs; genetically determined CYP polymorphism; chiefly nighttime symptoms of gastroesophageal reflux disease; non-acid refluxes; hypersensitive esophagus; overweight and obesity.
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Affiliation(s)
- Yu V Evsyutina
- Department of Internal Propedeutics, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia
| | - A S Trukhmanov
- Department of Internal Propedeutics, I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia
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31
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Avdeev VG. [Some issues of the diagnosis and treatment of gastroesophageal reflux disease]. TERAPEVT ARKH 2015. [PMID: 28635804 DOI: 10.17116/terarkh20158710120-124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The clinical inefficacy of proton pump inhibitors (PPIs) is very frequently encountered in nonerosive gastroesophageal reflux disease (NERD) in particular. Postprandial acid pocket, weak-acid or alkaline reflux, etc. are one of the causes of resistance to antisecretory drugs. Alginates serve as a good alternative to PPIs in treating NERD and gastroesophageal reflux in children and pregnant women. The alginate test may help diagnose NERD.
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Affiliation(s)
- V G Avdeev
- Department of Internal Medicine, Faculty of Fundamental Medicine, M.V. Lomonosov Moscow State University, Moscow, Russia
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32
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Sugimoto M, Shirai N, Nishino M, Kodaira C, Uotani T, Sahara S, Ichikawa H, Kagami T, Sugimoto K, Furuta T. Comparison of acid inhibition with standard dosages of proton pump inhibitors in relation to CYP2C19 genotype in Japanese. Eur J Clin Pharmacol 2014; 70:1073-1078. [PMID: 24996380 DOI: 10.1007/s00228-014-1713-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Accepted: 06/25/2014] [Indexed: 12/24/2022]
Abstract
INTRODUCTION The aim of therapeutic regimens using proton pump inhibitors (PPIs) in patients with acid-related diseases is to potently inhibit acid secretion for the full 24 h. However, optimum treatment is still unclear because the pharmacodynamics of PPIs differ among CYP2C19 genotypes and most of the previous studies have had loss of sample power. METHODS Using pH monitoring, we compared acid inhibition at standard dosage of omeprazole (20 mg, 50 times), lansoprazole (30 mg, 68 times), and rabeprazole (10 mg, 65 times) in Helicobacter pylori-negative healthy young Japanese volunteers. RESULTS Median pH with rabeprazole was 5.4 (3.3-7.5), which was significantly greater than with either omeprazole [4.4 (2.1-7.3)] or lansoprazole [4.8 (3.5-6.4)] (both P < 0.05). Median 24-h pH differed among the different CYP2C19 genotypes in all three PPIs. In CYP2C19 extensive metabolizers (EMs), the genotype that is refractory to PPI treatment, median pH with omeprazole, lansoprazole, and rabeprazole was 3.8 (2.1-4.4), 4.5 (3.5-5.3) and 4.8 (3.3-7.5), respectively. DISCUSSION Treatment with the selected PPIs at their standard dosages had difficulty maintaining acid inhibition for a full 24 h, especially in CYP2C19 EM. However, rabeprazole has the merit of less influence of CYP2C19 genotype compared with the other PPIs.
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Affiliation(s)
- Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan,
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Takahashi M, Saito T, Ito M, Tsukada C, Katono Y, Hosono H, Maekawa M, Shimada M, Mano N, Oda A, Hirasawa N, Hiratsuka M. Functional characterization of 21 CYP2C19 allelic variants for clopidogrel 2-oxidation. THE PHARMACOGENOMICS JOURNAL 2014; 15:26-32. [PMID: 25001882 DOI: 10.1038/tpj.2014.30] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/28/2014] [Revised: 03/30/2014] [Accepted: 05/22/2014] [Indexed: 11/09/2022]
Abstract
Genetic variations in cytochrome P450 2C19 (CYP2C19) contribute to interindividual variability in the metabolism of therapeutic agents such as clopidogrel. Polymorphisms in CYP2C19 are associated with large interindividual variations in the therapeutic efficacy of clopidogrel. This study evaluated the in vitro oxidation of clopidogrel by 21 CYP2C19 variants harboring amino acid substitutions. These CYP2C19 variants were heterologously expressed in COS-7 cells, and the kinetic parameters of clopidogrel 2-oxidation were estimated. Among the 21 CYP2C19 variants, 12 (that is, CYP2C19.5A, CYP2C19.5B, CYP2C19.6, CYP2C19.8, CYP2C19.9, CYP2C19.10, CYP2C19.14, CYP2C19.16, CYP2C19.19, CYP2C19.22, CYP2C19.24 and CYP2C19.25) showed no or markedly low activity compared with the wild-type protein CYP2C19.1B. This comprehensive in vitro assessment provided insights into the specific metabolic activities of CYP2C19 proteins encoded by variant alleles, and this may to be valuable when interpreting the results of in vivo studies.
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Affiliation(s)
- M Takahashi
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - T Saito
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - M Ito
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - C Tsukada
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - Y Katono
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - H Hosono
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - M Maekawa
- Department of Pharmacy, Tohoku University Hospital, Sendai, Japan
| | - M Shimada
- Department of Pharmacy, Tohoku University Hospital, Sendai, Japan
| | - N Mano
- Department of Pharmacy, Tohoku University Hospital, Sendai, Japan
| | - A Oda
- Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - N Hirasawa
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
| | - M Hiratsuka
- Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan
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Sugimoto M, Furuta T. Efficacy of tailored Helicobacter pylori eradication therapy based on antibiotic susceptibility and CYP2C19 genotype. World J Gastroenterol 2014; 20:6400-6411. [PMID: 24914361 PMCID: PMC4047325 DOI: 10.3748/wjg.v20.i21.6400] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2013] [Revised: 01/18/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
The cure rates of Helicobacter pylori (H. pylori) eradication therapy using a proton pump inhibitor (PPI) and antimicrobial agents such as amoxicillin, clarithromycin, and metronidazole are mainly influenced by bacterial susceptibility to antimicrobial agents and the magnitude of the inhibition of acid secretion. Annual cure rates have gradually decreased because of the increased prevalence of H. pylori strains resistant to antimicrobial agents, especially to clarithromycin. Alternative regimens have therefore been developed incorporating different antimicrobial agents. Further, standard PPI therapy (twice-daily dosing) often fails to induce a long-term increase in intragastric pH > 4.0. Increasing the eradication rate requires more frequent and higher doses of PPIs. Therapeutic efficacy related to acid secretion is influenced by genetic factors such as variants of the genes encoding drug-metabolizing enzymes (e.g., cytochrome P450 2C19, CYP2C19), drug transporters (e.g., multidrug resistance protein-1; ABCB1), and inflammatory cytokines (e.g., interleukin-1β). For example, quadruple daily administration of PPI therapy potently inhibits acid secretion within 24 h, irrespective of CYP2C19 genotype. Therefore, tailored H. pylori eradication regimens that address acid secretion and employ optimal antimicrobial agents based on results of antimicrobial agent-susceptibility testing may prove effective in attaining higher eradication rates.
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Masclee GMC, Sturkenboom MCJM, Kuipers EJ. A Benefit–Risk Assessment of the Use of Proton Pump Inhibitors in the Elderly. Drugs Aging 2014; 31:263-82. [DOI: 10.1007/s40266-014-0166-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Sahara S, Sugimoto M, Uotani T, Ichikawa H, Yamade M, Iwaizumi M, Yamada T, Osawa S, Sugimoto K, Umemura K, Miyajima H, Furuta T. Twice-daily dosing of esomeprazole effectively inhibits acid secretion in CYP2C19 rapid metabolisers compared with twice-daily omeprazole, rabeprazole or lansoprazole. Aliment Pharmacol Ther 2013; 38:1129-1137. [PMID: 24099474 DOI: 10.1111/apt.12492] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2013] [Revised: 07/24/2013] [Accepted: 08/28/2013] [Indexed: 12/14/2022]
Abstract
BACKGROUND Twice-daily dosing of proton pump inhibitors (PPIs) is used to treat Helicobacter pylori or acid-related diseases, such as gastro-oesophageal reflux disease (GERD) refractory to standard dose of a PPI. Genetic polymorphisms of CYP2C19 are involved to different extents in the metabolism of four kinds of PPIs (omeprazole, lansoprazole, rabeprazole and esomeprazole) available in Japan. AIM To compare acid-inhibitory effects of the four PPIs dosed twice daily in relation to CYP2C19 genotype. METHODS We performed 24-h pH monitoring studies on Day 7 of PPI treatment for 40 Japanese H. pylori-negative volunteers [15 CYP2C19 rapid metabolisers (RMs), 15 intermediate metabolisers (IMs) and 10 poor metabolisers (PMs)] using a randomised four-way crossover design: omeprazole 20 mg, esomeprazole 20 mg, lansoprazole 30 mg and rabeprazole 10 mg twice daily. RESULTS Although median pH values with esomeprazole, omeprazole, lansoprazole and rabeprazole were 5.7 (3.5-7.2), 5.5 (2.4-7.2), 5.5 (3.7-7.3) and 5.2 (2.5-7.3), respectively (no statistically significant differences), CYP2C19 genotype-dependent differences were smaller for esomeprazole and rabeprazole compared with values for omeprazole and lansoprazole. In CYP2C19 RMs, the median pH with esomeprazole [5.4 (3.5-6.8)] was significantly higher than those with omeprazole [5.0 (2.4-5.9), P = 0.018], lansoprazole [4.7 (3.7-5.5), P = 0.017] or rabeprazole [4.8 (2.5-6.4), P = 0.002]. In IMs and PMs, the median pH was >5.0 independent of the PPI. CONCLUSIONS In intermediate and rapid metabolisers of CYP2C19, PPIs dosed twice daily could attain sufficient acid suppression, while in CYP2C19 RMs, esomeprazole 20 mg twice daily caused the strongest inhibition of the four PPIs. Therefore, esomeprazole may be effective in Japanese population when dosed twice daily.
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Affiliation(s)
- S Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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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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Moraes-Filho JPP. Refractory gastroesophageal reflux disease. ARQUIVOS DE GASTROENTEROLOGIA 2013; 49:296-301. [PMID: 23329226 DOI: 10.1590/s0004-28032012000400012] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 08/16/2012] [Indexed: 02/06/2023]
Abstract
CONTEXT Gastroesophageal reflux disease (GERD) is a condition which develops when the reflux of stomach contents causes troublesome symptoms and/or complications. Its pathophysiology, diagnosis and treatment have frequently been analyzed but it is interesting to review some aspects of the GERD refractory patients to the proton pump inhibitors treatment. The treatment encompasses behavioral measures and pharmacological therapy. The majority of the patients respond well to proton pump inhibitors treatment but 20%-42% of them may not do so well. Patients who are unresponsible to 4-8 weeks' treatment with proton pump inhibitors (omeprazole, pantoprazole, rabeprazole, lansoprazole, esomeprazole, pantoprazole-Mg) might have so-called refractory GERD. RESULTS In some cases the patients are not real refractory because either they do not have GERD or the disease was not correctly treated, but the term refractory is still employed. Although debatable, the Brazilian GERD Consensus based upon evidences recommends as first step in the diagnosis, the upper digestive endoscopy to exclude the diagnosis of peptic ulcer and cancer and in some cases identify the presence of esophageal mucosa erosions. CONCLUSIONS The main causes of the so-called refractory GERD are: (1) functional heartburn; (2) low levels of adherence to proton pump inhibitors treatment; (3) inadequate proton pump inhibitors dosage; (4) wrong diagnosis; (5) co-morbidities and pill-induced esophagitis; (6) genotypic differences; (7) nonacid gastroesophageal reflux; (8) autoimmune skin diseases; (9) eosinophilic esophagitis.
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Hata S, Arai M, Maruoka D, Tanaka T, Matsumura T, Suzuki T, Nakagawa T, Katsuno T, Imazeki F, Yokosuka O. Intragastric acidity during the first day following administration of low-dose proton pump inhibitors: a randomized crossover study. Clin Res Hepatol Gastroenterol 2013; 37:296-301. [PMID: 22959094 DOI: 10.1016/j.clinre.2012.07.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2012] [Revised: 06/28/2012] [Accepted: 07/04/2012] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Low-dose proton pump inhibitors (PPIs) are often administrated as maintenance therapy for gastroesophageal reflux disease (GERD) and on-demand PPI therapy is a viable option for long-term management of GERD. The aim of this study is to investigate intragastric acidity during the first day following the administration of low-dose PPIs. SUBJECTS AND METHODS The study employed a crossover design. The subjects were 10 healthy volunteers who were administrated lansoprazole 15 mg (orally disintegrating) or rabeprazole 10mg. All subjects underwent pH monitoring with a wireless system during the first day after PPI administration. RESULTS There was no significant difference in the average intragastric pH during the first day of administration of lansoprazole and rabeprazole (3.3±1.1 vs. 3.2±0.7, paired t test), although the pH was significantly higher with both drugs as compared with the baseline (1.8±0.4, P<0.01). The pH 4 holding time ratio during the first day showed no significant difference between lansoprazole and rabeprazole (35.2±22.4% vs. 34.3±15.0%), and was also significantly higher than at baseline (0.35±1.73%, P<0.01). The two PPIs differed with respect to the peak of the pH 4 holding time ratio. CONCLUSIONS Lansoprazole 15 mg and rabeprazole 10 mg showed sufficient inhibition of intragastric acidity during the first day after PPI administration and the effects did not differ between drugs, although there was a difference in their time at which the peak effects were reached.
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Affiliation(s)
- Sachio Hata
- Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
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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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Sugimoto M, Shirai N, Nishino M, Kodaira C, Uotani T, Yamade M, Sahara S, Ichikawa H, Sugimoto K, Miyajima H, Furuta T. Rabeprazole 10 mg q.d.s. decreases 24-h intragastric acidity significantly more than rabeprazole 20 mg b.d. or 40 mg o.m., overcoming CYP2C19 genotype. Aliment Pharmacol Ther 2012; 36:627-634. [PMID: 22882464 DOI: 10.1111/apt.12014] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2012] [Revised: 06/26/2012] [Accepted: 07/20/2012] [Indexed: 12/14/2022]
Abstract
BACKGROUND Standard dosing (i.e. once daily) of proton pump inhibitors (PPIs) cannot inhibit acid secretion for a full 24 h. Better therapeutic regimens using PPIs are required to sustain potent acid inhibition for the full 24 h in all patients with acid-related diseases. AIM To evaluate acid inhibitory effects by different dosing times of a PPI at the same daily dosage, in a study involving 70 rounds of pH monitoring. METHODS Using pH monitoring, we evaluated the efficacy of different divided treatment regimens with the same total daily dose of rabeprazole (40 mg o.m., 15 rounds; 20 mg b.d., 20 rounds; 10 mg q.d.s., 35 rounds) on day 7 or 8 of PPI dosing. RESULTS In the study of divided treatment, the median pH (when administered once, twice or four times to achieve a daily dose of 40 mg) was 4.8 (3.6-6.4), 5.7 (4.1-7.4), 6.6 (4.9-8.4), respectively. When comparing the median pHs at the same CYP2C19 genotype among different dosing times of rabeprazole, the median pH attained with 10 mg q.d.s. was significantly higher than that in 40 mg o.m. or 20 mg b.d. Increase in the frequency of dosing effectively increased pH [median percent time of pH > 4.0 with q.d.s. therapy: 95.5% (63.2-100.0%)], irrespective to CYP2C19 genotype. CONCLUSION Four times daily dosing with rabeprazole 10 mg achieved potent acid inhibition, including during the night-time, suggesting its potential usefulness as a regimen for patients who are refractory to standard once daily PPI treatment.
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Affiliation(s)
- M Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan.
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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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Sugimoto M, Furuta T. Efficacy of esomeprazole in treating acid-related diseases in Japanese populations. Clin Exp Gastroenterol 2012; 5:49-59. [PMID: 22649281 PMCID: PMC3359912 DOI: 10.2147/ceg.s23926] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Esomeprazole (Nexium(®); AstraZeneca), the S-isomer of omeprazole, is the first proton pump inhibitor (PPI) to be developed as an optical isomer. Compared with omeprazole, esomeprazole has an improved pharmacokinetic profile with regards to CYP2C19 (S-mephenytoin 4'-hydroxylase) genotype, showing increased systemic exposure and less interindividual variability. Further, esomeprazole is a more potent acid inhibitor than other currently available PPIs and is therefore used as a first-line drug for acid-related diseases. While esomeprazole has been available in a number of countries worldwide, the compound only received authorized permission to be marketed in Japan in September 2011. The standard esomeprazole dose in Japan for the treatment of peptic ulcers and gastroesophageal reflux disease (GERD) is 20 mg. Other advised dosages are 10 mg for nonerosive reflux disease and 20 mg twice-daily dosing for eradication of Helicobacter pylori. In Japanese, the effective rate of esomeprazole 20 mg during 24 weeks for GERD patients is 92.0% (88.0%-96.0%), while the prevention of peptic ulcer development using 20 mg for 24 weeks in patients treated with nonsteroidal anti-inflammatory drugs is 96.0% (92.8%-99.1%). Although clinical data are limited, the usefulness of esomeprazole is expected in Japanese subjects given the reduced prevalence of CYP2C19 rapid metabolizers in Japan compared with Western countries.
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Affiliation(s)
- Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Shizuoka, Japan
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Huezo-Diaz P, Perroud N, Spencer EP, Smith R, Sim S, Virding S, Uher R, Gunasinghe C, Gray J, Campbell D, Hauser J, Maier W, Marusic A, Rietschel M, Perez J, Giovannini C, Mors O, Mendlewicz J, McGuffin P, Farmer AE, Ingelman-Sundberg M, Craig IW, Aitchison KJ. CYP2C19 genotype predicts steady state escitalopram concentration in GENDEP. J Psychopharmacol 2012; 26:398-407. [PMID: 21926427 DOI: 10.1177/0269881111414451] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In vitro work shows CYP2C19 and CYP2D6 contribute to the metabolism of escitalopram to its primary metabolite, N-desmethylescitalopram. We report the effect of CYP2C19 and CYP2D6 genotypes on steady state morning concentrations of escitalopram and N-desmethylescitalopram and the ratio of this metabolite to the parent drug in 196 adult patients with depression in GENDEP, a clinical pharmacogenomic trial. Subjects who had one CYP2D6 allele associated with intermediate metabolizer phenotype and one associated with poor metabolizer (i.e. IM/PM genotypic category) had a higher mean logarithm escitalopram concentration than CYP2D6 extensive metabolizers (EMs) (p = 0.004). Older age was also associated with higher concentrations of escitalopram. Covarying for CYP2D6 and age, we found those homozygous for the CYP2C19*17 allele associated with ultrarapid metabolizer (UM) phenotype had a significantly lower mean escitalopram concentration (2-fold, p = 0.0001) and a higher mean metabolic ratio (p = 0.0003) than EMs, while those homozygous for alleles conferring the PM phenotype had a higher mean escitalopram concentration than EMs (1.55-fold, p = 0.008). There was a significant overall association between CYP2C19 genotypic category and escitalopram concentration (p = 0.0003; p = 0.0012 Bonferroni corrected). In conclusion, we have demonstrated an association between CYP2C19 genotype, including the CYP2C19*17 allele, and steady state escitalopram concentration.
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Affiliation(s)
- Patricia Huezo-Diaz
- MRC SGDP Centre, Institute of Psychiatry at King's College London, London, UK
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Abstract
Genetic variation influences the absorption and efflux of drugs in the intestine, the metabolism of drugs in the liver and the effects of these drugs on their target proteins. Indeed, variations in genes whose products have a role in the pathophysiology of nonmalignant gastrointestinal diseases, such as IBD, have been shown to affect the response of patients to therapy. This Review provides an overview of pharmacogenetics in the management of nonmalignant gastrointestinal diseases on the basis of data from clinical trials. Genetic variants that have the greatest effect on the management of patients with IBD involve the metabolism of thiopurines. Variation in drug metabolism by cytochrome P450 enzymes also requires attention so as to avoid drug interactions in patients receiving tricyclic antidepressants and PPIs. Few genotyping tests are currently used in the clinical management of patients with nonmalignant gastrointestinal diseases, owing to a lack of data from clinical trials showing their effectiveness in predicting nonresponse or adverse outcomes. However, pharmacogenetics could have a beneficial role in enabling pharmacotherapy for nonmalignant gastrointestinal diseases to be targeted to the individual patient.
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Affiliation(s)
- Michael Camilleri
- College of Medicine, Mayo Clinic, Charlton, 8–110, 200 First Street, South West, Rochester, MN 55905, USA
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Abstract
Gastroesophageal reflux disease (GERD) affects 20-30% of the population in Western countries, and is one of the most common clinical problems in daily practice. GERD-associated functional and structural abnormalities are caused by recurrent exposure of the esophagus to acidic and nonacidic refluxate of gastric contents (containing duodenal and intestinal proteases as well as acid and gastric pepsin) from the stomach. Major progress has been made in the understanding of the molecular pathogenesis of GERD-associated mucosal inflammation, suggesting a complex and multifactorial pathogenesis and immune-mediated effects. This Review summarizes the complexity of mucosal pathogenesis, including microscopic changes, mucosal inflammation and GERD-specific molecular mediators, in the context of the clinical features and pathophysiological characteristics of GERD. The abnormal exposure of the esophagus to luminal contents leads to chronic mucosal inflammation that is characterized by the release of IL-8 specifically, as well as other proinflammatory mediators, from the esophageal mucosa. Evidence from animal studies indicates a stepwise inflammatory response by the epithelium, which attracts immune effector cells to infiltrate the mucosa. From bench to bedside, these novel molecular findings might provide new treatment options beyond current acid-suppressive therapy and the principle of inhibition of transient lower esophageal sphincter relaxation.
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Cavallari LH, Jeong H, Bress A. Role of cytochrome P450 genotype in the steps toward personalized drug therapy. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2011; 4:123-36. [PMID: 23226058 PMCID: PMC3513224 DOI: 10.2147/pgpm.s15497] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2011] [Indexed: 12/19/2022]
Abstract
Genetic polymorphism for cytochrome 450 (P450) enzymes leads to interindividual variability in the plasma concentrations of many drugs. In some cases, P450 genotype results in decreased enzyme activity and an increased risk for adverse drug effects. For example, individuals with the CYP2D6 loss-of-function genotype are at increased risk for ventricular arrhythmia if treated with usual does of thioridazine. In other cases, P450 genotype may influence the dose of a drug required to achieve a desired effect. This is the case with warfarin, with lower doses often necessary in carriers of a variant CYP2C9*2 or *3 allele to avoid supratherapeutic anticoagulation. When a prodrug, such as clopidogrel or codeine, must undergo hepatic biotransformation to its active form, a loss-of-function P450 genotype leads to reduced concentrations of the active drug and decreased drug efficacy. In contrast, patients with multiple CYP2D6 gene copies are at risk for opioid-related toxicity if treated with usual doses of codeine-containing analgesics. At least 25 drugs contain information in their US Food and Drug Administration-approved labeling regarding P450 genotype. The CYP2C9, CYP2C19, and CYP2D6 genes are the P450 genes most often cited. To date, integration of P450 genetic information into clinical decision making is limited. However, some institutions are beginning to embrace routine P450 genotyping to assist in the treatment of their patients. Genotyping for P450 variants may carry less risk for discrimination compared with genotyping for disease-associated variants. As such, P450 genotyping is likely to lead the way in the clinical implementation of pharmacogenomics. This review discusses variability in the CYP2C9, CYP2C19, and CYP2D6 genes and the implications of this for drug efficacy and safety.
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Affiliation(s)
- Larisa H Cavallari
- Department of Pharmacy Practice ; Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA
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50
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Furuta T, Shimatani T, Sugimoto M, Ishihara S, Fujiwara Y, Kusano M, Koike T, Hongo M, Chiba T, Kinoshita Y. Investigation of pretreatment prediction of proton pump inhibitor (PPI)-resistant patients with gastroesophageal reflux disease and the dose escalation challenge of PPIs-TORNADO study: a multicenter prospective study by the Acid-Related Symptom Research Group in Japan. J Gastroenterol 2011; 46:1273-1283. [PMID: 21861141 DOI: 10.1007/s00535-011-0446-2] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2011] [Accepted: 06/28/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUNDS Some non-erosive reflux disease (NERD) and reflux esophagitis (RE) patients are unresponsive to a proton pump inhibitor (PPI) at standard dose. We investigated the predictive marker of the efficacy of PPI for GERD patients including NERD and RE treated with standard and increased doses of a PPI. METHODS Patients with symptomatic gastroesophageal reflux disease (GERD) (NERD and RE) were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. The RPZ dosage was increased to 10 mg twice daily for an additional 2 weeks and again to 20 mg twice daily for another 2 weeks if heartburn was not relieved. Baseline characteristics and efficacy of RPZ were assessed on the basis of a heartburn diary and frequency scale for symptoms of GERD (FSSG). RESULTS Complete heartburn relief rates after 4 weeks were 42.5% (31/73) and 67.9% (19/28) in NERD and RE groups, respectively, which rose to 68.9 and 91.7% after dose escalation. Multivariate analysis revealed that parameters associated with resistance to RPZ 10 mg once daily were female, non-smoking, frequent heartburn, low score for question 4 (Q4) of the FSSG (subconsciously rubbing the chest), and high scores for Q3 (heavy stomach after meal) and Q7 (unusual sensation in the throat). Frequent heartburn and a high score for Q7 were associated with resistance to RPZ 20 mg twice daily. FSSG scores of patients resistant to RPZ were significantly higher in comparison with responders before and during treatment. CONCLUSIONS FSSG could predict response to a PPI for symptomatic GERD. Increase of RPZ dose is useful for treatment of GERD refractory to the standard dose of RPZ.
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Affiliation(s)
- Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu 431-3192, Japan.
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