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Adachi K, Ohyama K, Tanaka Y, Murayama N, Shimizu M, Saito Y, Yamazaki H. Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database. Biol Pharm Bull 2024; 47:1028-1032. [PMID: 38797695 DOI: 10.1248/bpb.b24-00145] [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] [Indexed: 05/29/2024]
Abstract
Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available. The maximum plasma concentration of omeprazole was pharmacokinetically modeled after a single oral 40-mg dose in P450 2C19-defective poor metabolizers and was 2.4-fold higher than that in extensive metabolizers. The modeled area under the hepatic concentration curves of omeprazole in P450 2C19 poor metabolizers after virtual daily 40-mg doses for 7 d was 5.2-fold higher than that in the extensive metabolizers. Omeprazole-induced P450 2C19 (approx. 2-fold), resulting in increased hepatic intrinsic clearance in repeated doses, was considered after the second day. Virtual plasma/hepatic exposure estimated using pharmacokinetic modeling in subjects with P450 2C19 poor metabolizers indicated that these exposure levels virtually estimated could be one of causal factors for unexpected hepatic disorders induced by prescribed omeprazole, such as those resulting from drug interactions with repeatedly co-administered medicines.
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Affiliation(s)
| | - Katsuhiro Ohyama
- School of Pharmacy, Tokyo University of Pharmacy and Life Sciences
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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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Bořilová Linhartová P, Zendulka O, Janošek J, Mlčůchová N, Cvanová M, Daněk Z, Kroupa R, Bartošová L, Lipový B. CYP2C19 Gene Profiling as a Tool for Personalized Stress Ulcer Prophylaxis With Proton Pump Inhibitors in Critically Ill Patients - Recommendations Proposal. Front Med (Lausanne) 2022; 9:854280. [PMID: 35899207 PMCID: PMC9309431 DOI: 10.3389/fmed.2022.854280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 06/03/2022] [Indexed: 11/13/2022] Open
Abstract
To this date, there are no recommendations for personalized stress ulcer prophylaxis (SUP) in critical care that would take the patient's individual genetic predispositions into account. Of drugs used for this purpose, proton pump inhibitors (PPIs) are the first-choice drugs in intensive care unit patients. The degradation of proton pump inhibitors is mediated by cytochrome P450 (CYP) enzymes; in particular, CYP2C19 and, to a lesser extent, CYP3A4 are involved. Expression and metabolic activity of, namely in, CYP2C19 is significantly affected by single nucleotide polymorphisms, the drug metabolization rate varies greatly from ultrarapid to poor and likely influences the optimal dosage. As these CYP2C19 predictive phenotypes via CYP2C19 haplogenotypes (rs12248560/rs4244285) can be relatively easily determined using the current standard equipment of hospital laboratories, we prepared a set of recommendations for personalized PPI-based stress ulcer prophylaxis taking into account the patient's CYP2C19 predictive phenotype determined in this way. These recommendations are valid, in particular, for European, American and African populations, because these populations have the high representations of the CYP2C19*17 allele associated with the overexpression of the CYP2C19 gene and ultrarapid degradation of PPIs. We propose the CYP2C19 gene profiling as a tool for personalized SUP with PPI in critically ill patients.
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Affiliation(s)
- Petra Bořilová Linhartová
- RECETOX, Faculty of Science, Masaryk University, Brno, Czechia
- Clinic of Maxillofacial Surgery, Faculty of Medicine, Institution Shared With University Hospital Brno, Masaryk University, Brno, Czechia
| | - Ondřej Zendulka
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Jaroslav Janošek
- Faculty of Medicine, Center for Health Research, University of Ostrava, Ostrava, Czechia
| | | | - Michaela Cvanová
- Faculty of Medicine, Institute of Biostatistics and Analyses, Masaryk University, Brno, Czechia
| | - Zdeněk Daněk
- RECETOX, Faculty of Science, Masaryk University, Brno, Czechia
- Clinic of Maxillofacial Surgery, Faculty of Medicine, Institution Shared With University Hospital Brno, Masaryk University, Brno, Czechia
| | - Radek Kroupa
- Department of Internal Medicine and Gastroenterology, Faculty of Medicine, Institution Shared With University Hospital Brno, Masaryk University, Brno, Czechia
| | - Ladislava Bartošová
- Department of Pharmacology, Faculty of Medicine, Masaryk University, Brno, Czechia
| | - Břetislav Lipový
- Department of Burns and Plastic Surgery, Faculty of Medicine, Institution Shared With University Hospital BrnoMasaryk University, Brno, Czechia
- *Correspondence: Břetislav Lipový
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Jeon J, Kim J. Risk of Post-Myocardial Infarction Pneumonia with Proton Pump Inhibitors, H2 Receptor Antagonists and Mucoprotective Agents: A Retrospective Nationwide Cohort Study. J Pers Med 2022; 12:jpm12010078. [PMID: 35055393 PMCID: PMC8778571 DOI: 10.3390/jpm12010078] [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: 11/09/2021] [Revised: 12/16/2021] [Accepted: 12/30/2021] [Indexed: 11/16/2022] Open
Abstract
Patients with myocardial infarction (MI) are at high risk of developing pneumonia. Proton pump inhibitors (PPI) and H2-receptor antagonists (H2RA) are commonly used acid-suppressive medications to the patients with MI for gastrointestinal (GI) protection, which may increase the risk for pneumonia. We evaluated whether PPI, H2RA, and mucoprotective agents without anti-acid properties increase the risk of post-MI pneumonia. We performed a retrospective cohort study based on the National Health Insurance Service—National Sample Cohort in Korea. The study included 3701 patients discharged with MI without prior history of pneumonia. During follow-up, treatments with PPI, H2RA, and mucoprotective agents were collected as time-dependent variables based on the prescription records. We performed multivariate time-dependent Cox regression analyses for the development of post-MI pneumonia. During the mean 4.85 ± 3.75 years follow-up, 999 participants developed pneumonia. In the multivariate analyses (adjusted hazard ratio; 95% confidence interval), the risk for pneumonia was significantly increased in treatment with PPI (2.25; 1.57–3.21) and H2RA (1.50; 1.16–1.93). Meanwhile, the risk for pneumonia was not increased in treatment with mucoprotective agents. When we evaluated GI bleeding event according to the medications as a secondary outcome analysis, mucoprotective agents were associated with increased GI bleeding risk, but PPI and H2RA were not. In the use of the GI medications in the treatment of patients with MI, the influence of these drugs on bleeding and pneumonia should be considered.
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Na JY, Jeon I, Yoon J, Choi Y, Yoon SH, Yu KS, Chung JY. Influence of CYP2C19 Polymorphisms on the Pharmacokinetics of Omeprazole in Elderly Subjects. Clin Pharmacol Drug Dev 2021; 10:1469-1477. [PMID: 34337876 DOI: 10.1002/cpdd.966] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Accepted: 05/03/2021] [Indexed: 11/11/2022]
Abstract
Omeprazole blocks the gastric H+ /K+ adenosine triphosphatase, thus inhibiting gastric acid secretion, and is metabolized by cytochrome P450 (CYP) 2C19. Due to the physiological changes in the elderly, there are different pharmacokinetic consequences compared to young people. The aim of this study was to evaluate the pharmacokinetic profiles of omeprazole in 15 elderly participants according to the CYP2C19 genotype. The concentration-time profiles of omeprazole and its metabolites, 5-hydroxy (5-OH) omeprazole and omeprazole sulfone, were similar between the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer groups. In contrast, when comparing the EM group and CYP2C19 poor metabolizer (PM) group, the EM/PM geometric mean ratio (95% confidence interval) of area under the plasma concentration-time curve from time of dosing to the last measurable concentration was 0.52 (0.27-1.01) and that of the IM group was 0.71 (0.32-1.59), indicating that the exposure of omeprazole in the PM group was increased. The exposure of 5-OH omeprazole was significantly decreased in the PM group when compared to the EM group, with an EM/PM geometric mean ratio (95% confidence interval) of 2.20 (1.50-3.22). In conclusion, the tendency of drug exposure according to the CYP2C19 genotype in the elderly and young adults was similar in that the exposure level was highest in the PM group. However, when compared to young adults, the difference between the genotype groups was smaller in the elderly.
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Affiliation(s)
- Joo Young Na
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Inseung Jeon
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Jangsoo Yoon
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Yewon Choi
- Genosco Inc, Billerica, Massachusetts, USA
| | - Seo Hyun Yoon
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Kyung-Sang Yu
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea
| | - Jae-Yong Chung
- Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Gyeonggi-do, Korea
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Moghadam MT, Chegini Z, Norouzi A, Dousari AS, Shariati A. Three-Decade Failure to the Eradication of Refractory Helicobacter pylori Infection and Recent Efforts to Eradicate the Infection. Curr Pharm Biotechnol 2021; 22:945-959. [PMID: 32767919 DOI: 10.2174/1389201021666200807110849] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Revised: 06/30/2020] [Accepted: 07/04/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND Helicobacter pylori causes dangerous and deadly diseases such as gastric cancer and duodenal ulcers. Eradication and treatment of this bacterium are very important due to the deadly diseases caused by H. pylori and the high cost of treatment for countries. METHODS Thus, we present a complete list of the most important causes of failure in the treatment and eradication of H. pylori, and address new therapeutic methods that may be effective in controlling this bacterium in the future. RESULTS Many efforts have been made to control and eradicate this bacterium over the years, but no success has been achieved since its eradication is a complex process affected by the bacterial properties and host factors. Previous studies have shown that various factors are involved in the failure to eradicate H. pylori, such as new genotypes of the bacterium with higher pathogenicity, inappropriate patient cooperation, mutations, biofilm formation and dormant forms that cause antibiotic resistance, acidic stomach pH, high bacterial load, smoking, immunosuppressive features and intracellular occurrence of H. pylori. On the other hand, recent studies reported that the use of probiotics, nanoparticles, antimicrobial peptides, natural product and vaccines can be helpful in the treatment and eradication of H. pylori infections. CONCLUSION Eradication of H. pylori is crucial for the treatment of important diseases such as gastric cancer. Therefore, it seems that identifying the failure causes of treating this bacterium can be helpful in controlling the infections. Besides, further studies on new therapeutic strategies may help eradicate H. pylori in the future.
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Affiliation(s)
- Majid T Moghadam
- Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Chegini
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Amin Norouzi
- Department of Microbiology and Virology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | | | - Aref Shariati
- Department of Microbiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Tan Q, Gao Y, Zhang P, Huo Y, Lu Y, Huang W. Comparison of Outcomes in Patients with Obesity Between Two Administration Routes of Omeprazole After Laparoscopic Sleeve Gastrectomy: An Open-Label Randomized Clinical Trial. Drug Des Devel Ther 2021; 15:1569-1576. [PMID: 33883880 PMCID: PMC8055283 DOI: 10.2147/dddt.s297360] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2021] [Accepted: 02/27/2021] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The effect of different administration routes of omeprazole remains unclear on the recovery in patients with obesity after laparoscopic sleeve gastrectomy (LSG). METHODS We designed a randomized clinical trial enrolling 120 patients with a BMI≥32.5 kg/m2 after LSG. They were randomized into two groups to be administered with omeprazole by rapid intravenous injection (group A) or by continuous micropump infusion (group B). The plasma concentration of omeprazole was monitored upon initiating administration. Change in intragastric pH and gastrointestinal symptoms during follow-up served as indicators for therapeutic evaluation. RESULTS Patients in the two groups showed no difference in the AUC curves (P=0.25), but group A had significantly higher peak concentration (P<0.001), and shorter time to reach peak concentration after administration (P<0.001), compared to group B. Before and after the administration of omeprazole, the average change in intragastric pH was much lower in group A (0.031 ± 0.61) than in group B (0.48 ± 0.74) (P=0.004). The incidence of gastrointestinal symptoms was similar between the two groups (P=0.85); however, the average duration of remaining symptoms was longer in group A (3.97 months; 95% CI, 2.90-5.04) than in group B (2.82 months; 95% CI, 2.01-3.63) (P=0.04). CONCLUSION Continuous micropump infusion of omeprazole may improve the outcomes in patients with obesity after LSG. TRIAL REGISTRATION China Clinical Trial Registration Center (ChiCTR), ChiCTR-IPR-17013365. Registered 13 November 2017. http://www.chictr.org.cn/showproj.aspx?proj=22892.
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Affiliation(s)
- Qin Tan
- Department of Critical Care, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Yanding Gao
- Department of Critical Care, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Pin Zhang
- Department of General Surgery, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Yan Huo
- Department of Pharmacy, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
| | - Yihan Lu
- Department of Epidemiology, School of Public Health, Fudan University, Shanghai, People’s Republic of China
- National Health Commission Key Laboratory of Health Technology Assessment, Fudan University, Shanghai, People’s Republic of China
| | - Weifeng Huang
- Department of Critical Care, The Sixth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China
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Nichols D, Arnold S, Weiss HL, Wu J, Durbin EB, Miller R, Kolesar J. Pharmacogenomic potential in advanced cancer patients. Am J Health Syst Pharm 2020; 76:415-423. [PMID: 31361818 DOI: 10.1093/ajhp/zxy079] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
PURPOSE The prevalence of pharmacogenetically actionable medications in advanced cancer patients whose therapy may be optimized with genotype data was determined. METHODS Patients enrolled in our institutional molecular tumor board observational cohort were included in this study. Collected data included demographics, type(s) of cancer, and outpatient medications. Medications were classified as "pharmacogenetically actionable" if there are Clinical Pharmacogenetics Implementation Consortium (CPIC) therapeutic recommendations for that medication based on the presence of germline variations. The prevalence of pharmacogenetically actionable medications in the study population was determined, and the frequency of opportunities for pharmacogenetic prescribing and adverse event (AE) mitigation were estimated. RESULTS In a cohort of 193 patients with advanced cancer, 65% of patients were taking a pharmacogenetically actionable medication. Approximately 10% of the outpatient medications taken by the study population had a pharmacogenetic association. The most common pharmacogenetically actionable medications being used were ondansetron (47%), capecitabine (10%), and sertraline (7%). Using published genetic variation frequencies and AE risk, we conservatively estimated that 7.1% of cancer patients would be eligible for genetic-based medication adjustment, and 101 AEs would be prevented in 10,000 patients genotyped. CONCLUSION Medications with pharmacogenetic associations are used commonly in the advanced cancer patient population. This widespread exposure supports the implementation of prospective genotyping in the treatment of these high-risk patients.
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Affiliation(s)
- Dan Nichols
- University of Kentucky HealthCare, Lexington, KY
| | - Susanne Arnold
- University of Kentucky College of Medicine, Lexington, KY
| | - Heidi L Weiss
- University of Kentucky College of Medicine, Lexington, KY
| | - Jianrong Wu
- University of Kentucky College of Medicine, Lexington, KY
| | - Eric B Durbin
- University of Kentucky College of Medicine, Lexington, KY
| | - Rachel Miller
- University of Kentucky College of Medicine, Lexington, KY
| | - Jill Kolesar
- University of Kentucky College of Pharmacy, Lexington, KY
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CYP2C19 and STAT6 Variants Influence the Outcome of Proton Pump Inhibitor Therapy in Pediatric Eosinophilic Esophagitis. J Pediatr Gastroenterol Nutr 2019; 69:581-587. [PMID: 31490856 PMCID: PMC6855320 DOI: 10.1097/mpg.0000000000002480] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Proton pump inhibitors (PPIs) are an effective treatment for eosinophilic esophagitis (EoE); however, only 30% to 60% of patients respond. Common genetic variants in CYP2C19 and STAT6 associate with PPI plasma concentration and magnitude of inflammatory response, respectively. Our objective was to determine if genetic variation in the genes for CYP2C19 and STAT6 influence differentiation between PPI responsive esophageal eosinophilia versus PPI nonresponsive EoE (PPI-REE, PPI-nonresponsive EoE). METHODS Genomic DNA was isolated from 92 esophageal tissue biopsies collected from participants of a prospective clinical trial of high-dose PPI therapy for esophageal eosinophilia in children. RESULTS Of the 92 patients examined, 57 (62%) were PPI-REE and 35 (38%) were PPI-nonresponsive EoE. Forty-six of the 92 patients were further characterized by pH probe monitoring; there was no association between reflux index and carriage of CYP2C1917 (P = 0.35). In children who received a PPI dose between ≥1.54 and ≤2.05 mg/kg/day, binary logistic regression modeling showed that carriage of CYP2C1917 associated with PPI-nonresponsive EoE (odds ratio (OR) [95% confidence interval (CI)] = 7.71 [1.21, 49.11], P = 0.031). Carriage of STAT6 allelic variant rs1059513 predicts PPI-REE (OR [95% CI] = 6.16 [1.44, 26.4], P = 0.028), whereas carriage of STAT6 rs324011 synergizes with CYP2C1917 to predict PPI-nonresponsive EoE (rs324011 OR [95% CI] = 5.56 [1.33, 20.72], P = 0.022; CYP2C1917 OR [95% CI] = 8.19[1.42, 50.57], P = 0.023). CONCLUSIONS Common variants in CYP2C19 and STAT6 associate with a PPI-nonresponsive EoE outcome of PPI therapy for esophageal eosinophilia suggesting that response rates may be improved by adopting a genotype-guided approach to PPI dosing.
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Lorenzo-Pouso AI, Pérez-Sayáns M, Rodríguez-Zorrilla S, Chamorro-Petronacci C, García-García A. Dissecting the Proton Transport Pathway in Oral Squamous Cell Carcinoma: State of the Art and Theranostics Implications. Int J Mol Sci 2019; 20:ijms20174222. [PMID: 31470498 PMCID: PMC6747091 DOI: 10.3390/ijms20174222] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 08/27/2019] [Accepted: 08/28/2019] [Indexed: 12/12/2022] Open
Abstract
Cancer cells overexpress proton exchangers at the plasma membrane in order acidify the extracellular matrix and maintain the optimal pH for sustaining cancer growth. Among the families of proton exchangers implicated in carcinogenesis, carbonic anhydrases (CAs), monocarboxylate transporters (MCTs), Na+/H+ exchangers (NHEs), sodium bicarbonate cotransporters (NBCs), and vacuolar ATPases (V-ATPases) are highlighted. Considerable research has been carried out into the utility of the understanding of these machineries in the diagnosis and prognosis of several solid tumors. In addition, as therapeutic targets, the interference of their functions has contributed to the discovery or optimization of cancer therapies. According to recent reports, the study of these mechanisms seems promising in the particular case of oral squamous cell carcinoma (OSCC). In the present review, the latest advances in these fields are summarized, in particular, the usefulness of proton exchangers as potential prognostic biomarkers and therapeutic targets in OSCC.
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Affiliation(s)
- Alejandro I Lorenzo-Pouso
- Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Odontology, University of Santiago de Compostela, GI-1319 Research Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15782, Spain.
| | - Mario Pérez-Sayáns
- Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Odontology, University of Santiago de Compostela, GI-1319 Research Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15782, Spain.
| | - Samuel Rodríguez-Zorrilla
- Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Odontology, University of Santiago de Compostela, GI-1319 Research Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15782, Spain
| | - Cintia Chamorro-Petronacci
- Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Odontology, University of Santiago de Compostela, GI-1319 Research Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15782, Spain
| | - Abel García-García
- Oral Medicine, Oral Surgery and Implantology Unit, Faculty of Medicine and Odontology, University of Santiago de Compostela, GI-1319 Research Group, Health Research Institute of Santiago de Compostela (IDIS), Santiago de Compostela, 15782, Spain
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11
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Tang M, Blake KV, Lima JJ, Mougey EB, Franciosi J, Schmidt S, Hossain MJ, Cobbaert M, Fischer BM, Lang JE. Genotype tailored treatment of mild symptomatic acid reflux in children with uncontrolled asthma (GenARA): Rationale and methods. Contemp Clin Trials 2019; 78:27-33. [PMID: 30659924 PMCID: PMC7039713 DOI: 10.1016/j.cct.2019.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 01/08/2019] [Accepted: 01/14/2019] [Indexed: 12/12/2022]
Abstract
Asthma causes enormous suffering and cost for children in the US and around the world [1-3]. Co-morbid gastroesophageal reflux disease (GERD) makes asthma management more difficult due to increased symptoms. Proton pump inhibitor (PPI) drugs are effective at improving to GERD symptoms, however they have demonstrated only modest and variable effects on asthma control in the setting of co-morbid GERD. Importantly, PPI metabolism and efficacy depend on CYP2C19 genotype. The Genotype Tailored Treatment of Symptomatic Acid Reflux in Children with Uncontrolled Asthma (GenARA) study is a randomized, double-blind, placebo-controlled trial to determine if genotype-tailored PPI dosing improves asthma symptoms among children with inadequately controlled asthma and GERD symptoms. This study has an innovative design to both assess the efficacy of genotype-tailored PPI dosing and perform pharmacokinetic modeling of the oral PPI Lansoprazole. Children ages 6-17 years old with clinician-diagnosed asthma and mild GERD symptoms will submit a saliva sample for CYP2C19 genotyping. Participants will undergo a two-step randomization to: (1) genotype-tailored versus conventional dosing of open-label oral lansoprazole for pharmacokinetic modeling, and (2) genotype-tailored lansoprazole daily versus placebo for 24 weeks to determine the effect of genotype-tailored PPI dosing on asthma control. Measures of asthma control, spirometry, and nasal washes during acute illnesses will be collected at 8-week intervals throughout the study. GenARA will better define the effects of CYP2C19 genotype on the dose response of lansoprazole in children and adolescents and assess if a novel dosing regimen improves GERD and asthma control.
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Affiliation(s)
- Monica Tang
- Division of Allergy/Immunology and Pulmonary Medicine, Duke University School of Medicine, Duke Children's Hospital and Health Center, Durham, NC, United States
| | - Kathryn V Blake
- Center for Pharmacogenomics and Translational Research, Nemours Children's Health System, Jacksonville, FL, United States
| | - John J Lima
- Center for Pharmacogenomics and Translational Research, Nemours Children's Health System, Jacksonville, FL, United States
| | - Edward B Mougey
- Center for Pharmacogenomics and Translational Research, Nemours Children's Health System, Jacksonville, FL, United States
| | - James Franciosi
- Department of Pediatrics, Nemours Children's Hospital, Nemours Children's Health System, Orlando, FL, United States
| | - Stephan Schmidt
- Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, United States
| | - Md Jobayer Hossain
- Department of Biomedical Research, Nemours/Alfred I. DuPont Hospital for Children, Wilmington, DE, United States
| | - Marjan Cobbaert
- Department of Pharmacometrics, Duke Clinical Research Institute, Durham, NC, United States
| | - Bernard M Fischer
- Division of Allergy/Immunology and Pulmonary Medicine, Duke University School of Medicine, Duke Children's Hospital and Health Center, Durham, NC, United States
| | - Jason E Lang
- Division of Allergy/Immunology and Pulmonary Medicine, Duke University School of Medicine, Duke Children's Hospital and Health Center, Durham, NC, United States.
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12
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Ayoub F, Khullar V, Banerjee D, Stoner P, Lambrou T, Westerveld DR, Hanayneh W, Kamel AY, Estores D. Once Versus Twice-Daily Oral Proton Pump Inhibitor Therapy for Prevention of Peptic Ulcer Rebleeding: A Propensity Score-Matched Analysis. Gastroenterology Res 2018; 11:200-206. [PMID: 29915630 PMCID: PMC5997469 DOI: 10.14740/gr1011w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Accepted: 04/10/2018] [Indexed: 12/26/2022] Open
Abstract
Background After inpatient management of upper gastrointestinal bleeding (GIB) due to peptic ulcer disease (PUD), oral proton pump inhibitor (PPI) therapy is recommended at discharge to decrease rebleeding risk and improve ulcer healing. Our aim is to determine whether once-daily oral PPI dosing at hospital discharge is associated with inferior 30-day rebleeding outcomes as compared to twice-daily dosing. Methods We retrospectively identified 233 patients admitted with signs and symptoms of upper GIB found to be due to PUD on upper endoscopy. After inpatient management, patients discharged on once-daily oral PPI were compared to those discharged on twice-daily therapy. We utilized propensity score matching based on Rockall scores to ensure the two groups were closely matched in terms of their baseline rebleeding risk. Primary outcome was the incidence of rebleeding within 30 days. Secondary outcomes were all-cause mortality, blood transfusion requirement, requirement for interventional radiology or surgery. Results Overall, 49 patients were discharged on once-daily and 184 on twice-daily PPI. Recurrent bleeding occurred in 18 patients (7.7%) within 30 days. There was no statistically significant difference in recurrent bleeding rates between once-daily (n = 7, 14.3%) as compared to twice-daily PPI (n = 11, 6%) (P = 0.053). In a 1:1 propensity score matched analysis, there was no statistically significant difference in 30-day recurrent bleeding rate between groups (14% once-daily vs. 4% twice-daily, P = 0.159). There were no differences in secondary outcomes. Conclusions Once-daily oral PPI dosing at hospital discharge was not associated with inferior outcomes compared to twice-daily dosing in patients hospitalized for upper GIB due to PUD.
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Affiliation(s)
- Fares Ayoub
- Department of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Vikas Khullar
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Debdeep Banerjee
- Department of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Patrick Stoner
- Department of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Tiffany Lambrou
- Department of Medicine, University of Florida, Gainesville, FL 32608, USA
| | | | - Wissam Hanayneh
- Department of Medicine, University of Florida, Gainesville, FL 32608, USA
| | - Amir Y Kamel
- Department of Pharmacy, University of Florida, Gainesville, FL, 32608, USA
| | - David Estores
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, FL 32608, USA
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13
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Bain KT, Schwartz EJ, Knowlton OV, Knowlton CH, Turgeon J. Implementation of a pharmacist-led pharmacogenomics service for the Program of All-Inclusive Care for the Elderly (PHARM-GENOME-PACE). J Am Pharm Assoc (2003) 2018; 58:281-289.e1. [PMID: 29602745 DOI: 10.1016/j.japh.2018.02.011] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Revised: 01/19/2018] [Accepted: 02/25/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVES To determine the feasibility of implementing a pharmacist-led pharmacogenomics (PGx) service for the Program of All-Inclusive Care for the Elderly (PACE). SETTING A national centralized pharmacy providing PGx services to community-based PACE centers. PRACTICE DESCRIPTION Individuals 55 years of age and older enrolled in PACE who underwent PGx testing as part of their medical care (n = 296). PRACTICE INNOVATION Pharmacist-led PGx testing, interpreting, and consulting. EVALUATION Implementation processes and roles were ascertained by reviewing policies and procedures for the PGx service and documented observations made by pharmacists providing the service. Genetic variants and drug-gene interactions (DGIs) were determined by interpretations of PGx test results. Types of recommendations provided by pharmacists were ascertained from PGx consultations. Prescribers' acceptance of recommendations were ascertained by documented responses or drug changes made after PGx consultations. RESULTS Challenges to implementation included lack of systems interoperability, limited access to medical electronic health records, determining prescribers' responses, and knowledge and competency gaps in PGx. Pharmacist roles most essential to overcoming challenges were interpreting and applying PGx data, determining how to disseminate those data to prescribers, advocating for appropriate PGx testing, and educating about the application of test results to clinical practice. Participants frequently used drugs posing DGI risks, with the majority (73.6%) reporting more than 1 interaction. The overwhelming majority (89.0%) of pharmacists' recommendations to mitigate risks were accepted by referring prescribers. CONCLUSION Implementing a pharmacist-led PGx service for PACE is feasible. Implementation of this service highlights the leadership role of pharmacists in moving PGx from research to practice.
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14
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Mermelstein J, Chait Mermelstein A, Chait MM. Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions. Clin Exp Gastroenterol 2018; 11:119-134. [PMID: 29606884 PMCID: PMC5868737 DOI: 10.2147/ceg.s121056] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
A significant percentage of patients with gastroesophageal reflux disease (GERD) will not respond to proton pump inhibitor (PPI) therapy. The causes of PPI-refractory GERD are numerous and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety of pharmacologic and procedural interventions that should be selected based on the underlying mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundoplication and Stretta. Several alternative and complementary treatments of possible benefit also exist.
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Affiliation(s)
- Joseph Mermelstein
- Gasteroenterology and Nutrition Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alanna Chait Mermelstein
- Department of Psychiatry and Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maxwell M Chait
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
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15
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Kiss ÁF, Vaskó D, Déri MT, Tóth K, Monostory K. Combination of CYP2C19 genotype with non-genetic factors evoking phenoconversion improves phenotype prediction. Pharmacol Rep 2017; 70:525-532. [PMID: 29665549 DOI: 10.1016/j.pharep.2017.12.001] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 11/29/2017] [Accepted: 12/01/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND CYP2C19 is an important drug-metabolizing enzyme, responsible for metabolism of approximately 10% of the drugs on the market. Large inter-individual differences exist in metabolic activities, which are primarily attributed to genetic polymorphism of CYP2C19 gene. Conflicting results have been published about the role of CYP2C19 polymorphisms in metabolism of CYP2C19 substrates and clinical outcomes; thus, we aimed to investigate CYP2C19 genotype-phenotype associations, and we sought to elicit potential causes of discrepancies in the genotype-based prediction by incorporating the liver donors' demographic data, drug administration events and pathological conditions. METHODS (S)-Mephenytoin was used to assess CYP2C19 activities in human liver microsomes derived from 114 Hungarian organ donors. CYP2C19 genotype was determined by SNP genotyping for CYP2C19*2, CYP2C19*3, CYP2C19*4 and CYP2C19*17 variants, and CYP2C19 mRNA levels were measured by qPCR method. Clinical data of the donors were considered in the genotype-based phenotype prediction. RESULTS CYP2C19 phenotype of 40% of the donors was well-predicted from the genotype data, whereas the phenotype of 13% was underestimated displaying higher activity, and of 47% was overestimated displaying lower activity than predicted from CYP2C19 genotype. Among the donors with overestimated phenotype, one was treated with CYP2C19 substrate/inhibitor, 9 were on amoxicillin-clavulanic acid therapy, 7 were chronic alcohol consumers and 9 had disease with inflammatory processes. CONCLUSIONS CYP2C19 genotype only partially determines the CYP2C19 phenotypic appearance; co-medication, diseases with inflammatory processes and aspecific factors, such as chronic alcohol consumption and amoxicillin-clavulanic acid therapy (or any drug therapy resulting in liver injury) seem to be potential phenotype-modifying factors.
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Affiliation(s)
- Ádám Ferenc Kiss
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Dorottya Vaskó
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Máté Tamás Déri
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Katalin Tóth
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary
| | - Katalin Monostory
- Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary.
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16
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Toda R, Shiramoto M, Komai E, Yoshii K, Hirayama M, Kawabata Y. Pharmacokinetics and Pharmacodynamics of Azeloprazole Sodium, a Novel Proton Pump Inhibitor, in Healthy Japanese Volunteers. J Clin Pharmacol 2017; 58:425-433. [DOI: 10.1002/jcph.1038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 10/06/2017] [Indexed: 01/16/2023]
Affiliation(s)
- Ryoko Toda
- Toxicology & Pharmacokinetics Research, Central Research Laboratories, Research & Development; Zeria Pharmaceutical Co. Ltd.,; Saitama Japan
| | | | - Emi Komai
- Clinical Research, Research & Development; Zeria Pharmaceutical Co., Ltd.,; Tokyo Japan
| | - Kazuyoshi Yoshii
- Toxicology & Pharmacokinetics Research, Central Research Laboratories, Research & Development; Zeria Pharmaceutical Co. Ltd.,; Saitama Japan
| | - Masamichi Hirayama
- Toxicology & Pharmacokinetics Research, Central Research Laboratories, Research & Development; Zeria Pharmaceutical Co. Ltd.,; Saitama Japan
| | - Yoshihiro Kawabata
- Toxicology & Pharmacokinetics Research, Central Research Laboratories, Research & Development; Zeria Pharmaceutical Co. Ltd.,; Saitama Japan
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17
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Yokota H, Sato K, Okuda Y, Kobayashi H, Takeda M, Asano M, Ito H, Miura M. Effects of Histamine 2-receptor Antagonists and Proton Pump Inhibitors on the Pharmacokinetics of Gefitinib in Patients With Non-small-cell Lung Cancer. Clin Lung Cancer 2017; 18:e433-e439. [PMID: 28579188 DOI: 10.1016/j.cllc.2017.05.010] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 05/01/2017] [Accepted: 05/02/2017] [Indexed: 12/21/2022]
Abstract
INTRODUCTION In this study, we investigated the degree of drug interactions between gefitinib and gastric acid suppressants (ie, histamine 2-receptor antagonists [H2RAs] or proton pump inhibitors [PPIs]) with a clinical standard dose in Japanese patients with non-small-cell lung cancer. METHODS Retrospectively, 47 patients were divided into 3 groups: gefitinib therapy with a PPI (15 patients) or an H2RA (8 patients) or gefitinib therapy alone (24 patients). On day 15 after beginning gefitinib therapy (administration at 08:00) with or without H2RA (administration twice daily at 08:00 and 18:30) or PPI (administration once daily at 08:00 or 18:30), whole blood samples were collected just prior to and at 1, 2, 4, 6, 8, 12, and 24 hours after administration. RESULTS The total area under the observed plasma concentration-time curve (AUC0-24) and the maximum and trough plasma concentrations of gefitinib with the PPI were significantly lower than those without the PPI. The AUC0-24 of gefitinib with PPI administration in either the morning or evening were significantly lower than those without PPI administration (P = .015 and .049, respectively); however, there were no significant differences in gefitinib AUC0-24 between patients taking PPI in the morning and evening. No significant differences were observed in gefitinib exposure among the 3 CYP2C19 genotypes. The AUC0-24 of gefitinib with H2RA tended to be lower than that without H2RA. CONCLUSION If the plasma concentrations of gefitinib cannot be monitored, the combination of gefitinib and PPI should be avoided, and an H2RA should also be used carefully.
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Affiliation(s)
- Hayato Yokota
- Department of Pharmacy, Akita University Hospital, Akita, Japan
| | - Kazuhiro Sato
- Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Yuji Okuda
- Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | | | - Masahide Takeda
- Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Mariko Asano
- Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Hiroshi Ito
- Department of Cardiovascular and Respiratory Medicine, Akita University Graduate School of Medicine, Akita, Japan
| | - Masatomo Miura
- Department of Pharmacy, Akita University Hospital, Akita, Japan.
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18
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Furuta T, Sugimoto M, Kodaira C, Nishino M, Yamade M, Uotani T, Sahara S, Ichikawa H, Kagami T, Iwaizumi M, Hamaya Y, Osawa S, Sugimoto K, Umemura K. Influence of low-dose proton pump inhibitors administered concomitantly or separately on the anti-platelet function of clopidogrel. J Thromb Thrombolysis 2017; 43:333-342. [PMID: 27981489 DOI: 10.1007/s11239-016-1460-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Proton pump inhibitors (PPIs) at low doses can effectively prevent gastrointestinal bleeding due to aspirin and are widely used in Japan for gastroprotection in patients taking anti-platelet agents. We examined the influence of different PPIs at low doses administered concomitantly or separately on anti-platelet functions of clopidogrel. In 41 healthy Japanese volunteers with different CYP2C19 genotypes who took clopidogrel 75 mg in the morning alone, or with omeprazole 10 mg, esomeprazole 10 mg, lansoprazole 15 mg, or rabeprazole 10 mg, either concomitantly in the morning or separately in the evening, we measured the inhibition of platelet aggregation (IPA, %) using VerifyNow P2Y12 assay at 4 h after the last clopidogrel dose on Day 7 of each regimen. IPA by clopidogrel with rabeprazole administered at lunchtime, approximately 4 h after clopidogrel, was also measured. Mean IPAs in those concomitantly receiving omeprazole, esomeprazole, lansoprazole or rabeprazole (47.2 ± 21.1%, 43.2 ± 20.2%, 46.4 ± 18.8%, and 47.3 ± 19.2%, respectively) were significantly decreased compared with those receiving clopidogrel alone (56.0%) (all ps < 0.001). This decrease was observed when PPIs were administered separately in the evening. However, IPA by clopidogrel with rabeprazole administered at lunchtime was 51.6%, which was markedly similar to that of clopidogrel alone (p = 0.114). All tested PPIs reduce the efficacy of clopidogrel when administered concomitantly. Our preliminary data suggest that administration of rabeprazole 4 h following clopidogrel may minimize potential drug-drug interactions.
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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, Shizuoka, Japan.
| | - Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Chise Kodaira
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Masafumi Nishino
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Mihoko Yamade
- Department of Clinical Oncology, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Shu Sahara
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Hitomi Ichikawa
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Takuma Kagami
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Moriya Iwaizumi
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
| | - Kazuo Umemura
- Department of Pharmacology, Hamamatsu University School of Medicine, Shizuoka, Japan
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Kawara F, Fujita T, Morita Y, Uda A, Masuda A, Saito M, Ooi M, Ishida T, Kondo Y, Yoshida S, Okuno T, Yano Y, Yoshida M, Kutsumi H, Hayakumo T, Yamashita K, Hirano T, Hirai M, Azuma T. Factors associated with residual gastroesophageal reflux disease symptoms in patients receiving proton pump inhibitor maintenance therapy. World J Gastroenterol 2017; 23:2060-2067. [PMID: 28373773 PMCID: PMC5360648 DOI: 10.3748/wjg.v23.i11.2060] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2016] [Revised: 01/24/2017] [Accepted: 02/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To elucidate the factors associated with residual gastroesophageal reflux disease (GERD) symptoms in patients receiving proton pump inhibitor (PPI) maintenance therapy in clinical practice.
METHODS The study included 39 GERD patients receiving maintenance PPI therapy. Residual symptoms were assessed using the Frequency Scale for Symptoms of GERD (FSSG) questionnaire and the Gastrointestinal Symptom Rating Scale (GSRS). The relationships between the FSSG score and patient background factors, including the CYP2C19 genotype, were analyzed.
RESULTS The FSSG scores ranged from 1 to 28 points (median score: 7.5 points), and 19 patients (48.7%) had a score of 8 points or more. The patients’ GSRS scores were significantly correlated with their FSSG scores (correlation coefficient = 0.47, P < 0.005). In erosive esophagitis patients, the FSSG scores of the CYP2C19 rapid metabolizers (RMs) were significantly higher than the scores of the poor metabolizers and intermediate metabolizers (total scores: 16.7 ± 8.6 vs 7.8 ± 5.4, P < 0.05; acid reflux-related symptom scores: 12 ± 1.9 vs 2.5 ± 0.8, P < 0.005). In contrast, the FSSG scores of the CYP2C19 RMs in the non-erosive reflux disease patients were significantly lower than those of the other patients (total scores: 5.5 ± 1.0 vs 11.8 ± 6.3, P < 0.05; dysmotility symptom-related scores: 1.0 ± 0.4 vs 6.0 ± 0.8, P < 0.01).
CONCLUSION Approximately half of the GERD patients receiving maintenance PPI therapy had residual symptoms associated with a lower quality of life, and the CYP2C19 genotype appeared to be associated with these residual symptoms.
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20
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Jaja C, Barrett N, Patel N, Lyon M, Xu H, Kutlar A. Progressing Preemptive Genotyping of CYP2C19 Allelic Variants for Sickle Cell Disease Patients. Genet Test Mol Biomarkers 2016; 20:609-615. [PMID: 27551817 DOI: 10.1089/gtmb.2016.0001] [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: 12/23/2022] Open
Abstract
AIMS Interindividual variability in drug response and adverse effects have been described for proton pump inhibitors, anticonvulsants, selective serotonin reuptake inhibitors, tricyclic antidepressants, and anti-infectives, but little is known about the safety and efficacy of these medications in patients with sickle cell disease (SCD). We genotyped the CYP2C19 gene which has been implicated in the metabolism of these drugs in an SCD patient cohort to determine the frequencies of reduced function, increased function, or complete loss-of-function variants. MATERIALS AND METHODS DNAs from 165 unrelated SCD patients were genotyped for nine CYP2C19 (*2, *3, *4, *5, *6, *7,*8, *12, and *17) alleles using the iPLEX® ADME PGx multiplex panel. RESULTS Three CYP2C19 alleles (*2, *12, and *17) were detected with the following frequencies: 0.209, 0.006, and 0.236, respectively. The predicted phenotype frequencies were distributed as extensive (31.5%), intermediate (24.8%), poor (5.5%), ultrarapid (30.3%), and unknown metabolizers (7.9%). DISCUSSION Prognostic genotyping is potentially useful for identifying SCD patients with allelic variants linked to proven clinical pharmacokinetic consequences for several drugs metabolized by the CYP2C19 gene. However, the main challenge to implementing a genetics-guided prescribing practice is ensuring concordance between CYP2C19 genotypes and metabolic phenotypes in SCD patients.
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Affiliation(s)
- Cheedy Jaja
- 1 College of Nursing, University of Cincinnati , Cincinnati, Ohio
| | - Nadine Barrett
- 2 Department of Medicine, Georgia Regents University , Augusta, Georgia
| | - Niren Patel
- 2 Department of Medicine, Georgia Regents University , Augusta, Georgia
| | - Matt Lyon
- 3 Department of Emergency Medicine, Georgia Regents University , Augusta, Georgia
| | - Hongyan Xu
- 4 Department of Biostatistics, Georgia Regents University , Augusta, Georgia
| | - Abdullah Kutlar
- 2 Department of Medicine, Georgia Regents University , Augusta, Georgia
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21
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Ahmed S, Zhou Z, Zhou J, Chen SQ. Pharmacogenomics of Drug Metabolizing Enzymes and Transporters: Relevance to Precision Medicine. GENOMICS PROTEOMICS & BIOINFORMATICS 2016; 14:298-313. [PMID: 27729266 PMCID: PMC5093856 DOI: 10.1016/j.gpb.2016.03.008] [Citation(s) in RCA: 181] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/11/2015] [Revised: 02/17/2016] [Accepted: 03/08/2016] [Indexed: 01/11/2023]
Abstract
The interindividual genetic variations in drug metabolizing enzymes and transporters influence the efficacy and toxicity of numerous drugs. As a fundamental element in precision medicine, pharmacogenomics, the study of responses of individuals to medication based on their genomic information, enables the evaluation of some specific genetic variants responsible for an individual’s particular drug response. In this article, we review the contributions of genetic polymorphisms to major individual variations in drug pharmacotherapy, focusing specifically on the pharmacogenomics of phase-I drug metabolizing enzymes and transporters. Substantial frequency differences in key variants of drug metabolizing enzymes and transporters, as well as their possible functional consequences, have also been discussed across geographic regions. The current effort illustrates the common presence of variability in drug responses among individuals and across all geographic regions. This information will aid health-care professionals in prescribing the most appropriate treatment aimed at achieving the best possible beneficial outcomes while avoiding unwanted effects for a particular patient.
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Affiliation(s)
- Shabbir Ahmed
- Department of Precision Medicine and Biopharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Zhan Zhou
- Department of Precision Medicine and Biopharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Jie Zhou
- Department of Precision Medicine and Biopharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Shu-Qing Chen
- Department of Precision Medicine and Biopharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; International Center for Precision Medicine, Zhejiang California International NanoSystems Institute, Hangzhou 310058, China.
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22
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Mermelstein J, Mermelstein AC, Chait MM. Proton pump inhibitors for the treatment of patients with erosive esophagitis and gastroesophageal reflux disease: current evidence and safety of dexlansoprazole. Clin Exp Gastroenterol 2016; 9:163-72. [PMID: 27471402 PMCID: PMC4948703 DOI: 10.2147/ceg.s91602] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Gastroesophageal reflux disease is the most common upper gastroenterology disorder in the US. It is associated with a variety of complications and significantly impacts quality of life. Proton pump inhibitors are the most effective treatment. Dexlansoprazole modified release (MR) is a proton pump inhibitor that employs a novel release formulation that prolongs its absorption and allows for more flexibility in dosing. Dexlansoprazole MR can be dosed without regard to food intake or time of day, and once-daily dosing may replace twice-daily dosing of other agents. Dexlansoprazole MR is effective for healing and maintenance of erosive esophagitis, and for the treatment of nonerosive disease, including nocturnal gastroesophageal reflux disease. Dexlansoprazole MR is safe and well tolerated, and can improve quality of life.
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Affiliation(s)
- Joseph Mermelstein
- Department of Medicine, Mount Sinai Beth Israel/Icahn School of Medicine
| | | | - Maxwell M Chait
- Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
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23
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Abstract
Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.
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24
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Kogame A, Takeuchi T, Nonaka M, Yamasaki H, Kawaguchi N, Bernards A, Tagawa Y, Morohashi A, Kondo T, Moriwaki T, Asahi S. Disposition and metabolism of TAK-438 (vonoprazan fumarate), a novel potassium-competitive acid blocker, in rats and dogs. Xenobiotica 2016; 47:255-266. [DOI: 10.1080/00498254.2016.1182667] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Affiliation(s)
- Akifumi Kogame
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Toshiyuki Takeuchi
- 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
| | - 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
| | - Ai Bernards
- Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan
| | - Yoshihiko Tagawa
- 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
| | - Takahiro Kondo
- 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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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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Lansoprazole Is Associated with Worsening Asthma Control in Children with the CYP2C19 Poor Metabolizer Phenotype. Ann Am Thorac Soc 2016; 12:878-85. [PMID: 25844821 DOI: 10.1513/annalsats.201408-391oc] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
RATIONALE Gastric acid blockade in children with asymptomatic acid reflux has not improved asthma control in published studies. There is substantial population variability regarding metabolism of and response to proton pump inhibitors based on metabolizer phenotype. How metabolizer phenotype affects asthma responses to acid blockage is not known. OBJECTIVES To determine how metabolizer phenotype based on genetic analysis of CYP2C19 affects asthma control among children treated with a proton pump inhibitor. METHODS Asthma control as measured by the Asthma Control Questionnaire (ACQ) and other questionnaires from a 6-month clinical trial of lansoprazole in children with asthma was analyzed for associations with surrogates of lansoprazole exposure (based on treatment assignment and metabolizer phenotype). Groups included placebo-treated children; lansoprazole-treated extensive metabolizers (EMs); and lansoprazole-treated poor metabolizers (PMs). Metabolizer phenotypes were based on CYP2C19 haplotypes. Carriers of the CYP2C19*2, *3, *8, *9, or *10 allele were PMs; carriers of two wild-type alleles were extensive metabolizers (EMs). MEASUREMENTS AND MAIN RESULTS Asthma control through most of the treatment period was unaffected by lansoprazole exposure or metabolizer phenotype. At 6 months, PMs displayed significantly worsened asthma control compared with EMs (+0.16 vs. -0.13; P = 0.02) and placebo-treated children (+0.16 vs. -0.23; P < 0.01). Differences in asthma control were not associated with changes in gastroesophageal reflux symptoms. Recent upper respiratory infection worsened asthma control, and this upper respiratory infection effect may be more pronounced among lansoprazole-treated PMs. CONCLUSIONS Children with the PM phenotype developed worse asthma control after 6 months of lansoprazole treatment for poorly controlled asthma. Increased exposure to proton pump inhibitor may worsen asthma control by altering responses to respiratory infections. Clinical trial registered with www.clinicaltrials.gov (NCT00604851).
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Litviakov NV, Freidin MB, Sazonov AE, Khalyuzova MV, Buldakov MA, Karbyshev MS, Albakh ЕN, Isubakova DS, Gagarin АA, Nekrasov GB, Mironova EB, Izosimov АS, Takhauov RM, Karpov АB. Different patterns of allelic imbalance in sporadic tumors and tumors associated with long-term exposure to gamma-radiation. MUTATION RESEARCH-GENETIC TOXICOLOGY AND ENVIRONMENTAL MUTAGENESIS 2015; 794:8-16. [PMID: 26653978 DOI: 10.1016/j.mrgentox.2015.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/16/2014] [Revised: 09/03/2015] [Accepted: 09/08/2015] [Indexed: 02/07/2023]
Abstract
The study aimed to reveal cancer related mutations in DNA repair and cell cycle genes associated with chronic occupational exposure to gamma-radiation in personnel of the Siberian Group of Chemical Enterprises (SGCE). Mutations were analyzed by comparing genotypes of malignant tumors and matched normal tissues of 255 cancer patients including 98 exposed to external gamma-radiation (mean dose 128.1±150.5mSv). Also a genetic association analysis was carried out in a sample of 149 cancer patients and 908 healthy controls occupationally exposed to gamma-radiation (153.2±204.6mSv and 150.5±211.2mSv, respectively). Eight SNPs of genes of DNA excision repair were genotyped (rs13181, rs1052133, rs1042522, rs2305427, rs4244285, rs1045642, rs1805419 and rs1801133). The mutation profiles in heterozygous loci for selected SNP were different between sporadic tumors and tumors in patients exposed to radiation. In sporadic tumors, heterozygous genotype Arg/Pro of the rs1042522 SNP mutated into Arg/0 in 15 cases (9.6%) and 0/Pro in 14 cases (8.9%). The genotype Lys/Gln of the rs13181 SNP mutated into Lys/0 and 0/Gln in 9 and 4 cases, respectively. In tumors of patients exposed to low-level radiation, the rs1042522 Arg/0 mutated genotype was found in 12 cases (12.1%), while in 2 cases (2%) 0/Pro mutation was observed. Finally, the rs13181 0/Gln mutated genotype was observed in 15 cases (16,5%) . Thus, our study showed the difference in patterns of allelic imbalance in tumors appeared under low-level radiation exposure and spontaneous tumors for selected SNPs. This suggests different mechanisms of inactivation of heterozygous genotypes in sporadic and radiation-induced tumors.
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Affiliation(s)
- Nikolai V Litviakov
- Seversk Biophysical Research Centre of the Federal Medical and Biological Agency, Seversk, Russia; Tomsk Cancer Research Institute, Tomsk, Russia; National Research Tomsk State University, Tomsk, Russia.
| | - Maxim B Freidin
- Population Genetics Laboratory, Research Institute for Medical Genetics, Tomsk, Russia
| | - Aleksey E Sazonov
- Seversk Biophysical Research Centre of the Federal Medical and Biological Agency, Seversk, Russia
| | - Maria V Khalyuzova
- Seversk Biophysical Research Centre of the Federal Medical and Biological Agency, Seversk, Russia; National Research Tomsk State University, Tomsk, Russia
| | - Mikhail A Buldakov
- Tomsk Cancer Research Institute, Tomsk, Russia; National Research Tomsk State University, Tomsk, Russia
| | - Mikhail S Karbyshev
- Tomsk Cancer Research Institute, Tomsk, Russia; National Research Tomsk State University, Tomsk, Russia
| | - Еlena N Albakh
- Seversk Biophysical Research Centre of the Federal Medical and Biological Agency, Seversk, Russia
| | - Daria S Isubakova
- Seversk Biophysical Research Centre of the Federal Medical and Biological Agency, Seversk, Russia
| | - Аleksey A Gagarin
- Clinical Hospital #81 of the Federal Medical and Biological Agency, Seversk, Russia
| | - Gennadiy B Nekrasov
- Clinical Hospital #81 of the Federal Medical and Biological Agency, Seversk, Russia
| | - Elena B Mironova
- Clinical Hospital #81 of the Federal Medical and Biological Agency, Seversk, Russia
| | - Аndrey S Izosimov
- Clinical Hospital #81 of the Federal Medical and Biological Agency, Seversk, Russia
| | - Ravil M Takhauov
- Seversk Biophysical Research Centre of the Federal Medical and Biological Agency, Seversk, Russia
| | - Аndrei B Karpov
- Seversk Biophysical Research Centre of the Federal Medical and Biological Agency, Seversk, Russia
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Lima JJ, Franciosi JP. Pharmacogenomic testing: the case for CYP2C19 proton pump inhibitor gene-drug pairs. Pharmacogenomics 2015; 15:1405-16. [PMID: 25303292 DOI: 10.2217/pgs.14.103] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The use of proton pump inhibitors (PPIs) in the treatment of gastroesophageal reflux and related diseases is increasing, especially in the pediatric population. Prolonged use of PPIs has been associated with several adverse effects, including potentially life-threatening gastric and respiratory infections, which are related to dose or to the degree of gastric acid suppression. Genetic variation in the CYP2C19 gene gives rise to poor and extensive metabolizer phenotypes, which influence PPI clearance, efficacy and exposure. A recent paper linked lansoprazole-associated respiratory infections in children with the poor metabolizer phenotype. The case is made for implementing pharmacogenomic testing for the CYP2C19-PPI gene-drug pair and to dose accordingly in order to minimize PPI-associated infections.
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Affiliation(s)
- John J Lima
- Center for Pharmacogenomics & Translational Research, Nemours Children's Clinic, 807 Children's Way, Jacksonville, FL 32207, USA
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Sychev DA, Denisenko NP, Sizova ZM, Grachev AV, Velikolug KA. The frequency of CYP2C19 genetic polymorphisms in Russian patients with peptic ulcers treated with proton pump inhibitors. PHARMACOGENOMICS & PERSONALIZED MEDICINE 2015; 8:111-4. [PMID: 26109874 PMCID: PMC4472152 DOI: 10.2147/pgpm.s78986] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Introduction Proton pump inhibitors, which are widely used as acid-inhibitory agents for the treatment of peptic ulcers, are mainly metabolized by 2C19 isoenzyme of cytochrome P450 (CYP2C19). CYP2C19 has genetic polymorphisms, associated with extensive, poor, intermediate or ultra-rapid metabolism of proton pump inhibitors. Genetic polymorphisms of CYP2C19 could be of clinical concern in the treatment of peptic ulcers with proton pump inhibitors. Aim To investigate the frequencies of CYP2C19*2, CYP2C19*3, and CYP2C19*17 alleles and genotypes in Russian patients with peptic ulcers. Methods We retrospectively reviewed the cases of 971 patients of Caucasian origin with Russian nationality from Moscow region with endoscopically and histologically proven ulcers, 428 males (44%) and 543 females (56%). The mean age was 44.6±11.9 years (range: 15–88 years). DNA was extracted from ethylenediaminetetraacetic acid whole blood samples (10 mL). The polymorphisms CYP2C19 681G.A (CYP2C19*2, rs4244285), CYP2C19 636 G.A (CYP2C19*3, rs4986893) and CYP2C19 -806 C.T (CYP2C19*17, rs12248560) were evaluated using real-time polymerase chain reaction. Results Regarding CYP2C19 genotype, 317 patients (32.65%) out of 971 were CYP2C19*1/*1 carriers classified as extensive metabolizers. Three hundred and eighty-six (39.75%) with CYP2C19*1/*17 or CYP2C19*17/*17 genotype were ultra-rapid metabolizers. Two hundred and fifty-one people (25.85%) were intermediate metabolizers with CYP2C19*1/*2, CYP2C19*2/*17, CYP2C19*1/*3, CYP2C19*3/*17 genotypes. Seventeen patients (1.75%) with CYP2C19*2/*2, CYP2C19*3/*3, CYP2C19*2/*3 genotypes were poor metabolizers. The allele frequencies were the following: CYP2C19*2 – 0.140, CYP2C19*3 – 0.006, CYP2C19*17 – 0.274. Conclusion There is a high frequency of CYP2C19 genotypes associated with modified response to proton pump inhibitors in Russian patients with peptic ulcers. Genotyping for CYP2C19 polymorphisms is suggested to be a useful tool for personalized dosing of proton pump inhibitors.
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Affiliation(s)
- D A Sychev
- Russian Medical Academy of Post-Graduate Education, Moscow, Russia ; I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - N P Denisenko
- Russian Medical Academy of Post-Graduate Education, Moscow, Russia ; I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | - Z M Sizova
- I.M. Sechenov First Moscow State Medical University, Moscow, Russia
| | | | - K A Velikolug
- Out-patient department Number 51 branch 3, Moscow, Russia
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Peng XE, Chen HF, Hu ZJ, Shi XS. Independent and combined effects of environmental factors and CYP2C19 polymorphisms on the risk of esophageal squamous cell carcinoma in Fujian Province of China. BMC MEDICAL GENETICS 2015; 16:15. [PMID: 25927305 PMCID: PMC4422422 DOI: 10.1186/s12881-015-0156-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Accepted: 02/18/2015] [Indexed: 12/28/2022]
Abstract
Background The purpose of this study was to explore the effects of CYP2C19 gene polymorphisms and various environmental factors and their interactions on the risk of esophageal squamous cell carcinoma (ESCC) in a Chinese Han population. Methods A 1:2 frequency-matched case control study of 285 patients and 570 controls was conducted from June 2010 to May 2011 in AnXi of Fujian province, China. Environmental factors were investigated using a self-administered questionnaire and genotypes were determined using polymerase chain reaction restriction fragment length polymorphism based methods. Unconditional logistic regression models were used for statistical evaluation. Results Current or former smoking, consumption of pickled vegetables or hot beverages/food, having a first degree relative with ESCC and history of reflux esophagitis were significantly associated with increased ESCC risk, whereas tea drinking and consumption of fresh vegetables and fruits were significantly associated with decreased risk. The CYP2C19*2 GA/AA genotype was significantly more prevalent in ESCC patients and individuals with at least one copy of the CYP2C19*2 A allele had a 3.19-fold increased risk (adjusted 95% confidence interval (CI): 2.21–4.61, P < 0.001) of ESCC compared with those without this allele. We found no significant associations between CYP2C19*3 genotypes and ESCC. The Cyp2C19*2 polymorphism appeared to have a multiplicative joint effect with tea drinking and hot beverage/food consumption (gene–tea drinking: Pinteraction = 0.042; hot beverage/food consumption: Pinteraction = 6.98 × 10−6) and an additive joint effect with pickled vegetable consumption (interaction contrast ratio = 1.96, 95% CI: 0.12–3.80). Conclusions Our findings suggest that the CYP2C19*2 polymorphism plays an important role in the development of ESCC in the Chinese population, modified by tea drinking and consumption of pickled vegetables or hot beverages/food. Further studies are warranted to confirm our results. Electronic supplementary material The online version of this article (doi:10.1186/s12881-015-0156-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xian-E Peng
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, 88 Jiaotong Road, Fuzhou, 350004, China. .,Key Laboratory of Ministry of Education for Gastrointestinal Cancer, Research Center of Molecular Medicine, Fujian Medical University, Fujian, China.
| | - Hua-Fang Chen
- CDC of XiaMen, 681-685Shengguang Road, Xiamen, China.
| | - Zhi-Jian Hu
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, 88 Jiaotong Road, Fuzhou, 350004, China.
| | - Xi-Shun Shi
- Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, 88 Jiaotong Road, Fuzhou, 350004, China.
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Iwakiri R, Higuchi K, Kato M, Fujishiro M, Kinoshita Y, Watanabe T, Takeuchi T, Yamauchi M, Sanomura M, Nakagawa H, Sugisaki N, Okada Y, Ogawa H, Arakawa T, Fujimoto K. Randomised clinical trial: prevention of recurrence of peptic ulcers by rabeprazole in patients taking low-dose aspirin. Aliment Pharmacol Ther 2014; 40:780-95. [PMID: 25100080 DOI: 10.1111/apt.12907] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Revised: 05/28/2014] [Accepted: 07/18/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND Few studies have evaluated the effects of rabeprazole on low-dose aspirin (LDA)-induced gastroduodenal injuries. AIM To conduct a randomised, double-blind, triple-dummy, active-controlled, multicentre trial, named the PLANETARIUM study, to assess the efficacy, dose-response relationship and safety of rabeprazole for peptic ulcer recurrence in Japanese patients on long-term LDA therapy. METHODS Eligible patients had a history of endoscopically confirmed peptic ulcers and were receiving long-term LDA (81 or 100 mg/day) therapy for cardiovascular or cerebrovascular protection. Subjects were randomly segregated into three groups receiving rabeprazole 10 mg once daily (standard dose in Japan), rabeprazole 5 mg once daily, or teprenone (geranylgeranylacetone; mucosal protective agent commercially available in Japan) 50 mg three times per day as an active control. The primary endpoint was recurrence of peptic ulcers over 24 weeks. RESULTS Among 472 randomised subjects, 452 subjects (n = 151, 150, 151, respectively) constituted the full analysis set. The cumulative recurrence rates of peptic ulcers over 24 weeks in the 10- and 5-mg rabeprazole groups were 1.4% and 2.8%, respectively, both of which were significantly lower than that in the teprenone group (21.7%). The cumulative occurrence rate of bleeding ulcers over 24 weeks in the teprenone group was 4.6%, while bleeding ulcers were not observed in the 10- or 5-mg rabeprazole groups. Rabeprazole was well tolerated at both doses. CONCLUSION Rabeprazole prevents the recurrence of peptic ulcers with no evidence of a major dose-response effect in subjects on low-dose aspirin therapy.
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Affiliation(s)
- R Iwakiri
- Department of Internal Medicine & Gastrointestinal Endoscopy, Saga Medical School, Saga, Japan
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Sugimoto M, Uotani T, Sahara S, Ichikawa H, Yamade M, Sugimoto K, Furuta T. Efficacy of tailored Helicobacter pylori eradication treatment based on clarithromycin susceptibility and maintenance of acid secretion. Helicobacter 2014; 19:312-318. [PMID: 24690010 DOI: 10.1111/hel.12128] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Insufficient acid inhibition during Helicobacter pylori eradication treatment and bacterial resistance to antibiotics often causes eradication failure. Four times daily dosing (q.i.d.) of a proton-pump inhibitor (PPI) achieves potent acid inhibition, suggesting its potential usefulness as a regimen for eradicating H. pylori infection. Therefore, a tailored eradication regimen based on antibiotic susceptibility and maintenance of acid inhibition should have a high success rate. We investigated the efficacy of such treatment based on clarithromycin (CAM) susceptibility. METHODS Using 153 H. pylori-positive Japanese patients, we investigated the efficacy of tailored eradication strategy: (1) Patients infected with CAM-sensitive H. pylori were treated with a PPI (rabeprazole 10 mg q.i.d.), amoxicillin 500 mg q.i.d., and CAM 200 mg b.i.d. (n = 89), and (2) patients infected with CAM-resistant were given the same doses of rabeprazole and amoxicillin and metronidazole 250 mg b.i.d. (n = 64) for 1 week. RESULTS In the tailored regimen group, the overall eradication rate was 96.7% (95% CI: 92.5-98.9%, 148/153) in the intention-to-treat (ITT) analysis and 97.4% (93.4-99.3%, 148/152) in the PP analysis. The eradication rates for the CAM- and metronidazole-based treatments were similar (95.5% and 98.4%, respectively, p = .400). The tailored treatment achieved a high eradication rate in CYP2C19 rapid metabolizers who were a resistance genotype for PPI treatment (94.3% (86.0-98.4%, 66/70)). DISCUSSION A tailored H. pylori eradication regimen based on CAM susceptibility and maintaining acid secretion (rabeprazole 10 mg q.i.d.) is useful because it can achieve an eradication rate exceeding 95%, irrespective of eradication history, thus overcoming differences among CYP2C19 genotypes.
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Affiliation(s)
- Mitsushige Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Shizuoka, Japan
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Uotani T, Sugimoto M, Nishino M, Ichikawa H, Sahara S, Yamade M, Iwaizumi M, Yamada T, Osawa S, Sugimoto K, Umemura K, Watanabe H, Miyajima H, Furuta T. Prevention of gastric mucosal injury induced by anti-platelet drugs by famotidine. J Clin Pharmacol 2014; 54:858-864. [PMID: 24615745 DOI: 10.1002/jcph.284] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 03/03/2014] [Indexed: 01/11/2025]
Abstract
Anti-platelet drug-induced gastric mucosal injury correlates with intragastric pH. Our aim was to investigate prophylaxis effects of famotidine, one of the representative histamine-2 receptor antagonists (H2RA), on gastric mucosal injury induced by dual therapy with low-dose aspirin and clopidogrel in relation to Helicobacter pylori (H. pylori) infection and CYP2C19 genotypes. This study was conducted for 20 healthy Japanese volunteers (10 H. pylori-positive and 10-negative subjects) with 100 mg aspirin plus 75 mg clopidogrel (AC) once-daily dosing and AC plus 20 mg famotidine twice-daily dosing (ACH). Mucosal injury was endoscopically assessed on day 3 and 7 and 24-hour intragastric pH and antiplatelet-function test was performed on day 7. Median pH in ACH was similar between CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM)/poor metabolizer (PM) and was significantly higher in H. pylori-positive than negative subjects (P < .05). Mucosal injury with ACH significantly decreased in both day 3 and 7 compared with AC, irrespective with H. pylori and CYP2C19 genotypes (P < .05). Although antiplatelet effect of clopidogrel in EM was significantly higher than that in IM/PM, the additional famotidine did not affect the effect. Anti-platelet drug-induced gastric injury was alleviated by famotidine without attenuation of anti-platelet functions irrespective of H. pylori and CYP2C19 genotypes.
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Affiliation(s)
- Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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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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Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
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Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3:1-17. [DOI: 10.5315/wjh.v3.i1.1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
As recognition of mast cell (MC) involvement in a range of chronic inflammatory disorders has increased, diagnosticians’ suspicions of MC activation disease (MCAD) in their chronically mysteriously inflamed patients have similarly increased. It is now understood that the various forms of systemic mastocytosis - diseases of inappropriate activation and proliferation of MCs seemingly driven by a small set of rare, usually constitutively activating mutations in assorted MC regulatory elements - comprise merely the tip of the MCAD iceberg, whereas the far larger and far more clinically heterogeneous (and thus more difficult to recognize) bulk of the iceberg consists of assorted forms of MC activation syndrome (MCAS) which manifest little to no abnormal MC proliferation and may originate from a far more heterogeneous set of MC mutations. It is reasonable to suspect MCAD when symptoms and signs of MC activation are present and no other diagnosis better accounting for the full range of findings is present. Initial laboratory assessment should include not only routine blood counts and serum chemistries but also a serum total tryptase level, which helps direct further evaluation for mastocytosis vs MCAS. Appropriate tissue examinations are needed to diagnose mastocytosis, while elevated levels of relatively specific mast cell mediators are sought to support diagnosis of MCAS. Whether assessing for mastocytosis or MCAS, testing is fraught with potential pitfalls which can easily yield false negatives leading to erroneous rejection of diagnostic consideration of MCAD in spite of a clinical history highly consistent with MCAD. Efforts at accurate diagnosis of MCAD are worthwhile, as many patients then respond well to appropriately directed therapeutic efforts.
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Mejia A, Kraft WK. Acid peptic diseases: pharmacological approach to treatment. Expert Rev Clin Pharmacol 2014; 2:295-314. [PMID: 21822447 DOI: 10.1586/ecp.09.8] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Acid peptic disorders are the result of distinctive, but overlapping pathogenic mechanisms leading to either excessive acid secretion or diminished mucosal defense. They are common entities present in daily clinical practice that, owing to their chronicity, represent a significant cost to healthcare. Key elements in the success of controlling these entities have been the development of potent and safe drugs based on physiological targets. The histamine-2 receptor antagonists revolutionized the treatment of acid peptic disorders owing to their safety and efficacy profile. The proton-pump inhibitors (PPIs) represent a further therapeutic advance due to more potent inhibition of acid secretion. Ample data from clinical trials and observational experience have confirmed the utility of these agents in the treatment of acid peptic diseases, with differential efficacy and safety characteristics between and within drug classes. Paradigms in their speed and duration of action have underscored the need for new chemical entities that, from a single dose, would provide reliable duration of acid control, particularly at night. Moreover, PPIs reduce, but do not eliminate, the risk of ulcers in patients taking NSAIDs, reflecting untargeted physiopathologic pathways and a breach in the ability to sustain an intragastric pH of more than 4. This review provides an assessment of the current understanding of the physiology of acid production, a discussion of medications targeting gastric acid production and a review of efficacy in specific acid peptic diseases, as well as current challenges and future directions in the treatment of acid-mediated diseases.
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Affiliation(s)
- Alex Mejia
- Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, 1170 Main Building, 132 South 10th Street, Philadelphia, PA 19107-5244, USA, Tel.: +1 203 243 7501
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Lima JJ, Lang JE, Mougey EB, Blake KB, Gong Y, Holbrook JT, Wise RA, Teague WG. Association of CYP2C19 polymorphisms and lansoprazole-associated respiratory adverse effects in children. J Pediatr 2013; 163:686-91. [PMID: 23623526 PMCID: PMC7274090 DOI: 10.1016/j.jpeds.2013.03.017] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 01/28/2013] [Accepted: 03/12/2013] [Indexed: 12/12/2022]
Abstract
OBJECTIVE To determine whether cytochrome P450 (CYP)2C19 haplotype associates with lansoprazole-associated adverse event frequency. STUDY DESIGN Respiratory adverse events from a clinical trial of lansoprazole in children with asthma were analyzed for associations with extensive or poor metabolizer (PM) phenotype based on CYP2C19 haplotypes. Carriers of CYP2C19*2, *3, *8, or *9 alleles were PMs; carriers of 2 wild-type alleles were extensive metabolizers (EMs). Plasma concentrations of lansoprazole were determined in PM and EM phenotypes. RESULTS The frequency of upper respiratory infection among PMs (n = 45) was higher than that among EMs (n = 91), which in turn was higher than that in placebo subjects (n = 135; P = .0039). The frequency of sore throat (ST) was similarly distributed among EMs and PMs (P = .0015). The OR (95% CI) for upper respiratory infections in PMs was 2.46 (1.02-5.96) (P = .046); for EMs, the OR (95% CI) was 1.55 (0.86-2.79). The OR (95% CI) for ST in EMs and PMs was 2.94 (1.23-7.05, P = .016) vs 1.97 (1.09-3.55, P = .024), respectively. Mean ± SD plasma concentrations of lansoprazole were higher in PMs than in EMs: 207 ± 179 ng/mL vs 132 ± 141 ng/mL (P = .04). CONCLUSIONS Lansoprazole-associated upper respiratory infections and ST in children are related in part to CYP2C19 haplotype. Our data suggest that lansoprazole-associated adverse events in children may be mitigated by adjusting the conventional dose in PMs. Additional studies are required to replicate our findings.
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Affiliation(s)
- John J Lima
- Center for Pharmacogenomics and Translational Research, Nemours Children's Clinic, Jacksonville, FL, USA.
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Functional polymorphisms in the CYP2C19 gene contribute to digestive system cancer risk: evidence from 11,042 subjects. PLoS One 2013; 8:e66865. [PMID: 23874401 PMCID: PMC3712993 DOI: 10.1371/journal.pone.0066865] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2013] [Accepted: 05/12/2013] [Indexed: 12/19/2022] Open
Abstract
Background CYP2C19 belongs to the cytochrome P450 superfamily of enzymes involved in activating and detoxifying many carcinogens and endogenous compounds, which has attracted considerable attention as a candidate gene for digestive system cancer. CYP2C19 has two main point mutation sites (CYP2C19*2, CYP2C19*3) leading to poor metabolizer (PM) phenotype. In the past decade, the relationship between CYP2C19 polymorphism and digestive system cancer has been reported in various ethnic groups; however, these studies have yielded contradictory results. Methods To clarify this inconsistency, we performed this meta-analysis. Databases including Pubmed, EMBASE, Web of Science and China National Knowledge Infrastructure (CNKI) were searched to find relevant studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. Results In total, 18 studies with 4,414 cases and 6,628 controls were included. Overall, significantly elevated digestive system cancer risk was associated CYP2C19 PM with OR of 1.66 (95%CI: 1.31–2.10, P<10−5) when all studies were pooled into the meta-analysis. There was strong evidence of heterogeneity (P = 0.006), which largely disappeared after stratification by cancer type. In the stratified analyses according to cancer type, ethnicity, control source and sample size, significantly increased risks were found. Conclusions In summary, our meta-analysis suggested that the PM phenotype caused by the variation on CYP2C19 gene is associated with increased risk of digestive system cancer, especially in East Asians.
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Yamane T, Umeda A, Shimao H, Ishii T. A Case of Refractory Gastric Cardia Ulcer in Which Marked Elevation of the Surrounding Mucosa was Observed During the Clinical Course. Gastroenterology Res 2013; 6:106-109. [PMID: 27785238 PMCID: PMC5051154 DOI: 10.4021/gr546w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/19/2013] [Indexed: 12/24/2022] Open
Abstract
A 55-year-old man visited our department because of epigastric pain. Upper gastrointestinal endoscopy revealed a small, undermined ulcer in the gastric cardia. He had no history of taking NSAIDs, and was positive for Helicobacter pylori (Hp) infection. After Hp eradication therapy followed by 8 weeks of proton pump inhibitor (PPI) administration, re-endoscopy showed that the ulcer had slightly shrunk without scarring, and the surrounding mucosa was markedly elevated, like in a submucosal tumor. Endoscopic ultrasonography, performed at the same time, showed thickening of the submucosal and muscular layers around the ulcer. After continuous PPI administration, the mucosal elevation disappeared, and the ulcer shrunk and later scarred. However, when the dose of PPI was reduced with the aim of discontinuing it after the confirmation of successful Hp eradication, the ulcer recurred. We report this case of gastric ulcer because of its peculiar clinical presentation.
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Affiliation(s)
- Tateki Yamane
- Division of Gastroenterology, Department of Internal Medicine, The International University of Health and Welfare, Shioya Hospital, Japan
| | - Akira Umeda
- Division of Pulmonology, Department Of Internal Medicine, The International University of Health and Welfare, Shioya Hospital, Japan
| | - Hitoshi Shimao
- Department of Surgery, The International University of Health and Welfare, Shioya Hospital, Japan
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Miwa H, Takubo K, Shimatani T, Furuta T, Oshima T, Tanaka J, Aida J, Ito M, Kurosawa S, Joh T, Wada T, Habu Y, Watanabe Y, Hongo M, Chiba T, Kinoshita Y. Histology of symptomatic gastroesophageal reflux disease: is it predictive of response to proton pump inhibitors? J Gastroenterol Hepatol 2013; 28:479-487. [PMID: 22989221 DOI: 10.1111/j.1440-1746.2012.07266.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 08/27/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIM To examine the differences in esophageal histopathology between non-erosive reflux disease (NERD) and reflux esophagitis (RE), and to investigate whether baseline esophageal histopathology can predict the therapeutic response to proton pump inhibitors (PPIs). METHOD The subjects comprised 94 patients with NERD (n = 71) or mild RE (n = 23). Tissue was biopsied from 5 cm above the squamo-columnar junction (SCJ), and the degree or presence of nine histopathological markers was assessed. The patients were treated with rabeprazole (RPZ) 10 mg once daily for 4 weeks. If complete heartburn relief was not achieved, RPZ was increased to 10 mg twice daily for another 2 weeks, and then to 20 mg twice daily for another 2 weeks if heartburn remained. RESULTS Features of esophageal histopathology 5 cm above the SCJ differed between NERD and RE patients. The esophageal histopathology in patients unresponsive to RPZ was characterized by Protein Gene Product (PGP) 9.5 negativity in those with NERD, and intraepithelial bleeding in those with RE. In addition, the combination of dilated intercellular spaces (DIS) (+)/PGP 9.5 (-) was indicative of strong resistance to PPI therapy in NERD patients. CONCLUSION The therapeutic efficacy of PPI can be predicted from the features of biopsied esophageal tissue. Factors predictive of resistance to treatment with PPI are negativity for PGP 9.5 in NERD patients and intraepithelial bleeding in RE patients.
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Affiliation(s)
- Hiroto Miwa
- Division of Upper Gastroenterology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.
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Lee SJ. Clinical Application of CYP2C19 Pharmacogenetics Toward More Personalized Medicine. Front Genet 2013; 3:318. [PMID: 23378847 PMCID: PMC3561709 DOI: 10.3389/fgene.2012.00318] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 12/20/2012] [Indexed: 12/12/2022] Open
Abstract
More than 30 years of genetic research on the CYP2C19 gene alone has identified approximately 2,000 reference single nucleotide polymorphisms (rsSNPs) containing 28 registered alleles in the P450 Allele Nomenclature Committee and the number continues to increase. However, knowledge of CYP2C19 SNPs remains limited with respect to biological functions. Functional information on the variant is essential for justifying its clinical use. Only common variants (minor allele frequency >5%) that represent CYP2C19*2, *3, *17, and others have been mostly studied. Discovery of new genetic variants is outstripping the generation of knowledge on the biological meanings of existing variants. Alternative strategies may be needed to fill this gap. The present study summarizes up-to-date knowledge on functional CYP2C19 variants discovered in phenotyped humans studied at the molecular level in vitro. Understanding the functional meanings of CYP2C19 variants is an essential step toward shifting the current medical paradigm to highly personalized therapeutic regimens.
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Affiliation(s)
- Su-Jun Lee
- Department of Pharmacology, Pharmacogenomics Research Center, Inje University College of Medicine, Inje University Busan, South Korea
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Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther 2013; 138:103-41. [PMID: 23333322 DOI: 10.1016/j.pharmthera.2012.12.007] [Citation(s) in RCA: 2719] [Impact Index Per Article: 226.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Accepted: 12/27/2012] [Indexed: 02/06/2023]
Abstract
Cytochromes P450 (CYP) are a major source of variability in drug pharmacokinetics and response. Of 57 putatively functional human CYPs only about a dozen enzymes, belonging to the CYP1, 2, and 3 families, are responsible for the biotransformation of most foreign substances including 70-80% of all drugs in clinical use. The highest expressed forms in liver are CYPs 3A4, 2C9, 2C8, 2E1, and 1A2, while 2A6, 2D6, 2B6, 2C19 and 3A5 are less abundant and CYPs 2J2, 1A1, and 1B1 are mainly expressed extrahepatically. Expression of each CYP is influenced by a unique combination of mechanisms and factors including genetic polymorphisms, induction by xenobiotics, regulation by cytokines, hormones and during disease states, as well as sex, age, and others. Multiallelic genetic polymorphisms, which strongly depend on ethnicity, play a major role for the function of CYPs 2D6, 2C19, 2C9, 2B6, 3A5 and 2A6, and lead to distinct pharmacogenetic phenotypes termed as poor, intermediate, extensive, and ultrarapid metabolizers. For these CYPs, the evidence for clinical significance regarding adverse drug reactions (ADRs), drug efficacy and dose requirement is rapidly growing. Polymorphisms in CYPs 1A1, 1A2, 2C8, 2E1, 2J2, and 3A4 are generally less predictive, but new data on CYP3A4 show that predictive variants exist and that additional variants in regulatory genes or in NADPH:cytochrome P450 oxidoreductase (POR) can have an influence. Here we review the recent progress on drug metabolism activity profiles, interindividual variability and regulation of expression, and the functional and clinical impact of genetic variation in drug metabolizing P450s.
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Saeed LH, Mayet AY. Genotype-phenotype analysis of CYP2C19 in healthy saudi individuals and its potential clinical implication in drug therapy. Int J Med Sci 2013; 10:1497-502. [PMID: 24046523 PMCID: PMC3775106 DOI: 10.7150/ijms.6795] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Accepted: 07/29/2013] [Indexed: 01/01/2023] Open
Abstract
UNLABELLED CYP2C19 is a cytochrome P450 enzyme, which is involved in the metabolism of some clinically important medications and is encoded by a highly polymorphic gene. There is no available data on the distribution of the CYP2C19 *4 and *17 mutant alleles in the Saudi Arabian population. The aim of the study was to determine different CYP2C19 mutant allele (*2, *4 and *17) frequencies in healthy Saudi subjects and to determine genotype frequencies for these mutations. The CYP2C19 genotypes were then classified into phenotypes. RESULT In 201 adults of Saudi ethnicity, the allele frequencies were CYP2C19*1 (62.9%), *17 (25.7%), *2 (11.2%) and *4 (0.2%). The most prevalent genotype combinations were CYP2C19 *1/*1 (40.3%) and *1/*17 (30.4%). The distribution of CYP2C19 phenotypes was divided into extensive metabolizers (EM) 77.6%, intermediate metabolizers (IM) 14.9%, ultra-rapid metabolizers (UM) 7% and poor metabolizers (PM) 0.4%. This finding has important clinical implications for the use of CYP2C19 metabolized medications in the Saudi population and further studies are needed.
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Affiliation(s)
- Leena H Saeed
- 1. King Fahad Medical City, P.O. Box 59046, Riyadh 11525, Kingdom of Saudi Arabia
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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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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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Aihara H, Sato A, Takeyasu N, Nishina H, Hoshi T, Akiyama D, Kakefuda Y, Watabe H, Aonuma K. Effect of individual proton pump inhibitors on cardiovascular events in patients treated with clopidogrel following coronary stenting:. Catheter Cardiovasc Interv 2012; 80:556-63. [DOI: 10.1002/ccd.23327] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2011] [Revised: 06/30/2011] [Accepted: 07/30/2011] [Indexed: 12/23/2022]
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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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Niioka T. Clinical usefulness of limited sampling strategies for estimating AUC of proton pump inhibitors. YAKUGAKU ZASSHI 2011; 131:407-13. [PMID: 21372537 DOI: 10.1248/yakushi.131.407] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Cytochrome P450 (CYP) 2C19 (CYP2C19) genotype is regarded as a useful tool to predict area under the blood concentration-time curve (AUC) of proton pump inhibitors (PPIs). In our results, however, CYP2C19 genotypes had no influence on AUC of all PPIs during fluvoxamine treatment. These findings suggest that CYP2C19 genotyping is not always a good indicator for estimating AUC of PPIs. Limited sampling strategies (LSS) were developed to estimate AUC simply and accurately. It is important to minimize the number of blood samples because of patient's acceptance. This article reviewed the usefulness of LSS for estimating AUC of three PPIs (omeprazole: OPZ, lansoprazole: LPZ and rabeprazole: RPZ). The best prediction formulas in each PPI were AUC(OPZ)=9.24 x C(6h)+2638.03, AUC(LPZ)=12.32 x C(6h)+3276.09 and AUC(RPZ)=1.39 x C(3h)+7.17 x C(6h)+344.14, respectively. In order to optimize the sampling strategy of LPZ, we tried to establish LSS for LPZ using a time point within 3 hours through the property of pharmacokinetics of its enantiomers. The best prediction formula using the fewest sampling points (one point) was AUC(racemic LPZ)=6.5 x C(3h) of (R)-LPZ+13.7 x C(3h) of (S)-LPZ-9917.3 x G1-14387.2×G2+7103.6 (G1: homozygous extensive metabolizer is 1 and the other genotypes are 0; G2: heterozygous extensive metabolizer is 1 and the other genotypes are 0). Those strategies, plasma concentration monitoring at one or two time-points, might be more suitable for AUC estimation than reference to CYP2C19 genotypes, particularly in the case of coadministration of CYP mediators.
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Kawai T, Takagi Y, Fukuzawa M, Yamagishi T, Goto S. The role of trefoil factor family in apparently healthy subjects administrated gastroprotective agents for the primary prevention of gastrointestinal injuries from low-dose acetylsalicylic acid: a preliminary study. J Clin Biochem Nutr 2011; 49:136-40. [PMID: 21980231 PMCID: PMC3171679 DOI: 10.3164/jcbn.11-10] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2011] [Accepted: 02/09/2011] [Indexed: 12/21/2022] Open
Abstract
It is well-known that acetylsalicylic acid induces gastrointestinal complication. Recently, trefoil factor family has been reported as a mucosal protective factor. We focused on trefoil factor family as one of defensive system for gastrointestinal injuries. The aim of this trial was to evaluate trefoil factor family levels in the serum of healthy subjects with low-dose acetylsalicylic acid. Low-dose acetylsalicylic acid with placebo or proton pump inhibitor or rebamipide were administered in 30 healthy subjects. Transnasal endoscopy was performed at 0, 24 h, 3 and 7 day. Changing of trefoil factor family (1,2,3) and numbers of gastric injuries were evaluated. The numbers of gastric injuries were significantly increased in the placebo group at 3 and 7 days. Injuries in the proton pump inhibitor group were not induced, in the rebamipide group were slightly induced. Trefoil factor family level in the placebo group were decreased in 3 and 7 days compared with prior to starting the trial. Trefoil factor family may have an important association with acetylsalicylic acid-induced gastrointestinal damage. Proton pump inhibitor and rebamipide prevented low-dose acetylsalicylic acid-induced gastrointestinal complications compared with the placebo group.
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Affiliation(s)
- Takashi Kawai
- Endoscopy Center, Tokyo Medical University Hospital, 6-7-1 Nishishinjuku, Shinjuku-ku, Tokyo 160-0023, Japan
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