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Wan X, Jiang H, Peng K. Comparison of Efficacy on First-Line Helicobacter Pylori Eradication Between Potassium-Competitive Acid Blocker (P-CAB)-Based Therapies Versus Proton-Pump Inhibitor (PPI)-Based Therapies: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials. J Clin Gastroenterol 2025:00004836-990000000-00445. [PMID: 40339055 DOI: 10.1097/mcg.0000000000002190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 03/24/2025] [Indexed: 05/10/2025]
Abstract
BACKGROUND Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects over half of the world population, accountable for 89% of all gastric cancer cases. The efficacy of the proton-pump inhibitor (PPI) based-triple therapy is declining, while the novel potassium-competitive acid blocker (P-CAB) based therapy gets new attention. However, it remains unclear regarding the optimal duration and number of comedication(s) for P-CAB-based regimens, which P-CAB is the best-in-class, and whether P-CABs perform better than all PPIs. OBJECTIVE To compare the efficacy on first-line H. pylori eradication between P-CAB-based therapies versus PPI-based therapies. METHODS A systematic review on randomized controlled trials, with network meta-analysis conducted under the Frequentist approach. The P-score method was used to rank the probability of being the best intervention. RESULTS For the first-line treatment eradicating H. pylori infection, the 7-day vonoprazan-based triple therapy (VAC7) has the highest P-score for the probability of being the best intervention (0.96). VAC7 has a significantly higher eradication rate of H. pylori than most PPI-based therapies, including esomeprazole-based, lansoprazole-based, pantoprazole-based, and omeprazole-based regimens, as well as the other P-CAB based regimens, such as tegroprazan-based triple regimen (OR: 2.41, 95% CI: 1.13-5.15). CONCLUSION Vonoprazan-based triple therapy has a higher eradication rate than PPI-based triple therapies, as well as other P-CABs based regimens. It remains unclear whether VAC7 is superior over vonoprazan-based dual therapy (VA7). Overall, VAC7 should be recommended for clinical and public health interventions, with VA7 as a possible alternative considering the local antimicrobial resistance profiles.
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Affiliation(s)
- Xiaoyu Wan
- Department of Technology and Informatics, The Hong Kong Polytechnic University, Hong Kong
| | - Heng Jiang
- Department of Medicine, Westchester Medical Center, Valhalla, NY
| | - Kangning Peng
- Department of Medicine, Cambridge Health Alliance, Cambridge
- Department of Medicine, Harvard Medical School, Boston, MA
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Moss SF, Chey WD, Daniele P, Pelletier C, Jacob R, Tremblay G, Hubscher E, Leifke E, Malfertheiner P. Brief communication: global temporal trends in the efficacy of clarithromycin-based regimens for the treatment of Helicobacter pylori infection. Therap Adv Gastroenterol 2023; 16:17562848231167284. [PMID: 37388121 PMCID: PMC10302680 DOI: 10.1177/17562848231167284] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Accepted: 03/15/2023] [Indexed: 07/01/2023] Open
Abstract
Background Helicobacter pylori eradication rates achieved with clarithromycin-based triple therapies are declining due to antibiotic resistance, but data regarding temporal changes in efficacy with these eradication therapies are scarce. Objective To evaluate the efficacy of clarithromycin-based triple eradication regimens over time. Design A comprehensive literature review and time-trend analysis. Data sources and methods Bibliographies of recently published systematic literature reviews were searched and supplemented with a targeted literature review conducted using Medline and Embase databases and ProQuest from conception to May 2021. Studies reporting H. pylori eradication rates of clarithromycin-based triple therapies were included and temporal trends were estimated using a random-effects model. Results Eradication rates for triple therapies containing proton pump inhibitors (PPIs), clarithromycin, and amoxicillin showed a significant decline over the past 23 years (p = 0.0315). However, this decline was not significant when eradication rates achieved with vonoprazan-based triple therapy were included (p = 0.3910). Conclusion Vonoprazan-based triple therapy partially mitigated the decline in eradication rates seen with PPI-based triple therapy, likely due to more powerful acid suppression of vonoprazan.
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Affiliation(s)
- Steven F. Moss
- Division of Gastroenterology, Alpert Medical School of Brown University, 222 Richmond St, Providence, RI 02903, USA
| | - William D. Chey
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, MI, USA
| | | | | | - Rinu Jacob
- Phathom Pharmaceuticals, Florham Park, NJ, USA
| | | | | | | | - Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto von Guericke University, Magdeburg, Germany
- LMU Medizinische Klinik und Poliklinik II, Muenchen, Germany
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3
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Zhao X, Zhang Z, Lu F, Xiong M, Jiang L, Tang K, Fu M, Wu Y, He B. Effects of CYP2C19 genetic polymorphisms on the cure rates of H. pylori in patients treated with the proton pump inhibitors: An updated meta-analysis. Front Pharmacol 2022; 13:938419. [PMID: 36278195 PMCID: PMC9582748 DOI: 10.3389/fphar.2022.938419] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Accepted: 09/12/2022] [Indexed: 11/28/2022] Open
Abstract
Background: The cure rates of Helicobacter pylori (H. pylori) treatment using a proton pump inhibitor (PPI) are gradually decreasing due to antibiotic resistance, poor compliance, high gastric acidity, and cytochrome P450 2C19 (CYP2C19) polymorphism, and the effects of PPI depend on metabolic enzymes, cytochrome P450 enzymes. The aim of this meta-analysis was to determine whether CYP2C19 polymorphisms affect H. pylori cure rates in patients treated with different proton pump inhibitors (PPIs) according to stratified analysis. Materials and methods: The literature was searched with the key words “H. pylori” and “CYP2C19” in PubMed, CNKI, and Wanfang up to 31 May 2022, and the studies were limited to clinical observational or randomized controlled trials (RCTs). Finally, seven RCTs and 29 clinical observational studies met the inclusion criteria and were used for the meta-analysis via STATA version 16. Results: The cure rates were significantly different between genotypes of homozygous extensive metabolizers (EM) and poor metabolizers (PM) (OR = 0.58, 95% CI: 0.47–0.71) and between EM and heterozygous extensive metabolizers (IM) (OR = 0.71, 95% CI: 0.59–0.86), but not between IM and PM. Moreover, there was a significantly lower H. pylori cure rate in EM subjects than that in IM subjects when treated with omeprazole (66.4% vs. 84.1%), lansoprazole (76.1% vs. 85.6%), but not rabeprazole, esomeprazole, or pantoprazole. In addition, there was a significantly lower H. pylori cure rate in EM subjects than that in IM subjects when treated with a PPIs for 7 days (77.4% vs. 82.1%), but not 14 days (85.4% vs. 90.0%). Conclusion: Carriers of CYP2C19 loss-of-function variant alleles (IM and PM) exhibit a significantly greater cure rate of H. pylori than noncarriers (EM) regardless of other factors (84.7% vs. 79.2%). In addition, pantoprazole- and rabeprazole-based quadruple therapy for H. pylori treatment is less dependent on the CYP2C19 genotype and should be prioritized in Asian populations with H. pylori.
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Affiliation(s)
- Xianghong Zhao
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Zhongqiu Zhang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Fang Lu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Department of Pharmacy, Nanjing First Hospital, China Pharmaceutical University, Nanjing, China
| | - Mengqiu Xiong
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Liping Jiang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ke Tang
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Min Fu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Yu Wu
- Division of Clinical Pharmacology, General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Bangshun He
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
- H. pylori Research Key Laboratory, Nanjing Medical University, Nanjing, China
- *Correspondence: Bangshun He,
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Malfertheiner P, Moss SF, Daniele P, Pelletier C, Jacob R, Tremblay G, Hubscher E, Leifke E, Chey WD. Potassium-Competitive Acid Blocker and Proton Pump Inhibitor-Based Regimens for First-Line Helicobacter pylori Eradication: A Network Meta-Analysis. GASTRO HEP ADVANCES 2022; 1:824-834. [PMID: 39131848 PMCID: PMC11307524 DOI: 10.1016/j.gastha.2022.06.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 06/13/2022] [Indexed: 08/13/2024]
Abstract
Background and Aims Effective acid suppression is a crucial component of Helicobacter pylori (H. pylori) eradication regimens. Approved treatments include dual, triple, and quadruple therapies composed of certain antibiotics in combination with proton pump inhibitors (PPIs). Vonoprazan, a potassium-competitive acid blocker, provides more potent and durable acid suppression than PPIs. We compared the efficacy of vonoprazan-based therapies vs approved standard regimens using new evidence from the phase 3 pHalconHP trial in North America and Europe. Methods Studies reporting first-line H. pylori eradication rates from empiric treatment with Food and Drug Administration-approved therapies and vonoprazan-containing therapies were identified via bibliographic searches of systematic literature reviews and a subsequent MEDLINE/Embase search using index terms for H. pylori and eradication. Randomized controlled trials comparing 2 or more relevant comparators were included in Bayesian network meta-analyses for grouped and distinct therapies. Results Twenty-three distinct regimens from 42 trials including 12,773 patients were identified. Vonoprazan-based triple therapy showed the highest relative efficacy (odds ratio: 2.73, 95% credible interval 2.11, 3.54) and 72.1% probability of being the best. North American, Western, and global scenarios were largely consistent. Vonoprazan-based therapies demonstrated higher odds of H. pylori eradication than each PPI-based triple therapy. Furthermore, vonoprazan-based triple therapy was superior to bismuth subcitrate quadruple therapy (odds ratio: 1.60, 95% credible interval: 1.07, 2.38). Conclusion Vonoprazan-based eradication regimens represent novel treatments for H. pylori infection on a global scale, offering efficacy that, in this analysis, is superior to PPI-based triple therapy and comparable or better than bismuth quadruple therapy.
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Affiliation(s)
- Peter Malfertheiner
- Department of Gastroenterology, Hepatology and Infectious Diseases, Otto v. Guericke University, Magdeburg, Germany
- LMU Medizinische Klinik und Poliklinik II, Muenchen, Germany
| | - Steven F. Moss
- Division of Gastroenterology, Alpert Medical School of Brown University, Providence, Rhode Island
| | - Patrick Daniele
- Real World and Advanced Analytics, Cytel, Inc, Waltham, Massachusetts
| | | | - Rinu Jacob
- Phathom Pharmaceuticals, Florham Park, New Jersey
| | - Gabriel Tremblay
- Real World and Advanced Analytics, Cytel, Inc, Waltham, Massachusetts
| | | | | | - William D. Chey
- Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan
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Ghazvini K, Kamali H, Hosseininasab-nodoushan SA, Keikha M. The CYP2C19 polymorphisms effects on H. pylori cure rate in proton pump inhibitor-based therapeutic regimens: An updated meta-analysis. GENE REPORTS 2021; 25:101340. [DOI: 10.1016/j.genrep.2021.101340] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Morino Y, Sugimoto M, Nagata N, Niikiura R, Iwata E, Hamada M, Kawai Y, Fujimiya T, Takeuchi H, Unezaki S, Kawai T. Influence of Cytochrome P450 2C19 Genotype on Helicobacter pylori Proton Pump Inhibitor-Amoxicillin-Clarithromycin Eradication Therapy: A Meta-Analysis. Front Pharmacol 2021; 12:759249. [PMID: 34721043 PMCID: PMC8553963 DOI: 10.3389/fphar.2021.759249] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Background: Proton pump inhibitors (PPIs) are the first-line treatment for acid-related diseases. The pharmacokinetics and therapeutic efficacy of PPIs, however, are influenced by genetic factors such as variants in genes encoding drug-metabolizing enzymes (e.g., cytochrome P450 2C19 [CYP2C19]) and drug transporters. We performed a meta-analysis to evaluate the influence of CYP2C19 genotype and PPI class, PPI dose, treatment duration and clarithromycin dose on the cure rate of PPI-containing Helicobacter pylori eradication therapy. Methods: Randomized control trials (RCTs) investigating cure rates using a PPI-amoxicillin-clarithromycin regimen among different CYP2C19 genotypes through May 2021 were included. Results: A total of 25 studies (5,318 patients) were included. The overall eradication rate in the intention-to-treat analysis was 79.0% (3,689/4,669, 95% confidence interval [CI]: 77.8-80.2%), and that in CYP2C19 extensive metabolizers (EMs), intermediate metabolizer (IMs) and poor metabolizers (PMs) was 77.7% (1,137/1,464, 95% CI: 75.3-79.6%), 81.2% (1,498/1,844, 95% CI: 79.3-83.0%) and 86.8% (644/742, 95% CI: 83.9-88.9%), respectively. Meta-analysis showed that the relaTakashitive risk of failed eradication in CYP2C19 EMs compared with IMs and PMs was 1.21 (95% CI: 1.06-1.39, P = 0.006) and 1.57 (95% CI: 1.27-1.94, P < 0.001), respectively, in the fixed-effects model. The cure rate of omeprazole and lansoprazole-containing eradication regimens differed among CYP2C19 genotypes (P < 0.05), while that of rabeprazole and esomeprazole-containing regimens was similar. Conclusion: The cure rates of PPI-amoxicillin-clarithromycin H. pylori eradication regimen, especially those containing omeprazole and lansoprazole, differ among CYP2C19 genotypes. Therefore, selection of a second-generation PPI or tailored treatment may achieve higher eradication rates than first-generation PPI-amoxicillin-clarithromycin triple regimen.
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Affiliation(s)
- Yuko Morino
- Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Mitsushige Sugimoto
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Naoyoshi Nagata
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Ryota Niikiura
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Eri Iwata
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Mariko Hamada
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Yusuke Kawai
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Tatsuhiro Fujimiya
- Department of Practical Pharmacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Hironori Takeuchi
- Department of Pharmacy, Tokyo Medical University Hospital, Tokyo, Japan
| | - Sakae Unezaki
- Department of Practical Pharmacy, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Takashi Kawai
- Department of Gastroenterological Endoscopy, Tokyo Medical University Hospital, Tokyo, Japan
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7
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Fu J, Sun CF, He HY, Ojha SC, Shi H, Deng CL, Sheng YJ. The effect of CYP2C19 gene polymorphism on the eradication rate of Helicobacter pylori by proton pump inhibitors-containing regimens in Asian populations: a meta-analysis. Pharmacogenomics 2021; 22:859-879. [PMID: 34414773 DOI: 10.2217/pgs-2020-0127] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Premise: The effects of proton pump inhibitors (PPI) depend on metabolic enzyme CYP2C19 that has different activity due to gene polymorphism. The purpose of this meta-analysis is to determine the potential effects of CYP2C19 polymorphism on the efficiency of PPI-based treatment. Materials & methods: The PubMed, EMBASE, Cochrane Library, etc. were searched for relevant articles published in English or Chinese from inception to 31 May 2020. Finally, 26 randomized controlled trials and 15 cohort studies met the inclusion criteria and used for the meta-analysis via STATA version 15. Results: Poor metabolizer (PM) genotype Helicobacter pylori eradication rates were highest for Asian individuals receiving triple or quadruple first-line therapy based on PPIs (p < 0.05). CYP2C19 polymorphism could influence H. pylori eradication rate only in Mainland China and Japan (p < 0.05). Conclusion: PM genotype facilitates the elimination of H. pylori in Asian populations. Rabeprazole-, esomeprazole- and pantoprazole-based eradication program was less affected by the CYP2C19 polymorphism.
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Affiliation(s)
- Juan Fu
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Chang-Feng Sun
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Infection & Immunity Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Hong-Yan He
- Experimental Teaching Center, School of Public Health of Southwest Medical University, Luzhou, 646000, China
| | - Suvash Chandra Ojha
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Infection & Immunity Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Han Shi
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Cun-Liang Deng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Infection & Immunity Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
| | - Yun-Jian Sheng
- Department of Infectious Diseases, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Department of Tuberculosis, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China.,Infection & Immunity Laboratory, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China
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Attia TZ, Yamashita T, Tsujino H, Derayea SM, Tsutsumi Y, Uno T. Effect of Drug Combination on Omeprazole Metabolism by Cytochrome P450 2C19 in Helicobacter pylori Eradication Therapy. Chem Pharm Bull (Tokyo) 2019; 67:810-815. [PMID: 31366830 DOI: 10.1248/cpb.c19-00084] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Helicobacter pylori (H. pylori) infection is common and can result in gastric and duodenal ulcers, and in some cases, gastric lymphoma and cancer. Omeprazole (OMP)-in combination with clarithromycin (CLR), amoxicillin (AMX), tinidazole (TND), or metronidazole (MET)-is used in double or triple combination therapy for eradication of H. pylori. However, the roles of the drugs other than OMP are not clearly understood. Therefore, in the present study, we aimed to investigate any effects of these drugs on OMP metabolism by wild-type CYP2C19 using spectroscopy and enzyme kinetics. The dissociation constants (Kd) for CYP2C19 with OMP, CLR, AMX, TND, and MET were 8.6, 126, 156, 174, and 249 µM, respectively. The intrinsic clearance of OMP was determined to be 355 mL/min/µmol of CYP2C19. Metabolism of OMP was significantly inhibited by 69, 66, 28, and 40% in the presence of CLR, TND, AMX, and MET, respectively. Moreover, the combination of CLR and TND resulted in 76% inhibition of OMP metabolism, while the combination of AMX and MET resulted in 48% inhibition of OMP metabolism. Both combinations of drugs not only have antibacterial effects, but also enhance the effect of OMP by inhibiting its metabolism by CYP2C19. These results indicate that drug-drug interactions of co-administered drugs can cause complex effects, providing a basis for OMP dose adjustment when used in combination therapy for H. pylori eradication.
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Affiliation(s)
- Tamer Z Attia
- Graduate School of Pharmaceutical Sciences, Osaka University.,Analytical Chemistry Department, Faculty of Pharmacy, Minia University
| | - Taku Yamashita
- School of Pharmacy and Pharmaceutical Sciences, Mukogawa Women's University
| | | | - Sayed M Derayea
- Analytical Chemistry Department, Faculty of Pharmacy, Minia University
| | - Yasuo Tsutsumi
- Graduate School of Pharmaceutical Sciences, Osaka University
| | - Tadayuki Uno
- Graduate School of Pharmaceutical Sciences, Osaka University
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Kato M, Ota H, Okuda M, Kikuchi S, Satoh K, Shimoyama T, Suzuki H, Handa O, Furuta T, Mabe K, Murakami K, Sugiyama T, Uemura N, Takahashi S. Guidelines for the management of Helicobacter pylori infection in Japan: 2016 Revised Edition. Helicobacter 2019; 24:e12597. [PMID: 31111585 DOI: 10.1111/hel.12597] [Citation(s) in RCA: 199] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2019] [Revised: 04/08/2019] [Accepted: 04/14/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Since "Helicobacter pylori (H. pylori) infection" was set as the indication in the Japanese Society for Helicobacter Research (JSHR) Guidelines 2009, eradication treatment for H. pylori gastritis is covered under insurance since 2013 in Japan, and the number of H. pylori eradication has rapidly increased. Under such circumstances, JSHR has made the third revision to the "Guidelines for diagnosis and treatment of H. pylori infection" for the first time in 7 years. METHODS The Guideline Committee held 10 meetings. Articles published between the establishment of the 2009 Guidelines and March 2016 were reviewed and classified according to the evidence level; the statements were revised on the basis of this review. After inviting public comments, the revised statements were finalized using the Delphi method. RESULTS There was no change in the basic policy that H. pylori infectious disease is an indication for eradication. Other diseases presumed to be associated with H. pylori infection were added as indications. Serum pepsinogen level, endoscopic examination, and X-ray examination were added to the diagnostic methods. The effects of 1-week triple therapy consisting of potassium-competitive acid blocker (P-CAB), amoxicillin, and clarithromycin have improved, and high eradication rates can also be expected with proton pump inhibitors (PPI) or P-CAB combined with amoxicillin and metronidazole. If the susceptibility test is not performed, the triple PPI or P-CAB/amoxicillin/metronidazole therapy should be chosen, because the PPI/amoxicillin/metronidazole combination demonstrated a significantly higher eradication rate than PPI/amoxicillin/clarithromycin. In the proposal for gastric cancer prevention, we divided gastric cancer prevention measures by age from adolescent to elderly, who are at an increased gastric cancer risk, and presented measures for gastric cancer prevention primarily based on H. pylori eradication. CONCLUSION We expect the revised guidelines to facilitate appropriate interventions for patients with H. pylori infection and accomplish its eradication and prevention of gastric cancer.
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Affiliation(s)
- Mototsugu Kato
- Department of Gastroenterology, National Hospital Organization Hakodate National Hospital, Hakodate, Hokkaido, Japan
| | - Hiroyoshi Ota
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, Nagano, Hyogo, Japan
| | - Masumi Okuda
- Department of Pediatrics, Hyogo College of Medicine, Nishinomiya, Hyogo, Japan
| | - Shogo Kikuchi
- Department of Public Health, Aichi Medical University School of Medicine, Nagakute, Aichi, Japan
| | - Kiichi Satoh
- Department of Gastroenterology, International University of Health and Welfare Hospital, Nasushiobara, Tochigi, Japan
| | | | - Hidekazu Suzuki
- Fellowship Training Center, Medical Education Center, Keio University School of Medicine, Tokyo, Japan
| | - Osamu Handa
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Katsuhiro Mabe
- Department of Gastroenterology, National Hospital Organization Hakodate National Hospital, Hakodate, Hokkaido, Japan
| | - Kazunari Murakami
- Department of Gastroenterology, Faculty of Medicine, Oita University, Oita, Japan
| | - Toshiro Sugiyama
- Department of Cancer Prevention and Therapeutics, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan
| | - Naomi Uemura
- Department of Gastroenterology, Kohnodai Hospital, National Center for Global Health and Medicine, Ichikawa, Japan
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10
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Arévalo Galvis A, Trespalacios Rangel AA, Otero Regino W. Personalized therapy for Helicobacter pylori: CYP2C19 genotype effect on first-line triple therapy. Helicobacter 2019; 24:e12574. [PMID: 30859680 DOI: 10.1111/hel.12574] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Triple therapy efficacy against Helicobacter pylori is low worldwide, and thus, alternatives must be sought to improve eradication. The aim of the present study was to determine CYP2C19 genetic polymorphism effect on H pylori eradication. METHODS A randomized, single-blinded clinical trial including 133 participants was carried out. H pylori infection was confirmed by histologic and microbiologic test. Antibiotic susceptibility to amoxicillin and clarithromycin was performed. CYP2C19 polymorphisms *1, *2, and *3 were analyzed by real-time PCR (Roche ®), and nested PCR for CYP2C19*17 polymorphisms. Participants were randomized into two groups for different H pylori therapies, one with standard omeprazole doses and another with omeprazole doses depending on CYP2C19 polymorphism. H pylori eradication was verified by stool antigen tests (Meridian ®). RESULTS The most common CYP2C19 polymorphism was *1/*1 in 54.9% of the participants followed by *17/*17 in 21.1%. Triple therapy efficacy with standard omeprazole doses versus personalized therapy based on CYP2C19 polymorphism by ITT analysis was 84% (95% CI: 0.73-0.91) vs 92.2% (95% CI: 0.82-0.97) (P = 0. 14), respectively. The efficacy by PP analysis was 92.1% (95% CI: 0.82-0.97) vs 100% (95% CI: 0.92-0.01) (P = 0.027), respectively. CONCLUSIONS The most frequent polymorphism was extensive PPI metabolizers (62.4%). Effectiveness of guided therapies by susceptibility test was good, yet they can be further improved by customized therapy based on CYP genotype. Therefore, high PPI (80 mg/d) doses are recommended for H pylori eradication therapies in Colombia. ClinicalTrials.gov ID: NCT03650543.
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Affiliation(s)
- Azucena Arévalo Galvis
- Laboratorio de Bacteriología Especial, Grupo de Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - Alba Alicia Trespalacios Rangel
- Laboratorio de Bacteriología Especial, Grupo de Enfermedades Infecciosas, Departamento de Microbiología, Facultad de Ciencias, Pontificia Universidad Javeriana, Bogotá, Colombia
| | - William Otero Regino
- Unidad de Gastroenterología, Facultad de Medicina, Universidad Nacional de Colombia, Bogotá, Colombia
- Unidad de Gastroenterología Clínica Fundadores, Bogotá, Colombia
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Sue S, Shibata W, Sasaki T, Kaneko H, Irie K, Kondo M, Maeda S. Randomized trial of vonoprazan-based versus proton-pump inhibitor-based third-line triple therapy with sitafloxacin for Helicobacter pylori. J Gastroenterol Hepatol 2019; 34:686-692. [PMID: 30151994 DOI: 10.1111/jgh.14456] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 08/15/2018] [Accepted: 08/20/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM This was a prospective, randomized trial of the efficacy of vonoprazan-based and proton-pump inhibitor-based 7-day triple regimens with amoxicillin and sitafloxacin as a third-line therapy for eradicating Helicobacter pylori after failure of clarithromycin-based and metronidazole-based first-line and second-line therapy. METHODS We enrolled 63 patients positive for H. pylori in whom first-line and second-line regimens for eradicating failed. Patients were randomized to the V-AS group (vonoprazan 20-mg bid, amoxicillin 750-mg bid, and sitafloxacin 100-mg bid for 7 days) or PPI-AS group (esomeprazole 20-mg bid, rabeprazole 10-mg bid, or lansoprazole 30-mg bid; amoxicillin 750-mg bid; and sitafloxacin 100-mg bid for 7 days). We assessed the outcome of eradication therapy using the 13 C-urea breath test. We evaluated safety using patient questionnaires. This study was registered in the UMIN Clinical Trials Registry (UMIN000016336). RESULTS The intention-to-treat and per-protocol eradication rates of V-AS were 75.8% (95% confidence interval [CI]: 57.7-88.9%) and 83.3% (95% CI: 65.3-94.4%), respectively. The respective eradication rates of PPI-AS were 53.3% (95% CI: 34.3-71.7%) and 57.1% (95% CI: 37.2-75.5%). In per-protocol analyses, the eradication rate of the V-AS group was significantly higher than that of the PPI-AS group (P = 0.043); however, no significant differences were observed in intention-to-treat analyses (P = 0.071). Questionnaire scores did not differ significantly between the groups. CONCLUSIONS The findings suggest that 7-day triple therapy with vonoprazan, amoxicillin, and sitafloxacin is more effective than proton-pump inhibitor, amoxicillin, and sitafloxacin as a third-line regimen for eradicating H. pylori.
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Affiliation(s)
- Soichiro Sue
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Wataru Shibata
- Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Tomohiko Sasaki
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Hiroaki Kaneko
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Kuniyasu Irie
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masaaki Kondo
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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12
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Sue S, Ogushi M, Arima I, Kuwashima H, Nakao S, Naito M, Komatsu K, Kaneko H, Tamura T, Sasaki T, Kondo M, Shibata W, Maeda S. Vonoprazan- vs proton-pump inhibitor-based first-line 7-day triple therapy for clarithromycin-susceptible Helicobacter pylori: A multicenter, prospective, randomized trial. Helicobacter 2018; 23:e12456. [PMID: 29271026 DOI: 10.1111/hel.12456] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The eradication rate of vonoprazan-based first-line triple therapy (combined with clarithromycin and amoxicillin) (V-AC) was reported to be 97.6% in patients with clarithromycin (CAM)-susceptible Helicobacter pylori in a phase III study, whereas our real-world, prospective, multicenter cohort study yielded an eradication rate <90%. OBJECTIVE To validate the eradication rate of V-AC using CAM-susceptible testing in a multicenter, prospective, randomized trial. METHODS We included 147 treatment-naïve H. pylori-positive patients [41 with CAM-resistant infections and 106 with CAM-susceptible infections]. The CAM-susceptible group patients were randomized to either the V-AC group (vonoprazan 20 mg bid, amoxicillin 750 mg bid, and clarithromycin 200 or 400 mg bid) or PPI-AC group (lansoprazole 30 mg, rabeprazole 10 mg, or esomeprazole 20 mg bid; amoxicillin 750 mg bid; and clarithromycin 200 or 400 mg bid). All CAM-resistant H. pylori were eradicated by V-AC, as measured by the urea breath test around 8 weeks after eradication. Safety was evaluated by patient questionnaires. RESULTS The intention-to-treat and per-protocol eradication rates of V-AC in the CAM-susceptible H. pylori-infected patients were 87.3% (95% confidence interval 75.5%-94.7%) and 88.9% (77.4%-95.8%). The respective eradication rates of PPI-AC were 76.5% (62.5%-87.2%) and 86.7% (73.2%-94.9%). No significant difference was observed between the V-AC and PPI-AC regimes in terms of the intention-to-treat (P = .21) or per-protocol (P = .77) analyses. The questionnaire scores did not differ significantly between the groups. Both the intention-to-treat and per-protocol eradication rates of V-AC in the CAM-resistant patients were 82.9% (67.9%-92.8%). CONCLUSION The eradication rate of V-AC treatment in the CAM-susceptible H. pylori-infected patients was <90%, as was that by PPI-AC, thus V-AC is not ideal regimen in CAM-susceptible H. pylori. However, the 82.9% eradication rate of V-AC in the CAM-resistant infections may indicate the potential of V-AC with modified dose, dosing interval, and treatment duration. (UMIN000016337).
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Affiliation(s)
- Soichiro Sue
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Marina Ogushi
- Department of Gastroenterology, Yokohama Hodogaya Central Hospital, Yokohama, Japan
| | - Isao Arima
- Department of Gastroenterology, Yokosuka City Hospital, Yokosuka, Kanagawa, Japan
| | - Hirofumi Kuwashima
- Department of Gastroenterology, Yokohama Hodogaya Central Hospital, Yokohama, Japan
| | - Satoshi Nakao
- Department of Gastroenterology, Yokosuka City Hospital, Yokosuka, Kanagawa, Japan
| | - Makoto Naito
- Department of Gastroenterology, Yokohama Hodogaya Central Hospital, Yokohama, Japan
| | - Kazuo Komatsu
- Department of Gastroenterology, Yokosuka City Hospital, Yokosuka, Kanagawa, Japan
| | - Hiroaki Kaneko
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Toshihide Tamura
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiko Sasaki
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Masaaki Kondo
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Wataru Shibata
- Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Shin Maeda
- Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Aguilera-Castro L, Martín-de-Argila-dePrados C, Albillos-Martínez A. Practical considerations in the management of proton-pump inhibitors. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2017; 108:145-53. [PMID: 26666270 DOI: 10.17235/reed.2015.3812/2015] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Proton-pump inhibitors (PPIs) are one of the most active ingredients prescribed in Spain. In recent decades there has been an overuse of these drugs in both outpatient clinics and hospitals that has lead to a significant increase in healthcare spending and to an increase in the risk of possible side effects. It is important for health professionals to know the accepted indications and the correct doses for the use of these drugs. On the market there are different types of PPI: omeprazole, pantoprazole, lansoprazole, rabeprazole and esomeprazole. Omeprazole is the oldest and most used PPI, being also the cheapest. Although there are no important differences between PPIs in curing diseases, esomeprazole, a new-generation PPI, has proved to be more effective in eradicating H. pylori and in healing severe esophagitis compared to other PPIs. In recent years the use of generic drugs has spread; these drugs have the same bioavailability than the original drugs. In the case of PPIs, the few comparative studies available in the literature between original and generic drugs have shown no significant differences in clinical efficacy.
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14
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Kuo CH, Lu CY, Shih HY, Liu CJ, Wu MC, Hu HM, Hsu WH, Yu FJ, Wu DC, Kuo FC. CYP2C19 polymorphism influences Helicobacter pylori eradication. World J Gastroenterol 2014; 20:16029-16036. [PMID: 25473155 PMCID: PMC4239489 DOI: 10.3748/wjg.v20.i43.16029] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Revised: 07/04/2014] [Accepted: 08/28/2014] [Indexed: 02/06/2023] Open
Abstract
The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.
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15
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Tang HL, Li Y, Hu YF, Xie HG, Zhai SD. Effects of CYP2C19 loss-of-function variants on the eradication of H. pylori infection in patients treated with proton pump inhibitor-based triple therapy regimens: a meta-analysis of randomized clinical trials. PLoS One 2013; 8:e62162. [PMID: 23646118 PMCID: PMC3639978 DOI: 10.1371/journal.pone.0062162] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2012] [Accepted: 03/18/2013] [Indexed: 12/31/2022] Open
Abstract
Background There are inconsistent conclusions about whether CYP2C19 variants could affect H. pylori eradication rate in patients treated with the proton pump inhibitor (PPI)-based therapy. We therefore performed a meta-analysis of randomized clinical trials (RCTs) to re-evaluate the impact of CYP2C19 variants on PPI-based triple therapy for the above indication. Methods All relevant RCTs in the PubMed, Cochrane Library, EMBASE, Web of Science and two Chinese databases (up to February 2013) were systematically searched, and a pooled analysis was performed with the odds ratio (OR) and 95% confidence interval (CI) by the STATA software. Results Sixteen RCT datasets derived from 3680 patients were included. There was no significant heterogeneity across the data available in this meta-analysis. There were significant differences in that rate between homozygous (HomEMs) and heterozygous (HetEMs) extensive metabolizers (OR 0.724; 95% CI 0.594–0.881), between HomEMs and poor metabolizers (PM) (OR 0.507; 95%CI 0.379–0.679), or between HetEMs and PMs (OR 0.688; 95%CI 0.515–0.920), regardless of the PPI being taken. Furthermore, sub-analysis of individual PPIs was carried out to explore the difference across all the PPIs used. A significantly low rate was seen in HomEMs vs. HetEMs taking either omeprazole (OR 0.329; 95%CI 0.195–0.553) or lansoprazole (OR 0.692; 95%CI 0.485–0.988), and also in HomEMs vs. PMs for omeprazole (OR 0.232; 95%CI 0.105–0.515) or lansoprazole (OR 0.441; 95%CI 0.252–0.771). However, there was no significant difference between HetEMs and PMs taking either one. No significant differences were observed for rabeprazole or esomeprazole across the CYP2C19 genotypes of interest. Conclusions Carriage of CYP2C19 loss-of-function variants is associated with increased H. pylori eradication rate in patients taking PPI-based triple therapies when omeprazole or lansoprazole is chosen. However, there is no a class effect after use of rabeprazole or esomeprazole.
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Affiliation(s)
- Hui-Lin Tang
- Department of Pharmacy, Peking University Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University Third Hospital, Beijing, China
| | - Yan Li
- Department of Pharmacy, Peking University Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University Third Hospital, Beijing, China
| | - Yong-Fang Hu
- Department of Pharmacy, Peking University Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University Third Hospital, Beijing, China
| | - Hong-Guang Xie
- General Clinical Research Center and Division of Clinical Pharmacology, Nanjing Medical University Nanjing First Hospital, Nanjing, China
- Department of Pharmacology, Nanjing Medical University School of Pharmacy, Nanjing, Jiangsu, China
- * E-mail: (S-DZ); (H-GX)
| | - Suo-Di Zhai
- Department of Pharmacy, Peking University Therapeutic Drug Monitoring and Clinical Toxicology Center, Peking University Third Hospital, Beijing, China
- * E-mail: (S-DZ); (H-GX)
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16
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Ma JD, Nafziger AN, Bertino JS. Genetic Polymorphisms of Cytochrome P450 Enzymes and the Effect on Interindividual, Pharmacokinetic Variability in Extensive Metabolizers. J Clin Pharmacol 2013; 44:447-56. [PMID: 15102864 DOI: 10.1177/0091270004264642] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
Genetic polymorphisms of cytochrome P450 (CYP) enzymes are one of the factors that contribute to the pharmacokinetic (PK) variability of drugs. PK variability is observed in the bimodal distribution between extensive metabolizers (EMs) and poor metabolizers (PMs). PK variability may also exist between individuals genotyped as homozygous EMs and heterozygous EMs. This may carry implications for drug dosing and drug response (e.g., risk of therapeutic failure or drug toxicity). Studies have reported significant PK differences between homozygous and heterozygous EMs. Some literature suggests that this distinction may be of clinical relevance. Due to study design limitations and data that are either sparse or conflicting, generalizations regarding the potential impact of the CYP genotype, within EMs, are difficult. Optimally designed clinical trials are needed. This review evaluates the potential impact of CYP genetic polymorphisms on interindividual PK variability of drugs within an EM population.
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Affiliation(s)
- Joseph D Ma
- Clinical Pharmacology Research Center, Bassett Healthcare, One Atwell Road, Cooperstown, NY 13326-1394, USA
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17
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McNicholl AG, Linares PM, Nyssen OP, Calvet X, Gisbert JP. Meta-analysis: esomeprazole or rabeprazole vs. first-generation pump inhibitors in the treatment of Helicobacter pylori infection. Aliment Pharmacol Ther 2012; 36:414-25. [PMID: 22803691 DOI: 10.1111/j.1365-2036.2012.05211.x] [Citation(s) in RCA: 132] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Revised: 04/05/2012] [Accepted: 06/20/2012] [Indexed: 12/12/2022]
Abstract
BACKGROUND The decreasing efficacy of H. pylori eradication treatments over time makes the search for better regimens and adjuvant medications a priority. AIM To conduct a meta-analysis of studies comparing rabeprazole or esomeprazole with other proton pump inhibitors (PPI) or with each other in H. pylori eradication treatment. SELECTION OF STUDIES Randomised clinical trials comparing esomeprazole or rabeprazole with first-generation PPIs (omeprazole-lansoprazole-pantoprazole) or with each other. RESULTS The meta-analysis (35 studies, 5998 patients) showed higher eradication rates for esomeprazole than for first-generation PPIs: 82.3% vs. 77.6%; OR = 1.32(1.01-1.73); NNT = 21. Rabeprazole also showed better results than first-generation PPIs: 80.5% vs. 76.2%; OR = 1.21(1.02-1.42); NNT = 23. PPI dosage sub-analysis: only esomeprazole 40 mg b.d. improved results [83.5% esomeprazole vs. 72.4% first generation; OR = 2.27(1.07-4.82); NNT = 9]. Whereas rabeprazole 10 and 20 mg b.d. maintained results, esomeprazole 20 mg b.d. obtained lower efficacy. Esomeprazole vs. rabeprazole sub-analysis (five studies): no significant differences were found: 78.7% vs. 76.7%; OR = 0.90(0.70-1.17). CYP2C19 sub-analysis: Genotype did not significantly affect eradication either in first [OR = 1.76(0.99-3.12)] or new generation [OR = 1.19(0.73-1.95)] PPIs. However, sub-analysis considering only extensive metaboliser patients showed higher eradication with new-generation PPIs [OR = 1.37(1.02-1.84)]. CONCLUSIONS Esomeprazole and rabeprazole show better overall H. pylori eradication rates than first-generation PPIs. This clinical benefit is more pronounced in esomeprazole 40 mg b.d. regimens. In CYP2C19 extensive metabolisers, new-generation PPIs are more effective than first-generation PPIs for H. pylori eradication. However, a general recommendation of using new-generation PPIs in all scenarios remains unclear.
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Affiliation(s)
- A G McNicholl
- Gastroenterology Unit, Hospital Universitario de la Princesa and Instituto de Investigación Sanitaria Princesa (IP), Madrid, Spain.
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Abstract
The purpose of this review is to discuss the clinical application of pharmacogenomics for select drug therapies (eg, proton pump inhibitors [PPIs], codeine, and carbamazepine) and to highlight limitations and challenges that preclude implementation of pharmacogenomics into clinical practice. Genetic polymorphisms of cytochrome P450 (CYP) enzymes and the presence of the human leukocyte antigen ( HLA) -B*1502 allele influence drug disposition and/or response. A portion of PPI pharmacokinetic and pharmacodynamic variability can be explained by CYP2C19 genotype. However, conflicting evidence exists related to Helicobacter pylori cure rates based on CYP2C19 genotype. For codeine, adverse drug reactions in neonates through breast-feeding from CYP2D6 ultra-rapid metabolizers have been reported. However, there is lack of conclusive evidence regarding the overall influence of CYP2D6 polymorphisms on codeine efficacy and toxicity. Although CYP2C19 and CYP2D6 genotyping tests are available, clinical utility remains low. The presence of the HLA-B*1502 allele is associated with carbamazepine-induced Stevens-Johnson syndrome (SJS) and/or toxic epidermal necrolysis (TEN). Pharmacogenomic testing is required prior to initiating carbamazepine in high-risk patients. Lack of sufficient resources, provider knowledge, and ethical, legal, and social issues are several limitations and challenges to implementing pharmacogenomic testing in clinical practice.
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Affiliation(s)
- Joseph D. Ma
- Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Kelly C. Lee
- Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Grace M. Kuo
- Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
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Sharma P, Johnson DA, Monyak JT, Illueca M. Race affects healing of erosive oesophagitis in patients treated with proton pump inhibitors. Aliment Pharmacol Ther 2011; 34:487-93. [PMID: 21682754 DOI: 10.1111/j.1365-2036.2011.04736.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Erosive oesophagitis appears to be more common in white vs. nonwhite patients with gastro-oesophageal reflux disease (GERD). AIM To evaluate the association between race and erosive oesophagitis healing in patients with GERD treated with once-daily proton pump inhibitors (PPIs). METHODS Data from five double-blind trials of once-daily treatment with esomeprazole 40mg vs. omeprazole 20mg or lansoprazole 30mg for erosive oesophagitis healing (evaluated at weeks 4 and 8 by endoscopy) were pooled and stratified by baseline race and Los Angeles (LA) severity grade. Multiple logistic regression models were fit with erosive oesophagitis healing (dependent variable) and race (independent variable), with adjustments for treatment, study, baseline LA grade, age, gender, BMI, Helicobacter pylori status, hiatal hernia and interactions of these factors with race. RESULTS Of 11,027 patients, 91% were white. Nonwhite (n=978) and black (n=613) patients were less likely to have severe baseline erosive oesophagitis (LA grade C or D) than white patients [adjusted OR: 0.69 (95% CI, 0.61-0.79) and 0.67 (0.57-0.78), respectively; P<0.0001]. At week 8, nonwhite and black patients had lower healing rates than white patients [OR: 0.75 (0.63-0.89) and 0.67 (0.54-0.83), respectively; P≤0.001]. Greater odds of healing were associated with less severe baseline LA grade, increasing age, hiatal hernia, esomeprazole treatment (vs. lansoprazole or omeprazole) and lansoprazole treatment (vs. omeprazole) (all P≤0.0009); no factor interacted significantly with race. CONCLUSIONS Nonwhite patients with GERD had less severe baseline erosive oesophagitis, but were less likely than white patients to have erosive oesophagitis healing after 8-week PPI therapy.
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Affiliation(s)
- P Sharma
- University of Kansas Medical Center and Veterans Affairs Medical Center, Kansas City, MO 64128, USA.
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Zhang L, Mei Q, Li QS, Hu YM, Xu JM. The effect of cytochrome P2C19 and interleukin-1 polymorphisms on H. pylori eradication rate of 1-week triple therapy with omeprazole or rabeprazole, amoxycillin and clarithromycin in Chinese people. J Clin Pharm Ther 2010; 35:713-22. [DOI: 10.1111/j.1365-2710.2009.01140.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Furuta T, Graham DY. Pharmacologic aspects of eradication therapy for Helicobacter pylori Infection. Gastroenterol Clin North Am 2010; 39:465-80. [PMID: 20951912 DOI: 10.1016/j.gtc.2010.08.007] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The commonly used regimens for the eradication of Helicobacter pylori infection consist of administration of proton pump inhibitors (PPIs) and 1 to 3 antimicrobial agents, such as amoxicillin, clarithromycin, metronidazole, fluoroquinolone, or tetracycline. Each agent has its own pharmacologic characteristics. PPIs are metabolized by cytochrome P450 2C19 (CYP2C19), which is polymorphic. CYP2C19 genotypic differences in the pharmacokinetics and pharmacodynamics of PPIs influence the eradication rates of H pylori infection by PPI-containing regimens. Amoxicillin is a time-dependent antibiotic, whereas clarithromycin, metronidazole, tetracycline, and fluoroquinolone are not. The plasma half-life of antimicrobial agents also differs among these antibiotics. To achieve consistently high eradication rates, the eradication regimens must be designed based on a good understanding of the resistance patterns of the bacteria and the pharmacologic characteristics of the agents used for H pylori eradication therapy.
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Affiliation(s)
- Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higsahi-Ku, Hamamatsu 431-3192, Japan.
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22
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Cho DK, Park SY, Kee WJ, Lee JH, Ki HS, Yoon KW, Cho SB, Lee WS, Joo YE, Kim HS, Choi SK, Rew JS. [The trend of eradication rate of Helicobacter pylori infection and clinical factors that affect the eradication of first-line therapy]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2010; 55:368-75. [PMID: 20571304 DOI: 10.4166/kjg.2010.55.6.368] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIMS Although triple combination therapy containing a proton pump inhibitor (PPI) and two antibiotics is considered as a standard regimen for the first-line anti-Helicobacter pylori treatment, the recent trend of eradication rates following this therapy has been declined in the last few years. The purpose of this study was to investigate the trend of H. pylori eradication rates over the last 9 years and to evaluate are clinical factors affecting eradication rates. METHODS From January 2001 to June 2009, H. pylori eradication rates in 709 patients with documented H. pylori infection who received triple combination therapy for 7 days were retrospectively evaluated according to years and various clinical factors. H. pylori status was evaluated by 13C urea breath test 4-6 weeks after completion of treatment. results: The overall H. pylori eradication rate was 77.0%. The annual eradication rates from year 2001 to 2009 were 78.9%, 72.5%, 81.0%, 75.0%, 79.1%, 77.1%, 77.8%, 77.8%, and 75.0% by per-protocol analysis. There was no decreasing tendency of the eradiation rate over 9 years (p=0.974). There was no statistical difference in the eradication rates according to age, sex, smoking, alcohol, NSAIDs, underlying diseases, endoscopic diagnosis, and PPI. However, the eradication rate was lower in patients who took aspirin (OR=0.509, 95% CI=0.292-0.887, p=0.001) and antibiotics within 6 months (OR=0.347, 95% CI=0.183-0.658, p=0.001). CONCLUSIONS The H. pylori eradication rate has not changed at Gwangju-Chonnam province in Korea for recent 9 years. Lower eradication rate in aspirin and antibiotics users warrants further attention.
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Affiliation(s)
- Dong Keun Cho
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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Kuo CH, Wang SSW, Hsu WH, Kuo FC, Weng BC, Li CJ, Hsu PI, Chen A, Hung WC, Yang YC, Wang WM, Wu DC. Rabeprazole can overcome the impact of CYP2C19 polymorphism on quadruple therapy. Helicobacter 2010; 15:265-272. [PMID: 20633187 DOI: 10.1111/j.1523-5378.2010.00761.x] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVES The prospective study was designed to clarify the impact of CYP2C19 on quadruple therapies and survey the efficacies of rabeprazole-based quadruple therapy for Helicobacter pylori infection after failure of standard triple therapies. PATIENTS AND METHODS From January 2007 to March 2009, 1055 H. pylori-infected patients received standard triple regimens (proton-pump inhibitor (PPI), clarithromycin, and amoxicillin). Helicobacter pylori eradication was achieved in 865 (81.9%) subjects. One hundred ninety eradication-failure patients were enrolled and randomly assigned to receive a 7-day eradication therapy. Ninety-six patients were treated with esomeprazole-based quadruple rescue therapies (EB), while 94 patients were treated with rabeprazole-based quadruple rescue therapies (RB). Follow-up endoscopy was done 16 weeks later to assess the treatment response. Patients' responses, CYP2C19 genotypes, and antibiotics resistances were also examined. RESULTS Intention-to-treat analysis revealed that RB had better eradication rates than EB (EB: 72.9%; 95% CI: 64.9-80.9% and RB: 78.7%; 95% CI 72.5-84.9%) (p value = .543). Per-protocol results were EB = 75.3%; 95% CI: 70.3-80.3% and RB = 85.1%; 95% CI: 80.6-89.6% (p value = .0401). Both regimens had similar compliance (p value = 0.155) and adverse events (p value = 0.219). We also surveyed those patients without resistance of any antibiotics. RB still showed better outcome than EB. Our data showed that esomeprazole-based regimen and CYP2C19 Hom EM genotype were important predictors for eradication failure. CONCLUSIONS In quadruple therapy, rabeprazole-based regimens had better efficacy than esomeprazole-based regimens. CYP2C19 polymorphism also played an important role in quadruple therapy. It seems advisable to change PPI to rabeprazole in second-line quadruple therapy.
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Affiliation(s)
- Chao-Hung Kuo
- Division of Internal Medicine, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung, Taiwan
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Lee JH, Jung HY, Choi KD, Song HJ, Lee GH, Kim JH. The Influence of CYP2C19 Polymorphism on Eradication of Helicobacter pylori: A Prospective Randomized Study of Lansoprazole and Rabeprazole. Gut Liver 2010; 4:201-6. [PMID: 20559522 DOI: 10.5009/gnl.2010.4.2.201] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2009] [Accepted: 01/19/2010] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND/AIMS The CYP2C19 polymorphism plays an important role in the metabolism of various proton-pump inhibitors. Several trials have produced conflicting data on eradication rates of Helicobacter pylori (H. pylori) among CYP2C19 genotypes. We investigated whether the CYP2C19 genotype affects the eradication rate of H. pylori by direct comparing the effects of lansoprazole- and rabeprazole-based triple therapies. METHODS A total of 492 patients infected with H. pylori was randomly treated with either 30 mg of lansoprazole or 20 mg of rabeprazole plus 500 mg of clarithromycin and 1,000 mg of amoxicillin twice daily for 1 week. CYP2C19 genotype status was determined by a PCR-restriction-fragment-length polymorphism method. After 7 to 8 weeks, H. pylori status was evaluated by a C(13)-urea breath test. RESULTS Four hundred and sixty-three patients were analyzed, and the eradication rate was 75.2% in a per-protocol analysis. Eradication rates for the lansoprazole regimen (n=234) were 73.8%, 80.7%, and 85.4% in the homozygous extensive (HomEM), heterozygous extensive (HetEM), and poor metabolizers (PM) groups, respectively (p=0.303). In the case of the rabeprazole regimen (n=229), the eradication rates were 68.6%, 73.0%, and 71.9% in the HomEM, HetEM, and PM groups, respectively (p=0.795). CONCLUSIONS The efficacies of triple therapies that include lansoprazole or rabeprazole are not affected by CYP2C19 genetic polymorphisms.
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Affiliation(s)
- Jeong Hoon Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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Lee VWY, Chau TS, Chan AKW, Lee KKC, Waye MMY, Ling TKW, Chan FKL. Pharmacogenetics of esomeprazole or rabeprazole-based triple therapy in Helicobacter pylori eradication in Hong Kong non-ulcer dyspepsia Chinese subjects. J Clin Pharm Ther 2010; 35:343-50. [PMID: 20831535 DOI: 10.1111/j.1365-2710.2009.01088.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Our study aimed to assess the effectiveness of esomeprazole or rabeprazole in combination with amoxicillin and clarithromycin for the eradication of Helicobacter pylori in Hong Kong non-ulcer dyspepsia (NUD) patients. METHODS A prospective clinical trial was conducted at the Alice Ho Miu ling Nethersole Hospital outpatient endoscopy center from June 2004 to December 2005. Participants received amoxicillin 1 g, clarithromycin 500 mg, and, esomeprazole 20 mg (EAC) or rabeprazole 20 mg (RAC), all given twice daily for 1 week. The H. pylori status was determined by the [13C] urea breath test at least 4 weeks after completion of the treatment. Mutation status of CYP2C19 in exon 4 and exon 5 associated with the poor metabolizer phenotype was determined. RESULTS The intention-to-treat eradication rates in patients treated with RAC and EAC were 77% and 84.6% respectively, and per protocol-based eradication rates were 83.7% and 88.9% respectively. The eradication rates did not vary with CYP2C19 phenotype found. For clarithromycin-sensitive strains, the cure rates were statistically significant regardless of CYP2C19 polymorphism (P < 0.0001). CONCLUSION Triple therapy with either EAC or RAC is effective for Hong Kong Chinese NUD patients with H. pylori infection. Success eradication was related to clarithromycin resistance and not CYP2C19 genotype.
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Affiliation(s)
- V W Y Lee
- School of Pharmacy, The Chinese University of Hong Kong, Hong Kong, China.
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Asaka M, Kato M, Takahashi SI, Fukuda Y, Sugiyama T, Ota H, Uemura N, Murakami K, Satoh K, Sugano K. Guidelines for the management of Helicobacter pylori infection in Japan: 2009 revised edition. Helicobacter 2010; 15:1-20. [PMID: 20302585 DOI: 10.1111/j.1523-5378.2009.00738.x] [Citation(s) in RCA: 292] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Over the past few years, the profile of Helicobacter pylori infection has changed in Japan. In particular, the relationship between H. pylori and gastric cancer has been demonstrated more clearly. Accordingly, the committee of the Japanese Society for Helicobacter Research has revised the guidelines for diagnosis and treatment of H. pylori infection in Japan. MATERIALS AND METHODS Four meetings of guidelines preparation committee were held from July 2007 to December 2008. In the new guidelines, recommendations for treatment have been classified into five grades according to the Minds Recommendation Grades, while the level of evidence has been classified into six grades. The Japanese national health insurance system was not taken into consideration when preparing these guidelines. RESULTS Helicobacter pylori eradication therapy achieved a Grade A recommendation, being useful for the treatment of gastric or duodenal ulcer, for the treatment and prevention of H. pylori-associated diseases such as gastric cancer, and for inhibiting the spread of H. pylori infection. Levels of evidence were determined for each disease associated with H. pylori infection. For the diagnosis of H. pylori infection, measurement of H. pylori antigen in the feces was added to the tests not requiring biopsy. One week of proton-pump inhibitor-based triple therapy (including amoxicillin and metronidazole) was recommended as second-line therapy after failure of first-line eradication therapy. CONCLUSION The revised Japanese guidelines for H. pylori are based on scientific evidence and avoid the administrative restraints that applied to earlier versions.
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Affiliation(s)
- Masahiro Asaka
- Department of Gastroenterology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
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Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41:89-295. [PMID: 19514967 DOI: 10.1080/03602530902843483] [Citation(s) in RCA: 536] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pharmacogenetics is the study of how interindividual variations in the DNA sequence of specific genes affect drug response. This article highlights current pharmacogenetic knowledge on important human drug-metabolizing cytochrome P450s (CYPs) to understand the large interindividual variability in drug clearance and responses in clinical practice. The human CYP superfamily contains 57 functional genes and 58 pseudogenes, with members of the 1, 2, and 3 families playing an important role in the metabolism of therapeutic drugs, other xenobiotics, and some endogenous compounds. Polymorphisms in the CYP family may have had the most impact on the fate of therapeutic drugs. CYP2D6, 2C19, and 2C9 polymorphisms account for the most frequent variations in phase I metabolism of drugs, since almost 80% of drugs in use today are metabolized by these enzymes. Approximately 5-14% of Caucasians, 0-5% Africans, and 0-1% of Asians lack CYP2D6 activity, and these individuals are known as poor metabolizers. CYP2C9 is another clinically significant enzyme that demonstrates multiple genetic variants with a potentially functional impact on the efficacy and adverse effects of drugs that are mainly eliminated by this enzyme. Studies into the CYP2C9 polymorphism have highlighted the importance of the CYP2C9*2 and *3 alleles. Extensive polymorphism also occurs in other CYP genes, such as CYP1A1, 2A6, 2A13, 2C8, 3A4, and 3A5. Since several of these CYPs (e.g., CYP1A1 and 1A2) play a role in the bioactivation of many procarcinogens, polymorphisms of these enzymes may contribute to the variable susceptibility to carcinogenesis. The distribution of the common variant alleles of CYP genes varies among different ethnic populations. Pharmacogenetics has the potential to achieve optimal quality use of medicines, and to improve the efficacy and safety of both prospective and currently available drugs. Further studies are warranted to explore the gene-dose, gene-concentration, and gene-response relationships for these important drug-metabolizing CYPs.
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Affiliation(s)
- Shu-Feng Zhou
- School of Health Sciences, RMIT University, Bundoora, Victoria, Australia.
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Yang JC, Yang YF, Uang YS, Lin CJ, Wang TH. Pharmacokinetic- pharmacodynamic analysis of the role of CYP2C19 genotypes in short-term rabeprazole-based triple therapy against Helicobacter pylori. Br J Clin Pharmacol 2009; 67:503-10. [PMID: 19552744 DOI: 10.1111/j.1365-2125.2009.03393.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
AIMS The aim was to explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against Helicobacter pylori infection. METHODS Patients with H. pylori infection were tested for CYP2C19 genotype as poor metabolizers (PMs) or extensive metabolizers (EMs, homozygous EM or heterozygous EM) and given rabeprazole for 7 days. Antibiotics (clarithromycin and amoxicillin) were given on days 1-4, days 4-7, or days 1-7. A direct link model with an effect compartment was used in the population pharmacokinetic-pharmacodynamic analysis. The status of H. pylori infection was evaluated. RESULTS Rabeprazole clearance was lower in CYP2C19 PMs than in EMs (with average values of 10.7 vs. 16.8 l h(-1) in PMs and EMs, respectively), resulting in higher plasma levels in the former group. The values of EC(50) and k(eo) of gastrin response increased with multiple doses of rabeprazole. The k(eo) values were lower in CYP2C19 PMs than in EMs on day 1 (0.012 vs. 0.017 x 10(-4) l min(-1)), and higher than in EMs on day 4 (0.804 vs. 0.169 x 10(-4) l min(-1)) of rabeprazole treatment. The predicted gastrin-time profile showed a higher response in CYP2C19 PMs than in EMs on days 4 and 7. Helicobacter pylori was eradicated in all CYP2C19 PMs except in one patient infected by a resistant strain. In contrast, in CYP2C19 EMs the eradication rates ranged from 58 to 85%. CONCLUSIONS CYP2C19 genotypes play a role in H. pylori eradication therapy. Rabeprazole-based short-term triple therapy may be applicable in CYP2C19 PMs for H. pylori eradication.
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Affiliation(s)
- Jyh-Chin Yang
- Department of Internal Medicine, Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan
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Zhao F, Wang J, Yang Y, Wang X, Shi R, Xu Z, Huang Z, Zhang G. Effect of CYP2C19 genetic polymorphisms on the efficacy of proton pump inhibitor-based triple therapy for Helicobacter pylori eradication: a meta-analysis. Helicobacter 2008; 13:532-541. [PMID: 19166419 DOI: 10.1111/j.1523-5378.2008.00643.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE CYP2C19 polymorphisms have been inconsistently reported to associate with the efficacy of proton pump inhibitor (PPI)-based triple therapies for eradicating Helicobacter pylori infection. The aim of this meta-analysis was to determine whether CYP2C19 polymorphism affect H. pylori eradication rates obtained with first-line PPI-based triple therapies. METHODS A systematic literature search was conducted up to July 2007 using Medline, PubMed, EMBase, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science, CNKI (Chinese), and Wanfang (Chinese) digital database. MeSH terms and keywords included proton pump inhibitor, omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomeprazole, cytochrome P4502C19 or CYP2C19, and Helicobacter pylori or H. pylori. Twenty articles met the inclusion criteria, and were included in the meta-analysis by using Review Manager 4.2.8. RESULTS Eradication rates were significantly different between poor metabolizers (PM) and heterozygous extensive metabolizers (HetEM) (odds ratio (OR) = 1.73, p = .002) and between PM and homozygous extensive metabolizers (HomEM) (OR = 2.79, p < .0001). Moreover, eradication rates were also significant difference between HetEM and HomEM (OR = 2.00, p < .0001). Triple omeprazole and lansoprazole therapies achieved higher H. pylori eradication rates in PM than in HomEM (OR = 4.28, p = .0005 for omeprazole and OR = 3.06, p = .001 for lansoprazole), and higher in HetEM than those in HomEM (OR = 3.22, p < .0001 for omeprazole and OR = 1.95, p = .040 for lansoprazole). Rabeprazole therapies had no significant effect on H. pylori eradication rates (between PM and HomEM, OR = 1.35, p = .610 and between HetEM and HomEM, OR = 1.57, p = .190). No significant difference in H. pylori eradication rates between PM and HetEM was observed in the three individual PPI therapies. CONCLUSION The efficacy of omeprazole- and lansoprazole-based first-line triple therapies at the standard doses is dependent on CYP2C19 genotype status, which appears not to affect the efficacy of the regimens including rabeprazole.
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Affiliation(s)
- Fujun Zhao
- Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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30
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Kang JM, Kim N, Lee DH, Park YS, Kim JS, Chang IJ, Song IS, Jung HC. Effect of the CYP2C19 polymorphism on the eradication rate of Helicobacter pylori infection by 7-day triple therapy with regular proton pump inhibitor dosage. J Gastroenterol Hepatol 2008; 23:1287-91. [PMID: 18637061 DOI: 10.1111/j.1440-1746.2008.05392.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND AND AIM Proton pump inhibitors (PPI) are mainly metabolized by cytochrome P450 2C19 (CYP2C19) in the liver. We investigated whether the CYP2C19 genotype plays a role in the eradication rate of Helicobacter pylori (H. pylori) infection in patients receiving pantoprazole- or esomeprazole-based triple therapy. METHODS A total of 327 patients infected with H. pylori were treated with either pantoprazole or esomeprazole, plus amoxicillin and clarithromycin for 7 days. The presence of the CYP2C19 genotype was determined by pyrosequencing. RESULTS The overall H. pylori eradication rate was 85%; 82.6% for the PAC regimen, and 88.3% for the EAC regimen; the differences were not statistically significant. The overall eradication rate in the poor metabolizer groups (PM) was significantly higher than in the extensive metabolizer groups (EM) (97.4% vs 83.3%; P = 0.016). The eradication rates in the EM and PM groups were 80.8% and 95.7% for the PAC regimen and 86.8% and 100% for the EAC regimen, respectively. CONCLUSION The results of this study suggest that the CYP2C19 genotype status may play a role in the H. pylori eradication rate in patients receiving pantoprazole or esomeprazole-based triple therapy.
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Affiliation(s)
- Jung Mook Kang
- Department of Internal Medicine and Liver Research Institute, Seoul National University Bundang Hospital, Seongnam, Gyeonggi-do, Korea
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Wijnen PAHM, Op den Buijsch RAM, Drent M, Kuijpers PMJC, Neef C, Bast A, Bekers O, Koek GH, Koek GH. Review article: The prevalence and clinical relevance of cytochrome P450 polymorphisms. Aliment Pharmacol Ther 2007; 26 Suppl 2:211-9. [PMID: 18081664 DOI: 10.1111/j.1365-2036.2007.03490.x] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND Most drugs currently used in clinical practice are effective in only 25% to 60% of patients, while adverse drug reactions (ADRs) as a consequence of treatment are estimated to cost billions of US dollars and tens of thousands of deaths. AIM To review the prevalence and clinical significance of cytochrome P450 polymorphisms. RESULTS The cytochrome P450 enzyme families 1-3 are responsible for 70 to 80% of all phase I dependent drug metabolisms. In 90% metabolic activity dependents on six enzymes: CYP1A2, CYP3A, CYP2C9, CYP2C19, CYP2D6 and CYP2E1. Polymorphisms in the CYP450 gene can influence metabolic activity of the subsequent enzymes. A poor metabolizer (PM) has no or very poor enzyme activity. A consequence of PM is drug toxicity if no other metabolic route is available, or when multiple drugs are metabolized by the same cytochrome. In that case dose reduction is an option to prevent toxic effects. CONCLUSIONS In the future genotyping should be considered to identify patients who might be at risk of severe toxic responses, in order to guide appropriate individual dosage. Medical therapy should be a close cooperation between clinicians, pharmacologists and laboratory specialists, leading to reduced therapeutic errors, ADRs and health care costs.
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Affiliation(s)
- P A H M Wijnen
- Department of Clinical Chemistry, University Hospital Maastricht, Maastricht, The Netherlands
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Furuta T, Sugimoto M, Shirai N, Ishizaki T. CYP2C19 pharmacogenomics associated with therapy of Helicobacter pylori infection and gastro-esophageal reflux diseases with a proton pump inhibitor. Pharmacogenomics 2007; 8:1199-1210. [PMID: 17924835 DOI: 10.2217/14622416.8.9.1199] [Citation(s) in RCA: 67] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Proton pump inhibitors (PPIs), such as omeprazole, lansoprazole and rabeprazole, are metabolized by CYP2C19 in the liver. There are genetic differences in the activity of this enzyme. Genotypes of CYP2C19 are classified into three groups, rapid metabolizer (RM: *1/*1), intermediate metabolizer (IM: *1/*X) and poor metabolizer (PM: *X/*X) (*1 and 'X' represent the wild-type and mutant allele, respectively). The pharmacokinetics and pharmacodynamics of PPIs differ among three different CYP2C19 genotype groups. Plasma PPI levels and intragastric pHs during PPI treatment in the RM group are lowest, those in the IM group come next, and those in the PM group are highest of the three groups. These CYP2C19 genotypic differences in pharmacokinetics and pharmacodynamics of PPIs influence the healing and eradication rates for the gastro-esophageal reflux disease and Helicobacter pylori infection by PPI-based regimens. Recently, the CYP2C19 genotype-based tailored therapy for H. pylori infection has been found to be effective. CYP2C19 pharmacogenetics should be taken into consideration for the personalization of a PPI-based therapy.
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Affiliation(s)
- Takahisa Furuta
- 1Hamamatsu University School of Medicine, Center for Clinical Research, 1-20-1, Handa-Yama, Higashi-Ku, Hamamatsu, 431-3192, Japan.
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Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clin Microbiol Rev 2007; 20:280-322. [PMID: 17428887 PMCID: PMC1865594 DOI: 10.1128/cmr.00033-06] [Citation(s) in RCA: 482] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The discovery of Helicobacter pylori in 1982 was the starting point of a revolution concerning the concepts and management of gastroduodenal diseases. It is now well accepted that the most common stomach disease, peptic ulcer disease, is an infectious disease, and all consensus conferences agree that the causative agent, H. pylori, must be treated with antibiotics. Furthermore, the concept emerged that this bacterium could be the trigger of various malignant diseases of the stomach, and it is now a model for chronic bacterial infections causing cancer. Most of the many different techniques involved in diagnosis of H. pylori infection are performed in clinical microbiology laboratories. The aim of this article is to review the current status of these methods and their application, highlighting the important progress which has been made in the past decade. Both invasive and noninvasive techniques will be reviewed.
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Affiliation(s)
- Francis Mégraud
- INSERM U853, and Université Victor Segalen Bordeaux 2, and Laboratoire de Bactériologie, Hôpital Pellegrin, Place Amélie Raba-Léon, 33076 Bordeaux cedex, France.
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Lee KKC. Discontinued drugs in 2005: pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs. Expert Opin Investig Drugs 2006; 15:1497-505. [PMID: 17107276 DOI: 10.1517/13543784.15.12.1497] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
This perspective is the fourth in a series of papers discussing drugs dropped from development in 2005, focusing on pulmonary-allergy, dermatological, gastrointestinal and arthritis drugs. A survey of discontinued drugs from 2005 is provided, based on data from the Pharmaprojects database, along with an analysis of economic considerations in developing new drugs.
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Affiliation(s)
- Kenneth K C Lee
- School of Pharmacy, Faculty of Medicine, Chinese University of Hong Kong, Shatin, NT, Hong Kong, China.
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Gardiner SJ, Begg EJ. Pharmacogenetics, drug-metabolizing enzymes, and clinical practice. Pharmacol Rev 2006; 58:521-90. [PMID: 16968950 DOI: 10.1124/pr.58.3.6] [Citation(s) in RCA: 235] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The application of pharmacogenetics holds great promise for individualized therapy. However, it has little clinical reality at present, despite many claims. The main problem is that the evidence base supporting genetic testing before therapy is weak. The pharmacology of the drugs subject to inherited variability in metabolism is often complex. Few have simple or single pathways of elimination. Some have active metabolites or enantiomers with different activities and pathways of elimination. Drug dosing is likely to be influenced only if the aggregate molar activity of all active moieties at the site of action is predictably affected by genotype or phenotype. Variation in drug concentration must be significant enough to provide "signal" over and above normal variation, and there must be a genuine concentration-effect relationship. The therapeutic index of the drug will also influence test utility. After considering all of these factors, the benefits of prospective testing need to be weighed against the costs and against other endpoints of effect. It is not surprising that few drugs satisfy these requirements. Drugs (and enzymes) for which there is a reasonable evidence base supporting genotyping or phenotyping include suxamethonium/mivacurium (butyrylcholinesterase), and azathioprine/6-mercaptopurine (thiopurine methyltransferase). Drugs for which there is a potential case for prospective testing include warfarin (CYP2C9), perhexiline (CYP2D6), and perhaps the proton pump inhibitors (CYP2C19). No other drugs have an evidence base that is sufficient to justify prospective testing at present, although some warrant further evaluation. In this review we summarize the current evidence base for pharmacogenetics in relation to drug-metabolizing enzymes.
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Affiliation(s)
- Sharon J Gardiner
- Department of Medicine, Christchurch School of Medicine, Private Bag 4345, Christchurch, New Zealand.
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Hu YM, Mei Q, Xu XH, Hu XP, Hu NZ, Xu JM. Pharmacodynamic and kinetic effect of rabeprazole on serum gastrin level in relation to CYP2C19 polymorphism in Chinese Hans. World J Gastroenterol 2006; 12:4750-3. [PMID: 16937451 PMCID: PMC4087845 DOI: 10.3748/wjg.v12.i29.4750] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To observe the pharmacokinetics and pharmaco-dynamics of rabeprazole and compare serum gastrin concentrations in different CYP2C19 genotype groups.
METHODS: The CYP2C19 genotype status of Chinese Han healthy volunteers was determined by polymerase chain reaction-restriction fragment length polymorphism method. Twenty H pylori-negative healthy subjects voluntary participated in the study. They were divided into the following three groups: homozygous extensive metabolizers (homEM), heterozygous extensive metabolizers (hetEM) and poor metabolizers (PM). After they orally received rabeprazole 20 mg once daily in the morning of d 1 and d 8, blood samples were collected at various time-points until 24 h after administration and intragastric pH values were monitored for 24 h by Digitrapper pH. Serum gastrin concentrations were measured by radioimmunoassay. Serum concentrations of rabeprazole were measured by high performance liquid chromatography.
RESULTS: The mean AUC values for rabeprazole after a single and repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM, or the hetEM and PM groups. No significant differences in intragastric pH medians were observed among the three different genotype groups after a single dose or repeated doses. The ratio of pH medians between d 1 and d 8 ranged from 84% to 108%. The mean gastrin AUC values were also different among the three genotype groups, with a relative ratio of 1.0, 1.2 and 1.5 after a single dose and 1.0, 1.5 and 1.6 after repeated doses in the homEM, hetEM and PM groups, respectively. The gastrin AUC values among the three different genotype groups showed no significant difference either after a single dose or repeated doses. The subject who had lower intragastric acidity showed higher serum gastrin levels and concentrations of rabeprazole.
CONCLUSION: In Chinese Han healthy people, the pharmacokinetics of rabeprazole are dependent on the CYP2C19 genotype status, but acid-inhibitory efficacy of rabeprazole and the gastrin level are not influenced significantly.
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Affiliation(s)
- Yong-Mei Hu
- Department of Gastroenterology, The First Affiliated Hospital, Anhui Medical University, Hefei 230022, Anhui Province, China.
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KAWAI T, KAWAKAMI K, KATAOKA M, TAIRA S, ITOI T, MORIYASU F, TAKAGI Y, AOKI T, RIMBARA E, NOGUCHI N, SASATSU M. Comparison of efficacies of dual therapy and triple therapy using rabeprazole in second-line eradication of Helicobacter pylori in Japan. ACTA ACUST UNITED AC 2006. [DOI: 10.1111/j.1746-6342.2006.00021.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Padol S, Yuan Y, Thabane M, Padol IT, Hunt RH. The effect of CYP2C19 polymorphisms on H. pylori eradication rate in dual and triple first-line PPI therapies: a meta-analysis. Am J Gastroenterol 2006; 101:1467-75. [PMID: 16863547 DOI: 10.1111/j.1572-0241.2006.00717.x] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PREMISE It has been suggested that proton pump inhibitor (PPI)-related differences in Helicobacter pylori eradication rates are partly because of CYP2C19 polymorphisms and there have been conflicting data in this area. We conducted a meta-analysis to investigate the evidence relating CYP2C19 to first-line H. pylori eradication rates. METHODS A search of the literature was conducted up to June 2005 using Medline, EMBase, and Cochrane Register of Controlled Trials (CENTRAL). Twenty-eight arms from 17 papers were extracted for omeprazole, lansoprazole, and rabeprazole, collectively. Review Manager 4.2.8 was used for analysis. RESULTS When all eradication rates, regardless of PPI used, were combined there was no significant difference between poor metabolizers (PM) and heterozygous extensive metabolizers (HetEMs) (odds ratio [OR]= 1.35, 95% confidence interval [CI] 0.89-2.07, p = 0.15); however, there was a significant difference between HetEM and homozygous extensive metabolizers (HomEMs) (OR = 1.90, 95% CI 1.38-2.60, p < 0.0001). Significant heterogeneity was observed in a HomEM and PM comparison, hence additional subanalysis of individual PPIs revealed that dual and triple omeprazole therapies significantly favored higher H. pylori eradication rates in PM over HomEM (OR = 4.03, 95% CI 1.97-8.28, p = 0.0001), and also over HetEM (OR = 2.24, 95% CI 1.09-4.61, p = 0.03). Dual and triple rabeprazole and triple lansoprazole therapies did not show significantly different H. pylori eradication rates between PM and HomEM (OR = 1.04, 95% CI 0.44-2.46, p = 0.25) and (OR = 1.80, 95% CI 0.67-4.85, p = 0.93), respectively. CONCLUSIONS The impact of CYP2C19 polymorphisms on H. pylori eradication rates in studied populations appears clinically relevant in patients prescribed omeprazole as a component of their dual- or triple-drug therapy, whereas regimens that include lansoprazole or rabeprazole are unaffected. The choice of PPI and/or dose rather than CYP2C19 genotyping could be a more practical approach to assure the highest H. pylori eradication rates in clinical settings.
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Affiliation(s)
- Sara Padol
- Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada
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SUZUKI T, MATSUO K, SAWAKI A, WAKAI K, HIROSE K, ITO H, SAITO T, NAKAMURA T, YAMAO K, HAMAJIMA N, TAJIMA K. Influence of smoking and CYP2C19 genotypes on H. pylori eradication success. Epidemiol Infect 2006; 135:171-6. [PMID: 16740190 PMCID: PMC2870552 DOI: 10.1017/s0950268806006613] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2006] [Indexed: 12/29/2022] Open
Abstract
CYP2C19 polymorphisms and smoking influence the efficacy of H. pylori eradication therapy, but interaction between the two have hitherto not been examined. A total of 142 H. pylori-positive patients who received triple drug therapy with lansoprazole, amoxicillin and clarithromycin were categorized into three groups with regard to diplotypes of CYP2C19: homozygous extensive metabolizer (homEM), heterozygous EM (hetEM), and poor metabolizer (PM). The overall success rate was 61.3%. Smoking was an independent risk factor of eradication failure (OR 2.81, 95% CI 1.14-6.91), whereas CYP2C19 polymorphisms were less influential. Among non-smokers, the homEM and hetEM groups showed worse eradication rates (58.5 and 67.3%) relative to PM (76.2%) as expected; however, an opposite trend was observed among smokers (homEM 50.0%, hetEM 46.7%, PM 20.0%), indicating possible interactions with CYP2C19 polymorphisms. Smoking has a greater influence on H. pylori eradication than the CYP2C19 genotype. Interaction between smoking and CYP2C19 should be examined in the future.
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Affiliation(s)
- T. SUZUKI
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan
- Department of Internal Medicine and Molecular Science, Nagoya City University Graduate School of Medical Science, Japan
| | - K. MATSUO
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan
- Author for correspondence: K. Matsuo, M.D., Ph.D., M.Sc., Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku Nagoya 464-8681, Japan. ()
| | - A. SAWAKI
- Department of Gastroenterology, Aichi Cancer Center Research Institute, Japan
| | - K. WAKAI
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan
| | - K. HIROSE
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan
| | - H. ITO
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan
| | - T. SAITO
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan
| | - T. NAKAMURA
- Department of Endoscopy, Aichi Cancer Center Research Institute, Japan
| | - K. YAMAO
- Department of Gastroenterology, Aichi Cancer Center Research Institute, Japan
| | - N. HAMAJIMA
- Department of Preventive Medicine/ Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, Japan
| | - K. TAJIMA
- Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan
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Alonso-Navarro H, Jiménez-Jiménez FJ, García-Agúndez JA. Papel del polimorfismo genético CYP2C19 en los efectos adversos a fármacos y en el riesgo para diversas enfermedades. Med Clin (Barc) 2006; 126:697-706. [PMID: 16759580 DOI: 10.1157/13088772] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
There are a great number of polymorphic genes in the human genome. Many of them codify enzymes that metabolizes drugs and xenobiotic agents, including carcinogens. Among the better known of them, there are a number of isozymes of the microsomal oxidative system (CYP3A4, CYP2C9, CYP2C19 y CYP2D6). This article reviews the following issues: a) frequency of presentation of the "poor metabolizer" genotype and/or phenotype for substrates of CYP2C19; b) role of CYP2C19 polymorphism on the metabolism of some drugs (mephenytoine and other antiepileptic drugs, proton pump inhibitors, several antidepressants and anxyolitics, the antimalaria aggent proguanyl, and propranolol, among others, use this metabolic pathway), and c) possible role of CYP2C19 polymorphism in the risk for development of neoplasia and other diseases (systemic lupus erythematosus, psoriasis, hip osteonecrosis, Alzheimer's disease, amyotrophic lateral sclerosis, essential tremor).
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Sharara AI. Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication. Expert Rev Anti Infect Ther 2005; 3:863-870. [PMID: 16307499 DOI: 10.1586/14787210.3.6.863] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Proton pump inhibitors have become one of the cornerstones in the treatment of Helicobacter pylori infection. Rabeprazole (Pariet) is a substituted benzimidazole proton pump inhibitor with potent gastric acid suppression properties. Its high acid-base dissociation constant allows activation over a broader pH range, resulting in quick, irreversible binding to the H+/K+-ATPase pump, and a more rapid onset of action compared with omeprazole, lansoprazole and pantoprazole. Unlike other proton pump inhibitors, the metabolism of rabeprazole is primarily via a nonenzymatic reduction to the thioether derivative, and the cytochrome P450 isoenzyme 2C19 is only partly involved in its metabolism. The effect of genetic polymorphism in cytochrome P450 isoenzyme 2C19 on the pharmacokinetics and pharmacodynamics of rabeprazole is therefore limited. In humans, once-daily dosing of 5-40 mg of rabeprazole inhibits gastric acid secretion in a dose-dependent manner. In vitro studies have shown that rabeprazole possesses more potent antibacterial properties against the growth of H. pylori than other proton pump inhibitors. Furthermore, its thioether derivative has more potent inhibitory in vitro activity against the growth and motility of clarithromycin-resistant H. pylori than other proton pump inhibitors or commonly used antimicrobials. Despite these inherent favorable characteristics of rabeprazole, randomized controlled trials have largely shown equivalence amongst proton pump inhibitors when used with two antibiotics in the eradication of H. pylori, with cure rates of 75-89% on an intent-to-treat basis. However, rabeprazole appears to consistently achieve such comparable eradication rates even when used at reduced doses (10 mg twice daily) as part of clarithromycin-based triple therapy.
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Affiliation(s)
- Ala I Sharara
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 11-0236/16-B, Beirut, Lebanon.
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Gawrońska-Szklarz B, Wrześniewska J, Starzyńska T, Pawlik A, Safranow K, Ferenc K, Droździk M. Effect of CYP2C19 and MDR1 polymorphisms on cure rate in patients with acid-related disorders with Helicobacter pylori infection. Eur J Clin Pharmacol 2005; 61:375-9. [PMID: 15976989 DOI: 10.1007/s00228-005-0901-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2004] [Accepted: 01/12/2005] [Indexed: 12/19/2022]
Abstract
A proton pump inhibitor (PPI) plus two antibiotics (amoxicillin and either clarithromycin or metronidazole) are recommended for treatment of acid-related disorders with Helicobacter pylori (H. pylori) infection. The aim of this pharmacogenetic study was to evaluate the efficacy of triple therapy with PPIs on eradication of H. pylori infection in relation to cytochrome P450 2C19 (CYP2C19) and P-glycoprotein (MDR1) gene polymorphisms. The retrospective study involved 70 Polish Caucasian patients with H. pylori infection, diagnosed and treated with one of the two different triple therapy regimens [omeprazole, amoxicillin, and clarithromycin (OAC) or pantoprazole, amoxicillin, and metronidazole (PAM)]. Using genomic DNA, CYP2C19 (*2 and *3) and C3435T MDR1 alleles were determined by means of polymerase chain reaction-restriction fragment length polymorphism assays. A significantly higher prevalence (P<0.05) of heterozygous extensive metabolizers (hetEM) with CYP2C19*1/*2 genotype (32.4% versus 8.3%) and homozygous with 3435TT MDR1 genotype (38.2% versus 13.9%) was found in patients cured after the first cycle of triple therapy than in patients with failure of eradication after the first cycle. CYP2C19*1/*2 and 3435TT MDR1 genotypes as well as PAM regimen of treatment were also predictive of successful eradication of H. pylori infection after the first cycle of triple therapy at univariate/multivariate logistic regression analysis. This pharmacogenetic study on the influence of different CYP2C19 and C3435T MDR1 genotypes on H. pylori eradication suggests that CYP2C19 and MDR1 polymorphisms may be independent predictable determinants of the efficacy of triple therapy including PPI. The PAM regimen of treatment seems to be more effective after the first cycle of the therapy than the OAC regimen.
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Affiliation(s)
- Barbara Gawrońska-Szklarz
- Department of Pharmacology, Pomeranian Medical University, Al. Powstańców Wlkp. 72, 70-111, Szczecin, Poland
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Hu YM, Xu JM, Mei Q, Xu XH, Xu SY. Pharmacodynamic effects and kinetic disposition of rabeprazole in relation to CYP2C19 genotype in healthy Chinese subjects. Acta Pharmacol Sin 2005; 26:384-8. [PMID: 15715938 DOI: 10.1111/j.1745-7254.2005.00047.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
AIM To investigate whether the pharmacodynamics and pharmacokinetics of rabeprazole are dependent on CYP2C19 genotype status in healthy Chinese Han subjects. METHODS The CYP2C19 genotype status of healthy Chinese Han volunteers was determined using the polymerase chain reaction-restriction fragment length polymorphism method. Twenty healthy subjects volunteered to participate in the study. There were seven homozygous extensive metabolizers (homEM), six heterozygous extensive metabolizers (hetEM), and seven poor metabolizers (PM). All subjects were Helicobactor pylori-negative, which was determined by sero-logy and 13C-urea breath tests. Rabeprazole (20 mg) was taken orally once daily in the morning for 8 days, and intragastric pH values were monitored for 24 h by Digitrapper pH after day 1 (single dose) and day 8 (repeated dose). Meanwhile, blood samples were collected at various time-points for 24 h after administration. The serum concentrations of rabeprazole were measured using high-performance liquid chromatography. RESULTS The mean area under the curve (AUC) values for rabeprazole differed among the three different genotype groups, with a relative ratio of 1.0, 1.3, and 1.8 after a single dose and 1.0, 1.1, and 1.7 after repeated doses in the homEM, hetEM, and PM groups, respectively. Mean AUC values for rabeprazole after a single dose and after repeated doses were significantly different between the homEM and PM groups, but not between the homEM and hetEM or hetEM and PM groups. No significant differences in intragastric pH median, pH>4 total time, and pH>4 time percentage of 24 h, were observed among the three different genotype groups after a single dose or after repeated doses of rabeprazole. CONCLUSION In healthy Chinese Han subjects, the pharmacokinetics of rabeprazole are dependent on a certain degree on CYP2C19 genotype status; however, the acid-inhibitory efficacy of rabeprazole is not influenced significantly by CYP2C19 genetic polymorphism.
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Affiliation(s)
- Yong-mei Hu
- Anhui Geriatric Institute, Hefei 230022, China.
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Albsoul-Younes A, Tayyem R, Najib N. Variable omeprazole kinetics in healthy Jordanian adults. Biopharm Drug Dispos 2005; 26:183-8. [PMID: 15906422 DOI: 10.1002/bdd.449] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
OBJECTIVES The objective of this study was to examine the pharmacokinetics of orally administered omeprazole in healthy adult Jordanian men. METHOD Plasma concentrations of omeprazole were measured over a 12 h period after administration of a single oral dose of 40 mg omeprazole (Losec), AstraZeneca, UK). Subjects were healthy adult Jordanian men age 18-38 (24 +/- 4, mean +/- SD). The pharmacokinetic parameters were derived from the plasma concentration-time profiles for AUC(0-t), AUC(0-inf), C(max), t(max), t(1/2e) and K(e). RESULTS The pharmacokinetic of omeprazole were scattered over a wide range. The median AUC(0-inf) was 784.86 +/- 1182.88 (ng.h/ml), and the median C(max) was 521 +/- 354 (ng/ml) (median +/- SD). In general, most subjects showed normal distribution (approximately 90%). Some subjects (10%) did show very high AUC and C(max) compared with the reported AUC and C(max) levels. These subjects had higher half-lives and lower rates of elimination. CONCLUSION Significant difference in the pharmacokinetics of omeprazole after a single dose administration was noted. Approximately 10% of the study group showed very high omeprazole plasma levels and AUCs. Differences in the pharmacokinetics might be due to differences in the genetic make-up of subjects.
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Affiliation(s)
- Abla Albsoul-Younes
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science & Technology, Jordan.
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Abstract
At present, antisecretory drugs--foremost among them the proton pump inhibitors (PPIs)--represent a keystone in Helicobacter pylori eradication therapy. The present article shall first compare the role of PPIs as compared with histamine H2 receptor antagonists, both of them in the role of antibiotic-associated antisecretory therapy, and shall then address the contribution of each of the various PPIs that have been developed until the present time to the H. pylori eradication therapies. In summary, it may be concluded that PPIs are more effective overall than H2 receptor antagonists when the two groups of antisecretory drugs are given at the usual standard doses together with antibiotics with the intention of eradicating H. pylori infection. However, all PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole) are equivalent when given together with two antibiotics to cure the infection.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Service, La Princesa University Hospital, Madrid, Spain.
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Roots I, Gerloff T, Meisel C, Kirchheiner J, Goldammer M, Kaiser R, Laschinski G, Brockmöller J, Cascorbi I, Kleeberg U, Hildebrandt AG. Pharmacogenetics‐Based New Therapeutic Concepts. Drug Metab Rev 2004; 36:617-38. [PMID: 15554239 DOI: 10.1081/dmr-200033458] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Pharmacogenetics, one of the fields of clinical pharmacology, studies how genetic factors influence drug response. If hereditary traits are taken into account appropriately before starting drug treatment, the type of drug and its dosage can be tailored to the individual patient's needs. Pharmacogenetics adds a considerable amount of stringency to the doctor's therapeutic approach. Today, it is the relationship between dosage requirements and genetic variations in drug metabolizing enzymes like cytochrome P450 (CYP) 2D6 and CYP2C19, or in drug transporters like p-glycoprotein, that is substantiated best. A standard dose will bring about more adverse effects than usual if enzymatic activity is lacking or feeble. Sometimes, however, therapeutic response might be better due to higher concentrations: proton pump inhibitors for eradication of Helicobacter pylori are more efficacious in carriers of a deficient CYP2C19 variant. The drug's interaction with its target (e.g. receptor) also depends on genetic factors. In some cases genetic tests can help distinguish between responders and non-responders of a specific drug treatment. The first pharmacogenetic tests are already on the market.
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Affiliation(s)
- Ivar Roots
- Institut für Klinische Pharmakologie, Charité-Universitätsmedizin Berlin, Campus Charitè Mitte, Humboldt-Universität zu Berlin, Berlin, Germany.
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Nada T, Ando T, Nobata K, Tsuzuki T, Minami M, Ina K, Iinuma Y, Ichiyama S, Ohta M, El-Omar E, Kusugami K, Goto H. DNA typing for Helicobacter pylori isolates from eradication-failed patients: comparison of the isolates before and after therapy. Aliment Pharmacol Ther 2004; 20 Suppl 1:39-47. [PMID: 15298604 DOI: 10.1111/j.1365-2036.2004.01968.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
BACKGROUND Failure of Helicobacter pylori eradication occurs frequently despite use of multiple microbial agents. AIM We aimed to study differences between H. pylori strains isolated before and after eradication failure. METHODS We treated 87 patients with peptic ulcer using triple therapy consisting of omeprazole plus combinations of clarithromycin, amoxicillin, or metronidazole. We studied the status of cagA, vacA, and iceA by PCR, and examined the differences in H. pylori isolates by pulsed-field gel electrophoresis and arbitrary primer polymerase chain reaction. The minimum inhibitory concentration of clarithromycin, amoxicillin, or metronidazole was determined by an agar dilution method. RESULTS Eradication therapy failed in 12 patients (14%); H. pylori isolates were obtained from all of these both before and after therapy. After eradication therapy, 10 patients were colonized with the same strain as before therapy, while the other two patients were colonized with different strains from those before therapy. In the former group, one isolate changed from metronidazole-sensitive to -resistant, one changed from clarithromycin- and metronidazole-sensitive to -resistant, and four were resistant to clarithromycin or metronidazole both before and after therapy. The other four isolates remained sensitive to clarithromycin and metronidazole after therapy. In the two patients who yielded apparently different isolates after therapy, they changed from clarithromycin- and metronidazole-sensitive to -resistant. CONCLUSION Eradication of H. pylori by first-line therapy is an important goal in the treatment of H. pylori-positive peptic ulcer, and that appropriate antimicrobial sensitivity testing should be conducted in patients with eradication failure.
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Affiliation(s)
- T Nada
- Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan
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Niu CY, Luo JY, Hao ZM. Genetic polymorphism analysis of cytochrome P4502C19 in Chinese Uigur and Han populations. ACTA ACUST UNITED AC 2004; 5:76-80. [PMID: 15612662 DOI: 10.1111/j.1443-9573.2004.00160.x] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To assess the genotype patterns of cytochrome P4502C19 in the Chinese Uigur and Han populations and compare them with other populations. METHODS Ninety-six Uigur and 104 Han healthy, unrelated subjects (Uigur: 51 males, 45 females, aged from 23 to 30 years; Han: 53 males, 51 females, aged from 21 to 26 years) were genotyped for CYP2C19 by the PCR-RFLP technique to identify the wild-type (wt) gene and two mutations, CYP2C19m1 in exon5 and CYP2C19m2 in exon 4. RESULTS In the Uigur, the incidence of the poor metabolizer phenotype was 4.17% (4 of 96 subjects with m1/m1 genotype) and that of the extensive metabolizer was 95.83% (92 of 96 subjects), consisting of 6 (6.25%) homozygous for CYP2C19wt (wt/wt) in both exon 4 and exon 5, 83 (86.46%) heterozygous for CYP2C19wt and CYP2C19m1 and 3 (3.13%) heterozygous for both wt/m1 and wt/m2. None of the Uigur subjects was homozygous for CYP2C19m2 (m2/m2) or heterozygous for wt/m2 or m1/m2. Thus in the Uigur, the frequency of the CYP2C19m1 allele was 0.4818, the CYP2C19m2 allele was 0.0078, and that of the CYP2C19wt was 0.5104. In the Han, the frequency of the CYP2C19m1 allele was 0.3333, the CYP2C19m2 allele was 0.0686, and the frequency of the CYP2C19wt was 0.6058. CYP2C19m1 was the majority of the two mutations found in the Uigur, which was consistent with the situation in the Han population, and the frequency of the CYP2C19m1 allele was approximately 60-fold that of the mutant allele CYP2C19m2. On the other hand, there were significant interethnic differences when the Uigur population was compared with other minorities with regard to the CYP2C19 genotype. CONCLUSIONS The results indicate that the distribution frequency of the poor and the extensive metabolizers in the Uigur population is significantly lower and higher, respectively (P < 0.025), than in the Han population. There are significant differences between the Uigur and Han populations regarding the CYP2C19 allele frequency, which is consistent with results for the Caucasian population. On the other hand, there are significant interethnic differences when the Uigur population is compared with the Miao and Dai populations.
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Affiliation(s)
- Chun Yan Niu
- Department of Gastroenterology, The Second Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China
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Take S, Mizuno M, Ishiki K, Nagahara Y, Yoshida T, Inaba T, Yamamoto K, Okada H, Yokota K, Oguma K, Shiratori Y. Interleukin-1beta genetic polymorphism influences the effect of cytochrome P 2C19 genotype on the cure rate of 1-week triple therapy for Helicobacter pylori infection. Am J Gastroenterol 2003; 98:2403-8. [PMID: 14638340 DOI: 10.1111/j.1572-0241.2003.07707.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Genetic polymorphism of interleukin (IL)-1beta is associated with differences in gastric acid suppression in response to Helicobacter pylori (H. pylori) infection. Thus, the polymorphism might affect H. pylori eradication therapy, as antibiotics used in treatment regimens may be acid sensitive. In this study, we examined the impact of IL-1beta genetic polymorphism on the cure rate of triple therapy for H. pylori in relation to cytochrome P (CYP) 2C19 genotype and antibiotic resistance. METHODS A total 249 patients with peptic ulcer disease were randomized to receive one of the following regimens: amoxicillin and clarithromycin together with omeprazole, lansoprazole, or rabeprazole. CYP2C19 and IL-1beta-511 genetic polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS The intention-to-treat-based overall cure rate was 74.3% (95% CI=68-79%). In the normal acid secretion IL-1beta genotype group, the cure rate among CYP2C19 poor metabolizers (93.3%, 95% CI=56-99%) was significantly higher than among subjects in the CYP2C19 homozygous (60.0%, 95% CI=38-78%) and heterozygous (63.6%, 95% CI=46-78%), i.e., extensive metabolizer, groups (p<0.05). In the low acid secretion IL-1beta genotype group, there was no difference in the cure rate among the CYP2C19 genotype groups. Multiple logistic regression analysis identified susceptibility to clarithromycin (p<0.0001) and CYP2C19 genotype status (p=0.03) as significant independent factors for treatment failure. CONCLUSION IL-1beta genetic polymorphism, although not an independent factor in treatment outcome, influences the impact of the CYP2C19 genotype on the cure rate of 1-wk triple therapy for H. pylori infection.
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Affiliation(s)
- Susumu Take
- Department of Medicine and Medical Science, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
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