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Wei S, Xu G, Zhou J, Ni Y. Structure-Guided Evolution of Cyclohexanone Monooxygenase Toward Bulky Omeprazole Sulfide: Substrate Migration and Stereoselectivity Inversion. Chemphyschem 2024; 25:e202400008. [PMID: 38514394 DOI: 10.1002/cphc.202400008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2024] [Revised: 03/06/2024] [Accepted: 03/20/2024] [Indexed: 03/23/2024]
Abstract
Structure-guided engineering of a CHMO from Amycolatopsis methanolica (AmCHMO) was performed for asymmetric sulfoxidation activity and stereoselectivity toward omeprazole sulfide. Initially, combinatorial active-site saturation test (CASTing) and iteratively saturation mutagenesis (ISM) were performed on 5 residues at the "bottleneck" of substrate tunnel, and MT3 was successfully obtained with a specific activity of 46.19 U/g and R-stereoselectivity of 99 % toward OPS. Then, 4 key mutations affecting the stereoselectivity were identified through multiple rounds of ISM on residues at the substrate binding pocket region, resulting MT8 with an inversed stereoselectivity from 99 % (R) to 97 % (S). MT8 has a greatly compromised specific activity of 0.08 U/g. By introducing additional beneficial mutations, MT11 was constructed with significantly increased specific activity of 2.29 U/g and stereoselectivity of 97 % (S). Enlarged substrate tunnel is critical to the expanded substrate spectrum of AmCHMO, while reshaping of substrate binding pocket is important for stereoselective inversion. Based on MD simulation, pre-reaction states of MT3-OPSproR, MT8-OPSproS, and MT11-OPSproS were calculated to be 45.56 %, 17.94 %, and 28.65 % respectively, which further confirm the experimental data on activity and stereoselectivity. Our results pave the way for engineering distinct activity and stereoselectivity of BVMOs toward bulky prazole thioethers.
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Affiliation(s)
- Shiyu Wei
- Institution: School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Address, Lanzhou Jiaotong University, Lanzhou, 730070, Gansu, China
- Department: Key laboratory of industrial Biotechnology. Institution: Ministry of Education, School of Biotechnology, Address, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Guochao Xu
- Department: Key laboratory of industrial Biotechnology. Institution: Ministry of Education, School of Biotechnology, Address, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Jieyu Zhou
- Department: Key laboratory of industrial Biotechnology. Institution: Ministry of Education, School of Biotechnology, Address, Jiangnan University, Wuxi, 214122, Jiangsu, China
| | - Ye Ni
- Department: Key laboratory of industrial Biotechnology. Institution: Ministry of Education, School of Biotechnology, Address, Jiangnan University, Wuxi, 214122, Jiangsu, China
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Zheng Z, Lu Z, Song Y. Long-term proton pump inhibitors use and its association with premalignant gastric lesions: a systematic review and meta-analysis. Front Pharmacol 2023; 14:1244400. [PMID: 37693896 PMCID: PMC10492503 DOI: 10.3389/fphar.2023.1244400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Accepted: 08/14/2023] [Indexed: 09/12/2023] Open
Abstract
Background: Long-term maintenance therapy with proton pump inhibitors (PPIs) is a common treatment strategy for acid-related gastrointestinal diseases. However, concerns have been raised about the potential increased risk of gastric cancer and related precancerous lesions with long-term PPI use. This systematic review and meta-analysis aimed to evaluate this potential risk. Methods: We searched PubMed, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials published before 1 March 2023, with no language restrictions. The primary endpoint was the occurrence and progression of gastric mucosal atrophy, intestinal metaplasia, Enterochromaffin-like (ECL) cell hyperplasia, gastric polyps, and gastric cancer during the trial and follow-up. Data were analysed using a random effects model. Results: Of the 4,868 identified studies, 10 met the inclusion criteria and were included in our analysis, comprising 27,283 participants. Compared with other treatments, PPI maintenance therapy for more than 6 months was associated with an increased risk of ECL cell hyperplasia (OR 3.01; 95% CI 1.29 to 7.04; p = 0.01). However, no significant increase was found in the risk of gastric mucosal atrophy (OR 1.01; 95% CI 0.55 to 1.85; p = 0.97), intestinal metaplasia (OR 1.14; 95% CI 0.49 to 2.68; p = 0.76), gastric polyps (OR 1.13; 95% CI 0.68 to 1.89; p = 0.64), or gastric cancer (OR 1.06; 95% CI 0.79 to 1.43; p = 0.71). Conclusion: This systematic review and meta-analysis does not support an increased risk of gastric cancer or related precancerous lesions with long-term PPI maintenance therapy. However, long-term PPI use should be monitored for potential complications such as ECL cell hyperplasia. Further studies are needed to confirm these findings and evaluate the safety of PPI maintenance therapy for acid-related gastrointestinal diseases. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, Identifier: PROSPERO (CRD42022379692).
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Affiliation(s)
- Zeyi Zheng
- School of Traditional Chinese Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Ziyu Lu
- School of Basic Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia, China
| | - Yani Song
- School of Water Resources and Hydropower Engineering, Wuhan University, Wuhan, Hubei, China
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Algabbani AM, Alkeridy WA, Alessa MA, Alrwisan AA. The inadvertent consequences of drug recalls: A case study of a recall of pantoprazole generics from the markets. Saudi Pharm J 2023; 31:1181-1185. [PMID: 37273266 PMCID: PMC10236367 DOI: 10.1016/j.jsps.2023.04.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 04/09/2023] [Indexed: 06/06/2023] Open
Abstract
Introduction Drug recalls may impact treatment plans or access to suitable therapies. Thus, they inadvertently affect treatment outcomes. Objective We aimed to examine the impact of recalls on patients' safety using pantoprazole-containing products recall as a case study in terms of the occurrence of potential drug-drug interactions (pDDIs). Methods This retrospective study used de-identified electronic health records of adult patients who had a prescription for oral proton pump inhibitors (PPIs) including pantoprazole, esomeprazole, lansoprazole, or omeprazole from April 2020 through September 2021 from a large tertiary care hospital. The study outcome definition was the prevalence of pDDIs in PPIs users before and after the recall date (March 2021). Changes in the prevalence of pDDIs were modeled using interrupted time-series. The rate ratio of pDDIs in the 12 months before and 6 months after the recall was modeled using negative binomial regression. Results A total of 1,826 pDDIs were identified, and the median monthly prevalence of pDDI before the recall was 102.5 which increased to 115.5 after the recall. A change in the level of pDDIs occurred immediately after the recall date, followed by a gradual decrease over time. The rate of pDDIs was 69% higher after the recall compared to the baseline (rate ratio 1.69; 95% confidence interval, 0.75-1.91). Discussion Recall of pantoprazole-containing products was associated with a higher rate of pDDIs. However, the prevalence of pDDIs gradually decreased over time. We highlight the importance of planning of recall process and coordinating all potential stakeholders to avoid potential harms.Word count: 1450.
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Affiliation(s)
| | - Walid A. Alkeridy
- King Saud University, Department of Medicine, College of Medicine, Riyadh, Saudi Arabia
- University of British Columbia, Department of Medicine, Geriatric Division, Vancouver, Canada
- General Administration of Home Health Care, Therapeutic Affairs Deputyship, Ministry of Health, Riyadh, Saudi Arabia
| | - Mohammed A. Alessa
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
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Novel Set of Highly Substituted Bis-pyridines: Synthesis, Molecular Docking and Drug-Resistant Antibacterial Profile. Future Med Chem 2022; 14:1881-1897. [PMID: 36420816 DOI: 10.4155/fmc-2022-0196] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Aims: Development of antimicrobial agents having the ability to prevent bacterial biofilm formation which causes serious health problems, especially with antibiotic-resistant bacterial strains. Materials and methods: The use of 1,3-diaryl enones as structural motifs to access the pyridine core. Antimicrobial activities of the synthesized compounds against methicillin-susceptible Staphylococcus aureus, methicillin-resistant S. aureus and vancomycin-resistant S. aureus bacterial strains were investigated. Results: The newly synthesized bis-enones were used as building blocks to access some novel highly substituted bis-pyridine derivatives. Several novel bis-compounds showed great bacterial biofilm eradication activity. Conclusion: A new series of bis-chalcones was synthesized and their structural diversity was exploited to access the corresponding, more biologically active, pyridine core. These bis-pyridines showed respectable antibacterial activities against various drug-resistant bacterial strains: namely, methicillin-susceptible, methicillin-resistant and vancomycin-resistant S. aureus.
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Hewetson M, Tallon R. Equine Squamous Gastric Disease: Prevalence, Impact and Management. VETERINARY MEDICINE (AUCKLAND, N.Z.) 2021; 12:381-399. [PMID: 35004264 PMCID: PMC8725839 DOI: 10.2147/vmrr.s235258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 12/07/2021] [Indexed: 12/12/2022]
Abstract
This narrative review explores the etiopathogenesis, clinical signs, diagnosis and treatment of ESGD (equine squamous gastric disease) and discusses the impact of this commonly encountered condition on the equine industry. ESGD refers specifically to peptic injury of the squamous mucosa of the stomach. Prevalence is highest in performance horses, but the disease has been documented across many breeds and ages, including in feral horses and foals. The pathogenesis of ESGD is well understood. Intensive management and exercise are important factors that contribute to a disruption of the normal stratification of gastric pH. This results in exposure of the vulnerable squamous mucosa to acid, leading to ulceration. Clinical signs are variable and there is little evidence to support a direct association between reported signs and the presence or absence of lesions seen on gastroscopy. Management is aimed at acid suppression and mitigation of known risk factors.
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Affiliation(s)
- Michael Hewetson
- Department of Clinical Science and Services, The Royal Veterinary College, North Mymms, Hertfordshire, UK
| | - Rose Tallon
- Department of Clinical Science and Services, The Royal Veterinary College, North Mymms, Hertfordshire, UK
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Wei P, Zhuo S, Fu Q, Wang H, Zong B, Cao B, Wang L. The efficacy and safety of the short-term combination therapy with ticagrelor and PPIs or H2RA in patients with acute STEMI who underwent emergency PCI. Clin Transl Sci 2021; 15:477-489. [PMID: 34670024 PMCID: PMC8841456 DOI: 10.1111/cts.13165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 08/31/2021] [Accepted: 09/05/2021] [Indexed: 11/27/2022] Open
Abstract
Combination therapy with platelet inhibitors and acid-suppressive agents is recommended for patients with acute ST-segment elevation myocardial infarction (STEMI) who underwent percutaneous coronary intervention (PCI), but there remains a paucity of data to evaluate both the efficacy and safety of these combinations. In this prospective study, a total of 170 patients with acute STEMI who underwent PCI were divided into four groups: pantoprazole + ticagrelor, omeprazole + ticagrelor, ranitidine + ticagrelor, and ticagrelor only. The risk of PCI, antithrombotic efficacy, cardiac function, and main end points were evaluated and compared. No significant differences were found in infarction-related artery perfusion indexes (thrombolysis in myocardial infarction [TIMI], corrected TIMI frame count), the incidence of stent thrombosis after PCI, platelet indicators (platelet count, mean platelet volume, and platelet distribution width), platelet activation (P-selectin and glycoprotein IIb/IIIa levels), platelet aggregation (thrombelastography indicators, such as ADP% and MAADP ), myocardial necrosis biomarker (creatine kinase isoenzyme-MB and cardiac troponin I) levels, brain natriuretic peptide levels, the incidence of ischemic end point events, and the incidence of other tissue and organ bleeding events among the four groups. The incidence of gastrointestinal (GI) bleeding events in the proton pump-inhibitor (PPI) group was significantly lower than that in the control group, whereas in the H2 receptor antagonist (H2RA) group it was not significantly different from the control group. The short-term combination therapy with ticagrelor and PPIs or H2RA is safe and effective in patients with acute STEMI after PCI. In addition, the PPIs combined with ticagrelor could reduce the incidence of GI bleeding events without increasing the incidence of ischemic events.
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Affiliation(s)
- Peng Wei
- Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Shujiang Zhuo
- Department of Cardiology, Hainan Provincial Hospital of Traditional Chinese Medicine, Haikou, China
| | - Qiang Fu
- Department of Cardiology, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Haibo Wang
- Department of Cardiology, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Bin Zong
- Department of Cardiology, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, China
| | - Bangming Cao
- Department of Cardiology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, China
| | - Liansheng Wang
- Department of Cardiology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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Abstract
As our population continues to age, the early diagnosis and optimal management of patients with gastroesophageal reflux disease becomes paramount. Maintaining a low threshold for evaluating atypical symptoms in this population is key to improving outcomes. Should patients develop complications including severe esophagitis, peptic stricture, or Barrett esophagus, then a discussion of medical, endoscopic, and surgical treatments that accounts for patient's comorbidities and survival is important. Advances in screening, surveillance, and endoscopic treatment of Barrett esophagus have allowed us to dispel concerns of futility and treat a larger subset of the at-risk population.
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Affiliation(s)
- Fouad Otaki
- Division of Gastroenterology and Hepatology, Oregon Health and Science University, L461, 3181 SouthWest Sam Jackson Park Road, Portland, OR 97229, USA.
| | - Prasad G Iyer
- Barrett's Esophagus Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First Street SouthWest, Rochester, MN 55905, USA
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Ivić MA, Lović J, Stevanović S, Nikolić N, Trišović N, Lađarević J, Vuković D, Drmanić S, Mladenović A, Jadranin M, Petrović S, Mijin D. Electrochemical behavior of esomeprazole: Its determination at Au electrode as standard and in injection powder combined with the study of its degradation. J Electroanal Chem (Lausanne) 2019. [DOI: 10.1016/j.jelechem.2019.113303] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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The potential role of potassium-competitive acid blockers in the treatment of gastroesophageal reflux disease. Curr Opin Gastroenterol 2019; 35:344-355. [PMID: 31045597 DOI: 10.1097/mog.0000000000000543] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW Gastroesophageal reflux disease (GERD) is primarily a motor disorder, but its pathogenesis is multifactorial. Although gastric acid secretion is usually normal in GERD patients, treatment with proton pump inhibitors (PPIs) has become the standard of care, despite increasing awareness of their shortcomings. In this article, a new class of antisecretory drugs (namely potassium-competitive acid blockers, P-CABs), developed to overcome these limitations, is discussed. RECENT FINDINGS P-CABs block the K exchange channel of the proton pump, resulting in rapid, competitive, reversible inhibition of acid secretion. These drugs offer a more rapid elevation of intragastric pH than PPIs, while maintaining similar antisecretory effect, the duration of which is dependent on half-life and can be prolonged with extended release formulations. Thus, P-CABs offer advances in the treatment of GERD including rapid heartburn relief, faster and more reliable healing of severe grades of erosive esophagitis, as a consequence of better control of nighttime acid secretion than PPIs. SUMMARY P-CABs overcome many of the drawbacks of PPIs. The unique antisecretory effects of vonoprazan might be especially useful in the long-term treatment of patients with Barrett's esophagus.
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Kim DK, Lee KH, Kim SJ, Kim SJ, Lee SJ, Park CH, Kim BT, Song GS, Moon BS, Ryu SY. Effects of Tegoprazan, a Novel Potassium-Competitive Acid Blocker, on Rat Models of Gastric Acid-Related Disease. J Pharmacol Exp Ther 2019; 369:318-327. [PMID: 30894456 DOI: 10.1124/jpet.118.254904] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 03/11/2019] [Indexed: 03/08/2025] Open
Abstract
Tegoprazan, a novel potassium-competitive acid blocker (P-CAB), is a next-generation therapeutics developed for the treatment of acid-related gastrointestinal diseases such as gastroesophageal reflux disease (GERD) and peptic ulcers. In the present study, the in vitro and in vivo pharmacological properties of tegoprazan were compared with those of esomeprazole, a representative proton pump inhibitor. In vitro enzyme assays were performed using ion-leaky vesicles containing gastric H+/K+-ATPases isolated from pigs. The in vivo efficacies of tegoprazan were evaluated in rat models of GERD and peptic ulcer. Tegoprazan inhibited the activity of porcine H+/K+-ATPase with an IC50 value of 0.53 μM in a reversible manner, whereas esomeprazole showed weak and irreversible inhibition with an IC50 value of 42.52 μM. In a GERD model, tegoprazan showed dose-dependent efficacy in inhibiting esophageal injury and gastric acid secretion with an ED50 of 2.0 mg/kg, which was 15-fold more potent than that of esomeprazole. In peptic ulcer models, tegoprazan exhibited superior antiulcer activity compared with esomeprazole. The ED50 of tegoprazan in the naproxen-, ethanol-, and water-immersion restraint stress-induced peptic ulcer models were 0.1, 1.4, and 0.1 mg/kg, respectively. In the acetic acid-induced peptic ulcer model, the curative ratio of tegoprazan at 10 mg/kg was higher than that of esomeprazole at 30 mg/kg (44.2% vs. 32.7%, respectively), after 5 days of repeated oral administration. Thus, tegoprazan is a novel P-CAB that shows potent and reversible inhibition of gastric H+/K+-ATPase and may provide stronger efficacy compared with previous proton pump inhibitors.
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Affiliation(s)
- Dong Kyu Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Keun-Ho Lee
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Sung-Jun Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Soo-Jin Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Song Jin Lee
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Chi Hye Park
- CJ HealthCare Corporation, Seoul, Republic of Korea
| | - Bong-Tae Kim
- CJ HealthCare Corporation, Seoul, Republic of Korea
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Pauwels A, Broers C, Vanuytsel T, Pardon N, Cocca S, Roman S, Zerbib F, Tack J, Farré R. A reduced esophageal epithelial integrity in a subgroup of healthy individuals increases with proton pump inhibitor therapy. United European Gastroenterol J 2018; 6:511-518. [PMID: 29881606 PMCID: PMC5987278 DOI: 10.1177/2050640617749115] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Accepted: 11/20/2017] [Indexed: 01/05/2023] Open
Abstract
INTRODUCTION Approximately 30% of healthy volunteers (HVs) show dilated intercellular spaces in the esophageal epithelium suggesting a functionally reduced epithelial integrity. We aimed to evaluate the presence of an altered epithelial integrity in HVs and whether physiological acid could explain such a difference. METHODS Biopsies for Ussing chamber experiments were taken between 3 cm and 5 cm proximal to the gastroesophageal junction. Twenty-four-hour impedance-pH (MII-pH) monitoring was performed in the same 15 HVs. MII-pH tracings from 24 HVs before and after treatment with esomeprazole (40 mg b.i.d., two weeks), a proton pump inhibitor, were analyzed. Reflux parameters and impedance baseline (IB) at different levels of the esophagus were calculated. RESULTS Epithelial integrity in the distal esophagus presents a large variability in vivo and in vitro (transepithelial electrical resistance 196.9 ± 16.27Ω. cm2; IB measurements 2022 ± 143.5Ω). Esomeprazole highly suppressed the total acid exposure time (AET) (1.9 (0.8-3.1) vs 0 (0-0)%, p < 0.0001). After splitting our participants into "high" and "low" IB, based on the median value, we observed only in the distal esophagus a higher total AET before (2.8 (1.6-4.8) vs 1.0 (0.5-2.2), p = 0.04) and increased IB values after esomeprazole (1620 (1347-1898) vs 2192 (1784-2503)Ω, p = 0.002) in the "low" IB group. CONCLUSION A subgroup of HVs presents a low epithelial integrity in the distal esophagus probably due to the increased presence of physiological acid reflux. Whether these individuals have a higher chance to develop gastroesophageal reflux disease is unknown. The role of epithelial integrity in symptom perception needs to be further explored.
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Affiliation(s)
- Ans Pauwels
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Charlotte Broers
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Tim Vanuytsel
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Nicolas Pardon
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Silvia Cocca
- Department of Digestive Diseases, Campus Bio-Medico University, Rome, Italy
| | - Sabine Roman
- Digestive Physiology, Hospices Civils de Lyon and Lyon I University; and LabTAU, Inserm U1032, Lyon, France
| | - Frank Zerbib
- Gastroenterology department, Hôpital Haut Lévêque, CHU de Bordeaux; and Université de Bordeaux, Bordeaux, France
| | - Jan Tack
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
| | - Ricard Farré
- Catholic University of Leuven, KU Leuven, Translational Research Center for Gastrointestinal Disorders (TARGID), Leuven, Belgium
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, (Ciberehd), Instituto de Salud Carlos III, Barcelona, Spain
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Sykes BW. Courses for horses: Rethinking the use of proton pump inhibitors in the treatment of equine gastric ulcer syndrome. EQUINE VET EDUC 2018. [DOI: 10.1111/eve.12894] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- B. W. Sykes
- School of Veterinary Sciences The University of Queensland Gatton Queensland Australia
- Bova Compounding Caringbah New South Wales Australia
- Luoda Pharma Pty Ltd Caringbah New South Wales Australia
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Scarpignato C, Gatta L. Acid Suppression for Management of Gastroesophageal Reflux Disease: Benefits and Risks. REFLUX ASPIRATION AND LUNG DISEASE 2018:269-291. [DOI: 10.1007/978-3-319-90525-9_23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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Gräßle S, Susanto S, Sievers S, Tavsan E, Nieger M, Jung N, Bräse S. Synthesis and Investigation of S-Substituted 2-Mercaptobenzoimidazoles as Inhibitors of Hedgehog Signaling. ACS Med Chem Lett 2017; 8:931-935. [PMID: 28947939 DOI: 10.1021/acsmedchemlett.7b00100] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2017] [Accepted: 07/28/2017] [Indexed: 12/22/2022] Open
Abstract
Due to the arising resistance of common drugs targeting the Hedgehog signaling pathway, the identification of new compound classes with inhibitory effect is urgently needed. We were able to identify S-alkylated 2-mercaptobenzoimidazoles as a new compound class that exhibits Hedgehog signaling activity in a low micromolar range. The scope of the 2-mercaptobenzoimidazole motif has been investigated by the syntheses of diverse derivatives, revealing that the elongation of the linker unit and the exchange of particular substitution patterns are tolerable with respect to the activity of the compound class.
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Affiliation(s)
- Simone Gräßle
- Institute
of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus
North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
| | - Steven Susanto
- Institute
of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus
North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
| | - Sonja Sievers
- Max Planck Institute of Molecular Physiology, Otto-Hahn-Str. 11, 44227 Dortmund, Germany
| | - Emel Tavsan
- Institute
of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus
North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
| | - Martin Nieger
- Department
of Chemistry, University of Helsinki, P.O. Box 55, FI-00014 Helsinki, Finland
| | - Nicole Jung
- Institute
of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus
North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
- Institute
of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg
6, 76131 Karlsruhe, Germany
| | - Stefan Bräse
- Institute
of Toxicology and Genetics, Karlsruhe Institute of Technology, Campus
North, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany
- Institute
of Organic Chemistry, Karlsruhe Institute of Technology, Fritz-Haber-Weg
6, 76131 Karlsruhe, Germany
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Broers C, Melchior C, Van Oudenhove L, Vanuytsel T, Van Houtte B, Scheerens C, Rommel N, Tack J, Pauwels A. The effect of intravenous corticotropin-releasing hormone administration on esophageal sensitivity and motility in health. Am J Physiol Gastrointest Liver Physiol 2017; 312:G526-G534. [PMID: 28336550 DOI: 10.1152/ajpgi.00437.2016] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 03/09/2017] [Accepted: 03/13/2017] [Indexed: 02/08/2023]
Abstract
Esophageal hypersensitivity is important in gastroesophageal reflux disease (GERD) patients who are refractory to acid-suppressive therapy. Stress affects visceral sensitivity and exacerbates heartburn in GERD. Peripheral CRH is a key mediator of the gut stress response. We hypothesize that CRH increases esophageal sensitivity and alters esophageal motility in health. Esophageal sensitivity to thermal, mechanical, electrical, and chemical stimuli was assessed in 14 healthy subjects after administration of placebo or CRH (100 μg iv). Perception scores were assessed for first perception, pain perception threshold (PPT), and pain tolerance threshold (PTT). Esophageal motility was investigated by high-resolution impedance manometry, before and after CRH and evaluated by distal contractile integral (DCI) and intrabolus pressure (IBP). Pressure flow analysis assessed bolus clearance (impedance ratio), degree of pressurization needed to propel bolus onward (IBP slope), and pressure flow (pressure flow index, PFI). Stress and mood were assessed during the study. Sensitivity to mechanical distention was increased after CRH compared with placebo (PPT: P = 0.0023; PTT: P = 0.0253). CRH had no influence on the other stimulations. DCI was increased for all boluses (liquid, P = 0.0012; semisolid, P = 0.0017; solid, P = 0.0107). Impedance ratio for liquid (P < 0.0001) and semisolid swallows (P = 0.0327) decreased after CRH. IBP slope increased after CRH for semisolid (P = 0.0041) and solid (P = 0.0003) swallows. PFI increased for semisolid (P = 0.0017) and solid swallows (P = 0.0031). CRH increased esophageal sensitivity to mechanical distention, not to the other stimulation modalities. CRH increased esophageal contractility and tone, decreased LES relaxation, increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow.NEW & NOTEWORTHY This is the first study to address the effect of corticotropin-releasing hormone (CRH) on esophageal sensitivity and alterations in motility in health. CRH administration increased esophageal sensitivity to mechanical distention. This effect is accompanied by an increase in esophageal contractility and tone and a decrease in lower esophageal sphincter relaxation. CRH increased esophageal bolus pressurization, improved esophageal bolus clearance, and increased pressure flow. The changes in esophageal contractile properties may underlie the increased sensitivity to mechanical distention after CRH.
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Affiliation(s)
- Charlotte Broers
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - Chloé Melchior
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium.,Institut National de la Santé et de la Recherche Médicale, UMR 1073, Institute for Research and Innovation in Biomedicine, Normandy University, Rouen, France; and.,Physiology and Gastroenterology Department, Rouen University Hospital, France
| | - Lukas Van Oudenhove
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - Tim Vanuytsel
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium.,Department of Gastroenterology, Leuven University Hospitals, Leuven, Belgium
| | - Brecht Van Houtte
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
| | - Charlotte Scheerens
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium.,Experimental Oto-Rhino-Laryngology, Department of Neurosciences, KU Leuven, Belgium
| | - Nathalie Rommel
- Experimental Oto-Rhino-Laryngology, Department of Neurosciences, KU Leuven, Belgium
| | - Jan Tack
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium; .,Department of Gastroenterology, Leuven University Hospitals, Leuven, Belgium
| | - Ans Pauwels
- Translational Research Center for Gastrointestinal Disorders, Department of Clinical and Experimental Medicine, KU Leuven, Belgium
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Sykes BW, Underwood C, Mills PC. The effects of dose and diet on the pharmacodynamics of esomeprazole in the horse. Equine Vet J 2017; 49:637-642. [PMID: 28117490 DOI: 10.1111/evj.12670] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Accepted: 01/18/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Esomeprazole warrants further investigation as a treatment for equine gastric ulcer syndrome. OBJECTIVES To investigate the duration of intraday acid suppression achieved with two doses of esomeprazole under two dietary conditions. STUDY DESIGN A four way crossover design. METHODS Six adult Thoroughbreds instrumented with percutaneous gastrotomy tubes were used. Intragastric pH was measured for continuous 23 h periods (08.00-07.00 h) for 6 consecutive days (Days 0-5). Baseline data was recorded on Day 0 and esomeprazole was administered on Days 1-5. Two doses (0.5 and 2.0 mg/kg bwt/day per os once daily) and two diets (a high grain/low fibre (HG/LF) and ad libitum hay (HAY) diet) were studied. Data for the percentage of time pH was above 4 (%tpH>4) and median intraday pH was reported for two measurement points and analysed using generalised estimating equations. RESULTS An inconsistent effect of both diet and dose was evident with mean %tpH>4 and mean of the median intraday pHs typically higher at the 2.0 mg/kg bwt dose and in HG/LF diet. A cumulative effect of dosing was present with the magnitude of acid suppression observed on Day 5 consistently higher than that observed on Day 1. The magnitude of acid suppression, at measurement point 1, compared favourably with previous reports on omeprazole and exceeded human therapeutic breakpoints for the 0.5 mg/kg bwt dose in the HG/LF diet and 2.0 mg/kg bwt dose in the HAY diet. MAIN LIMITATIONS Instrumentation may have modified gastric function and horses were not fasted or exercised. CONCLUSIONS The findings of the present study suggested that both dose and diet affect the response to esomeprazole in the horse and that a cumulative effect is present over the first 5 days of treatment. Further investigation into the clinical efficacy of esomeprazole and trials directly comparing esomeprazole and omeprazole appear to be warranted.
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Affiliation(s)
- B W Sykes
- School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia.,Bova Compounding, Caringbah, New South Wales, Australia
| | - C Underwood
- School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia
| | - P C Mills
- School of Veterinary Science, The University of Queensland, Gatton, Queensland, Australia
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Scarpignato C, Gatta L, Zullo A, Blandizzi C. Effective and safe proton pump inhibitor therapy in acid-related diseases - A position paper addressing benefits and potential harms of acid suppression. BMC Med 2016; 14:179. [PMID: 27825371 PMCID: PMC5101793 DOI: 10.1186/s12916-016-0718-z] [Citation(s) in RCA: 286] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2016] [Accepted: 10/14/2016] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The introduction of proton pump inhibitors (PPIs) into clinical practice has revolutionized the management of acid-related diseases. Studies in primary care and emergency settings suggest that PPIs are frequently prescribed for inappropriate indications or for indications where their use offers little benefit. Inappropriate PPI use is a matter of great concern, especially in the elderly, who are often affected by multiple comorbidities and are taking multiple medications, and are thus at an increased risk of long-term PPI-related adverse outcomes as well as drug-to-drug interactions. Herein, we aim to review the current literature on PPI use and develop a position paper addressing the benefits and potential harms of acid suppression with the purpose of providing evidence-based guidelines on the appropriate use of these medications. METHODS The topics, identified by a Scientific Committee, were assigned to experts selected by three Italian Scientific Societies, who independently performed a systematic search of the relevant literature using Medline/PubMed, Embase, and the Cochrane databases. Search outputs were distilled, paying more attention to systematic reviews and meta-analyses (where available) representing the best evidence. The draft prepared on each topic was circulated amongst all the members of the Scientific Committee. Each expert then provided her/his input to the writing, suggesting changes and the inclusion of new material and/or additional relevant references. The global recommendations were then thoroughly discussed in a specific meeting, refined with regard to both content and wording, and approved to obtain a summary of current evidence. RESULTS Twenty-five years after their introduction into clinical practice, PPIs remain the mainstay of the treatment of acid-related diseases, where their use in gastroesophageal reflux disease, eosinophilic esophagitis, Helicobacter pylori infection, peptic ulcer disease and bleeding as well as, and Zollinger-Ellison syndrome is appropriate. Prevention of gastroduodenal mucosal lesions (and symptoms) in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or antiplatelet therapies and carrying gastrointestinal risk factors also represents an appropriate indication. On the contrary, steroid use does not need any gastroprotection, unless combined with NSAID therapy. In dyspeptic patients with persisting symptoms, despite successful H. pylori eradication, short-term PPI treatment could be attempted. Finally, addition of PPIs to pancreatic enzyme replacement therapy in patients with refractory steatorrhea may be worthwhile. CONCLUSIONS Overall, PPIs are irreplaceable drugs in the management of acid-related diseases. However, PPI treatment, as any kind of drug therapy, is not without risk of adverse effects. The overall benefits of therapy and improvement in quality of life significantly outweigh potential harms in most patients, but those without clear clinical indication are only exposed to the risks of PPI prescription. Adhering with evidence-based guidelines represents the only rational approach to effective and safe PPI therapy. Please see related Commentary: doi: 10.1186/s12916-016-0724-1 .
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Affiliation(s)
- Carmelo Scarpignato
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Maggiore University Hospital, Cattani Pavillon, I-43125, Parma, Italy.
| | - Luigi Gatta
- Clinical Pharmacology & Digestive Pathophysiology Unit, Department of Clinical & Experimental Medicine, University of Parma, Maggiore University Hospital, Cattani Pavillon, I-43125, Parma, Italy
- Gastroenterology & Endoscopy Unit, Versilia Hospital, Azienda USL Toscana Nord Ovest, Lido di Camaiore, Italy
| | - Angelo Zullo
- Division of Gastroenterology & Digestive Endoscopy, Nuovo Regina Elena Hospital, Rome, Italy
| | - Corrado Blandizzi
- Division of Pharmacology, Department of Clinical & Experimental Medicine, University of Pisa, Pisa, Italy
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Mössner J. The Indications, Applications, and Risks of Proton Pump Inhibitors. DEUTSCHES ARZTEBLATT INTERNATIONAL 2016; 113:477-83. [PMID: 27476707 PMCID: PMC4973002 DOI: 10.3238/arztebl.2016.0477] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2015] [Revised: 03/17/2016] [Accepted: 03/17/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Proton pump inhibitors (PPI) are the most effective drugs for inhibiting gastric acid secretion. They have been in clinical use for more than 25 years, In 2014, 3.475 billion daily defined doses (DDD) of PPI were prescribed in Germany. This high number alone calls for a critical analysis of the spectrum of indications for PPI and their potential adverse effects. METHODS This review is based on pertinent publications retrieved by a selective search in the PubMed and Cochrane Library databases, with particular emphasis on randomized, prospective multicenter trials, cohort studies, case-control studies, and meta-analyses. RESULTS The inhibition of gastric acid secretion with PPI is successfully used for the treatment of gastroesophageal reflux disease and of gastric and duodenal ulcers, for the secondary prevention of gastroduodenal lesions that have arisen under treatment with nonsteroidal anti-inflammatory drugs and acetylsalicylic acid, and for the prevention of recurrent hemorrhage from ulcers after successful endoscopic hemostasis. PPI are given along with practically all antibiotic regimens for the eradication of Helicobacter pylori infection. The number of prescriptions for PPI has risen linearly over the past 25 years. As there has been no broadening of indications, one may well ask whether the current, extensive use of PPI is justified. There is evidence that patients taking PPI are at greater risk for fractures. Moreover, the vitamin B12 level should be checked occasionally in all patients taking PPI. CONCLUSION PPI are among the more effective drugs for the treatment of diseases associated with gastric acid. In view of their cost and potential adverse effects, they should only be prescribed for scientifically validated indications.
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Affiliation(s)
- Joachim Mössner
- Division of Gastroenterology and Rheumatology, Department of Internal Medicine, Neurology and Dermatology, University Hospital of Leipzig, Germany: Mössner
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19
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Susanto S, Jung N, Bräse S. Solid phase syntheses of S,N-substituted 2-mercaptobenzoimidazoles. RSC Adv 2016. [DOI: 10.1039/c6ra05702k] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
2-Mercaptobenzoimidazoles are an important class of heterocycles showing biological activity in diverse therapeutic applications.
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Affiliation(s)
- Steven Susanto
- Institute of Toxicology and Genetics
- Karlsruhe Institute of Technology (KIT)
- 76344 Eggenstein-Leopoldshafen
- Germany
| | - Nicole Jung
- Institute of Toxicology and Genetics
- Karlsruhe Institute of Technology (KIT)
- 76344 Eggenstein-Leopoldshafen
- Germany
- Institute of Organic Chemistry
| | - Stefan Bräse
- Institute of Toxicology and Genetics
- Karlsruhe Institute of Technology (KIT)
- 76344 Eggenstein-Leopoldshafen
- Germany
- Institute of Organic Chemistry
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20
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Asghar W, Pittman E, Jamali F. Comparative efficacy of esomeprazole and omeprazole: Racemate to single enantiomer switch. ACTA ACUST UNITED AC 2015; 23:50. [PMID: 26573220 PMCID: PMC4647708 DOI: 10.1186/s40199-015-0133-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2015] [Accepted: 11/05/2015] [Indexed: 12/12/2022]
Abstract
Background Both omeprazole and its S enantiomer (esomeprazole) have been available and used to treat symptoms of gastroesophageal reflux disease (GERD) and conditions associated with excessive stomach acid secretion for more than a decade. Controversy exists over improved efficacy of S enantiomer (esomeprazole) over parent racemate (omeprazole). However, a comparison of the clinical outcomes of these products may reveal the rationale for switching from the racemate to single enantiomer. Since enantiomers of omeprazole are equipotent, we compared the outcomes of equal doses of each product to see if both actually differ in their efficacy’s or the reported superiority of S enantiomer is just a dose effect. Methods A web search was carried out for randomized controlled trials with head-to-head comparisons of omeprazole and S-omeprazole. The data were abstracted and after calculating theodd ratios (OR) for the outcomes reported in each study, the combined overall odd ratios (OR’) were estimated. The random effect inverse variance method with omeprazole as the reference (OR” = 1) was used. Results Out of 1171 studies, 14 were deemed eligible. There was no significant difference in the therapeutic success between omeprazole and S-omeprazole as a part of triple therapy for the treatment of H. pylori in both intention-to-treat (OR’, 1.06; CI, 0.83, 1.36; p = 0.63) as well as per-protocol analysis (OR’, 1.07; CI, 0.84, 1.36; p = 0.57). For the treatment of gastro-oesophageal reflux disease, S-omeprazole was significantly but marginally superior to the racemate (OR’, 1.18; CI, 1.01, 1.38; p = 0.04). The two products were equipotent in all metrics used to assess intragastric pH except for the % patients maintaining a 24 h gastric pH above 4 (1.57; CI, 1.04, 2.381; p = 0.03). Conclusion The therapeutic benefit of chiral switch of omeprazole is questionable considering the substantially greater economic burden involved.
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Affiliation(s)
- Waheed Asghar
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 11361 - 87 Avenue, Edmonton, AB, T6G 2E1, Canada
| | - Elliot Pittman
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 11361 - 87 Avenue, Edmonton, AB, T6G 2E1, Canada
| | - Fakhreddin Jamali
- Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, 11361 - 87 Avenue, Edmonton, AB, T6G 2E1, Canada.
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Teng M, Khoo AL, Zhao YJ, Lin L, Lim BP, Wu TS, Dan YY. Meta-analysis of the effectiveness of esomeprazole in gastroesophageal reflux disease and Helicobacter pylori infection. J Clin Pharm Ther 2015; 40:368-75. [PMID: 25893507 DOI: 10.1111/jcpt.12277] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Accepted: 03/24/2015] [Indexed: 12/14/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Proton pump inhibitors (PPIs) are one of the most widely used classes of drugs. However, the quantum clinical benefit of newer and more expensive PPIs over the older generation PPIs remains uncertain. This meta-analysis sought to assess the clinical and safety profiles of esomeprazole versus omeprazole at pharmacologically equivalent doses in healing gastroesophageal reflux disease (GERD), peptic ulcer disease and eradicating Helicobacter pylori (H. pylori) infection. METHODS PubMed and the Cochrane Library were searched for randomized controlled trials comparing esomeprazole with omeprazole at all doses up to February 2015. Trials were assessed by two reviewers for eligibility according to predefined study inclusion criteria. Meta-analysis was conducted using a random effects model, and heterogeneity in the estimated effects was investigated using meta-regression. Sensitivity analysis was performed to test the robustness of the findings. RESULTS AND DISCUSSION Fifteen trials were included and none of which compared esomeprazole with omeprazole in peptic ulcer disease. The included studies had not evaluated esomeprazole 20 mg versus omeprazole 40 mg. In GERD, esomeprazole 40 mg (relative risk (RR) = 1·07; 95% confidence interval (CI) 1·02 to 1·12) and 20 mg (RR=1·04; 95% CI 1·01 to 1·08) significantly improved esophagitis healing when compared with omeprazole 20 mg at week 8. The corresponding numbers needed to treat were 17 and 30, respectively. No significant difference was observed between esomeprazole 20 mg and omeprazole 20 mg at week 4. In H. pylori eradication, there was no difference in the treatment effects between esomeprazole 20 mg and omeprazole 20 mg (RR = 1·01;95% CI 0·96 to 1·05). Their safety profiles were comparable. WHAT IS NEW AND CONCLUSION Esomeprazole demonstrated better esophagitis healing rate in patients with GERD than omeprazole at week 8. However, this clinical advantage diminished when both drugs were given at the same doses at week 4. Superiority of esomeprazole was not observed in the H. pylori eradication rates.
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Affiliation(s)
- M Teng
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - A L Khoo
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - Y J Zhao
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - L Lin
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - B P Lim
- Pharmacy and Therapeutics Office, Group Corporate Development, National Healthcare Group, Singapore
| | - T S Wu
- Department of Pharmacy, National University Hospital, Singapore
| | - Y Y Dan
- Department of Medicine, National University Hospital, Singapore.,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
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Kahrilas PJ, Persson T, Denison H, Wernersson B, Hughes N, Howden CW. Predictors of either rapid healing or refractory reflux oesophagitis during treatment with potent acid suppression. Aliment Pharmacol Ther 2014; 40:648-56. [PMID: 25039978 DOI: 10.1111/apt.12877] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2014] [Revised: 03/04/2014] [Accepted: 06/25/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND Little is known regarding patient characteristics that influence the speed of reflux oesophagitis (RO) healing. AIM To investigate patient characteristics that may influence RO healing rates. METHODS A post hoc analysis of clinical trial data for potent acid suppression treatment of RO (esomeprazole or AZD0865) was conducted. Group A underwent endoscopy at baseline, week 2 and 4, and group B at baseline, week 4 and 8. Group A patients were sub-grouped as 'rapid' (healed at 2 weeks) or unhealed at 2 weeks. Group B patients were sub-grouped as 'slow' (healed at 8 weeks, not at 4 weeks) or 'refractory' (not healed at 8 weeks). Logistic regression analysis was performed only for comparisons within group A. RESULTS At 2, 4 and 8 weeks, RO had healed in 68%, 65% and 61% of patients unhealed at previous endoscopy, respectively. Low-grade [vs. high-grade (C or D)] RO was the only independent predictor of rapid healing in group A after logistic regression analysis. Significantly more rapid healers had low grade RO (A or B) at baseline than patients with refractory RO (84% vs. 49%; P < 0.001), and significantly more refractory patients had frequent regurgitation at baseline than slow healers (80% vs. 63%; P = 0.039). CONCLUSIONS Low- (vs. high-) grade RO determines the most rapid benefit from acid suppression. Roughly two-thirds of patients healed with each time increment of potent acid suppression therapy. This suggests that some unhealed patients may still heal with continued therapy and that truly refractory RO is rare. (ClinicalTrials.gov: NCT00206245).
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Affiliation(s)
- P J Kahrilas
- Division of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
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Goirand F, Le Ray I, Bardou M. Pharmacokinetic evaluation of esomeprazole for the treatment of gastroesophageal reflux disease. Expert Opin Drug Metab Toxicol 2014; 10:1301-11. [PMID: 25019289 DOI: 10.1517/17425255.2014.939627] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases such as gastroesophageal reflux disease (GERD). They are recommended by the American College of Gastroenterology for healing erosive esophagitis (EO) and as long-term treatment in patients with healed EO. The available PPIs differ somewhat in their pharmacokinetics and clinical properties, but whether these differences are of clinical relevance is a matter of debate. Some safety concerns have been raised with the use of PPIs, mostly an increased incidence of infectious diseases such as community-acquired pneumonia or Clostridium difficile diarrhea. AREAS COVERED This article explores the results of clinical studies on the pharmacokinetics and pharmacodynamics of esomeprazole , as well as on its clinical efficacy to manage patients with GERD. EXPERT OPINION GERD is a public health concern as its worldwide incidence and associated complications are increasing alongside the exponentially increasing problem of obesity. PPIs are the first pharmacological option because of their efficacy and overall positive risk-to-benefit ratio. Improved efficacy with the use of stereospecific isomers of PPIs, such as esomeprazole, has not yet been convincingly demonstrated. Nevertheless, because of individual experience with former treatment, some patients may report better symptom control when treated with a specific PPI rather than with others.
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Affiliation(s)
- Françoise Goirand
- CRI U866, INSERM (Institut National de la Santé et de la Recherche Médicale) , Dijon , France
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Soumekh A, Schnoll-Sussman FH, Katz PO. Reflux and Acid Peptic Diseases in the Elderly. Clin Geriatr Med 2014; 30:29-41. [DOI: 10.1016/j.cger.2013.10.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Scott SA, Owusu Obeng A, Hulot JS. Antiplatelet drug interactions with proton pump inhibitors. Expert Opin Drug Metab Toxicol 2013; 10:175-89. [PMID: 24205916 DOI: 10.1517/17425255.2014.856883] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
INTRODUCTION Non-aspirin antiplatelet agents (e.g., clopidogrel, prasugrel, ticagrelor) are commonly prescribed for the prevention of recurrent cardiovascular events among patients with acute coronary syndromes (ACS) and/or those undergoing percutaneous coronary intervention (PCI). In addition, combination therapy with proton pump inhibitors (PPIs) is often recommended to attenuate gastrointestinal bleeding risk, particularly during dual antiplatelet therapy (DAPT) with clopidogrel and aspirin. Importantly, a pharmacological interaction between clopidogrel and some PPIs has been proposed based on mutual CYP450-dependent metabolism, but available evidence is inconsistent. AREAS COVERED This article provides an overview of the currently approved antiplatelet agents and PPIs, including their metabolic pathways. Additionally, the CYP450 isoenzyme at the center of the drug interaction, CYP2C19, is described in detail, and the available evidence on both the potential pharmacological interaction and influence on clinical outcomes are summarized and evaluated. EXPERT OPINION Although concomitant DAPT and PPI use reduces clopidogrel active metabolite levels and ex vivo-measured platelet inhibition, the influence of the drug interaction on clinical outcomes has been conflicting and largely reported from non-randomized observational studies. Despite this inconsistency, a clinically important interaction cannot be definitively excluded, particularly among patient subgroups with higher overall cardiovascular risk and potentially among CYP2C19 loss-of-function allele carriers.
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Affiliation(s)
- Stuart A Scott
- Icahn School of Medicine at Mount Sinai, Department of Genetics and Genomic Sciences , One Gustave L. Levy Place, Box 1497, New York, NY 10029 , USA +1 212 241 3780 ; +1 212 241 0139 ;
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Abstract
Gastro-oesophageal reflux disease develops when the reflux of gastric contents into the oesophagus results in troublesome symptoms and/or complications [1]. Refluxate contains predominantly acid which causes tissue injury at oesophageal and extra-oesophageal sites. It is one of the commonest gastrointestinal diagnosis worlds over. It is associated with chronic symptoms, reduced QOL, significant cost and serious complications. Goals of therapy are to provide symptom relief, heal oesophagitis and prevent long-term complications. Therapeutic measures are directed at reducing the noxiousness of the refluxate; reducing the gastro-oesophageal reflux; enhancing clearance; protecting the mucosa; reducing the mucosal sensitivity and improving healing. Acid suppression with proton pump inhibitors remains the cornerstone of therapy. Recent studies have resulted in better understanding of disease and relative efficacies of various strategies. This has paved way for a better evidence based approach. The therapy however needs to be individualized depending upon the clinical profile, disease severity, the dominant pathophysiological mechanism, cost, availability and individual preferences.
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Esophageal mucosal breaks in gastroesophageal reflux disease partially responsive to proton pump inhibitor therapy. Am J Gastroenterol 2013; 108:529-34. [PMID: 23318482 DOI: 10.1038/ajg.2012.447] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Approximately 20-30% of patients with gastroesophageal reflux disease (GERD) do not experience complete symptom resolution during proton pump inhibitor (PPI) therapy. The aim of this study was to determine the prevalence of esophageal mucosal breaks among patients who have a partial response to PPI therapy. METHODS This was an analysis of data from a phase 2b clinical trial carried out to assess the efficacy and safety of a reflux inhibitor, lesogaberan (AZD3355), as an add-on to PPI therapy in this patient population (clinicaltrials.gov reference: NCT01005251). A total of 661 patients with persistent GERD symptoms who had received a minimum of 4 weeks of PPI therapy were included in the study. The prevalence of esophageal mucosal breaks was assessed according to (i) the most recent endoscopy results from within the previous 24 months, if available ("historical" endoscopies), and (ii) the results of endoscopies performed at study baseline ("baseline" endoscopies). Baseline endoscopies were not carried out in patients who had a historical endoscopy showing an absence of esophageal mucosal breaks. RESULTS Historical endoscopy results were available for 244 patients, of whom 48 (19.7%) had esophageal mucosal breaks. Baseline endoscopies were carried out in 465 patients, of whom 146 (31.4%) had esophageal mucosal breaks. Sensitivity analyses showed a prevalence of esophageal mucosal breaks of 20-30%. In both the historical and baseline endoscopies, most esophageal mucosal breaks were Los Angeles grades A or B. CONCLUSIONS In patients with GERD symptoms partially responsive to PPI therapy, mild-to-moderate severity esophageal mucosal breaks are common (prevalence 20-30%), and may contribute to symptom etiology.
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Moayyedi P, Hunt R, Armstrong D, Lei Y, Bukoski M, White R. The impact of intensifying acid suppression on sleep disturbance related to gastro-oesophageal reflux disease in primary care. Aliment Pharmacol Ther 2013; 37:730-7. [PMID: 23432146 DOI: 10.1111/apt.12254] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2012] [Revised: 10/16/2012] [Accepted: 01/30/2013] [Indexed: 12/12/2022]
Abstract
BACKGROUND Sleep disturbance is common in patients with GERD but there has been little evaluation of this problem in primary care in patients already taking therapy. AIM To evaluate the impact of administering a questionnaire (PASS test) to identify patients with sleep problems and evaluate the efficacy of esomeprazole to improve sleep disturbance in patients with GERD. METHODS This was a primary care based cluster-randomised, open-label study where practices were assigned to intervention or control groups. PASS test failures continued current therapy (control) or were switched to 4 weeks' once-daily esomeprazole 20 or 40 mg (intervention). Patients were evaluated at the end of 4 weeks and the outcomes that were assessed were the sleep questions from the Quality of Life in Reflux and Dyspepsia (QOLRAD) questionnaire and the presence or absence of sleep disturbance from the PASS test questionnaire. RESULTS A total of 1388 patients with evaluable data at 4 weeks were included in the analysis and 825 reported GERD-related sleep disturbance at baseline. At 4 weeks, 161 of 291 of control patients (55%) reported continued sleep disturbance compared to 120 of 534 (22.5%) of intervention patients [number needed to treat of 3: 95% confidence intervals (CI): 2.5-4]. There was a mean improvement in QOLRAD scores related to sleep in the intervention patients compared to control patients (mean improvement = 4.91; 95% CI: 3.73-6.09). CONCLUSION A PASS strategy identifies GERD patients with sleep disturbance in primary care that will benefit from a change in acid-suppressive therapy. ClinicalTrials.gov identifier: NCT00392002; study code: D9612L00096.
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Affiliation(s)
- P Moayyedi
- Division of Gastroenterology, McMaster University, Hamilton, ON, Canada.
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Abstract
Acid suppression, with proton pump inhibitors (PPI), is the mainstay of therapy for reflux disease; despite this, symptoms and injury persist in many patients. Novel approaches have focused on (1) augmenting acid suppression with reformulated current PPIs, new PPIs or new acid pump blockers and (2) preventing reflux with reflux inhibitors. Other strategies to reduce reflux, improve gastric emptying or esophageal clearance, protect the mucosa, or reduce esophageal sensitivity are under investigation alone or in combination with PPIs; however, novel approaches face significant challenges. The safety and efficacy of current PPIs hamper demonstration of clinical superiority for new acid suppressants, and the multifactorial etiology of reflux disease means that monotherapy using a non-acid suppressant is unlikely to match PPI therapy while combination therapy will be superior only if susceptible patients can be identified reliably. Advances will come, not from a 'one size fits all' approach but rather from novel pharmaceuticals allied to novel investigations to permit targeted, personalized reflux therapy.
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Affiliation(s)
- Usha Dutta
- Division of Gastroenterology, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4K1, Canada
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Abstract
Proton pump inhibitors are widely used for the treatment of acid-related disorders. Rabeprazole is a potent and irreversible inhibitor of H(+)/K(+)-ATPase gastric pump, and it is indicated for the treatment of gastroesophageal reflux disease, Zollinger Ellison syndrome, duodenal and gastric ulcers and for the eradication of Helicobacter pylori in combination with antibiotics. Pharmacokinetic and pharmacodynamic data show that rabeprazole achieves a pronounced acid suppression from the first administration that is maintained with repeated use; this may translate into faster onset of symptom relief for patients, particularly suitable when the indication is for the on-demand long-term maintenance of gastroesophageal reflux disease. Due to its predominantly nonenzymatic metabolism, rabeprazole has a lower potential for drug-drug interactions. The objective of this article is to update efficacy and safety data of rabeprazole in the treatment of acid-related disorders, following a previous review dated 2008.
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Affiliation(s)
- Silvia Marelli
- Janssen-Cilag SpA, Via Buonarroti, 23, 20093 Cologno Monzese, Milan, Italy.
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Abstract
The incidence of gastroesophageal reflux disease (GERD) is increasing drastically in China. GERD could probably cause reflux esophagitis, chronic cough, asthma, Barrett's esophagus and adenocarcinoma, and frequently affects health-related quality of life. The use of proton pump inhibitors (PPIs) provides effective symptomatic relief in most patients; however, some patients appear refractory to the treatment with PPIs. The long term use of PPIs might also cause adverse effects, such as interstitial nephritis, fracture and small intestinal bacterial overgrowth. Many new drugs for GERD have emerged recently. This article reviews the advances in drug therapy for GERD.
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Chiba N, Fennerty MB. Gastroesophageal Reflux Disease. EVIDENCE‐BASED GASTROENTEROLOGY AND HEPATOLOGY 2010:17-61. [DOI: 10.1002/9781444314403.ch2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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[Evidence and uncertainties on the clinical use of proton pump inhibitors]. GASTROENTEROLOGIA Y HEPATOLOGIA 2010; 33 Suppl 1:5-10. [PMID: 20728783 DOI: 10.1016/s0210-5705(10)70002-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Proton pump inhibitors (PPI) are the most potent and effective drugs for the control of gastric acid secretion and constitute one of the most widely prescribed pharmacological groups worldwide. The safety and efficacy of PPI have been demonstrated in clinical practice and these drugs are currently the treatment of choice in peptic ulcer diseases, Helicobacter pylori infection, gastroesophageal reflux disease, nonsteroidal antiinflammatory drug gastropathy and functional dyspepsia. However, despite the excellent pharmacological profile of current PPI, their rapidity of action may be insufficient in some diseases, 24-hour acid inhibition is not always achieved and - to a greater or lesser extent depending on the distinct molecules of the PPI - there is interindividual variability in gastric antisecretory efficacy, depending on genetic polymorphism of CYP2C19, which could affect individual metabolism of the distinct PPI. New generations of these drugs will probably eliminate these deficiencies.
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Del Tacca M, Pasqualetti G, Di Paolo A, Virdis A, Massimetti G, Gori G, Versari D, Taddei S, Blandizzi C. Lack of pharmacokinetic bioequivalence between generic and branded amoxicillin formulations. A post-marketing clinical study on healthy volunteers. Br J Clin Pharmacol 2010; 68:34-42. [PMID: 19660001 DOI: 10.1111/j.1365-2125.2009.03399.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
AIMS There are concerns about the quality of generic drugs in the postmarketing setting. The aim was to establish whether two generic formulations of amoxicillin, available on the Italian market, fulfil the criteria for clinical pharmacokinetic bioequivalence vs. the branded drug. METHODS Two generic amoxicillin products (generic A and B) were selected among four fast-release tablet formulations available on the Italian market. Twenty-four healthy adult volunteers of either sex participated to a single-dose, randomized, three-treatment, crossover, single-blind bioequivalence study designed to compare generic A and B with branded amoxicillin. Plasma samples were collected at preset times for 24 h after dosing, and assayed for amoxicillin levels by high-performance liquid chromatography. RESULTS Ninety percent confidence intervals of AUC ratios were 0.8238, 1.0502 (ratio 0.9302) and 0.8116, 1.1007 (ratio 0.9452) for generic A and B vs. branded amoxicillin, respectively. Ninety percent confidence intervals of C(max) ratios were 0.7921, 1.0134 (ratio 0.8960) and 0.8246, 1.1199 (ratio 0.9610) for generic A and B vs. branded amoxicillin, respectively. The mean pharmacokinetic profiles showed that the AUC value of branded amoxicillin was 8.5 and 5.4% greater than that estimated for generic A and B, respectively. Few adverse events were recorded; these were not serious and occurred without apparent relationship to any specific amoxicillin formulation. CONCLUSIONS These results indicate that one of the two marketed amoxicillin generics analysed in the present study is not bioequivalent to the brand leader product for C(max) on the basis of single-dose pharmacokinetic assessment.
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Affiliation(s)
- Mario Del Tacca
- Clinical Pharmacology Centre for Drug Experimentation, Pisa University Hospital, Pisa, Italy.
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Efficacy of three different dosages of esomeprazole in the long-term management of reflux disease: a prospective, randomized study, using the wireless Bravo pH system. Am J Gastroenterol 2010; 105:308-13. [PMID: 19809412 DOI: 10.1038/ajg.2009.556] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Gastroesophageal reflux disease (GERD) is a chronic condition that usually requires long-term maintenance therapy with proton-pump inhibitors (PPIs). In clinical practice, patients receive PPIs at the lowest dose to control symptoms. However, it is not known whether this approach adequately controls acidic esophageal reflux. We sought to investigate the efficacy of three different dosages of esomeprazole in patients receiving maintenance therapy for GERD, using the Bravo pH system. METHODS Patients with a previous history of erosive esophagitis A or B (LA classification) that was healed at the time of enrollment or endoscopy-negative reflux disease (ENRD), documented with an abnormal pH study, were randomized to receive maintenance therapy with esomeprazole 40 mg twice daily (group A), once daily (group B), or every other day (group C). Intraesophageal pH was monitored for two consecutive days using the Bravo wireless system, 30 days after randomization. The parameters subjected to analysis were percent of total time pH<4 and the De Meester score. RESULTS The pH results from 73 patients (group A=24, group B=24, group C=25 patients) were subjected to final analysis. On the first day of the study, the mean (+/-s.d.) percent of total time pH <4 and the De Meester score were group A: 0.9(1.2) and 4.1(4.0); group B: 1.5(1.6) and 7.0(6.9); group C: 1.3(1.0) and 6.0(3.3), respectively (P=0.262 and 0.134, respectively). On the second day of the study, the corresponding values were group A: 0.7(1.0) and 3.9(5.9); group B: 1.5(1.8) and 6.4(6.6); group C: 7.0(4.4) and 29.4(19.4), respectively. The difference was statistically significant (P<0.0001 and <0.0001, respectively). Further analysis showed that patients not receiving PPI had a significantly higher mean percent of total time pH<4 and De Meester score as compared with patients on PPI once or twice daily (P<0.001 and <0.001 respectively). CONCLUSIONS The administration of esomeprazole 40 mg every other day does not control acidic esophageal reflux on the day off PPI. Esomeprazole 40 mg once daily effectively controls reflux of acid in patients with history of mild esophagitis or ENRD, whereas doubling the dose does not seem to confer any further advantage.
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Saccar CL. The pharmacology of esomeprazole and its role in gastric acid related diseases. Expert Opin Drug Metab Toxicol 2009; 5:1113-24. [PMID: 19606942 DOI: 10.1517/17425250903124363] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Esomeprazole (S-isomer of omeprazole) demonstrates a better pharmacokinetic/pharmacodynamic profile than the racemic product omeprazole. Esomeprazole's pharmacological activity of gastric acid secretion is through proton pump inhibition. The pharmacokinetic properties provide for an enhanced pharmacological effect. Esomeprazole is rapidly absorbed and the extent of absorption is higher resulting in higher systemic absorption of esomeprazole (bioavailability), which coupled with reduced clearance results in greater systemic exposure. This pharmacodynamic profile then provides for a prolongation of inhibition of gastric acid output and correlates well with its more beneficial therapeutic efficacy over omeprazole and some of the other proton-pump inhibitors. It has been well proven as an effective agent in the treatment of gastro-esophagitis reflux disease, (reflux esophagitis and non-erosive reflux disease), NSAID-induced gastric-intestinal symptoms and ulcers, Helicobacter pylori infection and Zollinger-Ellison syndrome. Esomeprazole has a good tolerability profile and a low potential for drug interaction.
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Nichita C, Abdou AEW, Maerten P, Herranz M, Mouret N, Thalmann C, Michetti PF, Dorta G. A single dose of intravenous esomeprazole decreases gastric secretion in healthy volunteers. Aliment Pharmacol Ther 2009; 30:1022-9. [PMID: 19702644 DOI: 10.1111/j.1365-2036.2009.04128.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 Data suggest that esomeprazole decreases gastric secretion. AIMS To assess the effect of a single i.v. esomeprazole dose on gastric secretion volume 3 h after drug administration, as a primary endpoint, and to evaluate, as secondary endpoints, the reduction 1 and 5 h after dosing; time when the gastric pH was <2.5 and esomeprazole's safety. METHODS In all, 23 healthy Helicobacter pylori-negative volunteers (10 men, 13 women, mean age 28.2 +/- 6) participated in this single-centre, randomized, double-blind, placebo-controlled, 2-way, single-dose cross-over study. In different sessions, volunteers received i.v. either esomeprazole 40 mg or placebo. An inserted double-lumen nasogastric tube perfused and aspirated gastric liquid. Mechanical fractioned aspiration measured secretion volume; aliquot spectrophotometry assessed gastric secretion volume lost to the duodenum. RESULTS Three hours post-i.v. esomeprazole, average gastric secretion decreased by 77.6% (vs. baseline) compared to placebo. Values 1 and 5 h after dosing were 73.5% and 74.5%. Five hours after esomeprazole, the gastric pH was <2.5 3.9% of the time and 73.3% after placebo (P < 0.002). Esomeprazole was well-tolerated. No serious adverse events occurred. CONCLUSIONS Intravenous esomeprazole decreases gastric secretions. The potential clinical impact in averting bronchoaspiration during anaesthesia induction and in intensive care patients should be investigated in further studies.
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Affiliation(s)
- C Nichita
- Department of Gastroenterology and Hepatology at the University Hospital in Lausanne, Switzerland.
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Edwards SJ, Lind T, Lundell L, DAS R. Systematic review: standard- and double-dose proton pump inhibitors for the healing of severe erosive oesophagitis -- a mixed treatment comparison of randomized controlled trials. Aliment Pharmacol Ther 2009; 30:547-56. [PMID: 19558609 DOI: 10.1111/j.1365-2036.2009.04077.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND No randomized controlled trial (RCT) has compared all European-licensed standard- and double-dose PPIs for the healing of severe erosive oesophagitis. AIM To compare the effectiveness of licensed doses of PPIs for healing severe erosive oesophagitis (i.e. esomeprazole 40 mg, lansoprazole 30 mg, omeprazole 20 mg and 40 mg, pantoprazole 40 mg and rabeprazole 20 mg). METHODS Systematic review of CENTRAL, EMBASE and MEDLINE for RCTs in patients with erosive oesophagitis (completed October 2008). Endoscopically verified healing rates at 4 and 8 weeks were extracted and re-calculated if not analysed by intention-to-treat. A mixed treatment comparison was used to combine direct treatment comparisons with indirect trial evidence while maintaining randomization. Odds ratios (OR) are reported compared to omeprazole 20 mg. RESULTS A total of 3021 papers were identified in the literature search; 12 were of sufficient quality to be included in the analysis. Insufficient data were available to included rabeprazole. Esomeprazole 40 mg was found to provide significantly higher healing rates at 4 weeks [OR 1.84, 95% Credible Interval (95% CrI): 1.50 to 2.22] and 8 weeks (OR 1.91, 95% CrI: 1.13 to 2.88). No other PPI investigated had significantly higher healing rates than omeprazole 20 mg. CONCLUSION Esomeprazole 40 mg consistently demonstrates higher healing rates compared with licensed standard- and double-dose PPIs.
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Affiliation(s)
- S J Edwards
- Outcomes Research, AstraZeneca UK Ltd, Luton, UK.
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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: 541] [Impact Index Per Article: 33.8] [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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Bytzer P. What makes individuals with gastroesophageal reflux disease dissatisfied with their treatment? Clin Gastroenterol Hepatol 2009; 7:816-22. [PMID: 19286478 DOI: 10.1016/j.cgh.2009.03.006] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2008] [Revised: 03/03/2009] [Accepted: 03/05/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Despite the efficacy of proton pump inhibitors (PPIs) as therapeutics for patients with gastroesophageal reflux disease (GERD) in randomized controlled trials, a number of studies have shown that a proportion of patients with GERD are not satisfied with their treatment. This article reviews the possible reasons why patients are dissatisfied with the way their disease is managed. METHODS Studies published between 1970 and 2007 were identified from PubMed, EMBASE, and the author's existing database. The 2708 publications were reviewed, and irrelevant ones were excluded. Eleven studies were found to be appropriate for use in this review. RESULTS Patients who are given prescriptions for PPIs tend to be more satisfied than those given H(2)-receptor antagonists. Partial responders are likely to be more dissatisfied than patients whose symptoms are fully resolved. A decrease in health-related quality of life is associated with greater dissatisfaction. Patients are more likely to be satisfied if they are taken seriously by their physician and if their symptoms are investigated. They are also more likely to be satisfied if the patient-physician consultation is interactive. CONCLUSIONS Patient satisfaction is a complex issue that depends on many factors. Patient satisfaction can be influenced by treatment regimen, general level of well-being, the bedside manner of the physician, and the quality of patient-physician communication. Improvements in recognition of GERD can improve management of the disease as well as patient satisfaction with their care and treatment.
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Affiliation(s)
- Peter Bytzer
- Department of Medical Gastroenterology, Køge University Hospital, University of Copenhagen, Copenhagen, Denmark
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Jian R. [Gastro-esophageal reflux through gastric antisecretory drugs]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2009; 33:614-624. [PMID: 19674856 DOI: 10.1016/j.gcb.2009.07.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2023]
Abstract
During the 20th century, gastro-esophageal reflux moved from the status of a rare and severe disease to that of a frequent disease occurring mostly, in the absence of any significant lesions. Proton pump inhibitors (PPIs) are the mainstay of its therapy and are prescribed mainly in an empirical way. Extradigestive manifestations require more accurate diagnostic tests and therapeutic management. The modalities of prescription of the PPIs quickly progressed toward the on-demand therapy and over-the-counter PPIs should become widespread. The relative failures of PPIs led to a profusion of new antisecretory agents but clinical improvements are presently disappointing and the rationale of this escalation is questionable. The concept of non acid gastro-esophageal reflux opens more innovative diagnostic and therapeutic perspectives which, however, must be validated. In this respect, endoscopic treatment needs more reliable techniques and more rigorous trials. Gastro-esophageal reflux refractory to PPIs corresponds mainly to functional esophageal disorders that need diagnostic and therapeutic improvements. Barrett's esophagus constitutes a major challenge for the next few years. Its screening and its prevention seem, for the moment, inaccessible. Its survey and the prevention of its complications should benefit from progress of diagnostic and interventional endoscopy.
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Affiliation(s)
- R Jian
- Service d'Hépatogastroentérologie, Hôpital Européen Georges-Pompidou, Université Paris-Descartes, 75015 Paris, France.
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Zhang HM, Miao YL. Advances in the clinical applications of esomeprazole. Shijie Huaren Xiaohua Zazhi 2009; 17:2064-2069. [DOI: 10.11569/wcjd.v17.i20.2064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Esomeprazole is the first proton pump inhibitor (PPI) to be developed as a single optical isomer. Ever since its first clinical application seven years ago, esomeprazole has attracted more and more attention due to relatively unique metabolism (compared to other PPIs), efficient and durable acid control, better safety and lower incidence of adverse reactions. In this article, we will review the clinical applications of esomeprazole in the treatment of gastroesophageal reflux disease (GERD), Helicobacter pylori infection, peptic ulcers, NSAID-related gastrointestinal disorders and upper gastrointestinal bleeding.
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Yu Y, Yao JF, Xia J, Zhao SM, Yu XF. Effect of esomeprazole and mosapride on the esophageal motility dysfunction in elderly patients with hypotensive LES: an analysis of 29 cases. Shijie Huaren Xiaohua Zazhi 2009; 17:1359-1362. [DOI: 10.11569/wcjd.v17.i13.1359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the therapeutic effect of esomeprazole and mosapride on aged hypotensive type LES esophageal motility dysfunction.
METHODS: A total of 57 aged hypotensive type LES esophageal motility dysfunction patients were divided into treatment group (n = 29) and control group (n = 28). Patients in treatment group were given esomeprazole 20 mg per day and mosapride 5 mg three times daily for 1 mo while patients in control group were given mosapride 5 mg three times daily for 1 mo. After medication treatment, the clinical symptoms, lower esophageal sphincter (LES) pressure and esophageal motility were observed.
RESULTS: Fifty seven cases of patients completed the study. The total effective rate of treatment group was 86.2%, which was significantly higher than that of control group (60.7%). LES pressure was improved significantly in both groups (1.82 ± 0.36 vs 1.09 ± 0.18, P < 0.001; 1.91 ± 0.45 vs 1.06 ± 0.17, P < 0.001, respectively). Esophageal motility became better in both groups, but no statistical difference was observed between them after treatment(48.3% vs 53.6%, P = 0.193).
CONCLUSION: Esomeprazole and mosapride are effective for aged hypotensive type LES esophageal motility dysfunction.
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Mejia A, K. Kraft W. ACID REFLUX AND ULCER DISEASE. PHARMACOLOGY AND THERAPEUTICS 2009:457-473. [DOI: 10.1016/b978-1-4160-3291-5.50035-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Jones R, Patrikios T. The effectiveness of esomeprazole 40 mg in patients with persistent symptoms of gastro-oesophageal reflux disease following treatment with a full dose proton pump inhibitor. Int J Clin Pract 2008; 62:1844-50. [PMID: 19166433 PMCID: PMC2680259 DOI: 10.1111/j.1742-1241.2008.01923.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
BACKGROUND Some patients with gastro-oesophageal reflux disease (GORD) remain symptomatic despite proton pump inhibitor (PPI) treatment. There is a need to determine the most appropriate management of these patients. AIMS To assess the effectiveness of esomeprazole 40 mg in GORD symptoms persisting in patients receiving a full daily dose PPI. METHODS In this multi-centre open label study patients who had received full daily dose PPI for 8 weeks, but were still experiencing persistent GORD symptoms, were treated with esomeprazole 40 mg for 8 weeks (n = 99). The primary outcome variable was the change in the frequency of heartburn. Patient-reported outcomes were also assessed using the Reflux Disease Questionnaire (RDQ) and the GORD Impact Scale (GIS). RESULTS The mean frequency of heartburn was reduced by 78% from 4.4 days a week to 1 day a week at the end of the 8-week treatment period (p < 0.0001). Other GORD symptoms were also significantly reduced following of treatment with esomeprazole (all p < 0.0001). All RDQ dimensions and the level of symptom control as measured by the GIS also showed significant improvement at 8 weeks. CONCLUSIONS In patients with persistent GORD symptoms despite full dose daily PPI therapy, esomeprazole 40 mg significantly improved the frequency and severity of all GORD symptoms.
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Affiliation(s)
- R Jones
- Department of General Practice & Primary Care, King's College London, London, UK.
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Abstract
Antisecretory therapies that raise intragastric pH provide the best healing of the esophageal mucosal damage that occurs in gastroesophageal reflux disease. Continuous maintenance therapy is also effective to reduce the likelihood of recurrence of esophagitis and control symptoms in the long term. Proton pump inhibitor (PPI) therapy is an effective approach for healing esophagitis and controlling symptoms. Endoscopic and surgical treatments may provide an option for patients who are refractory to PPIs in whom reflux has been clearly demonstrated. Long-term antireflux medication is often needed after surgical treatment because of persisting or recurrent pathologic reflux and symptoms. An alternative approach to controlling transient lower esophageal sphincter relaxations, such as the GABA-B agonists, deserves further study.
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Affiliation(s)
- Changcheng Wang
- Division of Gastroenterology, Department of Medicine, McMaster University Health Science Centre, 1200 Main Street West, HSC 4W8A, Hamilton, Ontario L8N 3Z5, Canada
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Wilder-Smith C, Backlund A, Eckerwall G, Lind T, Fjellman M, Röhss K. Effect of increasing esomeprazole and pantoprazole doses on acid control in patients with symptoms of gastro-oesophageal reflux disease: a randomized, dose-response study. Clin Drug Investig 2008; 28:333-43. [PMID: 18479175 DOI: 10.2165/00044011-200828060-00001] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
BACKGROUND AND OBJECTIVE In patients with gastro-oesophageal reflux disease (GORD), dose escalation or drug switching may be considered in those with symptoms that persist despite standard-dose proton pump inhibitor (PPI) therapy. This study set out to assess whether increasing the dosage of oral esomeprazole and pantoprazole improves acid control in GORD patients, and to compare the pharmacodynamic efficacy of esomeprazole and pantoprazole administered at different dosages. METHODS This was an open-label, randomized, six-way crossover study that included Helicobacter pylori-negative GORD patients (aged 20-60 years) with <30% of time with intragastric pH>4. Patients were treated with oral once-daily esomeprazole 20 mg, 40 mg and 80 mg, and pantoprazole 20 mg, 40 mg and 80 mg, for 5 days. The main outcome measures were time with intragastric pH>4 over 24 hours, median pH over 24 hours and area under the hydrogen ion versus time curve on day 5 for each treatment period. RESULTS Dose escalation with both PPIs improved acid control. The proportion of time with intragastric pH>4 (day 5) was 46.7% with esomeprazole 20 mg/day, 58.6% with esomeprazole 40 mg/day, and 65.8% with esomeprazole 80 mg/day; the corresponding percentages with pantoprazole were 28.6%, 36.9% and 44.9%, respectively. On a milligram-per-milligram basis, esomeprazole provided greater acid control than pantoprazole (p<0.001). CONCLUSION Dose escalation with oral esomeprazole and pantoprazole improves acid control in patients with GORD, although esomeprazole provides significantly greater acid control on a milligram-per-milligram basis.
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Affiliation(s)
- Clive Wilder-Smith
- Brain-Gut Research Group, Gastroenterology Group Practice, Berne, Switzerland.
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Abstract
PURPOSE To emphasize the relationship between gastroesophageal reflux disease (GERD) and asthma symptoms or exacerbations. DATA SOURCES Selective review of the scientific literature. CONCLUSIONS Although studies in recent years have offered insight into the relationship between GERD and asthma symptoms, many nurse practitioners (NPs) fail to recognize atypical GERD symptoms, which may explain difficult-to-treat asthma and exacerbation. It has become evident that patients suffering from persistent asthma display an increased prevalence of GERD. IMPLICATIONS FOR PRACTICE While there are increasing constraints that limit the provider-patient interaction time, it is imperative that NPs develop keen assessment skills to effectively diagnose and treat asthma symptoms that are a product of GERD. Awareness of the asthma-GERD relationship allows NPs to quickly obtain pertinent information and successfully determine how to efficiently treat symptomatic asthmatic patients.
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Affiliation(s)
- Sandra Huggins
- Southern Adventist University School of Nursing, Ooltewah, Tennessee 37363, USA.
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Pallotta S, Pace F, Marelli S. Rabeprazole: a second-generation proton pump inhibitor in the treatment of acid-related disease. Expert Rev Gastroenterol Hepatol 2008; 2:509-22. [PMID: 19072398 DOI: 10.1586/17474124.2.4.509] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Rabeprazole is a proton pump inhibitor (PPI) presenting a very advantageous pharmacodynamic and pharmacokinetic profile over older PPIs. In particular, this drug has a very fast onset of action, due to a short activation time and a very high pKa, and may therefore be defined as a 'second generation' PPI. The aim of this article is to provide an update on the pharmacology and clinical profile of rabeprazole and its use in acid-related disorders, with a particular focus on its role in gastroesophageal reflux disease; in the treatment and prevention of duodenal and gastric ulcers and Zollinger-Ellison syndrome; in the therapy of the extraesophageal manifestations of gastroesophageal reflux disease (in particular the respiratory and ear, nose and throat ones); and in the eradication of Helicobacter pylori.
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Affiliation(s)
- Stefano Pallotta
- University of Milan, Via GB Grassi, 74, 20157 Milano, MI, Italy.
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