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Properzi S, Stracci F, Rosi M, Lupi C, Villarini A, Gili A. Can a diet rich in Brassicaceae help control Helicobacter pylori infection? A systematic review. Front Med (Lausanne) 2024; 11:1454902. [PMID: 39741515 PMCID: PMC11685009 DOI: 10.3389/fmed.2024.1454902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Accepted: 11/11/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction Helicobacter pylori (Hp) infection is highly prevalent globally and poses a significant public health challenge due to its link with chronic gastritis, peptic ulcers, and gastric malignancies. Hp's persistence within the gastric environment, particularly in case of infection with virulent strains, triggers chronic inflammatory responses and mucosal damage. Antibiotic therapy is the primary approach for Hp eradication, but antibiotic resistance and adverse effects hinder treatment efficacy. Emerging evidence suggests that Brassicaceae-derived metabolites could serve as adjunctive therapy for Hp infection, offering potential antimicrobial and anti-inflammatory benefits. Methods A systematic literature review was conducted following PRISMA guidelines to assess the impact of Brassicaceae-rich diets on Hp infection control. Searches were performed in MEDLINE PubMed, Web of Science, and the Cochrane Library until 18 October 2023, without language or date restrictions. Eligible studies meeting PICOS criteria were included, encompassing populations infected with Hp or Hp-infected human cell cultures, interventions involving Brassicaceae consumption or its bioactive molecules, and outcomes related to Hp infection control, antibiotic therapy interactions, reduction of antibiotic side effects, and inflammation mitigation. Animal studies, cell line experiments, reviews unrelated to the research objectives, and studies on Hp-related gastric cancer were excluded. Results Available evidence indicates that Brassicaceae consumption exhibits the potential to reduce Hp colonization but achieving complete eradication of the pathogen remains challenging. Conflicting results regarding the efficacy of broccoli in Hp treatment emerge, with certain investigations suggesting limited effectiveness. Other studies point to a potential for heightened eradication rates when combined with standard triple therapy. Furthermore, promising outcomes are observed with broccoli extract supplements, indicating their role in mitigating Hp-induced gastric mucosal damage. In fact, it is noteworthy that sulforaphane and its derivatives manifest notable reductions in pro-inflammatory markers, indicative of their anti-inflammatory properties. Adverse events associated with antibiotic therapy seem unaffected by sulforaphane derivatives or probiotics. However, individual responses to these treatments vary, underscoring the unpredictability of their efficacy in ameliorating antibiotic therapy-related side effects. Conclusion Our systematic review highlights the potential of Brassicaceae-rich diets as adjunctive therapy for Hp infection, offering synergistic interactions with antibiotics and possibly mitigating antibiotic side effects and inflammation. Further research, particularly well-designed randomized trials, is warranted to elucidate the therapeutic efficacy and optimal utilization of Brassicaceae-derived metabolites in managing human Hp-related diseases.
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Affiliation(s)
- Sara Properzi
- Department of Medicine and Surgery, University of Perugia, Perugia, Umbria, Italy
| | - Fabrizio Stracci
- Department of Medicine and Surgery, University of Perugia, Perugia, Umbria, Italy
| | - Margherita Rosi
- Department of Medicine and Surgery, University of Perugia, Perugia, Umbria, Italy
| | - Chiara Lupi
- Department of Medicine and Surgery, University of Perugia, Perugia, Umbria, Italy
| | - Anna Villarini
- Department of Medicine and Surgery, University of Perugia, Perugia, Umbria, Italy
| | - Alessio Gili
- Department of Life Sciences, Health and Health Professions, Link Campus University, Rome, Italy
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Vieira RV, Peiter GC, de Melo FF, Zarpelon-Schutz AC, Teixeira KN. In silico prospective analysis of the medicinal plants activity on the CagA oncoprotein from Helicobacter pylori. World J Clin Oncol 2024; 15:653-663. [PMID: 38835850 PMCID: PMC11145963 DOI: 10.5306/wjco.v15.i5.653] [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] [Received: 12/15/2023] [Revised: 04/01/2024] [Accepted: 04/18/2024] [Indexed: 05/21/2024] Open
Abstract
BACKGROUND Colonization with Helicobacter pylori (H. pylori) has a strong correlation with gastric cancer, and the virulence factor CagA is implicated in carcinogenesis. Studies have been conducted using medicinal plants with the aim of eliminating the pathogen; however, the possibility of blocking H. pylori-induced cell differentiation to prevent the onset and/or progression of tumors has not been addressed. This type of study is expensive and time-consuming, requiring in vitro and/or in vivo tests, which can be solved using bioinformatics. Therefore, prospective computational analyses were conducted to assess the feasibility of interaction between phenolic compounds from medicinal plants and the CagA oncoprotein. AIM To perform a computational prospecting of the interactions between phenolic compounds from medicinal plants and the CagA oncoprotein of H. pylori. METHODS In this in silico study, the structures of the phenolic compounds (ligands) kaempferol, myricetin, quercetin, ponciretin (flavonoids), and chlorogenic acid (phenolic acid) were selected from the PubChem database. These phenolic compounds were chosen based on previous studies that suggested medicinal plants as non-drug treatments to eliminate H. pylori infection. The three-dimensional structure model of the CagA oncoprotein of H. pylori (receptor) was obtained through molecular modeling using computational tools from the I-Tasser platform, employing the threading methodology. The primary sequence of CagA was sourced from GenBank (BAK52797.1). A screening was conducted to identify binding sites in the structure of the CagA oncoprotein that could potentially interact with the ligands, utilizing the GRaSP online platform. Both the ligands and receptor were prepared for molecular docking using AutoDock Tools 4 (ADT) software, and the simulations were carried out using a combination of ADT and AutoDock Vina v.1.2.0 software. Two sets of simulations were performed: One involving the central region of CagA with phenolic compounds, and another involving the carboxy-terminus region of CagA with phenolic compounds. The receptor-ligand complexes were then analyzed using PyMol and BIOVIA Discovery Studio software. RESULTS The structure model obtained for the CagA oncoprotein exhibited high quality (C-score = 0.09) and was validated using parameters from the MolProbity platform. The GRaSP online platform identified 24 residues (phenylalanine and leucine) as potential binding sites on the CagA oncoprotein. Molecular docking simulations were conducted with the three-dimensional model of the CagA oncoprotein. No complexes were observed in the simulations between the carboxy-terminus region of CagA and the phenolic compounds; however, all phenolic compounds interacted with the central region of the oncoprotein. Phenolic compounds and CagA exhibited significant affinity energy (-7.9 to -9.1 kcal/mol): CagA/kaempferol formed 28 chemical bonds, CagA/myricetin formed 18 chemical bonds, CagA/quercetin formed 16 chemical bonds, CagA/ponciretin formed 13 chemical bonds, and CagA/chlorogenic acid formed 17 chemical bonds. Although none of the phenolic compounds directly bound to the amino acid residues of the K-Xn-R-X-R membrane binding motif, all of them bound to residues, mostly positively or negatively charged, located near this region. CONCLUSION In silico, the tested phenolic compounds formed stable complexes with CagA. Therefore, they could be tested in vitro and/or in vivo to validate the findings, and to assess interference in CagA/cellular target interactions and in the oncogenic differentiation of gastric cells.
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Affiliation(s)
| | | | - Fabrício Freire de Melo
- Universidade Federal da Bahia, Instituto Multidisciplinar em Saúde-Campus Anísio Teixeira, Vitória da Conquista 45029-094, Brazil
| | - Ana Carla Zarpelon-Schutz
- Universidade Federal do Paraná, Campus Toledo, Toledo 85919-899, Brazil
- Universidade Federal do Paraná-Setor Palotina, Programa de Pós-graduação em Biotecnologia, Palotina 85950-000, Brazil
| | - Kádima Nayara Teixeira
- Universidade Federal do Paraná, Campus Toledo, Toledo 85919-899, Brazil
- Universidade Federal do Paraná-Setor Palotina, Programa de Pós-graduação em Biotecnologia, Palotina 85950-000, Brazil
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Shah S, Khan M, Ali M, Wadood A, Ur Rehman A, Shah Z, Yousaf M, Salar U, Khan KM. Bis-1,3,4-Oxadiazole Derivatives as Novel and Potential Urease Inhibitors; Synthesis, In Vitro, and In Silico Studies. Med Chem 2022; 18:820-830. [PMID: 35232342 DOI: 10.2174/1573406418666220301161934] [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: 09/02/2021] [Revised: 12/22/2021] [Accepted: 01/06/2022] [Indexed: 11/22/2022]
Abstract
AIMS Synthesis of bis-1,3,4-oxadiazole derivatives as novel and potential urease inhibitors. BACKGROUND Despite many important biological activities associated with oxadiazoles, they are still neglected by medicinal chemists for their possible urease inhibitory activity. Keeping in view the countless importance of urease inhibitors, we have synthesized a new library of substituted bis-oxadiazole derivatives (1-21) to evaluate their urease inhibitory potential. OBJECTIVE Synthesis of substituted bis-oxadiazole derivatives (1-21) to evaluate their urease inhibitory potential. METHOD Bis-1,3,4-oxadiazole derivatives 1-21 were synthesized through sequential reactions using starting material isophthalic acid. Esterification reaction was done by refluxing in methanol for 2 h in the presence of the catalytic amount of concentrated H2SO4 till dissolution. In the second step, dimethyl isophthalate and hydrazine hydrate in excess (1:5) were refluxed in methanol to afford isophthalic dihydrazide. Then, isophthalic dihydrazide was treated with different substituted benzaldehydes in a 1:2 ratio under acidic conditions Result: In vitro urease, the inhibitory activity of the synthesized compounds were evaluated and results demonstrated good activities with IC50 values in the range of 13.46 ± 0.34 to 74.45 ± 3.81 µM as compared to the standard thiourea (IC50 = 21.13 ± 0.415 µM). Most of the compounds were found to be more potent than the standard. The structure-activity relationship (SAR) suggested that the variations in the inhibitory activities of the compounds were due to different substitutions. Furthermore; in silico study was also performed. CONCLUSION Current study identified a new class of urease inhibitors. All synthetic compounds 1-21 showed potent as well as good to moderate urease inhibitory activities except 3. SAR suggested that hydroxy-bearing analogs were identified exceptionally good. Molecular docking revealed many important interactions made by compounds with the active site of the urease enzyme.
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Affiliation(s)
- Sana Shah
- Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Khyber Pakhtunkhwa, Pakistan
| | - Momin Khan
- Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Khyber Pakhtunkhwa, Pakistan
| | - Mahboob Ali
- Department of Biochemistry, Abdul Wali Khan University, Mardan, Khyber Pakhtunkhwa, Pakistan
| | - Abdul Wadood
- School of Biological Sciences, University of California, Irvine, CA 92697-3900, U.S.A
| | - Ashfaq Ur Rehman
- Department of Chemistry, Bacha Khan University Charsadda, Charsadda-24420, Pakistan
| | - Zarbad Shah
- Department of Chemistry, Abdul Wali Khan University, Mardan-23200, Khyber Pakhtunkhwa, Pakistan
| | - Muhammad Yousaf
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Uzma Salar
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi 75270, Pakistan
| | - Khalid Mohammed Khan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi-75270, Pakistan
- Department of Clinical Pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, P.O. Box 31441, Dammam, Saudi Arabia
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Taha M, Ismail S, Imran S, Almandil NB, Alomari M, Rahim F, Uddin N, Hayat S, Zaman K, Ibrahim M, Alghanem B, Islam I, Farooq RK, Boudjelal M, Khan KM. Synthesis of new urease enzyme inhibitors as antiulcer drug and computational study. J Biomol Struct Dyn 2021; 40:8232-8247. [PMID: 33860726 DOI: 10.1080/07391102.2021.1910072] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
In search of potent urease inhibitor indole analogues (1-22) were synthesized and evaluated for their urease inhibitory potential. All analogues (1-22) showed a variable degree of inhibitory interaction potential having IC50 value ranging between 0.60 ± 0.05 to 30.90 ± 0.90 µM when compared with standard thiourea having IC50 value 21.86 ± 0.90 µM. Among the synthesized analogues, the compounds 1, 2, 3, 5, 6, 8, 12, 14, 18, 20 and 22 having IC50 value 3.10 ± 0.10, 1.20 ± 0.10, 4.60 ± 0.10, 0.60 ± 0.05, 5.30 ± 0.20, 2.50 ± 0.10, 7.50 ± 0.20, 3.90 ± 0.10, 3.90 ± 0.10, 2.30 ± 0.05 and 0.90 ± 0.05 µM respectively were found many fold better than the standard thiourea. All other analogues showed better urease interaction inhibition. Structure activity relationship (SAR) has been established for all analogues containing different substituents on the phenyl ring. To understand the binding interaction of most active analogues with enzyme active site docking study were performed.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Muhammad Taha
- Department of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Sukinah Ismail
- Department of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.,College of clinical pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Syahrul Imran
- Atta-ur-Rahman Institute for Natural Product Discovery, Universiti Teknologi MARA (UiTM), Bandar Puncak Alam, Selangor, Malaysia.,Faculty of Applied Science, UiTM Shah Alam, Shah Alam, Selangor, Malaysia
| | - Noor Barak Almandil
- Department of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Munther Alomari
- Department of Stem Cell Biology, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Fazal Rahim
- Department of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
| | - Nizam Uddin
- Department of Chemistry, University of Karachi, Karachi, Pakistan
| | - Shawkat Hayat
- Department of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
| | - Khalid Zaman
- Department of Chemistry, Hazara University, Mansehra, Khyber Pakhtunkhwa, Pakistan
| | - Mohamad Ibrahim
- Department of clinical pharmacy, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Bandar Alghanem
- Medical Research Core Facility and Platforms (MRCFP, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), NGHA, Riyadh, Saudi Arabia
| | - Imadul Islam
- Medical Research Core Facility and Platforms (MRCFP, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), NGHA, Riyadh, Saudi Arabia
| | - Rai Khalid Farooq
- Department of Neuroscience Research, Institute for Research and Medical Consultations (IRMC), Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
| | - Mohamed Boudjelal
- Medical Research Core Facility and Platforms (MRCFP, King Abdullah International Medical Research Center/King Saud bin Abdulaziz University for Health Sciences (KSAU-HS), King Abdulaziz Medical City (KAMC), NGHA, Riyadh, Saudi Arabia
| | - Khalid Mohammed Khan
- H. E. J. Research Institute of Chemistry, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
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El-Zahabi HSA, Abdulwahab HG, Edrees MM, Hegab AM. Utility of anthranilic acid and diethylacetylenedicarboxylate for the synthesis of nitrogenous organo/organometallic compounds as urease inhibitors. Arch Pharm (Weinheim) 2019; 352:e1800314. [PMID: 31210387 DOI: 10.1002/ardp.201800314] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 03/25/2019] [Accepted: 03/31/2019] [Indexed: 12/30/2022]
Abstract
Fumarate diester 3 was synthesized upon reacting anthranilic acid with diethylacetylenedicarboxylate. Compound 3 was reacted with different nucleophiles in mild reaction conditions. Selected reaction routes that afforded products 6, 9, 10, 11, and 12 were explained. The estimated mechanism for the reaction of 3 with ethylenediamine to afford 9 was proved by X-ray single-crystal and retro-synthetic reaction. Acetyl anthranilic acid was utilized with zinc and copper to afford the organometallic compounds 14a and 14b, respectively. Three single crystals were afforded for 3, 9 and the organocopper complex 14b. Target compounds were screened for their inhibitory potential against urease enzyme. Most compounds were more potent than thiourea as standard inhibitor, considering that oxopiperazine 9 exhibited double the activity: IC50 = 8.16 ± 0.65 µM (thiourea IC50 = 20.04 ± 0.33 µM). Docking studies were in agreement with the in vitro enzyme assay.
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Affiliation(s)
- Heba S A El-Zahabi
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Hanan G Abdulwahab
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy (Girls), Al-Azhar University, Cairo, Egypt
| | - Mastoura M Edrees
- Department of Organic Chemistry, National Organization for Drug Control and Research, Giza, Egypt
- Department of Chemistry, Faculty of Science, King Khalid University, Abha, Saudi Arabia
| | - Amany M Hegab
- Developmental Pharmacology Department, National Organization for Drug Control and Research, Giza, Egypt
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Kataria R, Khatkar A. In-silico design, synthesis, ADMET studies and biological evaluation of novel derivatives of Chlorogenic acid against Urease protein and H. Pylori bacterium. BMC Chem 2019; 13:41. [PMID: 31384789 PMCID: PMC6661759 DOI: 10.1186/s13065-019-0556-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Accepted: 03/15/2019] [Indexed: 12/26/2022] Open
Abstract
Background Plants have always played important role in treating human and animal diseases as a therapeutic agent for traditional medicine. Through extensive research throughout the world, potential of natural products have been identified to control the over activity of many enzymes. In-silico screening a library of chlorogenic acid derivatives highlighted some novel compounds which were found effective against urease enzyme and cancer causing H. Pylori bacterium. Selected top ligands possessing minimum binding energy and good docking score were synthesized in wet lab by suitable procedure and evaluated for urease enzyme inhibition and free radical scavenging property. Synthetic scheme includes three step reactions i. e protection of hydroxyl group of quinic acid part of chlorogenic acid with lactonisation process, anilide formation by reaction with substituted anilines followed by extraction with ethyl acetate under vacuum and deprotection of hydroxyl groups by treatment with hydrochloric acid. Results In-vitro results of the series concluded that compounds C4a, C4d and C4b (IC50 11.01 ± 0.013, 13.8 ± 0.041 and 15.86 ± 0.004 µM respectively in urease inhibition and 5.10 ± 0.018, 5.34 ± 0.007 and 6.01 ± 0.005 µM in antioxidant property against DPPH) were found to be significantly potent with excellent dock score − 10.091, − 10.603, − 9.833 and binding energy − 62.674, − 63.352, 56.267 kg/mol as compared to standard drugs thiourea and acetohydroxamic acid (− 3.459, − 3.049 and − 21.156 kJ/mol and − 17.454 kJ/mol) whereas compounds C4c, C4(e, h) exhibited moderate in vivo activity when compared to standard. Conclusions Selected candidates from the outcome of in vitro urease inhibitory were further examined for anti-H. Pylori activity by well diffusion method against H. pylori bacterium (DSM 4867). Compound C4a showed significant anti-H. Pylori activity with zone of inhibition 10.00 ± 0.00 mm and MIC value 500 μg/mL as compared to standard drug acetohydroxamic acid having zone of inhibition 9.00 ± 0.50 mm and MIC 1000 μg/mL. Molecular docking studies also showed that compounds show strong inhibition by forming strong hydrogen bonding interactions with residues of pocket site in target protein. Hence, the present investigation studies will provide a new vision for the discovery of potent agents against H. Pylori and urease associated diseases.
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Affiliation(s)
- Ritu Kataria
- International Institute of Pharmaceutical Sciences, Sonepat, Haryana India
| | - Anurag Khatkar
- 2Laboratory for Preservation Technology and Enzyme Inhibition Studies, Faculty of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak, Haryana India
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Debraekeleer A, Remaut H. Future perspective for potentialHelicobacter pylorieradication therapies. Future Microbiol 2018; 13:671-687. [PMID: 29798689 DOI: 10.2217/fmb-2017-0115] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Affiliation(s)
- Ayla Debraekeleer
- Department of Structural & Molecular Microbiology, VIB Center for Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium
- Department of Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
| | - Han Remaut
- Department of Structural & Molecular Microbiology, VIB Center for Structural Biology, VIB, Pleinlaan 2, 1050 Brussels, Belgium
- Department of Structural Biology Brussels, Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
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Naureen S, Chaudhry F, Asif N, Munawar MA, Ashraf M, Nasim FH, Arshad H, Khan MA. Discovery of indole-based tetraarylimidazoles as potent inhibitors of urease with low antilipoxygenase activity. Eur J Med Chem 2015; 102:464-70. [DOI: 10.1016/j.ejmech.2015.08.011] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2015] [Revised: 07/20/2015] [Accepted: 08/05/2015] [Indexed: 01/18/2023]
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Sadat A, Uddin G, Alam M, Ahmad A, Siddiqui BS. Structure activity relationship of bergenin, p-hydroxybenzoyl bergenin, 11-O-galloylbergenin as potent antioxidant and urease inhibitor isolated from Bergenia ligulata. Nat Prod Res 2015; 29:2291-4. [DOI: 10.1080/14786419.2015.1004173] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Affiliation(s)
- Anwar Sadat
- Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan
| | - Ghias Uddin
- Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan
| | - M. Alam
- Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan
| | - Ashfaq Ahmad
- Institute of Chemical Sciences, University of Peshawar, Peshawar 25120, Pakistan
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Wang YC. Medicinal plant activity on Helicobacter pylori related diseases. World J Gastroenterol 2014; 20:10368-10382. [PMID: 25132753 PMCID: PMC4130844 DOI: 10.3748/wjg.v20.i30.10368] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Revised: 01/17/2014] [Accepted: 04/03/2014] [Indexed: 02/06/2023] Open
Abstract
More than 50% of the world population is infected with Helicobacter pylori (H. pylori). The bacterium highly links to peptic ulcer diseases and duodenal ulcer, which was classified as a group I carcinogen in 1994 by the WHO. The pathogenesis of H. pylori is contributed by its virulence factors including urease, flagella, vacuolating cytotoxin A (VacA), cytotoxin-associated gene antigen (Cag A), and others. Of those virulence factors, VacA and CagA play the key roles. Infection with H. pylori vacA-positive strains can lead to vacuolation and apoptosis, whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer. Numerous medicinal plants have been reported for their anti-H. pylori activity, and the relevant active compounds including polyphenols, flavonoids, quinones, coumarins, terpenoids, and alkaloids have been studied. The anti-H. pylori action mechanisms, including inhibition of enzymatic (urease, DNA gyrase, dihydrofolate reductase, N-acetyltransferase, and myeloperoxidase) and adhesive activities, high redox potential, and hydrophilic/hydrophobic natures of compounds, have also been discussed in detail. H. pylori-induced gastric inflammation may progress to superficial gastritis, atrophic gastritis, and finally gastric cancer. Many natural products have anti-H. pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress. Anti-H. pylori induced gastric inflammatory effects of plant products, including quercetin, apigenin, carotenoids-rich algae, tea product, garlic extract, apple peel polyphenol, and finger-root extract, have been documented. In conclusion, many medicinal plant products possess anti-H. pylori activity as well as an anti-H. pylori-induced gastric inflammatory effect. Those plant products have showed great potential as pharmaceutical candidates for H. pylori eradication and H. pylori induced related gastric disease prevention.
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Smoking, Proton Pump Inhibitors and Antibiotic Administration as Factors Affecting Direct Screening of Helicobacter Pylori Infection Among Patients With Dyspepsia. ARCHIVES OF CLINICAL INFECTIOUS DISEASES 2014. [DOI: 10.5812/archcid.15774] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Ibrar A, Khan I, Abbas N. Structurally Diversified Heterocycles and Related Privileged Scaffolds as Potential Urease Inhibitors: A Brief Overview. Arch Pharm (Weinheim) 2013; 346:423-46. [DOI: 10.1002/ardp.201300041] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Revised: 03/29/2013] [Accepted: 04/03/2013] [Indexed: 12/31/2022]
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Hanif M, Shoaib K, Saleem M, Hasan Rama N, Zaib S, Iqbal J. Synthesis, urease inhibition, antioxidant, antibacterial, and molecular docking studies of 1,3,4-oxadiazole derivatives. ISRN PHARMACOLOGY 2012; 2012:928901. [PMID: 22934191 PMCID: PMC3425833 DOI: 10.5402/2012/928901] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2012] [Accepted: 06/24/2012] [Indexed: 11/23/2022]
Abstract
A series of eighteen 1,3,4-oxadiazole derivatives have been synthesized by treating aromatic acid hydrazides with carbon disulfide in ethanolic potassium hydroxide yielding potassium salts of 1,3,4-oxadiazoles. Upon neutralization with 1 N hydrochloric acid yielded crude crystals of 1,3,4-oxadiazoles, which were purified by recrystallization in boiling methanol. The synthesized 1,3,4-oxadiazoles derivatives were evaluated in vitro for their urease inhibitory activities, most of the investigated compounds were potent inhibitors of Jack bean urease. The molecular docking studies were performed by docking them into the crystal structure of Jack bean urease to observe the mode of interaction of synthesized compounds. The synthesized compounds were also tested for antibacterial and antioxidant activities and some derivatives exhibited very promising results.
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Affiliation(s)
- Muhammad Hanif
- Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
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Inhibition of biofilm formation by esomeprazole in Pseudomonas aeruginosa and Staphylococcus aureus. Antimicrob Agents Chemother 2012; 56:4360-4. [PMID: 22664967 DOI: 10.1128/aac.00544-12] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Staphylococcus aureus and Pseudomonas aeruginosa are common nosocomial pathogens responsible for biofilm-associated infections. Proton pump inhibitors (PPI), such as esomeprazole, may have novel antimicrobial properties. The objective of this study was to assess whether esomeprazole prevents sessile bacterial growth and biofilm formation and whether it may have synergistic killing effects with standard antibiotics. The antibiofilm activity of esomeprazole at 0.25 mM was tested against two strains each of S. aureus and P. aeruginosa. Bacterial biofilms were prepared using a commercially available 96-peg-plate Calgary biofilm device. Sessile bacterial CFU counts and biomass were assessed during 72 hours of esomeprazole exposure. The killing activities after an additional 24 hours of vancomycin (against S. aureus) and meropenem (against P. aeruginosa) treatment with or without preexposure to esomeprazole were also assessed by CFU and biomass analyses. P. aeruginosa and S. aureus strains exposed to esomeprazole displayed decreased sessile bacterial growth and biomass (P < 0.001, each parameter). After 72 h of exposure, there was a 1-log(10) decrease in the CFU/ml of esomeprazole-exposed P. aeruginosa and S. aureus strains compared to controls (P < 0.001). After 72 h of exposure, measured absorbance was 100% greater in P. aeruginosa control strains than in esomeprazole-exposed strains (P < 0.001). Increased killing and decreased biomass were observed for esomeprazole-treated bacteria compared to untreated controls exposed to conventional antibiotics (P < 0.001, each parameter). Reduced biofilm growth after 24 h was visibly apparent by light micrographs for P. aeruginosa and S. aureus isolates exposed to esomeprazole compared to untreated controls. In conclusion, esomeprazole demonstrated an antibiofilm effect against biofilm-producing S. aureus and P. aeruginosa.
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15
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Follmer C. Ureases as a target for the treatment of gastric and urinary infections. J Clin Pathol 2010; 63:424-30. [PMID: 20418234 DOI: 10.1136/jcp.2009.072595] [Citation(s) in RCA: 132] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Urease is known to be a major contributor to pathologies induced by Helicobacter pylori and Proteus species. In H pylori, urease allows the bacteria to survive in an acidic gastric environment during colonisation, playing an important role in the pathogenesis of gastric and peptic ulcers. Ureolytic activity also results in the production of ammonia in close proximity to the gastric epithelium, causing cell damage and inflammation. In the case of Proteus species (notably Proteus mirabilis) infection, stones are formed due to the presence of ammonia and carbon dioxide released by urease action. In addition, the ammonia released is able to damage the glycosaminoglycan layer, which protects the urothelial surface against bacterial infection. In this context, the administration of urease inhibitors may be an effective therapy for urease-dependent pathogenic bacteria. This is a review of the role of ureases in H pylori and Proteus species infections, focussing on the biochemical and clinical aspects of the most promising and/or potent urease inhibitors for the treatment of gastric and urinary tract infections.
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Affiliation(s)
- C Follmer
- Department of Physical Chemistry, Institute of Chemistry, Federal University of Rio de Janeiro, Rio de Janeiro 21941-909, Brazil.
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Yang JC, Lin CJ. CYP2C19 genotypes in the pharmacokinetics/pharmacodynamics of proton pump inhibitor-based therapy of Helicobacter pylori infection. Expert Opin Drug Metab Toxicol 2010; 6:29-41. [PMID: 19968574 DOI: 10.1517/17425250903386251] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
IMPORTANCE OF THE FIELD Proton pump inhibitors (PPIs) are potent gastric acid inhibitors. Therapies with a PPI and antibiotics are used to cure Helicobacter pylori (H. pylori) infection, which is closely related to many gastrointestinal diseases. Most PPIs are mainly metabolized by cytochrome 2C19 (CYP2C19). The genetic polymorphisms of CYP2C19 may lead to the differences in pharmacokinetics (PK), pharmacodynamics (PD) and clinical efficacy of PPIs. AREAS COVERED IN THIS REVIEW The roles of PPIs on the eradication of H. pylori are summarized. The impact f CYP2C19 polymorphism on the PK and PD of PPIs is addressed and related to the present status of therapy for H. pylori infection. The opinions on the strategy of PPIs-based therapies of H. pylori infection are provided. WHAT THE READER WILL GAIN Update the factors that may influence the PPIs-based therapies of H. pylori infection. TAKE HOME MESSAGE The eradication rates of H. pylori infection are significantly different between patients who are CYP2C19 extensive metabolizers and poor metabolizers, partly because of the differences in the PK and PD of PPIs. Nonetheless, the differences can be improved by adjusting the regimens of PPIs and using antibiotics that have less H. pylori-resistance.
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Affiliation(s)
- Jyh-Chin Yang
- National Taiwan University, Hospital and College of Medicine, Department of Internal Medicine, Taipei, Taiwan
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Qasim A, O'Morain CA, O'Connor HJ. Helicobacter pylori eradication: role of individual therapy constituents and therapy duration. Fundam Clin Pharmacol 2009; 23:43-52. [PMID: 19207543 DOI: 10.1111/j.1472-8206.2008.00635.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Treatment of Helicobacter pylori (H. pylori) infection has become a key factor in the management of dyspepsia and is the treatment of choice for peptic ulcer disease. First-line eradication regimens combining a proton pump inhibitor (PPI) with clarithromycin and amoxicillin or metronidazole are considered most effective when given for a minimum period of 1 week. Eradication regimens of shorter duration have shown promising results but clinical experience remains limited. Pharmacological properties such as bioavailability and plasma concentrations of individual PPIs differ between individuals but it remains unclear whether these differences impact on the efficacy of eradication therapy and are influenced by renal or hepatic impairment. Bioavailability of PPIs also differs and is impacted on by factors including intragastric pH, metabolic pathways, potency on an mg-for-mg basis and intrinsic antibacterial activity. Several significant pharmacokinetic differences between the PPIs do not seem to influence overall H. pylori eradication rates for first-line triple therapy. However, comparison of factors including pharmacokinetics and treatment duration may prove important in achieving successful eradication with second- and third-line treatments. Based on the factors which influence therapy outcome, we suggest an algorithm for the use of H. pylori eradication therapies.
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Affiliation(s)
- Asghar Qasim
- Clinical Medicine/Gastroenterology, Naas General Hospital, Kildare, Ireland
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18
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Bhat AR, Palled MS, Chatter M, Rajesh PNM. Reverse phase high performance liquid chromatographic determination of rabiprazole in tablet dosage form. Indian J Pharm Sci 2006. [DOI: 10.4103/0250-474x.26656] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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19
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Sharara AI. Rabeprazole: the role of proton pump inhibitors in Helicobacter pylori eradication. Expert Rev Anti Infect Ther 2005; 3:863-870. [PMID: 16307499 DOI: 10.1586/14787210.3.6.863] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Proton pump inhibitors have become one of the cornerstones in the treatment of Helicobacter pylori infection. Rabeprazole (Pariet) is a substituted benzimidazole proton pump inhibitor with potent gastric acid suppression properties. Its high acid-base dissociation constant allows activation over a broader pH range, resulting in quick, irreversible binding to the H+/K+-ATPase pump, and a more rapid onset of action compared with omeprazole, lansoprazole and pantoprazole. Unlike other proton pump inhibitors, the metabolism of rabeprazole is primarily via a nonenzymatic reduction to the thioether derivative, and the cytochrome P450 isoenzyme 2C19 is only partly involved in its metabolism. The effect of genetic polymorphism in cytochrome P450 isoenzyme 2C19 on the pharmacokinetics and pharmacodynamics of rabeprazole is therefore limited. In humans, once-daily dosing of 5-40 mg of rabeprazole inhibits gastric acid secretion in a dose-dependent manner. In vitro studies have shown that rabeprazole possesses more potent antibacterial properties against the growth of H. pylori than other proton pump inhibitors. Furthermore, its thioether derivative has more potent inhibitory in vitro activity against the growth and motility of clarithromycin-resistant H. pylori than other proton pump inhibitors or commonly used antimicrobials. Despite these inherent favorable characteristics of rabeprazole, randomized controlled trials have largely shown equivalence amongst proton pump inhibitors when used with two antibiotics in the eradication of H. pylori, with cure rates of 75-89% on an intent-to-treat basis. However, rabeprazole appears to consistently achieve such comparable eradication rates even when used at reduced doses (10 mg twice daily) as part of clarithromycin-based triple therapy.
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Affiliation(s)
- Ala I Sharara
- Division of Gastroenterology, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 11-0236/16-B, Beirut, Lebanon.
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20
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Wang YC, Huang TL. Screening of anti-Helicobacter pylori herbs deriving from Taiwanese folk medicinal plants. ACTA ACUST UNITED AC 2005; 43:295-300. [PMID: 15681161 DOI: 10.1016/j.femsim.2004.09.008] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2004] [Revised: 08/25/2004] [Accepted: 09/20/2004] [Indexed: 02/06/2023]
Abstract
In this study, extracts from 50 Taiwanese folk medicinal plants were examined and screened for anti-Helicobacter pylori activity. Ninety-five percent ethanol was used for herbal extraction. Paederia scandens (Lour.) Merr. (PSM), Plumbago zeylanica L. (PZL), Anisomeles indica (L.) O. Kuntze (AIOK), Bombax malabaricum DC. (BMDC) and Alpinia speciosa (J. C. Wendl.) K. Schum. (ASKS) and Bombax malabaricum DC. (BMDC) all demonstrated strong anti-H. pylori activities. The minimum inhibitory concentration values of the anti-H. pylori activity given by the five ethanol herb extracts ranged from 0.64 to 10.24 mg ml(-1). Twenty-six herbs, including Artemisia argvi Levl. et Vant (AALEV), Phyla nodiflora (Linn.) Greene (PNG) and others, showed moderate anti-H. pylori activity. The additional 19 herbs, including Areca catechu Linn. (ACL), Euphorbia hirta Linn. (EHL) and Gnaphalium adnatum Wall. ex DC. (GAWEDC), possessed lower anti-H. pylori effects. About half of the Taiwanese folk medicinal plants tested, demonstrated to possess higher anti-H. pylori activity.
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Affiliation(s)
- Yuan-Chuen Wang
- Department of Food Science, National Chung-Hsing University, 250 Kuokuang Road, Taichung 40227, Taiwan, 402, ROC.
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21
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Wang YC, Huang TL. Anti-Helicobacter pylori activity of Plumbago zeylanica L. ACTA ACUST UNITED AC 2005; 43:407-12. [PMID: 15708315 DOI: 10.1016/j.femsim.2004.10.015] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2004] [Revised: 10/15/2004] [Accepted: 10/18/2004] [Indexed: 12/16/2022]
Abstract
It has been shown that the presence of infection by Helicobacter pylori is strongly associated with gastric cancer and peptic ulceration. In western medicine, a 3-fold therapeutic regimen, emphasizing the use of antibiotics, is typically used to suppress H. pylori activity. However, antibiotic drug resistance frequently develops as a consequence of such treatment. In our previous study, 50 Taiwanese folk medicinal plants were screened for their anti-H. pylori activities. The results revealed that Plumbago zeylanica L. had the highest inhibitory effects against H. pylori. In this study, therefore, we have focused on establishing the anti-H. pylori activities of P. zeylanica L. Water and the organic solvents ethanol, ethyl acetate and acetone were used for P. zeylanica L. extraction, obtaining yields of 1.66-6.84% (w/w). Excluding the water extract, higher anti-H. pylori activity was demonstrated for all the extracts, both using the agar diffusion and dilution methods. The ethyl acetate extract exhibited the lowest minimum inhibitory concentrations against five H. pylori strains, of which ranged from 0.32 to 1.28 mg ml-1, followed, in ascending order, by the acetone, ethanol and water analogs. Bactericidal activity was determined for P. zeylanica L. extracts, with the lowest minimum bactericidal concentrations (5.12-20.48 mg ml-1) demonstrated for the ethyl acetate, followed, in ascending order, by the acetone and ethanol analogs. Bactericidal activity appeared to be in a dose-dependent manner. Through a broad pH range (2-7), bactericidal activity was not affected when extract concentrations were greater than or equal to the minimum bactericidal concentration. High stability was demonstrated for the ethyl acetate P. zeylanica L. extract within pH range of 1-7, exhibiting all pH treatments bactericidal activity.
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Affiliation(s)
- Yuan-Chuen Wang
- Department of Food Science, National Chung-Hsing University, 250 Kuokuang Road, Taichung 40227, Taiwan, 402, ROC.
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Holton J, Besset C, Youinou P, Vaira D. Emerging therapeutic targets in the eradication of Helicobacter pylori. ACTA ACUST UNITED AC 2005. [DOI: 10.1517/14728222.2.2.107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
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Abstract
At present, antisecretory drugs--foremost among them the proton pump inhibitors (PPIs)--represent a keystone in Helicobacter pylori eradication therapy. The present article shall first compare the role of PPIs as compared with histamine H2 receptor antagonists, both of them in the role of antibiotic-associated antisecretory therapy, and shall then address the contribution of each of the various PPIs that have been developed until the present time to the H. pylori eradication therapies. In summary, it may be concluded that PPIs are more effective overall than H2 receptor antagonists when the two groups of antisecretory drugs are given at the usual standard doses together with antibiotics with the intention of eradicating H. pylori infection. However, all PPIs (omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole) are equivalent when given together with two antibiotics to cure the infection.
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Affiliation(s)
- Javier P Gisbert
- Gastroenterology Service, La Princesa University Hospital, Madrid, Spain.
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24
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Krajewska B, Zaborska W, Chudy M. Multi-step analysis of Hg2+ ion inhibition of jack bean urease. J Inorg Biochem 2004; 98:1160-8. [PMID: 15149828 DOI: 10.1016/j.jinorgbio.2004.03.014] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2003] [Revised: 03/05/2004] [Accepted: 03/08/2004] [Indexed: 11/29/2022]
Abstract
We performed a multi-step analysis of the inhibition of jack bean urease by Hg(2+) ions that included residual activity measurements after incubation of the enzyme with the metal ion, reactivation of Hg(2+)-inhibited urease, protection of urease with thiol reagents prior to incubation with Hg(2+), progress curve analysis, and spectroscopic assay of thiol groups in urease-Hg(2+) complexes with a cysteine selective agent 5,5'-dithiobis(2-nitrobenzoic acid) (DTNB). Hg(2+) ions were found to form stable complexes with urease that could rapidly be reversed only by the treatment with dithiotreitol, and not by dilution or dialysis. The residual activity data interpreted in terms of the Hill equation revealed the multisite Hg(2+) inhibition of urease, and along with the DTNB thiol-assay they demonstrated the involvement in the reaction with Hg(2+) of six cysteine residues per enzyme subunit, including the active-site flap cysteine. The molar ratios of the inhibitor and enzyme imply that the inhibition consists of the formation of RSHgX complexes, X being a water molecule or an anion. The time-dependent Hg(2+) inhibitory action on urease determined in the system without enzyme preincubation was best described by slow-binding mechanism with the steady-state inhibition constant K(i) = 1.9 nM (+/-10%).
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Affiliation(s)
- Barbara Krajewska
- Faculty of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Kraków, Poland
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25
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Abstract
A variety of alpha-hydroxyketones (1-13) and alpha-diketones (14-20) were evaluated for their effect on the jack bean urease. Of 13 alpha-hydroxyketones (1-13) tested, 2,2'-thenoin (10) (IC(50)=0.18 mM), furoin (9) (IC(50)=0.36 mM), 2-hydroxy-1-phenylethanone (5) (IC(50)=0.47 mM) and acetol (1) (IC(50)=2.9 mM) showed potent inhibitory activity against the enzyme, comparable with hydroxyurea (IC(50)=0.1 mM). The inhibitory effects were completely blocked by 2-mercaptoethanol or dithiothreitol. A nickel ion influenced the inhibitory effects of 5 and 9 in a dose-dependent manner, but not of 1 and 10. On the other hand, the corresponding alpha-diketones such as 2,2'-thenil (20), furil (19) and PhCOCHO (14) exhibited little or no ability to inhibit the urease. We have demonstrated for the first time that some alpha-hydroxyketone derivatives show urease inhibitory activity, possibly by binding to cysteinyl residues in the active site.
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Affiliation(s)
- Toru Tanaka
- Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama 350-0295, Japan
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26
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Abstract
A variety of alpha,beta-unsaturated ketones were evaluated for their effect on the jack bean urease. Of 35 compounds tested, 2-cyclohepten-1-one (1), 2-cyclohexen-1-one (2), 2-cyclopenten-1-one (3), and 5,6-dihydro-2H-pyran-2-one (4) showed potent inhibitory activities against the enzyme. The most potent compound (1) (IC50=0.16 mM) showed similar inhibitory potency to hydroxyurea (IC50=0.095 mM). The inhibitory effects of 1, 2, 3, and 4 were significantly reduced by 2-mercaptoethanol or dithiothreitol. These data suggest that alpha,beta-unsaturated ketones inhibited the urease activity, possibly by a Michael-like addition of a protein SH group to the double bond of the alpha,beta-unsaturated carbonyl group.
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Affiliation(s)
- Toru Tanaka
- Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama 350-0295, Japan
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Suzuki H, Miyazawa M, Nagahashi S, Sato M, Bessho M, Nagata H, Miura S, Ishii H. Rabeprazole treatment attenuated Helicobacter pylori-associated gastric mucosal lesion formation in Mongolian gerbils. J Gastroenterol Hepatol 2003; 18:787-95. [PMID: 12795750 DOI: 10.1046/j.1440-1746.2003.03038.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Although rabeprazole (RPZ), a proton pump inhibitor, has been reported to have a bactericidal effect on Helicobacter pylori (H. pylori), no studies have been conducted regarding the effect of RPZ on gastric mucosal lesion formation caused by this bacterium. In the present study, we investigated the effect of RPZ on H. pylori-associated gastric mucosal lesion formation. METHODS Sixty-two male Mongolian gerbils were inoculated with H. pylori (ATCC43504) (Hp group) and 60 gerbils with the culture media alone (control group). Some gerbils in the Hp group and in the control group were injected with RPZ (1 mg/kg/day, for 7 days) at the 5th week. Gerbils were evaluated at the 12th, 24th and 48th weeks. RESULTS In the Hp group, all gerbils were persistently infected for 24 weeks, but 36% became negative for H. pylori at the 48th week. In the Hp + RPZ group, 18% of gerbils at the 12th week, 40% at the 24th week, and 80% at the 48th week, became negative for H. pylori. The level of neutrophil infiltration was significantly decreased in the Hp + RPZ group in comparison to the Hp group, possibly through the effects of RPZ on initial bacterial colonization and resultant inflammation. Even in the gerbils that became H. pylori-negative, the level of neutrophil infiltration was lower in the Hp + RPZ group than in the Hp group. RPZ treatment significantly increased the level of the reduced form of glutathione (GSH) at the 48th week. The elevated levels of the reduced form of GSH may have been reduced by an antioxidation process in the H. pylori-positive Hp + RPZ group. CONCLUSION Administration of RPZ not only inhibited gastric H. pylori colonization, but also reduced gastric mucosal inflammation in gerbils, possibly through its antibacterial action as well as pharmacological recruitment of the reduced form of GSH.
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Affiliation(s)
- Hidekazu Suzuki
- Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan.
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Gisbert JP, Khorrami S, Calvet X, Pajares JM. Systematic review: Rabeprazole-based therapies in Helicobacter pylori eradication. Aliment Pharmacol Ther 2003; 17:751-64. [PMID: 12641497 DOI: 10.1046/j.1365-2036.2003.01450.x] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
AIM To perform a systematic review of the efficacy of rabeprazole-based therapies in Helicobacter pylori eradication, and to conduct a meta-analysis comparing the efficacy of rabeprazole and other proton pump inhibitors when co-prescribed with antibiotics. METHODS Studies evaluating rabeprazole plus antibiotics were considered. Only randomized trials comparing rabeprazole and other proton pump inhibitors with antibiotics, and differing only in the proton pump inhibitor, were included in the meta-analysis. Electronic and manual bibliographic searches were conducted. The percentage (weighted mean) of successful eradication was calculated. Meta-analysis was performed by combining the odds ratios (OR) of the individual studies. RESULTS The eradication rates were as follows: 14-day rabeprazole-amoxicillin, 73%; rabeprazole-amoxicillin-clarithromycin for 3, 5, 7 and 10 days, 44%, 72%, 78% and 75%, respectively; low-dose rabeprazole (20 mg/day), amoxicillin and clarithromycin for 7 days, 81%; high-dose rabeprazole (40 mg/day), amoxicillin and clarithromycin for 7 days, 75%; 7-day rabeprazole-clarithromycin-nitroimidazole, 85%. Twelve comparative studies were included in the meta-analysis. The eradication rate with rabeprazole plus antibiotics was 79%; it was 77% with other proton pump inhibitors (OR = 1.15; 95% confidence interval, 0.93-1.42). Sub-analysis comparing rabeprazole at low doses (10 mg b.d.) with other proton pump inhibitors at standard doses (omeprazole 20 mg b.d. or lansoprazole 30 mg b.d.) showed no differences. CONCLUSIONS Rabeprazole achieves similar H. pylori eradication rates to omeprazole and lansoprazole when co-prescribed with antibiotics. Low doses of rabeprazole (10 mg b.d.), when administered with two antibiotics, may be sufficient to eradicate H. pylori infection.
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Affiliation(s)
- J P Gisbert
- Servicio de Aparato Digestivo, Hospital Universitario de la Princesa, Madrid, Spain.
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Inaba T, Mizuno M, Kawai K, Yokota K, Oguma K, Miyoshi M, Take S, Okada H, Tsuji T. Randomized open trial for comparison of proton pump inhibitors in triple therapy for Helicobacter pylori infection in relation to CYP2C19 genotype. J Gastroenterol Hepatol 2002; 17:748-53. [PMID: 12121503 DOI: 10.1046/j.1440-1746.2002.02790.x] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Genetic polymorphism of cytochrome P450 (CYP) 2C19 influences the efficacy of Helicobacter pylori eradication therapy with a proton pump inhibitor (PPI) and amoxicillin. However, in triple therapy (PPI plus amoxicillin and clarithromycin), little is known about the impact of CYP2C19 polymorphism, or the use of rabeprazole, which is not well metabolized by CYP2C19. The efficacy of three PPI (omeprazole, lansoprazole, and rabeprazole) in a 1-week triple regimen were compared in relation to CYP2C19 polymorphism. METHOD One hundred and eighty-three patients were randomized to receive one of the following regimens: amoxicillin 500 mg t.i.d., clarithromycin 200 mg t.i.d., and PPI (omeprazole 20 mg, lansoprazole 30 mg, or rabeprazole 10 mg) b.i.d. CYP2C19 polymorphism was analyzed by PCR restriction fragment length polymorphism. RESULTS Intention-to-treat-based overall cure rates for omeprazole, lansoprazole or rabeprazole regimens were 83.1% (95% confidence interval (CI): 69-89%), 86.7% (CI: 75-93%), and 76.6% (CI: 64-85%), respectively, without significant difference. The cure rate of the rabeprazole regimen (but not the lansoprazole or omeprazole regimens) tended to be correlated with CYP2C19 genotypes (P = 0.076). In patients with a homozygous extensive metabolizer genotype, the per protocol-based cure rate with rabeprazole (62.5%) was significantly lower than that with lansoprazole (90.0%; P = 0.038). CONCLUSION The overall cure rate of 1-week triple therapy for H. pylori eradication was not significantly different between regimens with omeprazole, lansoprazole or rabeprazole, but the impact of CYP2C19 genetic polymorphism on the cure rate appeared to differ between these PPI.
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Affiliation(s)
- Tomoki Inaba
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Japan
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Nagahara A, Miwa H, Yamada T, Kurosawa A, Ohkura R, Sato N. Five-day proton pump inhibitor-based quadruple therapy regimen is more effective than 7-day triple therapy regimen for Helicobacter pylori infection. Aliment Pharmacol Ther 2001; 15:417-21. [PMID: 11207518 DOI: 10.1046/j.1365-2036.2001.00929.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND There have been no reports that describe whether 5-day quadruple therapy (rabeprazole + amoxicillin + clarithromycin + metronidazole; RACM) could substitute for standard 7-day triple therapy as a first-line therapy for Helicobacter pylori. PATIENTS AND METHODS This study was designed as a randomized prospective single centre study. A total of 160 H. pylori-positive patients who had not received therapy were given either a 5-day RACM regimen (n=80, rabeprazole 20 mg b.d., amoxicillin 750 mg b.d., clarithromycin 200 mg b.d. and metronidazole 250 mg b.d.) or a 7-day RAC regimen (n=80, rabeprazole 20 mg b.d., amoxicillin 750 mg b.d. and clarithromycin 200 mg b.d.). Cure of the infection was assessed by a (13)C urea breath test 1 month after the completion of therapy. RESULTS The eradication rates of the 5-day RACM regimen and the 7-day RAC regimen were 93% (95% CI: 84--97%) and 81% (95% CI: 71--89%) by intention-to-treat analysis, 94% (95% CI: 86--98%) and 83% (95% CI: 73--91%) by all-patients-treated analysis analysis and 95% (95% CI: 87--98%; P < 0.05) and 82% (95% CI: 72--90%) by per protocol analysis, respectively. No serious adverse effect was observed, and 99% of the patients reported complete compliance. CONCLUSIONS The cure rate of the 5-day RACM regimen was more effective than the 7-day RAC regimen, suggesting that this regimen could be preferable as a first-line therapy for H. pylori infection.
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Affiliation(s)
- A Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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Isomoto H, Furusu H, Morikawa T, Mizuta Y, Nishiyama T, Omagari K, Murase K, Inoue K, Murata I, Kohno S. 5-day vs. 7-day triple therapy with rabeprazole, clarithromycin and amoxicillin for Helicobacter pylori eradication. Aliment Pharmacol Ther 2000; 14:1619-23. [PMID: 11121910 DOI: 10.1046/j.1365-2036.2000.00892.x] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AIM To determine whether a 5-day regimen with rabeprazole, clarithromycin and amoxicillin (RCA) was as effective as a 7-day regimen. METHODS A total of 139 H. pylori-infected patients were randomized to receive either a 5-day or 7-day course of rabeprazole 10 mg b.d., clarithromycin 400 mg b.d. and amoxicillin 750 mg b.d. Eradication was assessed by CLO test, histology and 13C-urea breath test. RESULTS On the intention-to-treat basis, eradication rates were 66% (46 out of 70) and 84% (58 out of 69) for the 5- and 7-day regimens, respectively (P < 0.05). Using per protocol analysis, eradication rates were 70% (46 out of 66) and 91% (58 out of 64) for the 5- and 7-day regimens, respectively (P < 0.01). Adverse events, which were observed in 14 patients from each group, caused discontinuation of treatment in only two patients, resulting in excellent compliance. CONCLUSIONS Our 5-day regimen of RCA yielded inferior results, whereas the 7-day regimen achieved an eradication rate exceeding 90% on the per protocol basis. Therefore, treatment regimens of less than 7 days for proton pump inhibitor-clarithromycin-amoxicillin therapies cannot be recommended.
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Affiliation(s)
- H Isomoto
- Second Department of Internal Medicine, Nagasaki University School of Medicine, Nagasaki, Japan.
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Tsutsui N, Taneike I, Ohara T, Goshi S, Kojio S, Iwakura N, Matsumaru H, Wakisaka-Saito N, Zhang HM, Yamamoto T. A novel action of the proton pump inhibitor rabeprazole and its thioether derivative against the motility of Helicobacter pylori. Antimicrob Agents Chemother 2000; 44:3069-73. [PMID: 11036024 PMCID: PMC101604 DOI: 10.1128/aac.44.11.3069-3073.2000] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
The motility of Helicobacter pylori was maximum at 37 degrees C and at pH 6. A newly developed proton pump inhibitor, rabeprazole (RPZ), and its thioether derivative (RPZ-TH) markedly inhibited the motility of H. pylori. The concentrations of the drug necessary to inhibit 50% of the motility were 0.25, 16, 16, and >64 microgram/ml for RPZ-TH, RPZ, lansoprazole, and omeprazole, respectively. No such inhibitory effects were observed with H(2) blockers or anti-H. pylori agents. The motilities of Campylobacter jejuni and C. coli-but not those of Vibrio cholerae O1 and O139, Vibrio parahaemolyticus, Salmonella enterica serovar Typhimurium, and Proteus mirabilis-were also inhibited. Prolonged incubation with RPZ or RPZ-TH inhibited bacterial growth of only H. pylori, except for a turbid colony mutant. The results indicate that RPZ and RPZ-TH have a characteristic inhibitory effect against the motility of H. pylori (spiral-shaped bacteria), which is distinguished from that against bacterial growth.
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Affiliation(s)
- N Tsutsui
- Department of Bacteriology, School of Medicine, Niigata University, 757 Ichibanchou, Niigata, Japan
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Cammarota G, Cianci R, Cannizzaro O, Cuoco L, Pirozzi G, Gasbarrini A, Armuzzi A, Zocco MA, Santarelli L, Arancio F, Gasbarrini G. Efficacy of two one-week rabeprazole/levofloxacin-based triple therapies for Helicobacter pylori infection. Aliment Pharmacol Ther 2000; 14:1339-1343. [PMID: 11012480 DOI: 10.1046/j.1365-2036.2000.00846.x] [Citation(s) in RCA: 125] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND One-week low-dose proton pump inhibitor-based triple therapies have usually proved to be effective treatments for Helicobacter pylori infection. AIM To investigate the eradication efficacy, safety profile and patient compliance of two triple therapies containing a standard dose of rabeprazole and a new fluoroquinolone, levofloxacin. METHODS One hundred patients referred to us for gastroscopy, who were H. pylori-positive, were consecutively recruited in a prospective, open-label study. The enrolled patients were randomised to receive a seven-day course of rabeprazole 20 mg o.d. plus levofloxacin 500 mg o.d. and either amoxycillin 1 g b.d. (RLA group) or tinidazole 500 mg b.d. (RLT group). Their H. pylori status was assessed by means of histology and rapid urease test at entry, and by 13C-urea breath test 8 weeks after the end of treatment. RESULTS All 100 enrolled patients completed the study. Forty-six of 50 patients treated with RLA (both PP and ITT analysis: 92%; 95% CI: 81-98%) and 45 of 50 with RLT (both PP and ITT analysis: 90%: 95% CI: 78-97%), became H. pylori-negative. Slight or mild side-effects occurred in 4 (8%) patients of the RLA group and in 5 (10%) of the RLT group. CONCLUSIONS This study demonstrates the efficacy of two 1-week rabeprazole-based triple therapies including levofloxacin to eradicate H. pylori. These regimens prove to be safe, well-tolerated, and achieved good eradication rates. Levofloxacin may be an effective alternative to clarithromycin in triple therapy regimens.
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Affiliation(s)
- G Cammarota
- Department of Internal Medicine, Catholic University of Rome, Italy.
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34
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Nagahara A, Miwa H, Ogawa K, Kurosawa A, Ohkura R, Iida N, Sato N. Addition of metronidazole to rabeprazole-amoxicillin-clarithromycin regimen for Helicobacter pylori infection provides an excellent cure rate with five-day therapy. Helicobacter 2000; 5:88-93. [PMID: 10849057 DOI: 10.1046/j.1523-5378.2000.00013.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
BACKGROUND New triple therapy for eradication of Helicobacter pylori based on a proton pump inhibitor (PPI) provides a cure rate of approximately 90% with few adverse effects. Recently, a PPI-based quadruple therapy, which consists of a PPI plus bismuth-based triple therapy for 7 days, has been studied, and a sufficient eradication rate has been achieved. However, a shorter duration results in improved compliance. In this study, newly developed short-term, simple twice-daily quadruple therapy consisting of rabeprazole, amoxicillin, clarithromycin, and metronidazole (RACM) was compared with a PPI-based triple-therapy regimen for eradication of H. pylori. PATIENTS AND METHODS This study was designed as a randomized open, prospective single-center study. Of a total of 105 H. pylori-positive patients, 55 received the RACM regimen for 5 days (rabeprazole, 10 mg bid; amoxicillin, 750 mg bid; clarithromycin, 200 mg bid; and metronidazole, 250 mg bid), and 50 received the RAC regimen for 5 days (rabeprazole, 10 mg bid; amoxicillin, 750 mg bid; and clarithromycin, 200 mg bid). Cure of the infection was assessed by HpSA (H. pylori stool antigen immunoassay) 1 month after completion of therapy. RESULTS The rates of eradication of H. pylori by RACM versus RAC were 94.5% (95% CI, 85-99) versus 80.0% (95% CI, 66-90) by intention-to-treat analysis; 98.1% (95% CI, 90-100) versus 87.0% (95% CI, 74-95) by all-patients-treated analysis; and 98.1% (95% CI, 90-100) versus 86.7% (95% CI, 73-95) by per-protocol analysis. No major adverse effects were reported, and 98.0% of patients reported complete compliance. CONCLUSIONS The simple twice-daily and short-term quadruple regimen for only 5 days provided an excellent eradication rate. Compliance with the regimen was high, and serious adverse effects were few. Therefore, the RACM regimen can be considered as safe and effective.
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Affiliation(s)
- A Nagahara
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
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35
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Kawakami Y, Akahane T, Yamaguchi M, Oana K, Takahashi Y, Okimura Y, Okabe T, Gotoh A, Katsuyama T. In vitro activities of rabeprazole, a novel proton pump inhibitor, and its thioether derivative alone and in combination with other antimicrobials against recent clinical isolates of Helicobacter pylori. Antimicrob Agents Chemother 2000; 44:458-61. [PMID: 10639386 PMCID: PMC89707 DOI: 10.1128/aac.44.2.458-461.2000] [Citation(s) in RCA: 42] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The MICs of rabeprazole sodium (RPZ), a newly developed benzimidazole proton pump inhibitor (PPI), against 133 clinical Helicobacter pylori strains revealed a higher degree of activity than the another two PPIs, lansoprazole and omeprazole. Time-kill curve assays of RPZ, when combined with amoxicillin, clarithromycin, or metronidazole, disclosed that synergistic effects were demonstrated in combination with each antibiotic examined. Moreover, no apparent antagonistic effect appeared among all of the strains tested.
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Affiliation(s)
- Y Kawakami
- Division of Clinical Microbiology, Department of Medical Technology, School of Allied Medical Sciences, Shinshu University, Matsumoto, Nagano, Japan
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36
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Robinson M. Review article: current perspectives on hypergastrinaemia and enterochromaffin-like-cell hyperplasia. Aliment Pharmacol Ther 1999; 13 Suppl 5:5-10. [PMID: 10555603 DOI: 10.1046/j.1365-2036.1999.00033.x] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Rabeprazole, a new benzimidazole proton pump inhibitor (PPI), is among a class of agents known to be very potent inhibitors of gastric acid secretion. PPIs inhibit hydrogen-potassium adenosine triphosphatase activity on the luminal surface of the parietal cell, effectively blocking the final common pathway for gastric acid secretion. Raising gastric pH stimulates the production of gastrin by G cells in the antrum of the stomach, which can lead to enterochromaffin-like (ECL)-cell hyperplasia. In the past, these changes have been viewed with concern, particularly in the light of studies in rats indicating that hypergastrinaemia and ECL-cell hyperplasia induce gastric carcinoid tumour formation. All available clinical data indicate that long-term PPI use does not lead to carcinoid tumour formation in humans. In fact, both serum gastrin elevation and ECL-cell hyperplasia are now generally viewed as normal physiological responses to gastric acid suppression. Serum gastrin concentrations, in particular, correlate well with gastric acid suppression, which has led to the use of gastrin response by some investigators as a surrogate marker of antisecretory effectiveness. Long-term tolerability data indicate that PPIs have a favourable side-effect profile. Data obtained from patients receiving acute or long-term maintenance rabeprazole therapy support this conclusion. Furthermore, neither animal nor human data obtained with rabeprazole suggest a significant risk for neoplastic changes secondary to hypergastrinaemia.
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Affiliation(s)
- M Robinson
- University of Oklahoma College of Medicine, Oklahoma Foundation for Digestive Research, Oklahoma City, USA.
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37
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Abstract
Rabeprazole is an inhibitor of the gastric proton pump. It causes dose-dependent inhibition of acid secretion and has a more rapid onset of action than omeprazole. Duodenal ulcers healed faster after treatment with rabeprazole 20 or 40 mg/day than placebo or ranitidine 150 mg 4 times daily and at a generally similar rate to omeprazole 20 mg/day in patients with duodenal ulcers; rabeprazole was similar or superior to these agents in relieving symptoms. Rabeprazole 20 and 40 mg/day healed gastric ulcers faster than placebo, and rabeprazole 20 mg/day healed ulcers at a similar healing rate, to omeprazole 20 mg/day in well controlled 6-week studies. Gastric ulcer symptom relief with rabeprazole was similar or superior to that provided by omeprazole or placebo. In 8-week studies in patients with gastro-oesophageal reflux disease (GERD), rabeprazole 10, 20 and 40 mg/day were more effective than placebo, rabeprazole 20 mg/day was more effective than ranitidine 150 mg twice daily, and rabeprazole 20 mg/day was similar in efficacy to omeprazole 20 mg/day. Symptom relief with rabeprazole in 8-week trials in patients with GERD was superior to that provided by placebo, and similar to ranitidine or omeprazole. Rabeprazole was similar to omeprazole and superior to placebo in both maintenance of healing and prevention of symptoms in patients with healed GERD in 1-year studies. One-week triple therapy with rabeprazole 20 mg twice daily plus 2 antibacterial agents achieved > or = 90% Helicobacter pylori eradication, but, as would be expected, a regimen of rabeprazole 20 mg twice daily plus 1 antibacterial agent was less successful. The drug was as effective as omeprazole and lansoprazole as part of triple therapy for H. pylori eradication. Rabeprazole successfully reduced acid output to target levels and prevented further pathological changes in 10 patients with Zollinger-Ellison syndrome. Usual dosages of rabeprazole are 20 mg/day for 4 weeks to treat duodenal ulcers, 6 weeks for gastric ulcers and 8 weeks for GERD, although some patients with duodenal ulcer may respond to a 10 mg/day dosage. For long term maintenance of GERD healing, 10 or 20 mg daily doses are adequate. Patients with hypersecretory states may need individualised dosages starting at 60 mg/day. The drug was well tolerated in clinical trials, with headache, rash, infection, diarrhoea and flu syndrome as the most common adverse events. In conclusion, rabeprazole appears to be a well tolerated proton pump inhibitor with a rapid onset of action and a low potential for drug interactions. The drug may be used to achieve healing and the relief of symptoms of duodenal ulcer, gastric ulcer and GERD, maintain GERD healing, and can form part of effective regimens to eradicate H. pylori.
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Affiliation(s)
- H D Langtry
- Adis International Limited, Auckland, New Zealand.
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38
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Abstract
Rabeprazole sodium is a new substituted benzimidazole proton pump inhibitor with several differences compared with existing proton pump inhibitors. In vitro and animal studies have demonstrated that rabeprazole is a more potent inhibitor of H+,K(+)-ATPase and acid secretion than omeprazole, and is a more rapid inhibitor of proton pumps than omeprazole, lansoprazole, or pantoprazole. This probably reflects rabeprazole's faster activation in the parietal cell canaliculus. In human studies, once-daily doses of 5-40 mg of rabeprazole inhibit gastric acid secretion in a dose-dependent fashion. A once-daily dose of 20 mg has consistently achieved profound decreases in 24-h intragastric acidity in single and repeat dosing studies, in healthy volunteers and patients with either peptic ulcer disease or gastro-oesophageal reflux disease. Significantly greater decreases in intragastric acidity are achieved on day 1 of dosing with rabeprazole 20 mg than with omeprazole 20 mg. As with other proton pump inhibitors, rabeprazole has in vitro antibacterial activity against Helicobacter pylori, with greater activity against this organism than either lansoprazole or omeprazole. In addition to inhibiting bacterial urease activity, rabeprazole binds to several molecules on H. pylori. Clinical trials are needed to assess the clinical importance of these findings, as well as to assess whether the potential advantages of rabeprazole result in clinical benefit for patients with acid-related diseases.
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Affiliation(s)
- M P Williams
- Department of Medicine, Royal Free Hospital, London, UK
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39
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Miwa H, Ohkura R, Murai T, Sato K, Nagahara A, Hirai S, Watanabe S, Sato N. Impact of rabeprazole, a new proton pump inhibitor, in triple therapy for Helicobacter pylori infection-comparison with omeprazole and lansoprazole. Aliment Pharmacol Ther 1999; 13:741-6. [PMID: 10383502 DOI: 10.1046/j.1365-2036.1999.00526.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
BACKGROUND A recent trend in curative therapy for Helicobacter pylori infection is the so-called triple therapy, which consists of a proton pump inhibitor (PPI) and two different antimicrobials. Various regimens employing this triple therapy have been reported. However, little is known about the effectiveness of rabeprazole, a recently developed proton pump inhibitor, when used in the triple therapy. AIM To validate its usefulness by comparing rabeprazole with omeprazole and lansoprazole, in combination with amoxycillin and clarithromycin. PATIENTS AND METHODS 221 H. pylori-positive patients with peptic ulcer disease were randomized to receive one of three different proton pump inhibitor/amoxycillin-clarithromycin (PPI/AC) regimens for 7 days. (i) OAC regimen (n = 75): omeprazole 20 mg b.d., amoxycillin (AMOX) 500 mg t.d.s. and clarithromycin (CAM) 200 mg b.d.; (ii) LAC regimen (n = 74): lansoprazole 30 mg b.d. , AMOX 500 mg t.d.s. and CAM 200 mg b.d.; and (iii) RAC regimen (n = 72): rabeprazole 20 mg b.d., AMOX 500 mg t.d.s. and CAM 200 mg b.d. Cure of the infection was determined by the 13C urea breath test 1 month after completion of the treatment. RESULTS Intention-to-treat based cure rates for OAC, LAC and RAC regimens were 85% (95% CI, 75-92), 84% (95%, CI 73-91) and 88% (95% CI, 78-94), respectively, and per protocol based cure rates of these regimens were 88% (95% CI, 78-94), 91% (95%, CI 82-99) and 93% (95% CI, 84-98), respectively. Adverse effects in the entire study population, which included diarrhoea, glossitis or skin rash, were reported by 15% of the patients, and complete compliance was achieved in 95% of these patients. CONCLUSION 1-week proton pump inhibitor/AC regimens for H. pylori infection were effective in the Japanese population. Rabeprazole can be considered as equivalent to omeprazole and lansoprazole in the PPI/AC triple therapy.
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Affiliation(s)
- H Miwa
- Department of Gastroenterology, Juntendo University, School of Medicine, Tokyo, Japan
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Lew EA, Barbuti RC, Kovacs TO, Sytnic B, Humphries TJ, Walsh JH. An ascending single-dose safety and tolerance study of an oral formulation of rabeprazole (E3810). Aliment Pharmacol Ther 1998; 12:667-72. [PMID: 9701531 DOI: 10.1046/j.1365-2036.1998.00356.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Proton pump inhibitors such as omeprazole produce a long-lasting inhibition of gastric acid secretion associated with significant increases in plasma gastrin. Rabeprazole (E3810) is a new substituted benzimidazole H+,K+ ATPase inhibitor. It acts as an irreversible, non-competitive inhibitor of the H+,K+ ATPase and preliminary studies demonstrate that rabeprazole produces a potent and long-lasting inhibition of gastric acid secretion and a low level of hypergastrinaemia. AIM This randomized, double-blind, placebo-controlled study was performed to further examine the effects of different single doses of rabeprazole on gastric acid secretion and serum gastrin. METHODS In this study, four groups of 10 healthy, non-smoking Helicobacter pylori-negative men (mean age 22.5 +/- 3.9 years) received single oral doses of 10, 20, 30 and 40 mg of rabeprazole. Two of the 10 volunteers in each group received placebo as part of the double-blind study design. All volunteers who entered into the study had a normal gastric acid secretory capacity as evaluated by pentagastrin challenge. Prior to administration of the first dose of test drug, volunteers underwent an inpatient 24-h measurement of baseline intragastric pH. One week later, volunteers received the test drug and again underwent an inpatient 24-h measurement of intragastric pH. During both periods, plasma samples were collected at specified intervals over 48 h and were sent for analysis of rabeprazole and gastrin levels. RESULTS Administration of rabeprazole resulted in a dose-dependent increase in the duration and extent of intragastric pH elevation. The response among all volunteers receiving drug was significantly different from placebo, with greater acid inhibition occurring in the 30 and 40 mg groups. In addition, there was also a dose-related increase in plasma gastrin. The pharmacokinetics of rabeprazole were similar to those of other proton pump inhibitors with a t1/2 of between 0.7 and 1.0 h. There were no clinically significant effects on patient laboratory tests or serious adverse events. CONCLUSIONS The results of this study suggest that rabeprazole is as potent as omeprazole and lansoprazole in inhibiting gastric acid secretion.
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Affiliation(s)
- E A Lew
- CURE/UCLA/Digestive Disease Research Center, Department of Medicine, West Los Angeles Veterans Administration Medical Center, Los Angeles, CA 90073, USA
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Abstract
Rabeprazole is a proton pump inhibitor with antisecretory properties. In vitro animal experiments have indicated that the inhibition of the proton pump by rabeprazole is partially reversible. Rabeprazole has 2- to 10-fold greater antisecretory activity than omeprazole in vitro. However, it dissociates more readily from H+,K(+)-ATPase than omeprazole, resulting in a shorter duration of action. In comparative clinical trials rabeprazole was significantly more effective than placebo, famotidine or ranitidine and as effective as omeprazole in the treatment of patients with erosive or ulcerative gastro-oesophageal reflux disease or gastric or duodenal ulcers. Healing rates with rabeprazole were independent of Helicobacter pylori status. Rabeprazole in combination with either clarithromycin and metronidazole or clarithromycin and amoxicillin or amoxicillin and metronidazole or clarithromycin for 7 days produced eradication of H. pylori in 100, 95, 90 and 63% of patients. The tolerability profile of rabeprazole 20mg once daily was similar to that of famotidine 20mg twice daily, ranitidine 150mg 4 times daily or omeprazole 20mg once daily in comparative trials. The adverse events reported with once daily administration of rabeprazole 20mg include malaise, nausea, diarrhoea, headache, dizziness and skin eruptions in 0.7 to 2.2% of patients.
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Affiliation(s)
- A Prakash
- Adis International Limited, Auckland, New Zealand.
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42
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Anti-Helicobacter pylori effect of costunolide isolated from the stem bark ofMagnolia sieboldii. Arch Pharm Res 1997; 20:275-9. [DOI: 10.1007/bf02976157] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/1997] [Indexed: 10/21/2022]
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