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Kang MK, Shin JH, Kim TJ, Lee JS, Yoon BW, Ko SB. Use of proton pump inhibitor may be associated with progression of cerebral small vessel disease. PLoS One 2022; 17:e0279257. [PMID: 36542643 PMCID: PMC9770424 DOI: 10.1371/journal.pone.0279257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
Proton pump inhibitors (PPIs) are widely used for the treatment of gastrointestinal diseases. However, recent studies have shown that chronic PPI use is associated with the progression of endothelial senescence and cerebrovascular diseases. We hypothesized that PPI users might be vulnerable to fast progression of cerebral small vessel disease (SVD) with cumulative effects. Four hundred and eleven patients, who underwent brain magnetic resonance imaging, more than twice between January 2010 and December 2016 were screened. Patients aged < 50 years, and those who had concomitant diseases that might affect the progression of cerebral SVD were excluded. Baseline characteristics were collected. We evaluated the severity of SVD using the Fazekas score, the number of cerebral microbleeds (CMBs), and assessed the progression of SVD or CMBs based on the cumulative dose of PPIs. Among the included patients (N = 137), 39 were PPI ever-users. Univariate Cox regression analysis showed that PPI use was independently associated with the progression of Fazekas score only in the deep white matter hyperintensities (WMH) (hazard ratio [HR] 2.891, 95% confidence interval [CI] 1.210-6.906, P = 0.017). In multivariate Cox regression analysis, long-term PPI use was associated with a progression of Fazekas score in the deep WMH (HR 3.453, 95% CI 1.027-9.475, P = 0.045). However, PPI use was not associated with the progression of CMB. The present study results suggest that long-term use of PPIs is associated with the progression of deep cerebral WMH. Further research is needed using a large number of patients to validate this relationship.
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Affiliation(s)
- Min Kyoung Kang
- Department of Neurology, Uijeongbu Eulji Medical Center, Uijeongbu, Gyeonggi, Republic of Korea
| | - Jung Hwan Shin
- Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Tae Jung Kim
- Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Ji Sung Lee
- Clinical Research Center, Asan Medical Center, Seoul, Republic of Korea
| | - Byung-Woo Yoon
- Department of Neurology, Uijeongbu Eulji Medical Center, Uijeongbu, Gyeonggi, Republic of Korea
| | - Sang-Bae Ko
- Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Neurology, Seoul National University College of Medicine, Seoul, Republic of Korea
- * E-mail:
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Thongon N, Chamniansawat S. Hippocampal synaptic dysfunction and spatial memory impairment in omeprazole-treated rats. Metab Brain Dis 2022; 37:2871-2881. [PMID: 36181652 DOI: 10.1007/s11011-022-01088-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 09/13/2022] [Indexed: 10/07/2022]
Abstract
Although the association of prolonged use of proton pump inhibitors, such as omeprazole, with memory impairment has been reported more than two decades ago, its underlying molecular mechanism is yet to be determined. Thus, in this study, we aimed to determine the mechanisms underlying the effect of prolonged omeprazole treatment on hippocampal synaptic function and spatial memory in male rats. Adult rats were subcutaneously administered with omeprazole for 12 or 24 weeks. Spatial memory was assessed using the Morris water maze (MWM) test. We examined the hippocampal protein expression of synaptic plasticity proteins, including the AMPA receptor subunit GluA1, postsynaptic density-95 (PSD-95), and activity-regulated cytoskeleton-associated protein (Arc), and the hippocampal expression and localization of androgen receptor (AR). In the MWM test, the escape latency was found to be significantly higher, and the number of platform crossings and the time spent in the target quadrant were significantly lower in the rats treated with omeprazole compared to the control rats. Hypomagnesemia and lower bone and brain Mg2+ content were also detected in the omeprazole-treated groups compared with the control group. The expression of GluA1, PSD-95, and Arc in the hippocampus and the expression of AR in the dentate gyrus and CA1 of the hippocampus were significantly lower in the omeprazole-treated groups than in the control group. These results suggest that prolonged omeprazole treatment might lead to memory deficit by impairing glutamate receptor trafficking or synaptic anchoring. Hypomagnesemia and brain Mg2+ deficiency may be, at least in part, involved in omeprazole-induced memory impairment.
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Affiliation(s)
- Narongrit Thongon
- Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Road, SaenSook Sub-district, Mueang District, 20131, Chonburi, Thailand
| | - Siriporn Chamniansawat
- Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Road, SaenSook Sub-district, Mueang District, 20131, Chonburi, Thailand.
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Lim IH, Lee SJ, Shin BS, Kang HG. Ilaprazole and Clopidogrel Resistance in Acute Stroke Patients. Biomedicines 2022; 10:biomedicines10061366. [PMID: 35740386 PMCID: PMC9219695 DOI: 10.3390/biomedicines10061366] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/30/2022] [Accepted: 06/06/2022] [Indexed: 01/01/2023] Open
Abstract
Clopidogrel, an antiplatelet agent used for secondary prevention of cerebrovascular diseases, is often taken with proton pump inhibitors (PPIs). Generally, the combined use of clopidogrel and PPIs causes adverse drug–drug interactions. VerifyNow is a quick and convenient method to confirm clopidogrel resistance (CR), which compromises adequate antithrombotic effects. We aimed to confirm CR, identify its factors, and determine the influence of the combination of ilaprazole and clopidogrel on clopidogrel using VerifyNow. In this retrospective study, we examined patients who were receiving clopidogrel after three months, starting within one week from the onset of cerebral infarction symptoms. Clinical records, imaging records, and diagnostic laboratory results, including P2Y12 reaction units (PRU), were compared and analyzed to check for CR. Additionally, the groups treated with either both ilaprazole and clopidogrel or with medications other than ilaprazole were comparatively analyzed. CR was defined as a PRU ≥240 after clopidogrel for three months. Among factors influencing CR by affecting clopidogrel metabolism, positive statistical correlations with age and alcohol consumption were confirmed. The diagnostic tests revealed a lower glomerular filtration rate and platelet count of the CR-positive group. This finding proved that the combination therapy of ilaprazole and clopidogrel is safe, as it does not interfere with the metabolism of clopidogrel.
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Affiliation(s)
- In Hwan Lim
- Department of Pharmacology, School of Medicine, Wonkwang University, Iksan 54538, Korea;
| | - Seung Jae Lee
- Department of Chemistry, Institute for Molecular Biology and Genetics, Jeonbuk National University, Jeonju 54907, Korea;
| | - Byoung-Soo Shin
- Department of Neurology, Jeonbuk National University, Jeonju 54907, Korea;
- Research Institute of Clinical Medicine, Jeonbuk National University, Jeonju 54907, Korea
- Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Korea
| | - Hyun Goo Kang
- Department of Neurology, Jeonbuk National University, Jeonju 54907, Korea;
- Research Institute of Clinical Medicine, Jeonbuk National University, Jeonju 54907, Korea
- Biomedical Research Institute, Jeonbuk National University Medical School and Hospital, Jeonju 54907, Korea
- Correspondence: ; Tel.: +82-63-250-1590
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Xu LY, Yu BY, Cen LS. New treatment for gastroesophageal reflux disease: Traditional Chinese medicine Xiaochaihu decoction. World J Gastroenterol 2022; 28:1184-1186. [PMID: 35431502 PMCID: PMC8985483 DOI: 10.3748/wjg.v28.i11.1184] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 09/17/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
Gastroesophageal reflux disease (GERD) has a high prevalence worldwide. Li et al performed a well-designed study on the efficacy of modified Xiaochaihu decoction (MXD) for GERD, which showed that MXD is an optional therapy for GERD beyond proton pump inhibitors (PPIs). The herbal granule administration mode minimized the bias from traditional herbal formula in clinical trials. One limitation of that study was that it lacked records of side effects and rescue medication. As a chronic disease with recurrent symptoms, GERD rehabilitation requires prolonged observation of the clinical course with MXD therapy.
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Affiliation(s)
- Li-Ying Xu
- Department of Emergency Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
| | - Bin-Yan Yu
- Department of Acupuncture and Moxibustion, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
| | - Lu-Sha Cen
- Department of Ophthalmology, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou 310006, Zhejiang Province, China
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Sanad MH, Eyssa HM, Marzook FA, Farag AB, Rizvi SFA, Mandal SK, Patnaik SS, Fouzy ASM. Optimized Chromatographic Separation and Bioevalution of Radioiodinated Ilaprazole as a New Labeled Compound for Peptic Ulcer Localization in Mice. RADIOCHEMISTRY 2022. [DOI: 10.1134/s1066362221060138] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Wilson JA, Stocken DD, Watson GC, Fouweather T, McGlashan J, MacKenzie K, Carding P, Karagama Y, Harries M, Ball S, Khwaja S, Costello D, Wood R, Lecouturier J, O'Hara J. Lansoprazole for persistent throat symptoms in secondary care: the TOPPITS RCT. Health Technol Assess 2021; 25:1-118. [PMID: 33492208 PMCID: PMC7869007 DOI: 10.3310/hta25030] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Persistent throat symptoms are commonly attributed to 'laryngopharyngeal reflux'. Despite a limited evidence base, these symptoms are increasingly being treated in primary care with proton pump inhibitors. OBJECTIVE To assess the value of proton pump inhibitor therapy in patients with persistent throat symptoms. DESIGN This was a double-blind, placebo-controlled, randomised Phase III trial. SETTING This was a multicentre UK trial in eight UK ear, nose and throat departments. PARTICIPANTS A total of 346 participants aged ≥ 18 years with persistent throat symptoms and a Reflux Symptom Index score of ≥ 10, exclusive of the dyspepsia item, were recruited. INTERVENTION Random allocation (1 : 1 ratio) to either 30 mg of lansoprazole twice daily or matched placebo for 16 weeks. MAIN OUTCOME MEASURE Symptomatic response (i.e. total Reflux Symptom Index score after 16 weeks of therapy). RESULTS A total of 1427 patients were screened and 346 were randomised. The mean age was 52 years (standard deviation 13.7 years, range 20-84 years); 150 (43%) participants were male and 196 (57%) were female; 184 (53%) participants had a mild Reflux Symptom Index minus the heartburn/dyspepsia item and 162 (47%) had a severe Reflux Symptom Index minus the heartburn/dyspepsia item. A total of 172 patients were randomised to lansoprazole and 174 were randomised to placebo. MAIN OUTCOMES A total of 267 participants completed the primary end-point visit (lansoprazole, n = 127; placebo, n = 140), of whom 220 did so between 14 and 20 weeks post randomisation ('compliant' group); 102 received lansoprazole and 118 received placebo. The mean Reflux Symptom Index scores at baseline were similar [lansoprazole 22.0 (standard deviation 8.0), placebo 21.7 (standard deviation 7.1), overall 21.9 (standard deviation 7.5)]. The mean Reflux Symptom Index scores at 16 weeks reduced from baseline in both groups [overall 17.4 (standard deviation 9.9), lansoprazole 17.4 (standard deviation 9.9), placebo 15.6 (standard deviation 9.8)]. Lansoprazole participants had estimated Reflux Symptom Index scores at 16 weeks that were 1.9 points higher (worse) than those of placebo participants (95% confidence interval -0.3 to 4.2; padj = 0.096), adjusted for site and baseline severity. SECONDARY OUTCOMES Ninety-five (43%) participants achieved a Reflux Symptom Index score in the normal range (< 12) at 16 weeks: 42 (41%) in the lansoprazole group and 53 (45%) in the placebo group. A total of 226 participants completed the end-of-trial follow-up visit (lansoprazole, n = 109; placebo, n = 117), of whom 181 were 'compliant'. The mean Reflux Symptom Index scores at 12 months reduced from baseline in both groups [lansoprazole 16.0 (standard deviation 10.8), placebo 13.6 (standard deviation 9.6), overall 14.7 (standard deviation 10.2)]. A total of 87 (48%) participants achieved a Reflux Symptom Index score in the normal range at 12 months: 33 (40%) in the lansoprazole group and 54 (55%) in the placebo group. Likewise, the Comprehensive Reflux Symptom Score and Laryngopharyngeal Reflux - Health Related Quality of Life total scores and subscales all showed very similar changes in the lansoprazole and placebo cohorts at both 16 weeks and 12 months. LIMITATIONS Drop-out rate and compliance are issues in pragmatic clinical trials. The Trial Of Proton Pump Inhibitors in Throat Symptoms (TOPPITS) aimed to detect clinically relevant difference with 90% power. The 346 randomised participants reduced to 283 at the primary end point; 267 completed the primary outcome measure, 220 within the protocol time scale. Despite this, the powers to detect the clinically relevant difference in Reflux Symptom Index score at 16 weeks were 82% (compliant comparison) and 89% (pragmatic comparison). The lack of difference between lansoprazole and placebo is generalisable across NHS clinics. CONCLUSIONS Participants on lansoprazole did not report significantly better outcomes than participants on placebo on any of the three patient-reported outcome tools (Reflux Symptom Index, Comprehensive Reflux Symptom Score and Laryngopharyngeal Reflux - Health Related Quality of Life). This multicentre, pragmatic, powered, definitive Phase III trial found no evidence of benefit for patients by treating persistent throat symptoms with lansoprazole. TRIAL REGISTRATION Current Controlled Trials ISRCTN38578686 and EudraCT number 2013-004249-17. FUNDING This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 3. See the NIHR Journals Library website for further project information.
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Affiliation(s)
- Janet A Wilson
- Ear, Nose and Throat Department, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
- Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
| | - Deborah D Stocken
- Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
| | - Gillian C Watson
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Tony Fouweather
- Biostatistics Research Group, Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
| | - Julian McGlashan
- Ear, Nose and Throat Department, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Kenneth MacKenzie
- Ear, Nose and Throat Department, NHS Greater Glasgow and Clyde, Glasgow, UK
| | - Paul Carding
- Oxford Institute of Nursing, Midwifery and Allied Health Research, Oxford Brookes University, Oxford, UK
| | - Yakubu Karagama
- Ear, Nose and Throat Department, Manchester University NHS Foundation Trust, Manchester, UK
| | - Meredydd Harries
- Ear, Nose and Throat Department, Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
| | - Stephen Ball
- Ear, Nose and Throat Department, City Hospitals Sunderland NHS Foundation Trust, Sunderland, UK
| | - Sadie Khwaja
- Ear, Nose and Throat Department, Stockport NHS Foundation Trust, Stockport, UK
| | - Declan Costello
- Ear, Nose and Throat Department, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK
| | - Ruth Wood
- Newcastle Clinical Trials Unit, Newcastle University, Newcastle upon Tyne, UK
| | - Jan Lecouturier
- Institute of Health and Society, Newcastle University, Newcastle upon Tyne, UK
| | - James O'Hara
- Ear, Nose and Throat Department, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
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PAŞALI KİLİT T, ONBAŞI K, ÖZYİĞİT F. Treatment Adherence Levels and Factors Affecting Adherence in Patients Receiving Osteoporosis Treatment. CLINICAL AND EXPERIMENTAL HEALTH SCIENCES 2020. [DOI: 10.33808/clinexphealthsci.533942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
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Leonov KA, Vishenkova DA, Bykov VV, Bakibaev AA. Determination of a New Antiulcer Drug in Rat Blood Plasma by Liquid Chromatography–Mass Spectrometry. JOURNAL OF ANALYTICAL CHEMISTRY 2019. [DOI: 10.1134/s1061934819140089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Khan S, Boateng J. Effects of Cyclodextrins (β and γ) and l-Arginine on Stability and Functional Properties of Mucoadhesive Buccal Films Loaded with Omeprazole for Pediatric Patients. Polymers (Basel) 2018; 10:E157. [PMID: 30966193 PMCID: PMC6415044 DOI: 10.3390/polym10020157] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2018] [Revised: 01/31/2018] [Accepted: 02/02/2018] [Indexed: 12/19/2022] Open
Abstract
Omeprazole (OME) is employed for treating ulcer in children, but is unstable and exhibits first pass metabolism via the oral route. This study aimed to stabilize OME within mucoadhesive metolose (MET) films by combining cyclodextrins (CD) and l-arginine (l-arg) as stabilizing excipients and functionally characterizing for potential delivery via the buccal mucosa of paediatric patients. Polymeric solutions at a concentration of 1% w/w were obtained by dispersing the required weight of metolose in 20% v/v ethanol as solvent at a temperature of 40 °C using polyethylene glycol (PEG 400) (0.5% w/w) as plasticizer. The films were obtained by drying the resulting polymer solutions at in an oven at 40 °C. Textural (tensile and mucoadhesion) properties, physical form (differential scanning calorimetry (DSC), X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy), residual moisture content (thermogravimetric analysis (TGA)) and surface morphology (scanning electron microscopy (SEM)) were investigated. Optimized formulations containing OME, CDs (β or γ) and l-arg (1:1:1) were selected to investigate the stabilization of the drug. The DSC, XRD, and FTIR showed possible molecular dispersion of OME in metolose film matrix. Plasticized MET films containing OME:βCD:l-arg 1:1:1 were optimum in terms of transparency and ease of handling and therefore further functionally characterized (hydration, mucoadhesion, in vitro drug dissolution and long term stability studies). The optimized formulation showed sustained drug release that was modelled by Korsmeyer⁻Peppas equation, while the OME showed stability under ambient temperature conditions for 28 days. The optimized OME loaded MET films stabilized with βCD and l-arg have potential for use as paediatric mucoadhesive buccal delivery system, which avoids degradation in the stomach acid as well as first pass metabolism in the liver.
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Affiliation(s)
- Sajjad Khan
- Department of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich at Medway, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
| | - Joshua Boateng
- Department of Pharmaceutical, Chemical and Environmental Sciences, Faculty of Engineering and Science, University of Greenwich at Medway, Central Avenue, Chatham Maritime, Kent ME4 4TB, UK.
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Aragão TP, Prazeres LDKTD, Brito SA, Neto PJR, Rolim LA, Almeida JRGDS, Caldas GFR, Wanderley AG. Contribution of Secondary Metabolites to the Gastroprotective Effect of Aqueous Extract of Ximenia americana L. (Olacaceae) Stem Bark in Rats. Molecules 2018; 23:E112. [PMID: 29315228 PMCID: PMC6017445 DOI: 10.3390/molecules23010112] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 12/27/2017] [Accepted: 01/04/2018] [Indexed: 02/07/2023] Open
Abstract
Ximenia americana L. (Olacaceae) is used in ethnomedicine as cicatrizant and for the treatment of gastric disorders. This study identified the chemical constituents of the aqueous extract of X. americana (XaAE) and evaluated its antiulcerogenic activity. After lyophilization, XaAE was analyzed by liquid chromatography-mass spectrometry (LC-MS) and its antiulcerogenic effect was evaluated in acute gastric lesions induced by ethanol, acidified ethanol, and indomethacin. Antisecretory action, mucus production and the participation of sulfhydryl groups (-SH) and nitric oxide (NO) were also investigated. The chromatographic analysis identified procyanidins B and C and catechin/epicatechin as major compounds. Oral administration of XaAE (100, 200 and 400 mg/kg) inhibited the gastric lesions induced by ethanol (76.1%, 77.5% and 100%, respectively), acidified ethanol (44.9%, 80.6% and 94.9%, respectively) and indomethacin (56.4%, 52.7% and 64.9%, respectively). XaAE reduced gastric contents and acidity (51.4% and 67.7%, respectively) but did not alter the production of gastric mucus. The reduction of the -SH and NO groups promoted by N-ethylmaleimide (NEM) and Nω-nitro-l-arginine-methyl-ester (L-NAME) respectively, reduced the gastroprotective effect of XaAE. In conclusion, XaAE has gastroprotective activity mediated in part by -SH, NO and antisecretory activity. This antiulcer action was initially correlated to its major constituents, procyanidins B and C and catechin/epicatechin.
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Affiliation(s)
- Ticiana Parente Aragão
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife 50740-521, PE, Brazil.
- Department of Nutrition, University of Pernambuco, Petrolina 56328-903, PE, Brazil.
| | | | - Samara Alves Brito
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife 50740-521, PE, Brazil.
| | - Pedro José Rolim Neto
- Laboratory of Medication Technology, Federal University of Pernambuco, Recife 50740-521, PE, Brazil.
| | - Larissa Araújo Rolim
- Central of Analysis of Drugs, Medicines and Food, Federal University of San Francisco Valley, Petrolina 56304-205, PE, Brazil.
| | | | - Germana Freire Rocha Caldas
- Graduate Program in Health Sciences, Biological and Health Sciences Center, Federal University of Maranhão, São Luís 65080-805, MA, Brazil.
| | - Almir Gonçalves Wanderley
- Department of Pharmaceutical Sciences, Federal University of Pernambuco, Recife 50740-521, PE, Brazil.
- Department of Physiology and Pharmacology, Federal University of Pernambuco, Recife 50670-901, PE, Brazil.
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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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Tommasi S, Elliot DJ, Hulin JA, Lewis BC, McEvoy M, Mangoni AA. Human dimethylarginine dimethylaminohydrolase 1 inhibition by proton pump inhibitors and the cardiovascular risk marker asymmetric dimethylarginine: in vitro and in vivo significance. Sci Rep 2017; 7:2871. [PMID: 28588208 PMCID: PMC5460274 DOI: 10.1038/s41598-017-03069-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 04/20/2017] [Indexed: 12/20/2022] Open
Abstract
Proton pump inhibitor (PPI)-induced inhibition of dimethylarginine dimethylaminohydrolase 1 (DDAH1), with consequent accumulation of the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), might explain the increased cardiovascular risk with PPI use. However, uncertainty exists regarding whether clinical PPI concentrations significantly inhibit DDAH1 under linear initial rate conditions, and whether PPI-induced DDAH1 inhibition significantly increases ADMA in humans. DDAH1 inhibition by esomeprazole, omeprazole, pantoprazole, lansoprazole and rabeprazole was determined by quantifying DDAH1-mediated L-citrulline formation in vitro. Plasma ADMA was measured in PPI users (n = 134) and non-users (n = 489) in the Hunter Community Study (HCS). At clinical PPI concentrations (0.1–10 μmol/L), DDAH1 retained >80% activity vs. baseline. A significant, reversible, time-dependent inhibition was observed with lansoprazole (66% activity at 240 min, P = 0.034) and rabeprazole (25% activity at 240 min, P < 0.001). In regression analysis, PPI use was not associated with ADMA in HCS participants (beta 0.012, 95% CI −0.001 to 0.025, P = 0.077). Furthermore, there were no differences in ADMA between specific PPIs (P = 0.748). At clinical concentrations, PPIs are weak, reversible, DDAH1 inhibitors in vitro. The lack of significant associations between PPIs and ADMA in HCS participants questions the significance of DDAH1 inhibition as a mechanism explaining the increased cardiovascular risk reported with PPI use.
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Affiliation(s)
- S Tommasi
- Department of Clinical Pharmacology, School of Medicine, Flinders University and Flinders Medical Centre, Adelaide, Australia
| | - D J Elliot
- Department of Clinical Pharmacology, School of Medicine, Flinders University and Flinders Medical Centre, Adelaide, Australia
| | - J A Hulin
- Department of Clinical Pharmacology, School of Medicine, Flinders University and Flinders Medical Centre, Adelaide, Australia
| | - B C Lewis
- Department of Clinical Pharmacology, School of Medicine, Flinders University and Flinders Medical Centre, Adelaide, Australia.,Flinders Centre for Innovation in Cancer, School of Medicine, Flinders University, Adelaide, Australia
| | - M McEvoy
- Centre for Clinical Epidemiology & Biostatistics, Hunter Medical Research Institute, University of Newcastle, Newcastle, Australia
| | - A A Mangoni
- Department of Clinical Pharmacology, School of Medicine, Flinders University and Flinders Medical Centre, Adelaide, Australia.
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Pello Lázaro AM, Cristóbal C, Franco-Peláez JA, Tarín N, Aceña Á, Carda R, Huelmos A, Martín-Mariscal ML, Fuentes-Antras J, Martínez-Millá J, Alonso J, Lorenzo Ó, Egido J, López-Bescós L, Tuñón J. Use of Proton-Pump Inhibitors Predicts Heart Failure and Death in Patients with Coronary Artery Disease. PLoS One 2017; 12:e0169826. [PMID: 28103324 PMCID: PMC5245803 DOI: 10.1371/journal.pone.0169826] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 12/22/2016] [Indexed: 12/11/2022] Open
Abstract
OBJECTIVES Proton-pump inhibitors (PPIs) seem to increase the incidence of cardiovascular events in patients with coronary artery disease (CAD), mainly in those using clopidogrel. We analysed the impact of PPIs on the prognosis of patients with stable CAD. METHODS We followed 706 patients with CAD. Primary outcome was the combination of secondary outcomes. Secondary outcomes were 1) acute ischaemic events (any acute coronary syndrome, stroke, or transient ischaemic attack) and 2) heart failure (HF) or death. RESULTS Patients on PPIs were older [62.0 (53.0-73.0) vs. 58.0 (50.0-70.0) years; p = 0.003] and had a more frequent history of stroke (4.9% vs. 1.1%; p = 0.004) than those from the non-PPI group, and presented no differences in any other clinical variable, including cardiovascular risk factors, ejection fraction, and therapy with aspirin and clopidogrel. Follow-up was 2.2±0.99 years. Seventy-eight patients met the primary outcome, 53 developed acute ischaemic events, and 33 HF or death. PPI use was an independent predictor of the primary outcome [hazard ratio (HR) = 2.281 (1.244-4.183); p = 0.008], along with hypertension, body-mass index, glomerular filtration rate, atrial fibrillation, and nitrate use. PPI use was also an independent predictor of HF/death [HR = 5.713 (1.628-20.043); p = 0.007], but not of acute ischaemic events. A propensity score showed similar results. CONCLUSIONS In patients with CAD, PPI use is independently associated with an increased incidence of HF and death but not with a high rate of acute ischaemic events. Further studies are needed to confirm these findings.
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Affiliation(s)
| | - Carmen Cristóbal
- Department of Cardiology, Hospital de Fuenlabrada, Madrid, Spain
- Rey Juan Carlos University, Alcorcón, Madrid, Spain
| | | | - Nieves Tarín
- Department of Cardiology, Hospital Universitario de Móstoles, Madrid, Spain
| | - Álvaro Aceña
- Department of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Rocío Carda
- Department of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Ana Huelmos
- Department of Cardiology, Hospital Universitario Fundación Alcorcón, Madrid, Spain
| | | | | | | | - Joaquín Alonso
- Rey Juan Carlos University, Alcorcón, Madrid, Spain
- Department of Cardiology, Hospital de Getafe, Madrid, Spain
| | - Óscar Lorenzo
- Autónoma University, Madrid, Spain
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
| | - Jesús Egido
- Autónoma University, Madrid, Spain
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- CIBERDEM, Madrid, Spain
| | | | - José Tuñón
- Department of Cardiology, IIS-Fundación Jiménez Díaz, Madrid, Spain
- Autónoma University, Madrid, Spain
- Laboratory of Vascular Pathology, IIS-Fundación Jiménez Díaz, Madrid, Spain
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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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15
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Ferstl FS, Kitay AM, Trattnig RM, Alsaihati A, Geibel JP. Secretagogue-dependent and -independent transport of zinc hydration forms in rat parietal cells. Pflugers Arch 2016; 468:1877-1883. [PMID: 27757581 DOI: 10.1007/s00424-016-1889-3] [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] [Received: 08/25/2016] [Revised: 09/26/2016] [Accepted: 09/28/2016] [Indexed: 12/19/2022]
Abstract
Prolonged exposure to gastric acid is a leading cause of gastroesophageal reflux disease (GERD) and esophagitis. With the ever increasing number of patients showing insensitivity to proton-pump-inhibitor (PPI) therapy with recurrence of symptoms over time, alternative treatment options remain an important issue. Previous studies from our laboratory have shown that a zinc sulfate salt can inhibit HCl generation at the cellular level of the parietal cell. In this paper, we examine the difference between two hydration forms of ZnSO4 (monohydrate H2O and heptahydrate 7H2O) in their entry characteristics into the parietal cell under several physiological conditions associated with acid secretion. Using the Zn sensitive fluorochrome Newport Green, we examined the rate of Zn entry in Δfluorescent units/second (ΔFU/second), at two different concentrations for both hydration states on both fasted and non-fasted animals. In a separate series of studies, we examined the effects of secretagogues on the entry rates and transport mechanisms. Exposure of the secretagogue carbachol transformed the resting parietal cell to an activated state and represents a stimulated condition through the neuronal pathway. The hormonal activation of the parietal cell was achieved by using histamine. Non-fasted conditions were considered to be a state between hormonal and neuronal activation. To demonstrate that ZnSO4 enters the parietal cell through the NKCC1 co-transporter, the inhibitor bumetanide was applied during secretagogue-stimulated acid secretion. Both salts, monohydrate and heptahydrate ZnSO4, show a concentration-dependent cell entry under all conditions studied. During stimulated acid secretion, induced through either the neuronal or the hormonal pathway, heptahydrate ZnSO4 enters the parietal cell significantly faster than monohydrate ZnSO4, whereas monohydrate ZnSO4 exhibits faster entry during resting conditions in fasted animals. At 30 μM following stimulation with histamine, heptahydrate ZnSO4 enters the cell faster than monohydrate ZnSO4 (ΔFU/second 30 μM ZnSO4*7H2O + histamine = 1.782, ΔFU/second 30 μM ZnSO4*H2O+histamine = 1.038, respectively). Three hundred micromolar, heptahydrate ZnSO4 shows a faster entry into the cells (ΔFU/second ZnSO4*7H2O300μM + carbachol = 4.02407) compared to monohydrate ZnSO4 (ΔFU/second ZnSO4*H2O300μM + carbachol = 3.225) following exposure to carbachol. The mechanism of entry of both salts was found to be predominantly via the basolateral NKCC1 transporter with the rate of zinc entry decreasing to minimal values (ΔFU/second = 0.275) after application of bumetanide during stimulated conditions.
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Affiliation(s)
- Florentina Sophie Ferstl
- Department of Surgery, School of Medicine, Yale University, BML 238, 310 Cedar St., New Haven, CT, 06511, USA.,Paracelsus Medical University, Salzburg, Austria
| | - Alice Miriam Kitay
- Department of Surgery, School of Medicine, Yale University, BML 238, 310 Cedar St., New Haven, CT, 06511, USA.,Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Rebecca Marion Trattnig
- Department of Surgery, School of Medicine, Yale University, BML 238, 310 Cedar St., New Haven, CT, 06511, USA.,Paracelsus Medical University, Salzburg, Austria
| | - Abrar Alsaihati
- Department of Surgery, School of Medicine, Yale University, BML 238, 310 Cedar St., New Haven, CT, 06511, USA
| | - John Peter Geibel
- Department of Surgery, School of Medicine, Yale University, BML 238, 310 Cedar St., New Haven, CT, 06511, USA. .,Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
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16
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Savarino E, Ottonello A, Martinucci I, Dulbecco P, Savarino V. Ilaprazole for the treatment of gastro-esophageal reflux. Expert Opin Pharmacother 2016; 17:2107-13. [DOI: 10.1080/14656566.2016.1232389] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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17
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Abstract
Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.
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18
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Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. PLoS One 2015; 10:e0124653. [PMID: 26061035 PMCID: PMC4462578 DOI: 10.1371/journal.pone.0124653] [Citation(s) in RCA: 214] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2015] [Accepted: 03/17/2015] [Indexed: 12/12/2022] Open
Abstract
Background and Aims Proton pump inhibitors (PPIs) have been associated with adverse clinical outcomes amongst clopidogrel users after an acute coronary syndrome. Recent pre-clinical results suggest that this risk might extend to subjects without any prior history of cardiovascular disease. We explore this potential risk in the general population via data-mining approaches. Methods Using a novel approach for mining clinical data for pharmacovigilance, we queried over 16 million clinical documents on 2.9 million individuals to examine whether PPI usage was associated with cardiovascular risk in the general population. Results In multiple data sources, we found gastroesophageal reflux disease (GERD) patients exposed to PPIs to have a 1.16 fold increased association (95% CI 1.09–1.24) with myocardial infarction (MI). Survival analysis in a prospective cohort found a two-fold (HR = 2.00; 95% CI 1.07–3.78; P = 0.031) increase in association with cardiovascular mortality. We found that this association exists regardless of clopidogrel use. We also found that H2 blockers, an alternate treatment for GERD, were not associated with increased cardiovascular risk; had they been in place, such pharmacovigilance algorithms could have flagged this risk as early as the year 2000. Conclusions Consistent with our pre-clinical findings that PPIs may adversely impact vascular function, our data-mining study supports the association of PPI exposure with risk for MI in the general population. These data provide an example of how a combination of experimental studies and data-mining approaches can be applied to prioritize drug safety signals for further investigation.
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20
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Huang C, Cen C, Ding X, Zhang H, Wu L. Effects of calcitriol on bone mineral density in patients treated with esomeprazole. PHARMACEUTICAL BIOLOGY 2014; 52:1341-1344. [PMID: 25046547 DOI: 10.3109/13880209.2014.892141] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
CONTEXT Proton pump inhibitor (PPI) increases the risk of decrease in bone mineral density (BMD). However, whether calcitrol improves this situation is unknown. OBJECTIVE The current study investigates the effects of calcitriol on BMD in patients with esomeprazole therapy. MATERIALS AND METHODS Three hundred and eighty-six participants with gastrointestinal ulcerations were enrolled and randomly assigned into controlled and supplemented groups. Participants in the controlled group were prescribed esomeprazole (20 mg/qd), while the supplemented group was prescribed esomeprazole (20 mg/qd) and calcitriol (2.5 μg/qd). BMD, serum levels of calcium, carboxy-terminal collagen crosslinks (CTX), and alkaline-phosphatase (ALP) were assessed. RESULTS (1) No significant between-group difference of age, gender, smoking, previous glucocorticoid use and hemoglobin level was found; (2) after 10.6 ± 0.8 d of PPI therapy, BMD T score in the controlled group was slightly increased compared with initial (-1.25 ± 0.08 versus -1.28 ± 0.06, p = 0.084), while there was no change in the supplemented group (-1.25 ± 0.05 versus -1.26 ± 0.03, p = 0.308); (3) during study termination, calcium level in the supplemented group was slightly higher than the controlled group (2.05 ± 0.03 mmol/L versus 2.01 ± 0.05 mmol/L, p = 0.073), while no significant differences of CTX (366.57 ± 43.71 pg/mL versus 373.15 ± 50.23 pg/mL, p = 0.036) and ALP were found among these two groups (50.47 ± 9.32 U/L versus 52.23 ± 10.45 U/L, p = 0.075). CONCLUSION Patients with gastrointestinal ulcerations with esomeprazole therapy, calcitriol supplement showed no efficacy on BMD changes.
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Affiliation(s)
- Congwu Huang
- Department of Gastroenterology, the Second Affiliated Hospital of Shantou University , Shantou , China
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21
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Toma W, Guimarães LL, Brito AR, Santos AR, Cortez FS, Pusceddu FH, Cesar A, Júnior LS, Pacheco MT, Pereira CD. Safflower oil: an integrated assessment of phytochemistry, antiulcerogenic activity, and rodent and environmental toxicity. REVISTA BRASILEIRA DE FARMACOGNOSIA-BRAZILIAN JOURNAL OF PHARMACOGNOSY 2014. [DOI: 10.1016/j.bjp.2014.09.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Wang Q, Ljung R, Lagergren J, Lu Y. Prognosis of concomitant users of clopidogrel and proton-pump inhibitors in a high-risk population for upper gastrointestinal bleeding. BMC Pharmacol Toxicol 2014; 15:22. [PMID: 24731755 PMCID: PMC4002561 DOI: 10.1186/2050-6511-15-22] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Accepted: 03/25/2014] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND It is unclear whether concomitant use of clopidogrel and proton-pump inhibitors (PPIs) increases the risk of recurrence of cardiovascular disease or death in patients at high risk of upper gastrointestinal (GI) bleeding. METHODS Based on the Swedish Patient Register, a cohort of cardiovascular disease (including acute myocardial infarction, stroke and angina, from 2006 to 2008) was selected from a population with any diagnosis of upper GI bleeding. Data on drug prescription was retrieved from the Prescribed Drug Register. Patients entered into the cohort after their first discharge for cardiovascular disease and were followed up to death, recurrence of cardiovascular disease, or 90 days. A Cox regression model was conducted and hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated to evaluate the risks among users of different drug prescriptions. RESULTS Patients who were current users of only PPIs (HR 2.02, 95% CI 1.19-3.44), only clopidogrel (HR 1.14, 95% CI 0.53-2.45) and nonusers of both (HR 2.36, 95% CI 1.39-4.00) were at a higher risk of death compared with patients with a concomitant use. Results were similar among 1779 patients who had any history of upper GI bleeding (HR 2.05, 95% CI 1.18-3.54; HR 1.25, 95% CI 0.57-2.72; HR 2.30, 95% CI 1.33-3.98, respectively). CONCLUSION Among patients at high risk of upper GI bleeding, those with a concomitant use of PPIs and clopidogrel were at a decreased risk of mortality, and possibly also a decreased risk of recurrence of cardiovascular disease.
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Affiliation(s)
- Qing Wang
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - Rickard Ljung
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Unit of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
| | - Jesper Lagergren
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Division of Cancer Studies, King’s College London, London, United Kingdom
| | - Yunxia Lu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, SE-171 76 Stockholm, Sweden
- Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom
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Tsuchie SY, Nani FS, Vieira JE. Incidence of postoperative dyspepsia is not associated with prophylactic use of drugs. SAO PAULO MED J 2014; 132:219-23. [PMID: 25055067 PMCID: PMC10496731 DOI: 10.1590/1516-3180.2014.1324676] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2013] [Revised: 09/05/2013] [Accepted: 09/09/2013] [Indexed: 11/22/2022] Open
Abstract
CONTEXT AND OBJECTIVE Preoperative fasting guidelines do not recommend H2 receptor antagonists or proton pump inhibitors. This study investigated prophylactic use of gastric protection and the incidence of dyspeptic symptoms in the immediate postoperative period. DESIGN AND SETTING Non-randomized observational investigation in a post-anesthesia care unit. METHODS American Society of Anesthesiologists risk classification ASAP1 and ASAP2 patients over 18 years of age were evaluated to identify dyspeptic symptoms during post-anesthesia care for up to 48 hours, after receiving or not receiving prophylactic gastric protection during anesthesia. History of dyspeptic symptoms and previous use of such medications were exclusion criteria. The odds ratio for incidence of dyspeptic symptoms with use of these medications was obtained. RESULTS This investigation studied 188 patients: 71% women; 50.5% ASAP1 patients. Most patients received general anesthesia (68%). Gastric protection was widely used (n = 164; 87.2%), comprising omeprazole (n = 126; 76.8%) or ranitidine (n = 38; 23.2%). Only a few patients did not receive any prophylaxis (n = 24; 12.8%). During the observation, 24 patients (12.8%) reported some dyspeptic symptoms but without any relationship with prophylaxis (relative risk, RR = 0.56; 95% confidence interval, CI: 0.23-1.35; P = 0.17; number needed to treat, NNT = 11). Omeprazole, compared with ranitidine, did not reduce the chance of having symptoms (RR = 0.65; 95% CI: 0.27-1.60; P = 0.26; NNT = 19). CONCLUSION This study suggests that prophylactic use of proton pump inhibitors or H2 receptor antagonists was routine for asymptomatic patients and was not associated with postoperative protection against dyspeptic symptoms.
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Affiliation(s)
- Sara Yumi Tsuchie
- Resident. Anesthesiology Program, Hospital das
Clínicas (HC), Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo,
Brazil
| | - Fernando Souza Nani
- MD. Anesthesiologist, Anesthesia Division, Hospital
das Clínicas, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo,
Brazil
| | - Joaquim Edson Vieira
- MD, PhD. Associate Professor, Department of
Surgery, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo,
Brazil
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24
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Keller J, Schinke T. The role of the gastrointestinal tract in calcium homeostasis and bone remodeling. Osteoporos Int 2013; 24:2737-48. [PMID: 23536255 DOI: 10.1007/s00198-013-2335-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Accepted: 02/25/2013] [Indexed: 12/11/2022]
Abstract
While skeletal biology was approached in a rather isolated fashion in the past, an increasing understanding of the interplay between extraskeletal organs and bone remodeling has been obtained in recent years. This review will discuss recent advances in the field that have shed light on how the gastrointestinal tract and bone relate to each other. In particular, the importance of the GI tract in maintaining calcium homeostasis and skeletal integrity will be reviewed as impaired gastric acid production represents a major public health problem with possible implications for sufficient calcium absorption. Osteoporosis, the most prevalent bone disease worldwide, is caused not only by intrinsic defects affecting bone cell differentiation and function but also by a large set of extrinsic factors including hormonal disturbances, malnutrition, and iatrogenic drug application. Given the skeletal requirements of calcium, amino acids, and energy for bone turnover and renewal, it is not surprising that the gastrointestinal (GI) tract is of major importance for skeletal integrity.
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Affiliation(s)
- J Keller
- Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246, Hamburg, Germany
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25
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Prakash Gupta RK, Pradeepa, Hanumanthappa M. In vitro antioxidant and H(+), K(+)-ATPase inhibition activities of Acalypha wilkesiana foliage extract. JOURNAL OF PHARMACY AND BIOALLIED SCIENCES 2013; 5:214-23. [PMID: 24082698 PMCID: PMC3778591 DOI: 10.4103/0975-7406.116822] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2012] [Revised: 02/16/2013] [Accepted: 03/28/2013] [Indexed: 11/07/2022] Open
Abstract
Aims: The aim of this study was to evaluate the antioxidant activty and anti-acid property of Acalypha wilkesiana foliage extract. Materials and Methods: Hot and cold aqueous extracts were prepared from healthy leaves of A. wilkesiana. Free radical scavenging activity and H+, K+-ATPase inhibition activities of aqueous foliage extracts was screened by in vitro models. Statistical Analysis Used: All experiments were performed in triplicate and results are expressed as mean ± SEM. Results: A. wilkesiana hot aqueous extract (AWHE) showed significant antioxidants and free radical scavenging activity. Further, AWHE has shown a potent H+, K+-ATPase inhibitory activity (IC50: 51.5 ± 0.28 μg/ml) when compare to standard proton pump inhibitor omeprazole (56.2 ± 0.64 μg/ml); however, latter activity is equal to A. wilkesiana cold aqueous extract (AWCE). Quantitative analysis of AWHE has revealed more content of phenols and flavonoids; this is found to be the reason for good antioxidant activity over AWCE. Molecular docking was carried out against H+, K+-ATPase enzyme crystal structure to validate the anti-acid activity of A. wilkesiana major phytochemicals. Conclusions: The present study indicates that the constituents of AWHE and AWCE have good antacid and free radical scavenging activity.
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Affiliation(s)
- Rajesh Kashi Prakash Gupta
- Department of PG Studies and Research in Biotechnology and Bioinformatics, Jnanasahyadri, Kuvempu University, Shankaraghatta, India
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Marusic S, Bacic-Vrca V, Obreli Neto PR, Franic M, Erdeljic V, Gojo-Tomic N. Actual drug-drug interactions in elderly patients discharged from internal medicine clinic: a prospective observational study. Eur J Clin Pharmacol 2013; 69:1717-24. [PMID: 23739998 DOI: 10.1007/s00228-013-1531-7] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 05/17/2013] [Indexed: 01/31/2023]
Abstract
PURPOSE The aim of the study was to evaluate the incidence and type of actual drug-drug interactions (DDIs) that result in adverse drug reactions (ADRs) or diminished therapeutic effect in elderly patients within 30 days of discharge from an internal medicine clinic. METHODS A prospective observational study was conducted at the Internal Medicine Clinic of University Hospital Dubrava, Zagreb, Croatia, between October and December 2011. Patients aged ≥ 65 years discharged from the Internal Medicine Clinic during the study period with a prescription for two or more medications were eligible for inclusion in the study. A total of 222 patients were ultimately enrolled in the study. For each patient, potential DDIs were identified using Lexi-Interact software. The follow-up visit was scheduled approximately 30 days after discharge. Causality between DDIs and ADRs or diminished therapeutic effect of drugs was assessed by two independent clinicians. RESULTS Potential DDIs were identified in 190 (85.6 %) patients. Actual DDIs were detected in 21 (9.5 %) patients. In 19 patients, DDIs resulted in an ADR. Diminished therapeutic effect resulting from DDIs was detected in two patients. Angiotensin-converting enzyme inhibitors were the drug class most frequently associated with DDI-related ADRs. CONCLUSIONS A significant incidence of actual DDIs suggests that DDIs play an important role in patient safety. Drug therapy should be initiated if absolutely necessary, and the number of drugs used to treat elderly patients should be minimized to reduce the incidence of DDI-related adverse patient outcomes.
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Affiliation(s)
- Srecko Marusic
- Department of Clinical Pharmacology, University Hospital Dubrava, Av. Gojka Suska 6, 10000 Zagreb, Croatia.
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Ghebremariam YT, LePendu P, Lee JC, Erlanson DA, Slaviero A, Shah NH, Leiper J, Cooke JP. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation 2013; 128:845-53. [PMID: 23825361 DOI: 10.1161/circulationaha.113.003602] [Citation(s) in RCA: 194] [Impact Index Per Article: 16.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Proton pump inhibitors (PPIs) are gastric acid-suppressing agents widely prescribed for the treatment of gastroesophageal reflux disease. Recently, several studies in patients with acute coronary syndrome have raised the concern that use of PPIs in these patients may increase their risk of major adverse cardiovascular events. The mechanism of this possible adverse effect is not known. Whether the general population might also be at risk has not been addressed. METHODS AND RESULTS Plasma asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. Elevated plasma ADMA is associated with increased risk for cardiovascular disease, likely because of its attenuation of the vasoprotective effects of endothelial nitric oxide synthase. We find that PPIs elevate plasma ADMA levels and reduce nitric oxide levels and endothelium-dependent vasodilation in a murine model and ex vivo human tissues. PPIs increase ADMA because they bind to and inhibit dimethylarginine dimethylaminohydrolase, the enzyme that degrades ADMA. CONCLUSIONS We present a plausible biological mechanism to explain the association of PPIs with increased major adverse cardiovascular events in patients with unstable coronary syndromes. Of concern, this adverse mechanism is also likely to extend to the general population using PPIs. This finding compels additional clinical investigations and pharmacovigilance directed toward understanding the cardiovascular risk associated with the use of the PPIs in the general population.
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Affiliation(s)
- Yohannes T Ghebremariam
- Department of Cardiovascular Sciences, Texas Methodist Hospital Research Institute, Houston, TX 77030, USA
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Sylvester KW, Cheng JW, Mehra MR. Esomeprazole and aspirin fixed combination for the prevention of cardiovascular events. Vasc Health Risk Manag 2013; 9:245-54. [PMID: 23696706 PMCID: PMC3658534 DOI: 10.2147/vhrm.s44265] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Low dose aspirin therapy plays a fundamental role in both the primary and secondary prevention of cardiovascular events. Although the evidence using low dose aspirin for secondary prevention is well-established, the decision to use aspirin for primary prevention is based on an evaluation of the patient’s risk of cardiovascular events compared to their risk of adverse events, such as bleeding. In addition to the risk of bleeding associated with long term aspirin administration, upper gastrointestinal side effects, such as dyspepsia often lead to discontinuation of therapy, which places patients at an increased risk for cardiovascular events. One option to mitigate adverse events and increase adherence is the addition of esomeprazole to the medication regimen. This review article provides an evaluation of the literature on the concomitant use of aspirin and esomeprazole available through February 2013. The efficacy, safety, tolerability, cost effectiveness, and patient quality of life of this regimen is discussed. A summary of the pharmacokinetic and pharmacodynamic interactions between aspirin and esomeprazole, as well as other commonly used cardiovascular medications are also reviewed. The addition of esomeprazole to low dose aspirin therapy in patients at high risk of developing gastric ulcers for the prevention of cardiovascular disease, significantly reduced their risk of ulcer development. Pharmacokinetic and pharmacodynamic studies suggested that esomeprazole did not affect the pharmacokinetic parameters or the antiplatelet effects of aspirin. Therefore, for those patients who are at a high risk of developing a gastrointestinal ulcer, the benefit of adding esomeprazole likely outweighs the risks of longer term proton pump inhibitor use, and the combination can be recommended. Administering the two agents separately may also be more economical. On the other hand, for those patients at lower risk of developing a gastrointestinal ulcer, both the additional risk and cost make the inclusion of a proton pump inhibitor unwarranted.
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Jarchow-MacDonald AA, Mangoni AA. Prescribing patterns of proton pump inhibitors in older hospitalized patients in a Scottish health board. Geriatr Gerontol Int 2013; 13:1002-9. [DOI: 10.1111/ggi.12047] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2013] [Indexed: 12/13/2022]
Affiliation(s)
| | - Arduino A Mangoni
- Division of Applied Medicine, School of Medicine and Dentistry; University of Aberdeen; Aberdeen; UK
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Bourne C, Charpiat B, Charhon N, Bertin C, Gouraud A, Mouchoux C, Skalli S, Janoly-Dumenil A. Effets indésirables émergents des inhibiteurs de la pompe à protons. Presse Med 2013; 42:e53-62. [DOI: 10.1016/j.lpm.2012.09.016] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2012] [Revised: 08/08/2012] [Accepted: 09/04/2012] [Indexed: 12/12/2022] Open
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McCarty MF. Dietary nitrate and reductive polyphenols may potentiate the vascular benefit and alleviate the ulcerative risk of low-dose aspirin. Med Hypotheses 2012; 80:186-90. [PMID: 23265354 DOI: 10.1016/j.mehy.2012.11.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2012] [Accepted: 11/17/2012] [Indexed: 12/23/2022]
Abstract
The recent revelation that daily low-dose aspirin not only lowers risk for vascular events, but also can notably decrease risk for a range of adenocarcinomas, decreasing total cancer mortality by about 20%, makes it highly desirable to implement this protective strategy on a population-wide basis. Nonetheless, the fact that low-dose aspirin approximately doubles risk for serious gastrointestinal bleeding may impede health authorities from recommending its use by people judged to be at low cardiovascular risk. Nitric oxide (NO) exerts gastroprotective effects by boosting blood flow and mucus production in the gastric mucosa - effects which demonstrably oppose the pro-ulcerative impact of aspirin and other NSAIDs. A nitrate-rich diet, as well as ingestion of reductive catechol-bearing polyphenols, can collaborate in promoting NO generation in gastric juice, and they are protective in rodent models of gastric ulceration. Moreover, a high-nitrate diet, as well as certain reductive polyphenols such as epicatechin and quercetin, can exert platelet-stabilizing effects complementary to those of aspirin, and act in other ways to preserve vascular health. Hence, diets rich in nitrate and reductive polyphenols have the potential to amplify the vascular-protective benefits of low-dose aspirin, while diminishing its pro-ulcerative risk. Low-dose aspirin may be more unequivocally recommendable within the context of such a dietary strategy.
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Affiliation(s)
- Mark F McCarty
- NutriGuard Research, 1051 Hermes Ave., Encinitas, CA 92024, United States.
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Durand C, Willett KC, Desilets AR. Proton Pump Inhibitor use in Hospitalized Patients: Is Overutilization Becoming a Problem? CLINICAL MEDICINE INSIGHTS. GASTROENTEROLOGY 2012; 5:65-76. [PMID: 24833936 PMCID: PMC3987764 DOI: 10.4137/cgast.s9588] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Proton pump inhibitors (PPIs) are among the most common classes of medications prescribed. Though they were previously thought of as safe, recent literature has shown risks associated with their use including increased risk for Clostridium difficile infection, pneumonia, and fractures. Due to these risks, it is important to determine if PPIs are being used appropriately. This review evaluates seven studies in hospitalized patients. Additionally, this review evaluates literature pertaining to recently discovered adverse reactions; all studies found PPIs are being overutilized. Findings highlight the importance of evaluating appropriate therapy with these agents and recommending discontinuation if a proper indication does not exist.
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Affiliation(s)
- Cheryl Durand
- Massachusetts College of Pharmacy and Health Sciences, Manchester, NH
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Farrell CP, Morgan M, Rudolph DS, Hwang A, Albert NE, Valenzano MC, Wang X, Mercogliano G, Mullin JM. Proton Pump Inhibitors Interfere With Zinc Absorption and Zinc Body Stores. Gastroenterology Res 2011; 4:243-251. [PMID: 27957023 PMCID: PMC5139861 DOI: 10.4021/gr379w] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/07/2011] [Indexed: 12/17/2022] Open
Abstract
Background Proton pump inhibitors (PPIs) cause a sharp elevation of gastro-duodenal luminal pH which in turn has resulted in reports of reduced absorption of magnesium and certain other nutrients. Methods Gastroesophageal reflux disease (GERD) patients on long-term PPI therapy (> 6 months) or healthy test subjects (not on any acid preventive or neutralizing medication) were administered oral doses of zinc gluconate (26.2 mg zinc, twice daily) for 14 days followed by 5 cc venous blood samples. Plasma was analyzed for total zinc content by atomic absorption spectrophotometry. Baseline plasma and red blood cell zinc levels were also measured in these two groups when not taking any zinc supplementation. Results Plasma zinc levels of healthy controls increased by 126% during the period of zinc supplementation compared to only a 37% increase for individuals on long-term PPI therapy. On their normal diet (with no zinc supplementation), PPI-users had a 28% lower plasma zinc level than healthy controls (P < 0.005). Conclusions PPI use dramatically reduces supplemental zinc uptake and can result in decreased zinc body stores. Certain individuals on long-term PPI therapy, such as infants being treated for colic, may be at risk for decreased systemic levels of trace metals needed for developmental, regenerative and immunological requirements.
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Affiliation(s)
- Christopher P Farrell
- Department of Gastrointestinal Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - Melissa Morgan
- Department of Gastrointestinal Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - David S Rudolph
- Department of Gastrointestinal Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - Austin Hwang
- Department of Gastrointestinal Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - Nicole E Albert
- Department of Internal Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - Mary C Valenzano
- Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - Xuexuan Wang
- Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - Giancarlo Mercogliano
- Department of Gastrointestinal Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
| | - James M Mullin
- Department of Gastrointestinal Medicine, Lankenau Medical Center, 100 Lancaster Avenue, Wynnewood, PA 19096, USA; Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA 19096, USA
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