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Cai Z, She J. Association Between Magnesium Depletion Score and Peripheral Artery Disease in Middle-Aged and Older Population. J Cardiovasc Transl Res 2025:10.1007/s12265-025-10615-0. [PMID: 40195213 DOI: 10.1007/s12265-025-10615-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2025] [Accepted: 03/24/2025] [Indexed: 04/09/2025]
Abstract
The magnesium depletion score (MDS) is considered a new valuable predictor of body magnesium status. This study aimed to explore the association between MDS and PAD among participants aged ≥ 40 years on the National Health and Nutrition Examination Survey in 1999-2004. Survey-weighted multivariable logistic regression and restricted cubic spline models were used to assess the association between MDS and PAD. Survey-weighted multivariable logistic regression showed a significant positive association between MDS and the prevalence of PAD. For each unit increase in MDS, the risk of PAD increased by 24%. Compared to individuals with MDS = 0, those with MDS ≥ 3 had a 95% higher risk of PAD. Restricted triple spline analysis showed a linear dose-response relationship between MDS and PAD risk. Subgroup analysis indicated that this positive association was stronger in individuals aged > 60 years. Numerous future longitudinal cohort studies are required to validate our findings.
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Affiliation(s)
- Zongao Cai
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Jiachen She
- Department of Nursing, Peking Union Medical College Hospital, Beijing, 100730, China.
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2
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Adella A, Gommers LMM, Bos C, Leermakers PA, de Baaij JHF, Hoenderop JGJ. Characterization of intestine-specific TRPM6 knockout C57BL/6 J mice: effects of short-term omeprazole treatment. Pflugers Arch 2025; 477:99-109. [PMID: 39266724 PMCID: PMC11711252 DOI: 10.1007/s00424-024-03017-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Revised: 09/04/2024] [Accepted: 09/05/2024] [Indexed: 09/14/2024]
Abstract
The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg2+ balance. Disturbance in Mg2+ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4 days) omeprazole treatment on intestinal Mg2+ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6-/-) mice. To do this, forty-eight adult male C57BL/6 J mice (50% TRPM6fl/fl and 50% Vill1-TRPM6-/-) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20 mg/kg bodyweight omeprazole or placebo for 4 days. Vill1-TRPM6-/- mice had a significantly lower 25Mg2+ absorption compared to control TRPM6fl/fl mice, accompanied by lower Mg2+ serum levels, and urinary Mg2+ excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn2+ transporter Slc30a10. However, no changes in Mn2+ serum, urine, and feces levels were observed. Moreover, 4 days omeprazole treatment did not affect Mg2+ homeostasis as no changes in serum 25Mg2+ and total Mg2+ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6-/- mice have a lower Mg2+ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg2+ absorption in both Vill1-TRPM6-/- and TRPM6fl/fl mice. This suggests that TRPM6-mediated Mg2+ absorption in the intestines is not affected by short-term PPI administration.
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Affiliation(s)
- Anastasia Adella
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Lisanne M M Gommers
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Caro Bos
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Pieter A Leermakers
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Jeroen H F de Baaij
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost G J Hoenderop
- Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, The Netherlands.
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Cai Z, She J, Liu X, Li R, Guo S, Han Z, Zhou J, Zhang H, Xu Y, Zhang G, Zhou Z, Guo X, Wu S. Associations between magnesium depletion score and depression among individuals aged 20 to 60 years. J Trace Elem Med Biol 2024; 86:127543. [PMID: 39406123 DOI: 10.1016/j.jtemb.2024.127543] [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: 03/27/2024] [Revised: 09/26/2024] [Accepted: 10/06/2024] [Indexed: 12/08/2024]
Abstract
BACKGROUND Magnesium is closely associated with depression. The study aims to explore the relationship between magnesium depletion score (MDS), used to evaluate the body's magnesium deficiency status, and depression. METHODS This population-based cross-sectional study used data from the National Health and Nutrition Examination Survey in 2005-2018 and included adults aged 20 to 60 years. Depression was determined using the Patient Health Questionnaire-9 (PHQ-9). MDS was a practical assessment instrument used to assess the status of magnesium deficiency. Multivariable logistic and restricted cubic spline models were used to assess the associations between MDS and depression. RESULTS Among the 18247 adults, 1753 participants were diagnosed with depression. Multivariable logistic regression analysis indicated that when MDS was treated as a continuous variable, each one-unit increase in MDS was associated with an odds ratio (OR) for depression of 1.15 (1.04, 1.26). When MDS was considered a categorical variable, compared to participants with MDS of 0, the ORs for depression for those with MDS of 1, 2, and ≥3 were 1.03 (0.87, 1.21), 1.41 (1.12, 1.78), and 1.58 (1.06, 2.35), respectively. Restricted cubic spline analysis showed that there was no non-linear relationship between MDS and the prevalence of depression. Subgroup analyses indicated the positive associations between MDS and depression were generally similar in different populations. CONCLUSIONS MDS may be positively associated with the prevalence of depression. In the future, additional longitudinal studies are needed to validate our findings and investigate potential mechanisms.
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Affiliation(s)
- Zongao Cai
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jiachen She
- Department of Nursing, Peking Union Medical College Hospital, Beijing, China
| | - Xiaozhu Liu
- Department of Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China
| | - Ruihui Li
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Shuang Guo
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zeyang Han
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Jiyang Zhou
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hairong Zhang
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Yudi Xu
- Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ge Zhang
- Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Zhaokai Zhou
- Department of Urology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Xueli Guo
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
| | - Shiyong Wu
- Department of Vascular Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
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Philippoteaux C, Paccou J, Chazard E, Cortet B. Proton pump inhibitors, bone and phosphocalcic metabolism. Joint Bone Spine 2024; 91:105714. [PMID: 38458487 DOI: 10.1016/j.jbspin.2024.105714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/10/2024] [Accepted: 02/18/2024] [Indexed: 03/10/2024]
Abstract
Proton pump inhibitors (PPIs) are widely used for acid-related gastrointestinal disorders; however, concerns have arisen about their prolonged and inappropriate use. Although generally considered safe, recent evidence has linked PPI use with an increased risk of kidney disease, stomach cancer, pneumonia, dementia, cardiovascular events and potential bone health problems. This systematic review examines the effects of PPIs on bone health, including osteoporosis and changes in phosphocalcic and magnesium metabolism, through a comprehensive analysis of the recent literature. The relationship between PPIs, bone mineral density and fracture risk, especially in populations with comorbidities, is complex and we propose a focus based on recent data. Studies of the effect of PPI use on bone mineral density have shown mixed results and require further investigation. Observational studies have indicated an increased risk of fractures, particularly vertebral fractures, associated with PPI use. Recent meta-analyses have confirmed an association between PPI use and hip fractures with a dose-dependent effect. More recently, PPIs have been associated with serious disturbances in phosphocalcic and magnesium metabolism that require careful management and discontinuation. Proton pump inhibitor-induced hypomagnesemia (PPIH) is a well-established phenomenon. In addition, hypocalcemia secondary to severe hypomagnesemia has been described. Despite growing evidence of PPI-related risks, further research is essential to better understand the complex mechanisms, as most data are from observational studies and do not establish a causal relationship. This review emphasizes the need for judicious prescription practices, particularly in long-term use scenarios and rheumatological contexts.
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Affiliation(s)
- Cécile Philippoteaux
- Rheumatology Department, Lille University Hospital, Lille, France; Public Health Department, University Lille, CHU de Lille, ULR 2694, CERIM, METRICS, Lille, France.
| | - Julien Paccou
- Rheumatology Department, Lille University Hospital, Lille, France; Rheumatology Department, Lille University, Lille University Hospital, MabLab, Lille, France
| | - Emmanuel Chazard
- Public Health Department, University Lille, CHU de Lille, ULR 2694, CERIM, METRICS, Lille, France
| | - Bernard Cortet
- Rheumatology Department, Lille University Hospital, Lille, France; Rheumatology Department, Lille University, Lille University Hospital, MabLab, Lille, France
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Famouri F, Tavahen N, Gholami H, Yazdi M, Heidari-Beni M, Momenzadeh M. The Effect of Omeprazole on Urinary Magnesium Excretion in Children with Peptic Diseases. J Res Pharm Pract 2024; 13:53-57. [PMID: 39830949 PMCID: PMC11737616 DOI: 10.4103/jrpp.jrpp_35_24] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2024] [Revised: 03/12/2024] [Accepted: 03/27/2024] [Indexed: 01/22/2025] Open
Abstract
Objective This study investigates the impact of omeprazole on urinary magnesium (Mg) excretion in children undergoing treatment for peptic disease. Specifically, it examines how omeprazole influences the fractional excretion of Mg. Methods This single-arm clinical trial was conducted from 2020 to 2021. With 44 children diagnosed with acid peptic disease who received omeprazole (1-2 mg/kg/day) for 3 months at the Gastroenterology Clinic of Imam Hossein Hospital, Isfahan, Iran. Serum and urine levels of Mg and creatinine were measured before and after the intervention using the Pars Azmoon Kit, following the kits guidelines. The fractional excretion of Mg was then calculated using standard formulas. Findings The mean urinary Mg levels decreased significantly from 4.96 ± 2.48 mg/dL before treatment to 1.46 ± 0.63 mg/dL after treatment (P < 0.001). Serum Mg levels also significantly declined from 1.90 ± 0.20 mg/dL before treatment to 1.37 ± 0.03 mg/dL after treatment (P < 0.01). The mean fractional excretion of Mg decreased from 5.2% ± 1.2% before therapy to 1.7% ± 0.63% after treatment (P < 0.01). Serum creatinine levels showed a slight increase from 0.62 ± 0.19 mg/dL to 0.67 ± 0.13 mg/dL (P = 0.053), whereas urinary creatinine levels increased by 20.80 ± 18.77 mg/dL (P < 0.001). Conclusion The observed hypomagnesemia is not attributable to increased urinary Mg loss. Instead, the kidneys appear to compensate for the reduced serum Mg levels by decreasing urinary Mg excretion, thereby conserving Mg in the body following omeprazole treatment.
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Affiliation(s)
- Fatemeh Famouri
- Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
- Metabolic Liver Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Nirvana Tavahen
- Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
- Metabolic Liver Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hossein Gholami
- Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
- Metabolic Liver Disease Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Maryam Yazdi
- Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
- Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Motahar Heidari-Beni
- Department of Pediatrics, Isfahan University of Medical Sciences, Isfahan, Iran
- Child Growth and Development Research Center, Research Institute for Primordial Prevention of Non-communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahnaz Momenzadeh
- Department of Clinical Pharmacy and Pharmacy Practice, Isfahan University of Medical Sciences, Isfahan, Iran
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Miedziaszczyk M, Idasiak-Piechocka I. Safety analysis of co-administering tacrolimus and omeprazole in renal transplant recipients - A review. Biomed Pharmacother 2023; 166:115149. [PMID: 37619481 DOI: 10.1016/j.biopha.2023.115149] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 07/01/2023] [Accepted: 07/07/2023] [Indexed: 08/26/2023] Open
Abstract
Tacrolimus is a calcineurin inhibitor used to prevent rejection in allogenic solid organ transplant recipients, which is metabolized in the liver with cytochrome P450 isoforms 3A4 and 3A5 (CYP3A4, CYP3A5). In turn, proton pump inhibitors (PPIs), such as Omeprazole - a substrate and inhibitor of CYP2C19 and CYP3A4 enzymes - are administered to kidney transplant patients in order to prevent duodenal and gastric ulcer disease, associated with the glucocorticoid treatment. Simultaneous administration of both drugs in renal patients has the potential to trigger drug interactions. In fact, there are several mechanisms which may impact the pharmacokinetics of tacrolimus. Inhibition of the CYP2C19 isoform may suppress the metabolism of omeprazole, subsequently altering its metabolic pathway to be metabolized by the CYP3A4 enzyme in order to maintain adequate biotransformation. Therefore, the competition for CYP3A4 may affect the metabolism of tacrolimus and result in its increased plasma concentrations, as well as in adverse reactions. Another mechanism has been related to the genetic polymorphism of the CYP2C19 isoform. Since all these interactions may lead to dysfunctions of the transplanted kidney, it seems significant to eliminate their consequences, for instance via the administration of drugs which are neither substrates, nor inhibitors of the CYP3A4 enzyme. Finally, the nephrotoxic effect of omeprazole should also be accounted for. Bearing in mind the aforementioned observations, the aim of the presented paper was to review the available studies addressing the effect of omeprazole on the pharmacokinetics of tacrolimus.
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Affiliation(s)
- Miłosz Miedziaszczyk
- Department of Nephrology, Transplantology and Internal Medicine, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland.
| | - Ilona Idasiak-Piechocka
- Department of Nephrology, Transplantology and Internal Medicine, Poznan University of Medical Sciences, Przybyszewskiego 49, 60-355 Poznan, Poland
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Ye L, Zhang C, Duan Q, Shao Y, Zhou J. Association of Magnesium Depletion Score With Cardiovascular Disease and Its Association With Longitudinal Mortality in Patients With Cardiovascular Disease. J Am Heart Assoc 2023; 12:e030077. [PMID: 37681518 PMCID: PMC10547298 DOI: 10.1161/jaha.123.030077] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 08/03/2023] [Indexed: 09/09/2023]
Abstract
Background Dietary magnesium and serum magnesium play an important part in cardiovascular disease (CVD). However, the association between magnesium depletion score (MDS) and CVD development and prognosis remains unclear. This analysis examines the cross-sectional relationship between MDS and CVD, and the longitudinal association between MDS and all-cause and CVD mortality in individuals with CVD. Methods and Results In all, 42 711 individuals were selected from the National Health and Nutrition Examination Survey, including 5015 subjects with CVD. The association between MDS and total and individual CVDs was examined using the survey-weighted multiple logistic regression analysis. Among 5011 patients with CVD, 2285 and 927 participants were recorded with all-cause and CVD deaths, respectively. We applied survey-weighted Cox proportional hazards regression analyses to investigate the impact of MDS on the mortality of individuals with CVD. The CVD group had higher MDS levels than the non-CVD groups. After controlling all confounding factors, individuals with MDS of 2 and ≥3 had higher odds of total CVD and specific CVD than those with MDS of 0. Besides, each 1-unit increase in MDS was strongly related to the risk of total CVD and specific CVD. The relationship between MDS and total CVD was stable and significant in all subgroups. The fully adjusted Cox regression model indicated that high MDS, irrespective of MDS as a categorical or continuous variable, was significantly associated with an elevated risk of all-cause and CVD deaths. Conclusions MDS is a vital risk factor for the prevalence and mortality of individuals with CVD.
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Affiliation(s)
- Liu Ye
- The First BranchThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Cheng Zhang
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Qin Duan
- The First BranchThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Yue Shao
- Department of Cardiothoracic SurgeryThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
| | - Jianzhong Zhou
- Department of CardiologyThe First Affiliated Hospital of Chongqing Medical UniversityChongqingChina
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Romero Calvo L, Garcia-Blanco MJ, Valenzuela F, Álvarez Granda J. Osmotic Demyelination Syndrome in a Normonatremic Patient Under Treatment With Proton Pump Inhibitors. Cureus 2023; 15:e44472. [PMID: 37791144 PMCID: PMC10544346 DOI: 10.7759/cureus.44472] [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] [Accepted: 08/31/2023] [Indexed: 10/05/2023] Open
Abstract
A 66-year-old woman was admitted to the emergency department with diarrhea, nausea, and vomiting as well as low-grade fever. She was initially treated with ciprofloxacin and metronidazole with symptomatic improvement and was discharged. One week later, she returned to the emergency department for gait instability, dizziness, and vomiting and had a witnessed generalized tonic-clonic seizure in the hospital. During both admissions, the presence of ionic alterations such as severe hypomagnesemia, hypophosphatemia, and hypokalemia stood out, while sodium levels remained normal. Among her antecedents, she had a hiatal hernia and had been receiving treatment with omeprazole for years.
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Affiliation(s)
- Lidia Romero Calvo
- Internal Medicine, Hospital Central de la Defensa Gomez Ulla, Madrid, ESP
| | - Maria J Garcia-Blanco
- Medicine, Universidad de Alcalá, Alcalá de Henares, ESP
- Internal Medicine, Hospital Central de la Defensa Gomez Ulla, Madrid, ESP
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Magnesium Administration in Chronic Kidney Disease. Nutrients 2023; 15:nu15030547. [PMID: 36771254 PMCID: PMC9920010 DOI: 10.3390/nu15030547] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/24/2023] Open
Abstract
Awareness of the clinical relevance of magnesium in medicine has increased over the last years, especially for people with chronic kidney disease (CKD), due to magnesium's role in vascular calcification and mineral metabolism. The inverse association between serum magnesium and clinically relevant, adverse outcomes is well-established in people with CKD. Subsequent intervention studies have focused on the effect of magnesium administration, mainly in relation to cardiovascular diseases, mineral bone metabolism, and other metabolic parameters. The most commonly used routes of magnesium administration are orally and by increasing dialysate magnesium. Several oral magnesium formulations are available and the daily dosage of elemental magnesium varies highly between studies, causing considerable heterogeneity. Although data are still limited, several clinical studies demonstrated that magnesium administration could improve parameters of vascular function and calcification and mineral metabolism in people with CKD. Current clinical research has shown that magnesium administration in people with CKD is safe, without concerns for severe hypermagnesemia or negative interference with bone metabolism. It should be noted that there are several ongoing magnesium intervention studies that will contribute to the increasing knowledge on the potential of magnesium administration in people with CKD.
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Chamniansawat S, Suksridechacin N, Thongon N. Current opinion on the regulation of small intestinal magnesium absorption. World J Gastroenterol 2023; 29:332-342. [PMID: 36687126 PMCID: PMC9846944 DOI: 10.3748/wjg.v29.i2.332] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/25/2022] [Accepted: 11/19/2022] [Indexed: 01/06/2023] Open
Abstract
Magnesium (Mg2+) has an important role in numerous biological functions, and Mg2+ deficiency is associated with several diseases. Therefore, adequate intestinal absorption of Mg2+ is vital for health. The small intestine was previously thought to absorb digested Mg2+ exclusively through an unregulated paracellular mechanism, which is responsible for approximately 90% of total Mg2+ absorption. Recent studies, however, have revealed that the duodenum, jejunum, and ileum absorb Mg2+ through both transcellular and paracellular routes. Several regulatory factors of small intestinal Mg2+ uptake also have been explored, e.g., parathyroid hormone, fibroblast growth factor-23, apical acidity, proton pump inhibitor, and pH-sensing channel and receptors. The mechanistic factors underlying proton pump inhibitor suppression of small intestinal Mg2+, such as magnesiotropic protein dysfunction, higher mucosal bicarbonate secretion, Paneth cell dysfunction, and intestinal inflammation, are currently being explored. The potential role of small intestinal microbiomes in Mg2+ absorption has also been proposed. In this article, we reviewed the current knowledge on the mechanisms and regulatory factors of small intestinal Mg2+ absorption.
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Affiliation(s)
- Siriporn Chamniansawat
- Division of Anatomy, Department of Medical Sciences, Faculty of Allied Health Sciences, Burapha University, Muang 20131, Chonburi, Thailand
| | - Nasisorn Suksridechacin
- Biodiversity Research Centre, Thailand Institute of Scientific and Technological Research, Khlong Luang 12120, Pathum Thani, Thailand
| | - Narongrit Thongon
- Division of Physiology, Department of Medical Sciences, Faculty of Allied Health Sciences, Burapha University, Muang 20131, Chonburi, Thailand
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11
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Gommers LMM, Hoenderop JGJ, de Baaij JHF. Mechanisms of proton pump inhibitor-induced hypomagnesemia. Acta Physiol (Oxf) 2022; 235:e13846. [PMID: 35652564 PMCID: PMC9539870 DOI: 10.1111/apha.13846] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022]
Abstract
Proton pump inhibitors (PPIs) reliably suppress gastric acid secretion and are therefore the first-line treatment for gastric acid-related disorders. Hypomagnesemia (serum magnesium [Mg2+ ] <0.7 mmol/L) is a commonly reported side effect of PPIs. Clinical reports demonstrate that urinary Mg2+ excretion is low in PPI users with hypomagnesemia, suggesting a compensatory mechanism by the kidney for malabsorption of Mg2+ in the intestines. However, the exact mechanism by which PPIs cause impaired Mg2+ absorption is still unknown. In this review, we show that current experimental evidence points toward reduced Mg2+ solubility in the intestinal lumen. Moreover, the absorption pathways in both the small intestine and the colon may be reduced by changes in the expression and activity of key transporter proteins. Additionally, the gut microbiome may contribute to the development of PPI-induced hypomagnesemia, as PPI use affects the composition of the gut microbiome. In this review, we argue that the increase of the luminal pH during PPI treatment may contribute to several of these mechanisms. Considering the fact that bacterial fermentation of dietary fibers results in luminal acidification, we propose that targeting the gut microbiome using dietary intervention might be a promising treatment strategy to restore hypomagnesemia in PPI users.
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Affiliation(s)
- Lisanne M. M. Gommers
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
| | - Joost G. J. Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
| | - Jeroen H. F. de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen the Netherlands
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12
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Abstract
Magnesium (Mg2+) is the second most abundant intracellular and fourth extracellular cation found in the body and is involved in a wide range of functions in the human cell and human physiology. Its role in most of the enzyme processes (ATP-ases)-stabilisation of nucleic acids (DNA, RNA), regulation of calcium and potassium ion channels, proliferation, glucose metabolism and apoptosis-make it one of the most important cations in the cell. Three pathogenetic mechanisms are mainly implicated in the development of hypomagnesaemia: reduced food intake, decreased intestinal absorption and increased renal excretion of Mg2+. This review presents the function of Mg2+, how it is handled in the kidney and the drugs that cause hypomagnesaemia. The frequency and the number of drugs like diuretics and proton-pump inhibitors (PPIs) that are used daily in medical practice are discussed in order to prevent and treat adverse effects by providing an insight into Mg2+ homeostasis.
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Affiliation(s)
- Periklis Katopodis
- Department of Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, London, UB8 3PH, UK.
| | - Emmanouil Karteris
- Department of Biosciences, College of Health and Life Sciences, Brunel University London, Uxbridge, London, UB8 3PH, UK
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Increased colonic K + excretion through inhibition of the H,K-ATPase type 2 helps reduce plasma K + level in a murine model of nephronic reduction. Sci Rep 2021; 11:1833. [PMID: 33469051 PMCID: PMC7815745 DOI: 10.1038/s41598-021-81388-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 12/21/2020] [Indexed: 11/09/2022] Open
Abstract
Hyperkalemia is frequently observed in patients at the end-stage of chronic kidney disease (CKD), and has possible harmful consequences on cardiac function. Many strategies are currently used to manage hyperkalemia, one consisting of increasing fecal K+ excretion through the administration of cation-exchange resins. In this study, we explored another more specific method of increasing intestinal K+ secretion by inhibiting the H,K-ATPase type 2 (HKA2), which is the main colonic K+ reabsorptive pathway. We hypothetised that the absence of this pump could impede the increase of plasma K+ levels following nephronic reduction (N5/6) by favoring fecal K+ secretion. In N5/6 WT and HKA2KO mice under normal K+ intake, the plasma K+ level remained within the normal range, however, a load of K+ induced strong hyperkalemia in N5/6 WT mice (9.1 ± 0.5 mM), which was significantly less pronounced in N5/6 HKA2KO mice (7.9 ± 0.4 mM, p < 0.01). This was correlated to a higher capacity of HKA2KO mice to excrete K+ in their feces. The absence of HKA2 also increased fecal Na+ excretion by inhibiting its colonic ENaC-dependent absorption. We also showed that angiotensin-converting-enzyme inhibitor like enalapril, used to treat hypertension during CKD, induced a less severe hyperkalemia in N5/6 HKA2KO than in N5/6 WT mice. This study therefore provides the proof of concept that the targeted inhibition of HKA2 could be a specific therapeutic maneuver to reduce plasma K+ levels in CKD patients.
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The Perilous PPI: Proton Pump Inhibitor as a Cause of Clinically Significant Hypomagnesaemia. J ASEAN Fed Endocr Soc 2021; 35:109-113. [PMID: 33442177 PMCID: PMC7784231 DOI: 10.15605/jafes.035.01.18] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2020] [Accepted: 02/26/2020] [Indexed: 11/22/2022] Open
Abstract
Proton pump inhibitors (PPIs) are the mainstay of therapy for all gastric acid related diseases and are commonly used in current clinical practice. Although widely regarded as safe, PPIs have been associated with a variety of adverse effects, including hypomagnesaemia. The postulated mechanism of PPI-related hypomagnesaemia involves inhibition of intestinal magnesium absorption via transient receptor potential melastin (TRPM) 6 and 7 cation channels. PPIinduced hypomagnesaemia (PPIH) has become a well recognized phenomenon since it was first reported in 2006. Clinical concerns arise from growing number of case reports presenting PPIH as a consequence of long-term PPI use, with more than 30 cases published to date. In this article, we report 2 cases of PPIH associated with the use of pantoprazole. Both patients presented with severe hypomagnesaemia and hypocalcaemia. One of them had associated hypokalemia and cardiac arrhythmia. A casual relation with PPIs postulated and supported by resolution of electrolyte abnormalities after discontinuation of PPIs.
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15
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Suksridechacin N, Kulwong P, Chamniansawat S, Thongon N. Effect of prolonged omeprazole administration on segmental intestinal Mg 2+ absorption in male Sprague-Dawley rats. World J Gastroenterol 2020; 26:1142-1155. [PMID: 32231419 PMCID: PMC7093313 DOI: 10.3748/wjg.v26.i11.1142] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 02/06/2020] [Accepted: 03/05/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND The exact mechanism of proton pump inhibitors (PPIs)-induced hypomagnesemia (PPIH) is largely unknown. Previous studies proposed that PPIH is a consequence of intestinal Mg2+ malabsorption. However, the mechanism of PPIs-suppressed intestinal Mg2+ absorption is under debate.
AIM To investigate the effect of 12-wk and 24-wk omeprazole injection on the total, transcellular, and paracellular Mg2+ absorption in the duodenum, jejunum, ileum, and colon of male Sprague-Dawley rats.
METHODS The rats received 20 mg/kg∙d subcutaneous omeprazole injection for 12 or 24 wk. Plasma and urinary Mg2+, Ca2+, and PO43− levels were measured. The plasma concentrations of 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF-23), epidermal growth factor (EGF), and insulin were also observed. The duodenum, jejunum, ileum, and colon of each rat were mounted onto individual modified Using chamber setups to study the rates of total, transcellular, and paracellular Mg2+ absorption simultaneously. The expression of transient receptor potential melastatin 6 (TRPM6) and cyclin M4 (CNNM4) in the entire intestinal tract was also measured.
RESULTS Single-dose omeprazole injection significantly increased the intraluminal pH of the stomach, duodenum, and jejunum. Omeprazole injection for 12 and 24 wk induced hypomagnesemia with reduced urinary Mg2+ excretion. The plasma Ca2+ was normal but the urinary Ca2+ excretion was reduced in rats with PPIH. The plasma and urinary PO43− levels increased in PPIH rats. The levels of 1α,25(OH)2D3 and FGF-23 increased, whereas that of plasma EGF decreased in the omeprazole-treated rats. The rates of the total, transcellular, and paracellular Mg2+ absorption was significantly lower in the duodenum, jejunum, ileum, and colon of the rats with PPIH than in those of the control rats. The percent suppression of Mg2+ absorption in the duodenum, jejunum, ileum, and colon of the rats with PPIH compared with the control rats was 81.86%, 70.59%, 69.45%, and 39.25%, respectively. Compared with the control rats, the rats with PPIH had significantly higher TRPM6 and CNNM4 expression levels throughout the intestinal tract.
CONCLUSION Intestinal Mg2+ malabsorption was observed throughout the intestinal tract of rats with PPIH. PPIs mainly suppressed small intestinal Mg2+ absorption. Omeprazole exerted no effect on the intraluminal acidic pH in the colon. Thus, the lowest percent suppression of total Mg2+ absorption was found in the colon. The expression levels of TRPM6 and CNNM4 increased, indicating the presence of a compensatory response to Mg2+ malabsorption in rats with PPIH. Therefore, the small intestine is an appropriate segment that should be modulated to counteract PPIH.
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Affiliation(s)
- Nasisorn Suksridechacin
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
| | - Punnisa Kulwong
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
| | - Siriporn Chamniansawat
- Division of Anatomy, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
| | - Narongrit Thongon
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
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16
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Roni MSR, Li G, Mikulsky BN, Knutson DE, Mian MY, Zahn NM, Cook JM, Stafford DC, Arnold LA. The Effects of pH on the Structure and Bioavailability of Imidazobenzodiazepine-3-Carboxylate MIDD0301. Mol Pharm 2020; 17:1182-1192. [PMID: 32069056 DOI: 10.1021/acs.molpharmaceut.9b01210] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
We describe the effects of pH on the structure and bioavailability of MIDD0301, an oral lead compound for asthma. MIDD0301 interacts with peripheral GABAA receptors to reduce lung inflammation and airway smooth muscle constriction. The structure of MIDD0301 combines basic imidazole and carboxylic acid function in the same diazepine scaffold, resulting in high solubility at neutral pH. Furthermore, we demonstrated that MIDD0301 can interconvert between a seven-membered ring structure at neutral pH and an acyclic compound at or below pH 3. Both structures have two stable conformers in solution that can be observed by 1H NMR at room temperature. Kinetic analysis showed opening and closing of the seven-membered ring of MIDD0301 at gastric and intestinal pH, occurring with different rate constants. However, in vivo studies showed that the interconversion kinetics are fast enough to yield similar MIDD0301 blood and lung concentrations for neutral and acidic formulations. Importantly, acidic and neutral formulations of MIDD0301 exhibit high lung distribution with low concentrations in brain. These findings demonstrate that MIDD0301 interconverts between stable structures at neutral and acidic pH without changes in bioavailability, further supporting its formulation as an oral asthma medication.
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Affiliation(s)
- M S Rashid Roni
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States
| | - Guanguan Li
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States
| | | | - Daniel E Knutson
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States
| | - Md Yeunus Mian
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States
| | - Nicolas M Zahn
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States
| | - James M Cook
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States
| | - Douglas C Stafford
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States.,Pantherics Incorporated, La Jolla, California 92037, United States
| | - Leggy A Arnold
- Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53201, United States.,Pantherics Incorporated, La Jolla, California 92037, United States
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17
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Walter C, Rafael C, Lasaad S, Baron S, Salhi A, Crambert G. H,K-ATPase type 2 regulates gestational extracellular compartment expansion and blood pressure in mice. Am J Physiol Regul Integr Comp Physiol 2020; 318:R320-R328. [PMID: 31913688 DOI: 10.1152/ajpregu.00067.2019] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The modifications of the hemodynamic system and hydromineral metabolism are physiological features characterizing a normal gestation. Thus, the ability to expand plasma volume without increasing the level of blood pressure is necessary for the correct perfusion of the placenta. The kidney is essential in this adaptation by reabsorbing avidly sodium and fluid. In this study, we observed that the H,K-ATPase type 2 (HKA2), an ion pump expressed in kidney and colon and already involved in the control of the K+ balance during gestation, is also required for the correct plasma volume expansion and to maintain normal blood pressure. Indeed, compared with WT pregnant mice that exhibit a 1.6-fold increase of their plasma volume, pregnant HKA2-null mice (HKA2KO) only modestly expand their extracellular volume (×1.2). The renal expression of the epithelial Na channel (ENaC) α- and γ-subunits and that of the pendrin are stimulated in gravid WT mice, whereas the Na/Cl- cotransporter (NCC) expression is downregulated. These modifications are all blunted in HKA2KO mice. This impeded renal adaptation to gestation is accompanied by the development of hypotension in the pregnant HKA2KO mice. Altogether, our results showed that the absence of the HKA2 during gestation leads to an "underfilled" situation and has established this transporter as a key player of the renal control of salt and potassium metabolism during gestation.
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Affiliation(s)
- Christine Walter
- Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Sorbonne Paris Cité Université, Université Paris Descartes, Université Paris Diderot, Paris, France.,Centre National de la Recherche Scientifique, ERL 8228, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
| | - Chloé Rafael
- Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Sorbonne Paris Cité Université, Université Paris Descartes, Université Paris Diderot, Paris, France.,Centre National de la Recherche Scientifique, ERL 8228, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
| | - Samia Lasaad
- Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Sorbonne Paris Cité Université, Université Paris Descartes, Université Paris Diderot, Paris, France.,Centre National de la Recherche Scientifique, ERL 8228, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
| | - Stéphanie Baron
- Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Sorbonne Paris Cité Université, Université Paris Descartes, Université Paris Diderot, Paris, France.,Centre National de la Recherche Scientifique, ERL 8228, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France.,Hôpital Européen Georges Pompidou, Laboratoire de Physiologie, Paris, France
| | - Amel Salhi
- Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Sorbonne Paris Cité Université, Université Paris Descartes, Université Paris Diderot, Paris, France.,Centre National de la Recherche Scientifique, ERL 8228, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
| | - Gilles Crambert
- Centre de Recherche des Cordeliers, Institut National de la Santé et de la Recherche Médicale, Sorbonne Université, Sorbonne Paris Cité Université, Université Paris Descartes, Université Paris Diderot, Paris, France.,Centre National de la Recherche Scientifique, ERL 8228, Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
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18
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Wiciński M, Malinowski B, Puk O, Górski K, Adamkiewicz D, Chojnacki G, Walczak M, Wódkiewicz E, Szambelan M, Adamska P, Skibińska K, Socha M, Słupski M, Pawlak-Osińska K. Possible Effects of Proton Pump Inhibitors on Hearing Loss Development. BIOMED RESEARCH INTERNATIONAL 2019; 2019:4853695. [PMID: 31915695 PMCID: PMC6935450 DOI: 10.1155/2019/4853695] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 05/24/2019] [Accepted: 07/09/2019] [Indexed: 12/14/2022]
Abstract
Considered safe and often available as over-the-counter (OTC) drugs, proton pump inhibitors (PPI) are one of the most frequently used medicines. Over recent years much research analyzing PPI has been conducted and these studies shed light on PPI side effects and the mechanisms of these processes. In this study we summarize the findings of these studies and through deduction present some hypotheses on the impact of PPI on health. Of particular interest is the impact of PPI on hearing loss development. However, despite this side effect being localized, its mechanisms are complex, systemic and involve changes in whole body. This paper summarizes how through, inter alia, alterations in the circulatory system, respiratory system, central nervous system and metabolism PPI can cause hearing impairment, which can occur in every age group and is connected with long-term use of this group of drugs. This article also discusses the role PPI plays in the acceleration of presbycusis development, in relation to the fact that older people are the group who most frequently use PPI in long term. Hearing loss negatively impacts affects quality of life, especially among older patients who are also the most afflicted group; administration of PPI should therefore be considered carefully, taking into consideration all potential benefits and side effects.
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Affiliation(s)
- Michał Wiciński
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Bartosz Malinowski
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Oskar Puk
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Karol Górski
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Dawid Adamkiewicz
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Grzegorz Chojnacki
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Maciej Walczak
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Eryk Wódkiewicz
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Monika Szambelan
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Paulina Adamska
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Kamila Skibińska
- Department of Pharmacology and Therapeutics, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Maciej Socha
- Department of Obstetrics, Gynecology and Gynecological Oncology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Ujejskiego 75, 85-168 Bydgoszcz, Poland
| | - Maciej Słupski
- Department of Hepatobiliary and General Surgery, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, M. Curie 9, 85-090 Bydgoszcz, Poland
| | - Katarzyna Pawlak-Osińska
- Department of Pathophysiology of Hearing and Balance System, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
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19
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Lee L, Ramos-Alvarez I, Ito T, Jensen RT. Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome. Int J Mol Sci 2019; 20:5128. [PMID: 31623145 PMCID: PMC6829234 DOI: 10.3390/ijms20205128] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 10/08/2019] [Accepted: 10/13/2019] [Indexed: 02/07/2023] Open
Abstract
The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25-70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10-20 years). Zollinger-Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.
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Affiliation(s)
- Lingaku Lee
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka 812-8582, Japan.
| | | | - Tetsuhide Ito
- Neuroendocrine Tumor Centra, Fukuoka Sanno Hospital, International University of Health and Welfare 3-6-45 Momochihama, Sawara-Ku, Fukuoka 814-0001, Japan.
| | - Robert T Jensen
- Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD 20892-1804, USA.
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20
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Gommers LMM, Ederveen THA, van der Wijst J, Overmars-Bos C, Kortman GAM, Boekhorst J, Bindels RJM, de Baaij JHF, Hoenderop JGJ. Low gut microbiota diversity and dietary magnesium intake are associated with the development of PPI-induced hypomagnesemia. FASEB J 2019; 33:11235-11246. [PMID: 31299175 DOI: 10.1096/fj.201900839r] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Proton pump inhibitors (PPIs) are used by millions of patients for the treatment of stomach acid-reflux diseases. Although PPIs are generally considered safe, about 13% of the users develop hypomagnesemia. Despite rising attention for this issue, the underlying mechanism is still unknown. Here, we examine whether the gut microbiome is involved in the development of PPI-induced hypomagnesemia in wild-type C57BL/6J mice. After 4 wk of treatment under normal or low dietary Mg2+ availability, omeprazole significantly reduced serum Mg2+ levels only in mice on a low-Mg2+ diet without affecting the mRNA expression of colonic or renal Mg2+ transporters. Overall, 16S rRNA gene sequencing revealed a lower gut microbial diversity in omeprazole-treated mice. Omeprazole induced a shift in microbial composition, which was associated with a 3- and 2-fold increase in the abundance of Lactobacillus and Bifidobacterium, respectively. To examine the metabolic consequences of these microbial alterations, the colonic composition of organic acids was evaluated. Low dietary Mg2+ intake, independent of omeprazole treatment, resulted in a 10-fold increase in formate levels. Together, these results imply that both omeprazole treatment and low dietary Mg2+ intake disturb the gut internal milieu and may pose a risk for the malabsorption of Mg2+ in the colon.-Gommers, L. M. M., Ederveen, T. H. A., van der Wijst, J., Overmars-Bos, C., Kortman, G. A. M., Boekhorst, J., Bindels, R. J. M., de Baaij, J. H. F., Hoenderop, J. G. J. Low gut microbiota diversity and dietary magnesium intake are associated with the development of PPI-induced hypomagnesemia.
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Affiliation(s)
- Lisanne M M Gommers
- Department of Physiology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RADBOUDUMC), Nijmegen, The Netherlands
| | - Thomas H A Ederveen
- Center for Molecular and Biomolecular Informatics (CMBI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.,NIZO Food Research, Ede, The Netherlands
| | - Jenny van der Wijst
- Department of Physiology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RADBOUDUMC), Nijmegen, The Netherlands
| | - Caro Overmars-Bos
- Department of Physiology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RADBOUDUMC), Nijmegen, The Netherlands
| | | | - Jos Boekhorst
- Center for Molecular and Biomolecular Informatics (CMBI), Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (Radboudumc), Nijmegen, The Netherlands.,NIZO Food Research, Ede, The Netherlands
| | - René J M Bindels
- Department of Physiology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RADBOUDUMC), Nijmegen, The Netherlands
| | - Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RADBOUDUMC), Nijmegen, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center (RADBOUDUMC), Nijmegen, The Netherlands
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21
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Magnesium: A Magic Bullet for Cardiovascular Disease in Chronic Kidney Disease? Nutrients 2019; 11:nu11020455. [PMID: 30813254 PMCID: PMC6412491 DOI: 10.3390/nu11020455] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Revised: 02/17/2019] [Accepted: 02/19/2019] [Indexed: 12/19/2022] Open
Abstract
Magnesium is essential for many physiological functions in the human body. Its homeostasis involves dietary intake, absorption, uptake and release from bone, swifts between the intra- and extracellular compartment, and renal excretion. Renal excretion is mainly responsible for regulation of magnesium balance. In chronic kidney disease (CKD), for a long time the general policy has been limiting magnesium intake. However, this may not be appropriate for many patients. The reference ranges for magnesium are not necessarily optimal concentrations, and risks for insufficient magnesium intake exist in patients with CKD. In recent years, many observational studies have shown that higher (in the high range of “normal” or slightly above) magnesium concentrations are associated with better survival in CKD cohorts. This review gives an overview of epidemiological associations between magnesium and overall and cardiovascular survival in patients with CKD. In addition, potential mechanisms explaining the protective role of magnesium in clinical cardiovascular outcomes are described by reviewing evidence from in vitro studies, animal studies, and human intervention studies with non-clinical endpoints. This includes the role of magnesium in cardiac arrhythmia, heart failure, arterial calcification, and endothelial dysfunction. Possible future implications will be addressed, which will need prospective clinical trials with relevant clinical endpoints before these can be adopted in clinical practice.
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22
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Thongon N, Chamniansawat S. The inhibitory role of purinergic P2Y receptor on Mg 2+ transport across intestinal epithelium-like Caco-2 monolayer. J Physiol Sci 2019; 69:129-141. [PMID: 30032468 PMCID: PMC10717015 DOI: 10.1007/s12576-018-0628-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2018] [Accepted: 07/13/2018] [Indexed: 02/06/2023]
Abstract
The mechanism of proton pump inhibitors (PPIs) suppressing intestinal Mg2+ uptake is unknown. The present study aimed to investigate the role of purinergic P2Y receptors in the regulation of Mg2+ absorption in normal and omeprazole-treated intestinal epithelium-like Caco-2 monolayers. Omeprazole suppressed Mg2+ transport across Caco-2 monolayers. An agonist of the P2Y2 receptor, but not the P2Y4 or P2Y6 receptor, suppressed Mg2+ transport across control and omeprazole-treated monolayers. Omeprazole enhanced P2Y2 receptor expression in Caco-2 cells. Forskolin and P2Y2 receptor agonist markedly enhanced apical HCO3- secretion by control and omeprazole-treated monolayers. The P2Y2 receptor agonist suppressed Mg2+ transport and stimulated apical HCO3- secretion through the Gq-protein coupled-phospholipase C (PLC) dependent pathway. Antagonists of cystic fibrosis transmembrane conductance regulator (CFTR) and Na+-HCO3- cotransporter-1 (NBCe1) could nullify the inhibitory effect of P2Y2 receptor agonist on Mg2+ transport across control and omeprazole-treated Caco-2 monolayers. Our results propose an inhibitory role of P2Y2 on intestinal Mg2+ absorption.
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Affiliation(s)
- Narongrit Thongon
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd, Saensook, Muang, Chonburi, 20131, Thailand.
| | - Siriporn Chamniansawat
- Division of Anatomy, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd, Saensook, Muang, Chonburi, 20131, Thailand
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23
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Cheminet G, Clain G, Jannot AS, Ranque B, Passeron A, Michon A, De Luna G, Diehl JL, Oudard S, Cellier C, Karras A, Vedié B, Prot-Bertoye C, Pouchot J, Arlet JB. Extreme hypomagnesemia: characteristics of 119 consecutive inpatients. Intern Emerg Med 2018; 13:1201-1209. [PMID: 29951810 DOI: 10.1007/s11739-018-1898-7] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/25/2018] [Accepted: 06/16/2018] [Indexed: 01/24/2023]
Abstract
Extreme hypomagnesemia (hypoMg) can be encountered in many situations, but little data currently exist. Our aim is to describe the epidemiological, clinical, etiological characteristics, and the biological abnormalities of consecutive inpatients with extreme hypomagnesemia. In our observational monocentric study, between 1st July 2000 and April 2015, all inpatients with extreme hypomagnesemia, defined by at least one plasma magnesium concentration (PMg) below 0.3 mmol/L, were included. Demographic, clinical, biological characteristics and the drugs prescribed before the qualifying PMg measurement were retrospectively collected. 41,069 patients had at least one PMg assessment. The prevalence of extreme hypomagnesemia is 0.3% (119 inpatients). The median age is 70 years, 52% are women. The patients were mainly hospitalized in intensive care (n = 37, 31.1%), oncology (n = 21, 17.6%), gastroenterology (n = 18, 15.1%) and internal medicine (n = 16, 13.4%) departments. One hundred patients (84%) had a medical history of gastrointestinal disease (39% with bowel resections, 24% with stoma), and 50 (42%) had a cancer history. The drugs most commonly prescribed (known to induce hypoMg) are proton pump inhibitors (PPI) (n = 77, 70%), immunosuppressive regimens (n = 25, 22.5%), platinum salt-based chemotherapies (n = 19, 17.1%), and diuretics (n = 22, 19.8%). The suspected causes of hypomagnesemia are often multiple, but drugs (46%, including PPI in 19%) and chronic gastrointestinal disorders (37%) are prominent. Associated electrolyte disturbances include hypocalcemia (77%) and mild hypokalemia (51%). The 1-month mortality from all causes is 16%. Extreme hypomagnesemia is rare in inpatients, and is frequently associated with severe hypocalcemia. Digestive disorders and drugs are the main contributory causes.
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Affiliation(s)
- Geoffrey Cheminet
- Service de Médecine Interne, Internal medicine Department, Georges Pompidou European Hospital, AP-HP, 20 rue Leblanc, 75015, Paris, France
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
| | - Gabrielle Clain
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
- Medical Information Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Anne-Sophie Jannot
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
- Medical Information Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Brigitte Ranque
- Service de Médecine Interne, Internal medicine Department, Georges Pompidou European Hospital, AP-HP, 20 rue Leblanc, 75015, Paris, France
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
| | - Amélie Passeron
- Service de Médecine Interne, Internal medicine Department, Georges Pompidou European Hospital, AP-HP, 20 rue Leblanc, 75015, Paris, France
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
| | - Adrien Michon
- Service de Médecine Interne, Internal medicine Department, Georges Pompidou European Hospital, AP-HP, 20 rue Leblanc, 75015, Paris, France
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
| | - Gonzalo De Luna
- Service de Médecine Interne, Internal medicine Department, Georges Pompidou European Hospital, AP-HP, 20 rue Leblanc, 75015, Paris, France
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
| | - Jean-Luc Diehl
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
- Medical Intensive Care Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Stéphane Oudard
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
- Oncology Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Christophe Cellier
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
- Gastroenterology Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Alexandre Karras
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
- Nephrology Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Benoit Vedié
- Biochemistry Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Caroline Prot-Bertoye
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
- Renal Physiology Department, Georges Pompidou European Hospital, AP-HP, Paris, France
| | - Jacques Pouchot
- Service de Médecine Interne, Internal medicine Department, Georges Pompidou European Hospital, AP-HP, 20 rue Leblanc, 75015, Paris, France
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France
| | - Jean-Benoît Arlet
- Service de Médecine Interne, Internal medicine Department, Georges Pompidou European Hospital, AP-HP, 20 rue Leblanc, 75015, Paris, France.
- Faculté de Médecine Paris Descartes, Sorbonne Paris-Cité, Paris, France.
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24
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Nie M, Bal MS, Liu J, Yang Z, Rivera C, Wu XR, Hoenderop JGJ, Bindels RJM, Marciano DK, Wolf MTF. Uromodulin regulates renal magnesium homeostasis through the ion channel transient receptor potential melastatin 6 (TRPM6). J Biol Chem 2018; 293:16488-16502. [PMID: 30139743 DOI: 10.1074/jbc.ra118.003950] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2018] [Revised: 08/21/2018] [Indexed: 12/15/2022] Open
Abstract
Up to 15% of the population have mild to moderate chronic hypomagnesemia, which is associated with type 2 diabetes mellitus, hypertension, metabolic syndrome, and chronic kidney disease. The kidney is the key organ for magnesium homeostasis, but our understanding of renal magnesium regulation is very limited. Uromodulin (UMOD) is the most abundant urinary protein in humans, and here we report that UMOD has a role in renal magnesium homeostasis. Umod-knockout (Umod -/-) mice excreted more urinary magnesium than WT mice and displayed up-regulation of genes promoting magnesium absorption. The majority of magnesium is absorbed in the thick ascending limb. However, both mouse strains responded similarly to the diuretic agent furosemide, indicating appropriate function of the thick ascending limb in the Umod -/- mice. Magnesium absorption is fine-tuned in the distal convoluted tubule (DCT) via the apical magnesium channel transient receptor potential melastatin 6 (TRPM6). We observed decreased apical Trpm6 staining in the DCT of Umod -/- mice. Applying biotinylation assays and whole-cell patch-clamp recordings, we found that UMOD enhances TRPM6 cell-surface abundance and current density from the extracellular space. UMOD physically interacted with TRPM6 and thereby impaired dynamin-dependent TRPM6 endocytosis. WT mice fed a low-magnesium diet had an increased urinary UMOD secretion compared with the same mice on a regular diet. Our results suggest that increased urinary UMOD secretion in low-magnesium states reduces TRPM6 endocytosis and thereby up-regulates TRPM6 cell-surface abundance to defend against further urinary magnesium losses.
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Affiliation(s)
| | | | - Jie Liu
- From the Departments of Pediatrics and
| | - Zhufeng Yang
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390
| | | | - Xue-Ru Wu
- the Departments of Urology and Pathology, New York University School of Medicine, New York, New York 10016, and
| | - Joost G J Hoenderop
- the Department of Physiology, Radboud Center for Molecular Life Sciences, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands
| | - René J M Bindels
- the Department of Physiology, Radboud Center for Molecular Life Sciences, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands
| | - Denise K Marciano
- Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390
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25
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Leenders NHJ, van Ittersum FJ, Hoekstra T, Hoenderop JGJ, Vervloet MG. Routine hemodialysis induces a decline in plasma magnesium concentration in most patients: a prospective observational cohort study. Sci Rep 2018; 8:10256. [PMID: 29980722 PMCID: PMC6035165 DOI: 10.1038/s41598-018-28629-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Accepted: 06/26/2018] [Indexed: 12/25/2022] Open
Abstract
In hemodialysis patients, lower plasma magnesium (Mg) concentrations are associated with a higher overall and cardiovascular mortality. The optimal concentration appears to be above the reference range for the healthy population. Plasma Mg is not routinely measured after hemodialysis. Aim of this study was to determine the effect of routine hemodialysis on plasma Mg. Plasma Mg was measured in duplicate before (Mgpre) and after (Mgpost) dialysis in 6 consecutive hemodialysis sessions of 34 patients using a fixed 0.50 mmol/L dialysate Mg concentration. Mean Mgpre was 0.88 mmol/L (±0.14) and mean Mgpost was statistically significantly lower: mean intra-dialytic decline 0.10 mmol/L (95%-CI 0.06-0.13). A 0.10 mmol/L higher Mgpre was associated with a 0.03 mmol/L higher Mgpost (95%-CI 0.024-0.037). At a Mgpre of 0.74 mmol/L, Mgpost equalled Mgpre. There was an intra-dialytic decline of plasma Mg at higher Mgpre values and an increase at lower Mgpre values. In conclusion, in the majority of the hemodialysis patients, Mgpre concentrations are in the reference range of the healthy population, which may be too low for hemodialysis patients. Routine hemodialysis with the widely used 0.50 mmol/L dialysate Mg concentration, further declines magnesium in the majority of patients. Current dialysate Mg concentrations may be too low.
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Affiliation(s)
- Nicoline H J Leenders
- Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands.
- Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands.
| | - Frans J van Ittersum
- Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands
| | - Tiny Hoekstra
- Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Marc G Vervloet
- Department of Nephrology, VU University Medical Center, Amsterdam, The Netherlands
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26
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William JH, Richards K, Danziger J. Magnesium and Drugs Commonly Used in Chronic Kidney Disease. Adv Chronic Kidney Dis 2018; 25:267-273. [PMID: 29793666 DOI: 10.1053/j.ackd.2018.01.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2017] [Revised: 01/20/2018] [Accepted: 01/22/2018] [Indexed: 12/20/2022]
Abstract
As with other electrolytes, magnesium homeostasis depends on the balance between gastrointestinal absorption and kidney excretion. Certain drugs used commonly in patients with CKD can decrease gastrointestinal ingestion and kidney reclamation, and potentially cause hypomagnesemia. Other magnesium-containing drugs such as laxatives and cathartics can induce hypermagnesemia, particularly in those with impaired glomerular filtration and magnesium excretion. In this review, we will discuss the potential magnesium complications associated with a range of commonly encountered drugs in the care of CKD patients, discuss the potential mechanisms, and provide basic clinical recommendations.
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27
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Abstract
Proton-pump inhibitors (PPIs) are the most effective therapy for the full spectrum of gastric-acid-related diseases. However, in the past decade, a steadily increasing list of complications following long-term use of PPIs has been reported. Their potent acid-suppressive action induces several structural and functional changes within the gastric mucosa, including fundic gland polyps, enterochromaffin-like cell hyperplasia and hypergastrinaemia, which can be exaggerated in the presence of Helicobacter pylori infection. As discussed in this Review, most associations of PPIs with severe adverse events are not based on sufficient evidence because of confounding factors and a lack of plausible mechanisms. Thus, a causal relationship remains unproven in most associations, and further studies are needed. Awareness of PPI-associated risks should not lead to anxiety in patients but rather should induce the physician to consider the appropriate dosing and duration of PPI therapy, including long-term monitoring strategies in selected groups of patients because of their individual comorbidities and risk factors.
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28
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de Ávila BEF, Angsantikul P, Li J, Angel Lopez-Ramirez M, Ramírez-Herrera DE, Thamphiwatana S, Chen C, Delezuk J, Samakapiruk R, Ramez V, Obonyo M, Zhang L, Wang J. Micromotor-enabled active drug delivery for in vivo treatment of stomach infection. Nat Commun 2017; 8:272. [PMID: 28814725 PMCID: PMC5559609 DOI: 10.1038/s41467-017-00309-w] [Citation(s) in RCA: 354] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 06/19/2017] [Indexed: 12/30/2022] Open
Abstract
Advances in bioinspired design principles and nanomaterials have led to tremendous progress in autonomously moving synthetic nano/micromotors with diverse functionalities in different environments. However, a significant gap remains in moving nano/micromotors from test tubes to living organisms for treating diseases with high efficacy. Here we present the first, to our knowledge, in vivo therapeutic micromotors application for active drug delivery to treat gastric bacterial infection in a mouse model using clarithromycin as a model antibiotic and Helicobacter pylori infection as a model disease. The propulsion of drug-loaded magnesium micromotors in gastric media enables effective antibiotic delivery, leading to significant bacteria burden reduction in the mouse stomach compared with passive drug carriers, with no apparent toxicity. Moreover, while the drug-loaded micromotors reach similar therapeutic efficacy as the positive control of free drug plus proton pump inhibitor, the micromotors can function without proton pump inhibitors because of their built-in proton depletion function associated with their locomotion.Nano- and micromotors have been demonstrated in vitro for a range of applications. Here the authors demonstrate the in-vivo therapeutic use of micromotors to treat H. pylori infection.
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Affiliation(s)
| | - Pavimol Angsantikul
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Jinxing Li
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA
| | | | | | - Soracha Thamphiwatana
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Chuanrui Chen
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Jorge Delezuk
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Richard Samakapiruk
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Valentin Ramez
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA
| | - Marygorret Obonyo
- Department of Medicine, University of California San Diego, La Jolla, CA, 92093, USA
| | - Liangfang Zhang
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA.
| | - Joseph Wang
- Department of NanoEngineering, University of California San Diego, La Jolla, CA, 92093, USA.
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29
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Eberhard J, Macdonald A, Cundy T. Severe proton pump inhibitor-induced hypomagnesaemia in a mother and daughter. Intern Med J 2017; 47:341-342. [DOI: 10.1111/imj.13366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2016] [Revised: 08/10/2016] [Accepted: 09/13/2016] [Indexed: 11/27/2022]
Affiliation(s)
- Jeff Eberhard
- Department of Medicine; Wellington Hospital; Wellington New Zealand
| | | | - Tim Cundy
- Department of Medicine; University of Auckland; Auckland New Zealand
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30
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Thongon N, Penguy J, Kulwong S, Khongmueang K, Thongma M. Omeprazole suppressed plasma magnesium level and duodenal magnesium absorption in male Sprague-Dawley rats. Pflugers Arch 2016; 468:1809-1821. [PMID: 27866273 DOI: 10.1007/s00424-016-1905-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2016] [Revised: 10/18/2016] [Accepted: 11/09/2016] [Indexed: 02/06/2023]
Abstract
Hypomagnesemia is the most concerned side effect of proton pump inhibitors (PPIs) in chronic users. However, the mechanism of PPIs-induced systemic Mg2+ deficit is currently unclear. The present study aimed to elucidate the direct effect of short-term and long-term PPIs administrations on whole body Mg2+ homeostasis and duodenal Mg2+ absorption in rats. Mg2+ homeostasis was studied by determining the serum Mg2+ level, urine and fecal Mg2+ excretions, and bone and muscle Mg2+ contents. Duodenal Mg2+ absorption as well as paracellular charge selectivity were studied. Our result showed that gastric and duodenal pH markedly increased in omeprazole-treated rats. Omeprazole significantly suppressed plasma Mg2+ level, urinary Mg2+ excretion, and bone and muscle Mg2+ content. Thus, omeprazole induced systemic Mg2+ deficiency. By using Ussing chamber techniques, it was shown that omeprazole markedly suppressed duodenal Mg2+ channel-driven and Mg2+ channel-independent Mg2+ absorptions and cation selectivity. Inhibitors of mucosal HCO3- secretion significantly increased duodenal Mg2+ absorption in omeprazole-treated rats. We therefore hypothesized that secreted HCO3- in duodenum decreased luminal proton, this impeded duodenal Mg2+ absorption. Higher plasma total 25-OH vitamin D, diuresis, and urine PO43- were also demonstrated in hypomagnesemic rats. As a compensatory mechanism for systemic Mg2+ deficiency, the expressions of duodenal transient receptor potential melastatin 6 (TRPM6), cyclin M4 (CNNM4), claudin (Cldn)-2, Cldn-7, Cldn-12, and Cldn-15 proteins were enhanced in omeprazole-treated rats. Our findings support the potential role of duodenum on the regulation of Mg2+ homeostasis.
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Affiliation(s)
- Narongrit Thongon
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd., Saensook, Muang, Chonburi, 20131, Thailand.
| | - Jirawat Penguy
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd., Saensook, Muang, Chonburi, 20131, Thailand
| | - Sasikan Kulwong
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd., Saensook, Muang, Chonburi, 20131, Thailand
| | - Kanyanat Khongmueang
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd., Saensook, Muang, Chonburi, 20131, Thailand
| | - Matthana Thongma
- Division of Physiology, Department of Biomedical Sciences, Faculty of Allied Health Sciences, Burapha University, 169 Long-Hard Bangsaen Rd., Saensook, Muang, Chonburi, 20131, Thailand
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31
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Hess MW, de Baaij JHF, Broekman M, Bisseling TM, Haarhuis B, Tan A, Te Morsche R, Hoenderop JGJ, Bindels RJM, Drenth JPH. Inulin significantly improves serum magnesium levels in proton pump inhibitor-induced hypomagnesaemia. Aliment Pharmacol Ther 2016; 43:1178-85. [PMID: 27086738 DOI: 10.1111/apt.13619] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 01/26/2016] [Accepted: 03/18/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND Proton pump inhibitors (PPI) are among the most widely prescribed drugs to treat gastric acid-related disorders. PPI-induced hypomagnesaemia, a defect in intestinal absorption of Mg(2+) , can be a severe side effect of chronic PPI use. AIM To restore serum Mg(2+) concentrations in PPI-induced hypomagnesaemia patients by dietary supplementation with inulin fibres. METHODS Eleven patients with PPI-induced hypomagnesaemia and 10 controls were treated with inulin (20 g/day). Each trial consisted of two cycles of 14-day inulin treatment followed by a washout period of 14 days. Patients continued to use their PPI. Serum Mg(2+) levels served as the primary endpoint. RESULTS Inulin significantly enhanced serum Mg(2+) levels from 0.60 to 0.68 mmol/L in PPI-induced hypomagnesaemia patients, and from 0.84 to 0.93 mmol/L in controls. As a consequence 24 h urinary Mg(2+) excretion was significantly increased in patients with PPI-induced hypomagnesaemia (0.3-2.2 mmol/day). Symptoms related to hypomagnesaemia, including muscle cramps and paraesthesia, were reduced during intervention with inulin. CONCLUSION Inulin increases serum Mg(2+) concentrations under PPI maintenance in patients with PPI-induced hypomagnesaemia.
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Affiliation(s)
- M W Hess
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - J H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - M Broekman
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - T M Bisseling
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - B Haarhuis
- Department of Gastroenterology, Bernhoven Hospital, Uden, The Netherlands
| | - A Tan
- Department of Gastroenterology, Canisius-Wilhelmina-Hospital, Nijmegen, The Netherlands
| | - R Te Morsche
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - J G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - R J M Bindels
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - J P H Drenth
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, The Netherlands
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32
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Zhang F, Wang L, Wang JJ, Luo PF, Wang XT, Xia ZF. The caspase-1 inhibitor AC-YVAD-CMK attenuates acute gastric injury in mice: involvement of silencing NLRP3 inflammasome activities. Sci Rep 2016; 6:24166. [PMID: 27053298 PMCID: PMC4823746 DOI: 10.1038/srep24166] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 03/22/2016] [Indexed: 12/30/2022] Open
Abstract
This study evaluated the protective effects of inhibiting caspase-1 activity or gastric acid secretion on acute gastric injury in mice. AC-YVAD-CMK, omeprazole, or vehicle were administered to mice before cold-restraint stress- or ethanol-induced gastric injury. Survival rates and histological evidence of gastric injury of mice pretreated with AC-YVAD-CMK or omeprazole, and exposed to cold-restraint stress, improved significantly relative to the vehicle group. The increased levels of tumour necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-18 following cold-stress injury were decreased by AC-YVAD-CMK, but not omeprazole, pretreatment. The increased expression of CD68 in gastric tissues was inhibited significantly by AC-YVAD-CMK pretreatment. Inhibiting caspase-1 activity in the NLRP3 inflammasome decreased gastric cell apoptosis, and the expression of Bax and cleaved caspase-3. AC-YVAD-CMK pretreatment significantly inhibited cold-restraint stress-induced increases in the expression of phosphorylated IκB-alpha and P38. General anatomy and histological results showed the protective effect of AC-YVAD-CMK on ethanol-induced acute gastric injury. Overall, our results showed that the caspase-1 inhibitor AC-YVAD-CMK protected against acute gastric injury in mice by affecting the NLRP3 inflammasome and attenuating inflammatory processes and apoptosis. This was similar to the mechanism associated with NF-κB and P38 mitogen-activated protein kinase signalling pathways.
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Affiliation(s)
- Fang Zhang
- Department of Burn Surgery, the Second Military Medical University Affiliated Changhai Hospital, Shanghai 200433, China.,Number 73901 Troop of PLA, Shanghai 200439
| | - Liang Wang
- Department of Burn Surgery, the Second Military Medical University Affiliated Changhai Hospital, Shanghai 200433, China
| | - Jun-Jie Wang
- Department of Burn Surgery, the Second Military Medical University Affiliated Changhai Hospital, Shanghai 200433, China
| | - Peng-Fei Luo
- Department of Burn Surgery, the Second Military Medical University Affiliated Changhai Hospital, Shanghai 200433, China
| | - Xing-Tong Wang
- Department of Burn Surgery, the Second Military Medical University Affiliated Changhai Hospital, Shanghai 200433, China
| | - Zhao-Fan Xia
- Department of Burn Surgery, the Second Military Medical University Affiliated Changhai Hospital, Shanghai 200433, China
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33
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William JH, Danziger J. Proton-pump inhibitor-induced hypomagnesemia: Current research and proposed mechanisms. World J Nephrol 2016; 5:152-157. [PMID: 26981439 PMCID: PMC4777786 DOI: 10.5527/wjn.v5.i2.152] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2015] [Revised: 11/20/2015] [Accepted: 01/04/2016] [Indexed: 02/06/2023] Open
Abstract
Since the early reports nearly a decade ago, proton-pump inhibitor-induced hypomagnesemia (PPIH) has become a well-recognized phenomenon. While many observational studies in the inpatient and outpatient populations have confirmed the association of PPI exposure and serum magnesium concentrations, there are no prospective, controlled studies to support causation. Molecular mechanisms of magnesium transporters, including the pH-dependent regulation of transient receptor potential melastatin-6 transporters in the colonic enterocyte, have been proposed to explain the effect of PPIs on magnesium reabsorption, but may be a small part of a more complicated interplay of molecular biology, pharmacology, and genetic predisposition. This review explores the current state of research in the field of PPIH and the proposed mechanisms of this effect.
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Begley J, Smith T, Barnett K, Strike P, Azim A, Spake C, Richardson T. Proton pump inhibitor associated hypomagnasaemia - a cause for concern? Br J Clin Pharmacol 2016; 81:753-8. [PMID: 26613375 DOI: 10.1111/bcp.12846] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2015] [Revised: 11/05/2015] [Accepted: 11/12/2015] [Indexed: 12/28/2022] Open
Abstract
AIMS In recent years, there have been a number of case reports of severe hypomagnesaemia associated with proton pump inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. METHODS To our knowledge, we are the first to perform a prospective study to explore specifically proton pump inhibitor associated hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long term PPIs cross-sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. RESULTS For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross-sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. CONCLUSION We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually.
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Affiliation(s)
- Joe Begley
- Department of Clinical Biochemistry, Royal Bournemouth Hospital, Bournemouth
| | - Trevor Smith
- Department of Gastroenterology, Southampton Universities Hospital, Southampton
| | - Kirsty Barnett
- Department of Gastroenterology, Royal Bournemouth Hospital, Bournemouth
| | - Paul Strike
- Department of Statistics, Salisbury Hospital, Salisbury
| | - Adnan Azim
- Diabetes and Endocrine Centre, Royal Bournemouth Hospital, Bournemouth
| | - Claire Spake
- Diabetes and Endocrine Centre, Royal Bournemouth Hospital, Bournemouth
| | - Tristan Richardson
- Diabetes and Endocrine Centre, Royal Bournemouth Hospital, Bournemouth.,Centre of Postgraduate Medical Research and Education, Bournemouth University, Bournemouth, UK
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Stark CM, Nylund CM. Side Effects and Complications of Proton Pump Inhibitors: A Pediatric Perspective. J Pediatr 2016; 168:16-22. [PMID: 26409307 DOI: 10.1016/j.jpeds.2015.08.064] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2015] [Revised: 07/10/2015] [Accepted: 08/26/2015] [Indexed: 02/06/2023]
Affiliation(s)
- Christopher M Stark
- Department of Pediatrics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD
| | - Cade M Nylund
- Department of Pediatrics, F. Edward Hebert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD.
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William JH, Danziger J. Magnesium Deficiency and Proton-Pump Inhibitor Use: A Clinical Review. J Clin Pharmacol 2015; 56:660-8. [DOI: 10.1002/jcph.672] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 10/30/2015] [Indexed: 12/11/2022]
Affiliation(s)
| | - John Danziger
- Division of Nephrology; Beth Israel Deaconess Medical Center; Boston MA
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Proton Pump Inhibitor Use and Magnesium Concentrations in Hemodialysis Patients: A Cross-Sectional Study. PLoS One 2015; 10:e0143656. [PMID: 26618538 PMCID: PMC4664382 DOI: 10.1371/journal.pone.0143656] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2015] [Accepted: 11/06/2015] [Indexed: 12/15/2022] Open
Abstract
Magnesium concentration is a proven predictor of mortality in hemodialysis patients. Recent reports have indicated that proton pump inhibitor (PPI) use affects serum magnesium levels, however few studies have investigated the relationship between PPI use and magnesium levels in hemodialysis patients. This study aimed to clarify the association between PPI use and serum magnesium levels in hemodialysis patients. We designed this cross sectional study and included 1189 hemodialysis patients in stable condition. Associations between PPI and magnesium-related factors, as well as other possible confounders, were evaluated using a multiple regression model. We defined hypomagnesemia as a value < 2.0 mg/dL, and created comparable logistic regression models to assess the association between PPI use and hypomagnesemia. PPI use is associated with a significantly lower mean serum magnesium level than histamine 2 (H2) receptor antagonists or no acid-suppressive medications (mean [SD] PPI: 2.52 [0.45] mg/dL; H2 receptor antagonist: 2.68 [0.41] mg/dL; no acid suppressive medications: 2.68 [0.46] mg/dL; P = 0.001). Hypomagnesemia remained significantly associated with PPI (adjusted OR, OR: 2.05; 95% CI: 1.14–3.69; P = 0.017). PPI use is associated with an increased risk of hypomagnesemia in hemodialysis patients. Future prospective studies are needed to explore magnesium replacement in PPI users on hemodialysis.
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Dietary Inulin Fibers Prevent Proton-Pump Inhibitor (PPI)-Induced Hypocalcemia in Mice. PLoS One 2015; 10:e0138881. [PMID: 26397986 PMCID: PMC4580428 DOI: 10.1371/journal.pone.0138881] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 09/04/2015] [Indexed: 12/26/2022] Open
Abstract
Background Proton-pump inhibitor-induced hypomagnesemia (PPIH) is the most recognized side effect of proton-pump inhibitors (PPIs). Additionally, PPIH is associated with hypocalcemia and hypokalemia. It is hypothesized that PPIs reduce epithelial proton secretion and thereby increase the pH in the colon, which may explain the reduced absorption of and Mg2+ and Ca2+. Fermentation of dietary oligofructose-enriched inulin fibers by the microflora leads to acidification of the intestinal lumen and by this enhances mineral uptake. This study aimed, therefore, to improve mineral absorption by application of dietary inulin to counteract PPIH. Methods Here, C57BL/J6 mice were supplemented with omeprazole and/or inulin. Subsequently, Mg2+ and Ca2+ homeostasis was assessed by means of serum, urine and fecal electrolyte measurements. Moreover, the mRNA levels of magnesiotropic and calciotropic genes were examined in the large intestine and kidney by real-time PCR. Results Treatment with omeprazole significantly reduced serum Mg2+ and Ca2+ levels. However, concomitant addition of dietary inulin fibers normalized serum Ca2+ but not serum Mg2+ concentrations. Inulin abolished enhanced expression of Trpv6 and S100g in the colon by omeprazole. Additionally, intestinal and renal mRNA levels of the Trpm6 gene were reduced after inulin intake. Conclusions This study suggests that dietary inulin counteracts reduced intestinal Ca2+ absorption upon PPI treatment. In contrast, inulin did not increase intestinal absorption of Mg2+ sufficiently to recover serum Mg2+. The clinical potential of dietary inulin treatment should be the subject of future studies.
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Kieboom BCT, Kiefte-de Jong JC, Eijgelsheim M, Franco OH, Kuipers EJ, Hofman A, Zietse R, Stricker BH, Hoorn EJ. Proton pump inhibitors and hypomagnesemia in the general population: a population-based cohort study. Am J Kidney Dis 2015; 66:775-82. [PMID: 26123862 DOI: 10.1053/j.ajkd.2015.05.012] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 05/01/2015] [Indexed: 12/20/2022]
Abstract
BACKGROUND Proton pump inhibitor (PPI) use has been associated with hypomagnesemia in case reports and hospital-based cohort studies. Our objective was to determine whether PPI use is associated with hypomagnesemia in the general population and whether this is also found in histamine 2 receptor antagonist (H2RA) users. STUDY DESIGN Prospective cohort study. SETTING & PARTICIPANTS 9,818 individuals from the general population (Rotterdam Study). PREDICTOR PPI use and H2RA use compared to no use. OUTCOMES & MEASUREMENTS Serum magnesium and hypomagnesemia (serum magnesium ≤ 1.44 mEq/L). Analyses were adjusted for age, sex, body mass index, kidney function, comorbid conditions, and alcohol and diuretic use. RESULTS Serum magnesium level was 0.022 mEq/L lower in PPI users (n=724; 95% CI, -0.032 to -0.014 mEq/L) versus those with no use. PPI use was associated with increased risk of hypomagnesemia (n=36; OR, 2.00; 95% CI, 1.36-2.93) compared to no use. Effect modification was found between the use of PPIs and loop diuretics; in participants using loop diuretics (n=270), PPI use was associated with a further increased risk of hypomagnesemia (n=5; OR, 7.22; 95% CI, 1.69-30.83) compared to no use. The increased risk with PPIs was only seen after prolonged use (range, 182-2,618 days; OR, 2.99; 95% CI, 1.73-5.15). Including dietary magnesium intake into the model did not alter results (available for 2,504 participants, including 231 PPI users). H2RA users (n=250) also had a lower serum magnesium level (-0.016 [95% CI, -0.032 to -0.002] mEq/L) and increased risk of hypomagnesemia (n=12; OR, 2.00; 95% CI, 1.08-3.72) compared to those with no use, but no interaction with loop diuretics. LIMITATIONS Cross-sectional analysis with single serum magnesium measurement. CONCLUSIONS PPI use is associated with hypomagnesemia in the general population. Prolonged PPI use and concomitant loop diuretic use are associated with a stronger risk increase. Similar but weaker associations were found in H2RA users, except for interaction with loop diuretics.
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Affiliation(s)
- Brenda C T Kieboom
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Inspectorate of Health Care, Utrecht, the Netherlands
| | - Jessica C Kiefte-de Jong
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Leiden University College, The Hague, the Netherlands
| | - Mark Eijgelsheim
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Oscar H Franco
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Ernst J Kuipers
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Albert Hofman
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Robert Zietse
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Bruno H Stricker
- Department of Epidemiology, Erasmus Medical Center, Rotterdam, the Netherlands; Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands; Inspectorate of Health Care, Utrecht, the Netherlands.
| | - Ewout J Hoorn
- Department of Internal Medicine, Erasmus Medical Center, Rotterdam, the Netherlands
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Atkinson NSS, Reynolds DJM, Travis SPL. 'Lemonade Legs': Why do Some Patients Get Profound Hypomagnesaemia on Proton-Pump Inhibitors? Intest Res 2015; 13:227-32. [PMID: 26130997 PMCID: PMC4479737 DOI: 10.5217/ir.2015.13.3.227] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 04/30/2015] [Accepted: 04/30/2015] [Indexed: 12/14/2022] Open
Abstract
Proton pump inhibitors (PPIs) are widely used though an association with hypomagnesaemia and hypocalcaemia has only been described since 2006. Patients typically present after years of stable dosing with musculoskeletal, neurological or cardiac arrhythmic symptoms, but it is likely that many cases are under-recognised. Magnesium levels resolve rapidly on discontinuation of PPI therapy and hypomagnesaemia recurs rapidly on rechallenge with any agent in the class. The cellular mechanisms of magnesium homeostasis are increasingly being understood, including both passive paracellular absorption through claudins and active transcellular transporters, including the transient receptor potential channels (TRPM6) identified in the intestine and nephron. PPIs may alter luminal pH by modulating pancreatic secretions, affecting non-gastric H+K+ATPase secretion, altering transporter transcription or channel function. A small reduction in intestinal absorption appears pivotal in causing cumulative deficiency. Risk factors have been associated to help identify patients at risk of this effect but clinical vigilance remains necessary for diagnosis.
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Affiliation(s)
- Nathan S S Atkinson
- Translational Gastroenterology Unit and Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
| | - D John M Reynolds
- Department of Acute General Medicine, Oxford University Hospitals Trust, University of Oxford, Oxford, UK
| | - Simon P L Travis
- Translational Gastroenterology Unit and Nuffield Department of Experimental Medicine, University of Oxford, Oxford, UK
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de Baaij JHF, Hoenderop JGJ, Bindels RJM. Magnesium in man: implications for health and disease. Physiol Rev 2015; 95:1-46. [PMID: 25540137 DOI: 10.1152/physrev.00012.2014] [Citation(s) in RCA: 996] [Impact Index Per Article: 99.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Magnesium (Mg(2+)) is an essential ion to the human body, playing an instrumental role in supporting and sustaining health and life. As the second most abundant intracellular cation after potassium, it is involved in over 600 enzymatic reactions including energy metabolism and protein synthesis. Although Mg(2+) availability has been proven to be disturbed during several clinical situations, serum Mg(2+) values are not generally determined in patients. This review aims to provide an overview of the function of Mg(2+) in human health and disease. In short, Mg(2+) plays an important physiological role particularly in the brain, heart, and skeletal muscles. Moreover, Mg(2+) supplementation has been shown to be beneficial in treatment of, among others, preeclampsia, migraine, depression, coronary artery disease, and asthma. Over the last decade, several hereditary forms of hypomagnesemia have been deciphered, including mutations in transient receptor potential melastatin type 6 (TRPM6), claudin 16, and cyclin M2 (CNNM2). Recently, mutations in Mg(2+) transporter 1 (MagT1) were linked to T-cell deficiency underlining the important role of Mg(2+) in cell viability. Moreover, hypomagnesemia can be the consequence of the use of certain types of drugs, such as diuretics, epidermal growth factor receptor inhibitors, calcineurin inhibitors, and proton pump inhibitors. This review provides an extensive and comprehensive overview of Mg(2+) research over the last few decades, focusing on the regulation of Mg(2+) homeostasis in the intestine, kidney, and bone and disturbances which may result in hypomagnesemia.
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Affiliation(s)
- Jeroen H F de Baaij
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Joost G J Hoenderop
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
| | - René J M Bindels
- Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands
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Abstract
PURPOSE OF REVIEW The tight control of blood magnesium (Mg) levels is of central importance for numerous physiological processes. A persistent low Mg status (hypomagnesemia) is associated with severe health risks and is involved in the pathogenesis of type 2 diabetes mellitus, osteoporosis, asthma, and heart and vascular diseases. The current view has expanded significantly as a result of the identification of novel genes and regulatory pathways involved in hypomagnesemic disorders. This review aims to give an up-to-date overview of transient receptor potential melastatin 6 (TRPM6) regulation and its role in the maintenance of Mg homeostasis. RECENT FINDINGS The epithelial Mg channel TRPM6 is considered to be the Mg entry pathway in the distal convoluted tubule of the kidney, where it functions as gatekeeper for controlling the body's Mg balance. Various factors and hormones contribute not only to the function, but also to the dysregulation of TRPM6, which has a substantial impact on renal Mg handling. Recent genetic and molecular studies have further elucidated the signaling processes of epithelial Mg transport, including their effect on the expression and function of TRPM6. SUMMARY Knowledge of TRPM6 functioning is of vital importance to decipher its role in Mg handling and will, in particular, provide a molecular basis for achieving a better understanding of Mg mal(re)absorption and hence systemic Mg balance.
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Lindner G, Funk GC, Leichtle AB, Fiedler GM, Schwarz C, Eleftheriadis T, Pasch A, Mohaupt MG, Exadaktylos AK, Arampatzis S. Impact of proton pump inhibitor use on magnesium homoeostasis: a cross-sectional study in a tertiary emergency department. Int J Clin Pract 2014; 68:1352-7. [PMID: 24898571 DOI: 10.1111/ijcp.12469] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2013] [Accepted: 05/01/2014] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND To date, the use of proton pump inhibitors (PPIs) has been associated with a low risk of hypomagnesaemia and associated adverse outcomes. We hypothesised that a better risk estimate could be derived from a large cohort of outpatients admitted to a tertiary emergency department (ED). METHODS A cross-sectional study was performed in 5118 patients who had measurements of serum magnesium taken on admission to a large tertiary care ED between January 2009 and December 2010. Hypomagnesaemia was defined as a serum magnesium concentration < 0.75 mmol/l. Demographical data, serum electrolyte values, data on medication, comorbidities and outcome with regard to length of hospital stay and mortality were analysed. RESULTS Serum magnesium was normally distributed where upon 1246 patients (24%) were hypomagnesaemic. These patients had a higher prevalence of out-of-hospital PPI use and diuretic use when compared with patients with magnesium levels > 0.75 mmol/l (both p < 0.0001). In multivariable regression analyses adjusted for PPIs, diuretics, renal function and the Charlson comorbidity index score, the association between use of PPIs and risk for hypomagnesaemia remained significant (OR = 2.1; 95% CI: 1.54-2.85). While mortality was not directly related to low magnesium levels (p = 0.67), the length of hospitalisation was prolonged in these patients even after adjustment for underlying comorbid conditions (p < 0.0001). CONCLUSION Use of PPIs predisposes patients to hypomagnesaemia and such to prolonged hospitalisation irrespective of the underlying morbidity, posing a critical concern.
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Affiliation(s)
- G Lindner
- Department of Emergency Medicine, Inselspital University of Bern, Bern, Switzerland
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Blaine J, Chonchol M, Levi M. Renal control of calcium, phosphate, and magnesium homeostasis. Clin J Am Soc Nephrol 2014; 10:1257-72. [PMID: 25287933 DOI: 10.2215/cjn.09750913] [Citation(s) in RCA: 441] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Calcium, phosphate, and magnesium are multivalent cations that are important for many biologic and cellular functions. The kidneys play a central role in the homeostasis of these ions. Gastrointestinal absorption is balanced by renal excretion. When body stores of these ions decline significantly, gastrointestinal absorption, bone resorption, and renal tubular reabsorption increase to normalize their levels. Renal regulation of these ions occurs through glomerular filtration and tubular reabsorption and/or secretion and is therefore an important determinant of plasma ion concentration. Under physiologic conditions, the whole body balance of calcium, phosphate, and magnesium is maintained by fine adjustments of urinary excretion to equal the net intake. This review discusses how calcium, phosphate, and magnesium are handled by the kidneys.
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Affiliation(s)
- Judith Blaine
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Michel Chonchol
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado
| | - Moshe Levi
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Denver, Aurora, Colorado
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Toh JWT, Ong E, Wilson R. Hypomagnesaemia associated with long-term use of proton pump inhibitors. Gastroenterol Rep (Oxf) 2014; 3:243-53. [PMID: 25138239 PMCID: PMC4527261 DOI: 10.1093/gastro/gou054] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 07/15/2014] [Indexed: 12/13/2022] Open
Abstract
Hypomagnesaemia and associated hypocalcaemia and hypoparathyroidism have been increasingly recognised as rare long-term side-effects of proton pump inhibitors (PPIs). The PPIs may inhibit active magnesium (Mg) absorption by interfering with transcellular transient receptor potential melastatin-6 and -7 (TRPM 6 and 7) channels. More recent cell culture studies have suggested concomitant inhibition of passive Mg absorption by omeprazole. After being treated with a range of PPIs, the four patients in our case series developed hypomagnesaemia, which responded to withdrawal of therapy and initiation of Mg replacement. Their clinical course and management demonstrate key aspects of hypomagnesaemia associated with long-term use of PPIs.
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Affiliation(s)
- James Wei Tatt Toh
- General Surgery, Liverpool Hospital, University of New South Wales, Liverpool, New South Wales, Australia,
| | - Evonne Ong
- University of New South Wales Clinical School, Liverpool, New South Wales, Australia and
| | - Robert Wilson
- Upper Gastrointestinal Surgery, Liverpool Hospital, University of New South Wales, Liverpool, New South Wales, Australia
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Sachs G, Shin JM, Munson K, Scott DR. Gastric acid-dependent diseases: a twentieth-century revolution. Dig Dis Sci 2014; 59:1358-69. [PMID: 24852882 DOI: 10.1007/s10620-014-3104-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Affiliation(s)
- George Sachs
- Department of Medicine, David Geffen School of Medicine, The Veterans Administration Greater Los Angeles Healthcare System, University of California at Los Angeles, Bldg 113, Rm 324 11301 Wilshire Blvd., Los Angeles, CA, 90073, USA,
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Abstract
TRPM6 is a bifunctional protein comprising a TRP cation channel segment covalently linked to an α-type serine/threonine protein kinase. TRPM6 is expressed in the intestinal and renal epithelial cells. Loss-of-function mutations in the human TRPM6 gene give rise to hypomagnesemia with secondary hypocalcemia (HSH), suggesting that the TRPM6 channel kinase plays a central role in systemic Mg(2+) homeostasis. In contrast, Trpm6 null mice show a delay in prenatal development, neural tube defects, and prenatal death. Possible functions of TRPM6 in prenatal and adult organisms will be discussed in this chapter.
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Affiliation(s)
- Vladimir Chubanov
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians University Munich, Goethestrasse 33, Munich, 80336, Germany,
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