Nephrocalcinosis in children who received high-dose vitamin D.

BACKGROUND: Vitamin D supplements are readily available as over-the-counter preparations. However, although rare, cases of vitamin D overdose still occur and are associated with nephrocalcinosis and life-threatening hypercalcemia. Errors in manufacturing of nutritional supplements may be a cause of vitamin D intoxication in children. This study aimed to identify factors associated with vitamin D overdose-related nephrocalcinosis in children due to manufacturing errors in supplements. METHODS: This retrospective study reviewed medical charts of pediatric patients with non-registered supplement-related vitamin D overdose at a tertiary referral hospital between 2006 and 2011. Clinical and laboratory characteristics of patients with or without nephrocalcinosis were evaluated. Receiver operating characteristics curve and area under the receiver operating characteristics curve were used to determine the most predictive value of each characteristic. RESULTS: A total of 44 patients (males: 29; age: 7-62 months) were included. Age ≤ 16.5 months, body weight ≤ 10.25 kg, body height ≤ 78.5 cm, body surface area (BSA) ≤ 0.475 m2, 25-hydroxyvitamin D3 ≥ 143 ng/mL, and calcium ≥ 10.65 mg/dL were predictive of developing nephrocalcinosis with a sensitivity and specificity of > 60%. Univariant analysis revealed that BSA was the most significant anthropometric prognostic factor (odds ratio: 12.09; 95% confidence interval: 2.61-55.72; P = 0.001). CONCLUSIONS: Children with smaller BSAs were more vulnerable to high-dose vitamin D3-related nephrocalcinosis. Physicians and parents should be aware of the potential adverse effects of vitamin D overdose in children. A higher resolution version of the Graphical abstract is available as Supplementary information.

Predictive and prognostic value of magnesium serum level in FOLFIRI plus cetuximab or bevacizumab treated patients with stage IV colorectal cancer: results from the FIRE-3 (AIO KRK-0306) study.

Magnesium wasting is a frequent side effect of epidermal growth factor receptor (EGFR)-antibody treatment as magnesium-absorption mechanisms are dependent on EGFR signaling. EGFR-inhibition results in decreased renal reabsorption. There is evidence that hypomagnesemia during cetuximab treatment correlates with response. The prognostic role of hypomagnesemia during bevacizumab treatment has not been studied yet. Here, we evaluate the prognostic value of hypomagnesemia in patients with metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab as first-line therapy. A total of 391 of 752 patients of the firstline irinotecan study population had magnesium levels measured at baseline and for the first three cycles (6 weeks) of treatment. Of those, 240 had Rat Sarkoma wildtype tumors. Overall hypomagnesemia was more common in the cetuximab compared to the bevacizumab arm (80 vs. 43%, P < 0.005). During therapy, magnesium showed a time-dependent decrease to 80% of baseline in the cetuximab and to 89% in the bevacizumab arm. Whereas magnesium continued to decrease over time in the cetuximab-treated patients, it remained stable in the bevacizumab-treated. Overall response rate (ORR) was associated with higher magnesium at week 6 (20.9 vs. 79.1%, P = 0.041). Bevacizumab-treated patients with magnesium levels below the median value at week 6 had a significantly longer progression-free survival (PFS; 11.7 vs. 9.9 months, P = 0.034; hazard ratio 0.73) and a trend towards longer overall survival (OS) (29.6 vs. 23.2 months, P = 0.089; hazard ratio 0.77). Hypomagnesemia at predefined time points and magnesium nadir had no significant effect on ORR, OS and PFS in the cetuximab arm. Our data show different magnesium kinetics in patients with metastatic colorectal cancer treated with cetuximab or bevacizumab. For patients treated with cetuximab, hypomagnesemia did not have an impact on response and survival. Hypomagnesemia might have a prognostic value in bevacizumab treatment.

Growth suppression of human oral cancer cells by candidate agents for cetuximab-side effects.

Cetuximab, an inhibitor of the epidermal growth factor receptor that is used widely to treat human cancers including oral squamous cell carcinoma (OSCC), has characteristic side effects of skin rash and hypomagnesemia. However, the mechanisms of and therapeutic agents for skin rashes and hypomagnesemia are still poorly understood. Our gene expression profiling analyses showed that cetuximab activates the p38 MAPK pathways in human skin cells (human keratinocyte cell line [HaCaT]) and inhibits c-Fos-related signals in human embryonic kidney cells (HEK293). We found that while the p38 inhibitor SB203580 inhibited the expression of p38 MAPK targets in HaCaT cells, flavagline reactivated c-Fos-related factors in HEK293 cells. It is noteworthy that, in addition to not interfering with the effect of cetuximab by both compounds, flavagline has additive effect for OSCC growth inhibition in vivo. Collectively, our results indicate that combination of cetuximab and these potential therapeutic agents for cetuximab-related toxicities could be a promising therapeutic strategy for patients with OSCC.

Effects of bodybuilding supplements on the kidney: A population-based incidence study of biopsy pathology and clinical characteristics among middle eastern men.

BACKGROUND: The incidence of kidney diseases among bodybuilders is unknown. METHODS: Between January 2011 and December 2019, the Iraqi Kurdistan 15 to 39 year old male population averaged 1,100,000 with approximately 56,000 total participants and 25,000 regular participants (those training more than 1 year). Annual age specific incidence rates (ASIR) with (95% confidence intervals) per 100,000 bodybuilders were compared with the general age-matched male population. RESULTS: Fifteen male participants had kidney biopsies. Among regular participants, diagnoses were: focal segmental glomerulosclerosis (FSGS), 2; membranous glomerulonephritis (MGN), 2; post-infectious glomeruonephritis (PIGN), 1; tubulointerstitial nephritis (TIN), 1; and nephrocalcinosis, 2. Acute tubular necrosis (ATN) was diagnosed in 5 regular participants and 2 participants training less than 1 year. Among regular participants, anabolic steroid use was self-reported in 26% and veterinary grade vitamin D injections in 2.6%. ASIR for FSGS, MGN, PIGN, and TIN among regular participants was not statistically different than the general population. ASIR of FSGS adjusted for anabolic steroid use was 3.4 (- 1.3 to 8.1), a rate overlapping with FSGS in the general population at 2.0 (1.2 to 2.8). ATN presented as exertional muscle injury with myoglobinuria among new participants. Nevertheless, ASIR for ATN among total participants at 1.4 (0.4 to 2.4) was not significantly different than for the general population at 0.3 (0.1 to 0.5). Nephrocalcinosis was only diagnosed among bodybuilders at a 9-year cumulative rate of one per 314 vitamin D injectors. CONCLUSIONS: Kidney disease rates among bodybuilders were not significantly different than for the general population, except for nephrocalcinosis that was caused by injections of veterinary grade vitamin D compounds.

Use of mechanistic information to derive chemical-specific adjustment factors - Refinement of risk assessment.

When extrapolating data from animal toxicological studies a default factor (dUF) of 100 is applied to derive a heath based guidance value. The UF takes into account the interspecies differences (ID) and the intraspecies variability (IV). When re-evaluating the safety of phosphates used as food additives nephrocalcinosis was identified as the critical endpoint. The underlying mechanism for nephrocalcinosis was attributed to the precipitation of calcium phosphate in the kidney, depending on its solubility, irrespective of the species and the population. Based on the mechanism, the volume of primary urine, for which the glomerular filtration rate (GFR) was used as a proxy, was considered to be the only parameter relevant for ID and IV. Median value of GFR in rats was 4.0 ml/min/kg bw. In humans it was 1.6 ml/min/kg bw in healthy adults and 0.9 in elderly. These values were calculated from the distribution of the GFR data from 8 studies in rats (n = 191), 16 studies in adults (n = 1540) and 5 studies in elderly (n = 2608). Multiplying the distribution of the ratio rat/healthy humans (ID) with the distribution of the ratio healthy humans/elderly human (IV) resulted in a phosphate specific factor of 4.5 (3.3-6.7) (median; 25th - 75th percentile).

Hypomagnesemia and Survival in Patients with Ovarian Cancer Who Received Chemotherapy with Carboplatin.

BACKGROUND: Hypomagnesemia is a known side effect of several antineoplastic agents, but its impact on outcomes of patients with cancer is not well understood. We examined whether magnesium abnormalities affect survival in patients with ovarian cancer who receive chemotherapy containing carboplatin. MATERIALS AND METHODS: We included patients with advanced ovarian cancer who had undergone surgery and chemotherapy between January 1, 2004, and December 31, 2014, at our institution. Inclusion criteria were age 18 years or older, pathology of high-grade serous carcinoma, first treatment (surgery or chemotherapy) within 60 days of diagnosis, and chemotherapy containing carboplatin. The final cohort consisted of 229 patients. Vital signs and laboratory tests were recorded at baseline and during the treatment course. The associations between magnesium abnormalities (and other clinical characteristics) and survival were analyzed. RESULTS: The median patient age was 64 years. Higher baseline heart rate (beats per minute; hazard ratio [HR] = 1.02, p = .002) and greater frequency of hypomagnesemia during the treatment course (HR = 1.05, p = .002) were significantly associated with shorter survival independent of completeness of tumor reduction (HR = 1.60, p = .02), and International Federation of Gynecology and Obstetrics stage (HR = 1.63, p = .01). CONCLUSION: Baseline heart rate and the frequency of hypomagnesemia episodes during treatment are prognostic of survival for patients with advanced ovarian cancer receiving carboplatin-containing chemotherapy and tumor reductive surgery. Future research is needed for strategies to detect and prevent hypomagnesemia in this patient population. IMPLICATIONS FOR PRACTICE: Despite standard laboratory tests and intravenous magnesium replacement prior to each cycle of chemotherapy, hypomagnesemia remains a common side effect of platinum-based chemotherapy. This study revealed that frequent occurrence of hypomagnesemia during the course of treatment including carboplatin-containing chemotherapy and tumor reductive surgery was strongly predictive of shorter survival in patients with advanced ovarian cancer. Strategies to effectively mitigate hypomagnesemia, such as more frequent detection, dietary recommendations, and timely replacement, should be considered in the overall cancer treatment plan for these patients.

Proton pump inhibitors not associated with hypomagnesemia, regardless of dose or concomitant diuretic use.

BACKGROUND AND AIM: Proton pump inhibitors (PPIs) are among the most commonly prescribed medications worldwide, with dramatic efficacy for upper gastrointestinal acid-related disorders. In recent years, however, the safety of long-term PPI use has been questioned. One issue based on scant and conflicting literature is the possibility of PPI-related hypomagnesemia. Our purpose was to assess for any clinically significant alteration in serum magnesium levels in large groups of patients taking different PPIs in varying doses, with or without diuretics. METHODS: This was a retrospective review of patient records at time of hospitalization, from February 2012 to December 2014. Two thousand four hundred patients were randomly selected from a pool of 12 058 magnesium levels performed at or within 24 h of hospital admission. Patients were categorized in six groups based on outpatient PPI and/or diuretic use. The main outcome studied was hypomagnesemia, defined as serum magnesium level < 1.6 mg/dL. RESULTS: Mean magnesium levels were normal in PPI users (1.84 ± 0.29 mg/dL [normal 1.6 to 2.5 mg/dL]) and PPI nonusers (1.85 ± 0.30 mg/dL), P = 0.40, and there was no statistical difference in the prevalence of hypomagnesemia (14.7% vs 15.1%, P = 0.77). In separate groups, there were also no significant differences in serum magnesium levels between those taking PPIs of varying doses, with or without concomitant diuretics, and those not taking PPIs or diuretics. CONCLUSION: Regardless of PPI dosage or concomitant diuretics prescribed, magnesium levels were unaffected. Routine screening of serum magnesium in PPI patients appears unnecessary.

Proton pump inhibitors and hospitalization with hypomagnesemia: a population-based case-control study.

BACKGROUND: Some evidence suggests that proton pump inhibitors (PPIs) are an under-appreciated risk factor for hypomagnesemia. Whether hospitalization with hypomagnesemia is associated with use of PPIs is unknown. METHODS AND FINDINGS: We conducted a population-based case-control study of multiple health care databases in Ontario, Canada, from April 2002 to March 2012. Patients who were enrolled as cases were Ontarians aged 66 years or older hospitalized with hypomagnesemia. For each individual enrolled as a case, we identified up to four individuals as controls matched on age, sex, kidney disease, and use of various diuretic classes. Exposure to PPIs was categorized according to the most proximate prescription prior to the index date as current (within 90 days), recent (within 91 to 180 days), or remote (within 181 to 365 days). We used conditional logistic regression to estimate the odds ratio for the association of outpatient PPI use and hospitalization with hypomagnesemia. To test the specificity of our findings we examined use of histamine H2 receptor antagonists, drugs with no causal link to hypomagnesemia. We studied 366 patients hospitalized with hypomagnesemia and 1,464 matched controls. Current PPI use was associated with a 43% increased risk of hypomagnesemia (adjusted odds ratio, 1.43; 95% CI 1.06-1.93). In a stratified analysis, the risk was particularly increased among patients receiving diuretics, (adjusted odds ratio, 1.73; 95% CI 1.11-2.70) and not significant among patients not receiving diuretics (adjusted odds ratio, 1.25; 95% CI 0.81-1.91). We estimate that one excess hospitalization with hypomagnesemia will occur among 76,591 outpatients treated with a PPI for 90 days. Hospitalization with hypomagnesemia was not associated with the use of histamine H2 receptor antagonists (adjusted odds ratio 1.06; 95% CI 0.54-2.06). Limitations of this study include a lack of access to serum magnesium levels, uncertainty regarding diagnostic coding of hypomagnesemia, and generalizability of our findings to younger patients. CONCLUSIONS: PPIs are associated with a small increased risk of hospitalization with hypomagnesemia among patients also receiving diuretics. Physicians should be aware of this association, particularly for patients with hypomagnesemia. Please see later in the article for the Editors' Summary.

Regulatory T cells improve nephrocalcinosis but not dystrophic cardiac calcinosis in DBA/2 mice.

Nephrocalcinosis is characterized by aberrant deposition of calcium in the kidneys and is seen in phosphate nephropathy, primary hyperparathyroidism, and distal renal tubular acidosis. To further evaluate the specific pathophysiologic role of T cells in ectopic calcification, we used DBA/2 mice that are prone to develop nephrocalcinosis and dystrophic cardiac calcinosis. Female DBA/2 mice were depleted of T cells (n = 10) or regulatory T cells (Tregs) (n = 15) using either an anti-CD3ɛ or an anti-CD25 monoclonal antibody and compared with isotype-treated controls (n = 9; n = 15), respectively. After this immunomodulation, the DBA/2 mice were given a high-phosphate diet for 9 days and the degree of calcification was assessed by microcomputed tomography. Successful depletion was confirmed by flow cytometry of splenocytes. In DBA/2 mice, the high-phosphate diet induced a phenotype of nephrocalcinosis and dystrophic cardiac calcinosis. T-cell depletion significantly increased renal calcification in microcomputed tomography (P = 0.022). Concordantly, Treg depletion significantly deteriorated acute phosphate nephropathy (P = 0.039) and was associated with a significantly increased mortality rate (P = 0.004). Immunomodulation had no impact on the amount of cardiac calcification. Semiquantitative histopathologic evaluations with Alizarin Red staining independently confirmed the respective radiologic measurements. In summary, our data suggest a pivotal role of T cells, particularly Tregs, in the progression of nephrocalcinosis and emphasize the fact that inflammation deteriorates the outcome in acute phosphate nephropathy.

"Ghosts in my body": Seizure-like presentation of hypocalcemic tetany secondary to hypomagnesemia in a patient receiving cetuximab therapy for metastatic medulloblastoma.

Cetuximab, a monoclonal antibody specific for epidermal growth factor receptor, is increasingly used off-label and in early-phase trials for pediatric malignancies. Here, we report a patient with metastatic medulloblastoma receiving therapy with cyclophosphamide, vinblastine, and cetuximab. During evaluation for possible seizures, he was noted to be severely hypocalcemic, hypokalemic, and hypomagnesemic, a consequence of the blockade of renal epidermal growth factor receptor expression. His symptoms rapidly abated with intravenous electrolyte repletion. This case highlights the clinical heterogeneity of tetany and the importance of careful laboratory screening for known adverse effects of chemotherapy, particularly when newer biological agents are used off-study in combination chemotherapeutic regimens.

[A 78-year-old female patient with dizziness, apraxia and seizure under proton pump inhibitor therapy]. / 78-jährige Patientin mit Unwohlsein, Schwindel, Apraxie und Krampfanfall unter Protonenpumpeninhibitortherapie.

We report about a female patient with severe hypomagnesemia under therapy with proton pump inhibitors (PPI) who presented with a cerebral seizure. Chronic use of PPIs can cause hypomagnesemia. Because of mostly unspecific symptoms which become symptomatic only with severe deficiency, the disease pattern is underdiagnosed. Hypomagnesemia is currently coming increasingly more to the forefront of medical literature.

Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17.

BACKGROUND: Cetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. PATIENTS AND METHODS: Day 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. RESULTS: The median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12-2.33), P = 0.01 and 2.08 (95% CI 1.32-3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0-1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). CONCLUSIONS: In contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

Development of an animal model of nephrocalcinosis via selective dietary sodium and chloride depletion.

BACKGROUND: Nephrocalcinosis (NC) is an important clinical problem seen in critically ill preterm neonates treated with loop diuretics. No reliable animal models are available to study the pathogenesis of NC in preterm infants. The purpose of this study was to develop a reproducible and clinically relevant animal model of NC for these patients and to explore the impact of extracellular fluid (ECF) volume contraction induced by sodium and chloride depletion in this process. METHODS: Three-week-old weanling Sprague-Dawley rats were fed diets deficient in either chloride or sodium or both. A subgroup of rats from each dietary group was injected daily with furosemide (40 mg/kg i.p.). RESULTS: Rats fed a control diet, with or without furosemide, or a chloride-depleted diet alone, did not develop NC. By contrast, 50% of the rats injected with furosemide and fed the chloride-depleted diet developed NC. Moreover, 94% of the rats fed the combined sodium- and chloride-depleted diet developed NC, independently of furosemide use. NC was associated with the development of severe ECF volume contraction; hypochloremic, hypokalemic, metabolic alkalosis; increased phosphaturia; and growth retardation. CONCLUSION: Severe ECF volume contraction induced by chronic sodium and chloride depletion appears to play an important role in the pathogenesis of NC.

Combined phospho- and glycoproteome enrichment in nephrocalcinosis tissues of phytate-fed rats.

RATIONALE: Protein post-translational modifications (PTMs) are directly involved in protein function and cellular activities. Among them, glycosylation and phosphorylation are particularly important modifications on proteins located at extracellular and intracellular domains, respectively. However, the combined detection using phospho- and glycoproteomics is limited mainly due to protocol differences. METHODS: In this study, we developed a novel method for both phospho- and glycoproteome detection from a single sample batch, in which a titanium dioxide cartridge was used to capture the phosphoproteome, and the flow-through solution was processed for capturing N-linked glycopeptides using hydrazide resin. RESULTS: By using 1 mg of protein from kidney tissue lysates from normal and diseased rats, we concurrently identified 437 glycosites/358 phosphosites and 468 glycosites/369 phosphosites in normal and disease kidneys, respectively, by liquid chromatography/tandem mass spectrometric analysis. CONCLUSIONS: Compared with individual PTM analyses, the combined PTM analysis clearly provides more broad implications for PTMs related to the pathological status and discovery of biomarker candidates. Furthermore, the combined protocol thoroughly showed its advantages in enrichment efficiency and biological interpretation compared with current methods.

Isolated hypomagnesemia in a patient treated with capecitabine.

Hypomagnesemia is known to occur for a variety of renal, gastrointestinal and other causes, and is often associated with other electrolyte and metabolic disturbances. We present a case of isolated hypomagnesemia in a patient who had been treated with the chemotherapy agent capecitabine. The approach to diagnosis and treatment is discussed. We postulate that capecitabine may cause isolated hypomagnesemia, possibly due to renal magnesium loss.

Prophylactic effect of coconut water (Cocos nucifera L.) on ethylene glycol induced nephrocalcinosis in male wistar rat.

PURPOSE: Many medicinal plants have been employed during ages to treat urinary stones though the rationale behind their use is not well established. Thus, the present study was proposed to evaluate the effect of coconut water as a prophylactic agent in experimentally induced nephrolithiasis in a rat model. MATERIALS AND METHODS: The male Wistar rats were divided randomly into three groups. Animals of group I (control) were fed standard rat diet. In group II, the animals were administrated 0.75% ethylene glycol in drinking water for the induction of nephrolithiasis. Group III animals were administrated coconut water in addition to ethylene glycol. All the treatments were continued for a total duration of seven weeks. RESULTS AND CONCLUSION: Treatment with coconut water inhibited crystal deposition in renal tissue as well as reduced the number of crystals in urine. Furthermore, coconut water also protected against impaired renal function and development of oxidative stress in the kidneys. The results indicate that coconut water could be a potential candidate for phytotherapy against urolithiasis.

Effects of cinacalcet in renal transplant patients with hyperparathyroidism.

BACKGROUND: Cinacalcet decreases serum parathyroid hormone (PTH) and calcium concentrations in kidney transplant recipients with autonomous hyperparathyroidism. Long-term treatment with cinacalcet may increase urinary calcium excretion and the risk of renal calcium deposits and may alter renal graft function. METHODS: We studied 71 renal recipients with hypercalcemic hyperparathyroidism. Of these patients, 34 received cinacalcet between month 3 and month 12 after renal transplantation. We compared phosphate calcium balance, measured glomerular filtration rate (GFR) and renal biopsies in cinacalcet-treated and non-cinacalcet-treated patients. Measurements were performed before initiating cinacalcet treatment (month 3) and at month 12. RESULTS: Patients treated with cinacalcet had more severe hyperparathyroidism. Serum PTH concentration decreased in both groups between months 3 and 12, but the decrease was much more important in cinacalcet-treated patients. Urinary calcium excretion significantly increased under cinacalcet treatment and was more than twice as high at month 12 as in patients who did not receive cinacalcet treatment. However, the hypercalciuria was not associated with an increase in calcium deposits on renal biopsies or an alteration of measured GFR. CONCLUSIONS: Despite sustained and marked hypercalciuria induced by cinacalcet treatment, cinacalcet does not have adverse effects on GFR or on renal graft calcium deposits in the first year following renal transplantation.

Recent safety concerns with proton pump inhibitors.

There have been recent concerns about the safety of proton pump inhibitors (PPIs). We focus here on 3 specific concerns-the possible interaction between PPIs and clopidogrel, the postulated link between PPI use and fractures, and the possibility that long-term PPI use might lead to hypomagnesemia. There is evidence for an in vitro interaction between clopidogrel and at least some PPIs. The Food and Drug Administration (FDA) has warned against the use of certain PPIs by patients on clopidogrel. However, a randomized controlled trial that compared clopidogrel alone with the combination of clopidogrel and omeprazole found no increase in adverse cardiovascular outcomes and a reduction in the rate of adverse gastrointestinal outcomes attributable to omeprazole. PPI use may be a weak risk factor for certain fractures, but the quality of evidence is relatively poor and there is a strong possibility of confounding. The mechanism whereby PPI use might increase fracture risk is unknown. Currently, no additional measures concerning calcium supplementation or bone mineral density monitoring are recommended for patients on a PPI. The FDA has suggested monitoring serum magnesium levels in patients on PPI therapy. The mechanism and frequency of PPI-induced hypomagnesemia are unclear. PPI treatment should not be withheld from patients who genuinely require it, but the PPI should be taken in the lowest effective dose and only for as long as clinically indicated. The same is, of course, true for all medicines. The benefits of PPI therapy greatly outweigh the risks.

Omeprazole- and esomeprazole-associated hypomagnesaemia: data mining of the public version of the FDA Adverse Event Reporting System.

OBJECTIVE: Case reports showing that proton-pump inhibitors (PPIs), omeprazole and esomeprazole, can cause hypomagnesaemia have been accumulating since 2006. In this study, the reports submitted to the Adverse Event Reporting System (AERS) of the US Food and Drug Administration (FDA) were evaluated to assess omeprazole and esomeprazole in terms of susceptibility to hypomagnesaemia. METHODS: After a revision of arbitrary drug names and the deletion of duplicated submissions, the reports involving omeprazole and esomeprazole were analyzed. Standardized official pharmacovigilance tools were used for the quantitative detection of a signal, i.e., an association between a drug and an adverse drug event, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. RESULTS: A total of 22,017,956 co-occurrences were found in 1,644,220 reports from 2004 to 2009, where a co-occurrence was a pair of a drug and an adverse drug event. In total, 818 and 743 adverse drug events were listed as omeprazole- and esomeprazole-associated, with hypomagnesaemia ranking 85th and 135th, respectively. Although both PPIs were associated with hypomagnesaemia, the statistical metrics suggested that the association was more noteworthy for omeprazole. CONCLUSION: The data obtained in this study do not provide sufficient evidence to recommend systematic monitoring of magnesium levels in plasma, but chronic exposure to a PPI can lead to severe hypomagnesaemia.