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Objective: To investigate the incidence and severity of adverse drug reactions of cyclosporine using AUC-targeted therapeutic drug monitoring (TDM) compared to trough level (C trough )-targeted TDM in adult allogeneic stem cell recipients., Methods: Blind, monocenter, intervention study. Subjects were 1:1 randomized into either an AUC group or a C trough group. Adverse drug reactions were accessed two and four weeks after start of treatment., Results: Forty patients were included, resulting in 15 evaluable subjects (AUC group) and 13 evaluable subjects (C trough group). Grade two/three toxicity was observed in 46% (C trough group) versus 60% of subjects (AUC group) (P = .463). There was no significant difference between two and four weeks after start of cyclosporine for nausea (P = .142 resp. P = .122), renal dysfunction (P = .464 resp. P = 1.000), and hypomagnesemia (P = 1.000 resp. P = .411). Subjects in the AUC group reached the therapeutic goal earlier (72,7% versus 43,0% at third sampling point, P = .332) and were within the target range more consistently., Conclusion: This study showed no reduction in incidence and severity of cyclosporine-induced toxicity with AUC- versus trough level-targeted TDM. Although modeled dosing based on AUC led to faster optimal target attainment, this did not result in less toxicity in the early days after transplantation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Omeprazole is a potent inhibitor of gastric acid secretion. It was reported that omeprazole induced dramatic gastric mucosa morphologic changes from the resting state to the stimulated state. However, the effect of omeprazole administration on the ultrastructure and absorptive function of small intestines was largely unknown. Here, male Sprague-Dawley rats were daily treated with a single dose of omeprazole for 12 or 24 weeks. Ultrastructure intestinal mucosal change in duodenum, jejunum, and ileum was observed. We also determined small intestine inflammation, using intraepithelial lymphocytes activation. Finally, magnesium levels were measured in plasma, urine, feces, muscle, and bone to determine systemic magnesium balance. Omeprazole-treated rats had significantly decreased the width of tight junction, villous length, and absorptive area of duodenum, jejunum, and ileum compared to control rats. The small intestine of the omeprazole-treated group showed significantly higher intraepithelial lymphocytes activation levels compared with the control group. Lower secretory granules of Paneth cells at the base of the crypts were showed in omeprazole-treated rats. They also had significantly lower plasma, urinary, bone, and muscle Mg 2+ contents indicating hypomagnesemia with systemic magnesium deficiency. In conclusion, prolonged omeprazole treatment-induced small intestinal inflammation and villous atrophy, which led to decrease small intestinal magnesium absorption in the condition of proton pump inhibitor-induced hypomagnesemia.

Hypomagnesemia is very commonly observed in cancer patients, most frequently in association with therapy with cetuximab (CTX), a monoclonal antibody targeting the epithelial growth factor receptor (EGFR). CTX-induced hypomagnesemia has been ascribed to renal magnesium (Mg) wasting. Here, we sought to clarify whether CTX may also influence intestinal Mg absorption and if Mg supplementation may interfere with CTX activity. We used human colon carcinoma CaCo-2 cells as an in vitro model to study the mechanisms underlying Mg transport and CTX activity. Our findings demonstrate that TRPM6 is the key channel that mediates Mg influx in intestinal cells and that EGF stimulates such influx; consequently, CTX downregulates TRPM6-mediated Mg influx by interfering with EGF signaling. Moreover, we show that Mg supplementation does not modify either the CTX IC50 or CTX-dependent inhibition of ERK1/2 phosphorylation. Our results suggest that reduced Mg absorption in the intestine may contribute to the severe hypomagnesemia that occurs in CTX-treated patients, and Mg supplementation may represent a safe and effective nutritional intervention to restore Mg status without impairing the CTX efficacy.

Purpose: Cetuximab and panitumumab are monoclonal antibodies that target the epidermal growth factor receptor (EGFR). Treatment with cetuximab and panitumumab commonly causes hypomagnesemia, and optimal management of this adverse effect remains unclear. Here, we evaluated the optimal magnesium replacement points based on the risk of severe hypomagnesemia in colorectal cancer patients who received cetuximab or panitumumab., Methods: We retrospectively evaluated 184 patients who received cetuximab or panitumumab for colorectal cancer at Ogaki Municipal Hospital (Ogaki, Japan) between January 2010 and December 2019. Univariate analyses were conducted to evaluate the relationship between patient baseline characteristics and development of hypomagnesemia following cetuximab or panitumumab treatment. Variables that were significantly associated with hypomagnesemia in the univariate analyses as well as previously reported risk factors were entered into a multivariate logistic regression model., Results: The incidence of hypomagnesemia was associated with panitumumab treatment, pre-replenishment serum magnesium concentration, treatment duration, and treatment line. Severe hypomagnesemia post-cetuximab or panitumumab treatment was significantly associated with low baseline magnesium concentrations (< 1.8 mg/dL; odds ratio 18.100, 95% confidence interval 1.570-210.000; p = 0.020) and low serum magnesium concentrations during treatment (< 1.1 mg/dL; odds ratio 93.800, 95% confidence interval 3.510-2510.000; p = 0.007)., Conclusion: To minimize the risk of severe hypomagnesemia during anti-EGFR treatment, magnesium replenishment should be initiated in patients with pre-replenishment concentrations of < 1.8 mg/dL, preferably before reaching intra-treatment concentrations of < 1.1 mg/dL.

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.

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., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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., (© 2018 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

In our clinical experience, we have encountered patients who developed hypomagnesemia after the introduction of teriparatide. Some trials have reported hypomagnesemia as an adverse event during teriparatide treatment, but this issue had never been studied specifically. Our objective was twofold: 1) determine the incidence of hypomagnesemia (serum magnesium <0.7 mmol/L) associated with teriparatide in a retrospective cohort and 2) identify the predisposing factors to hypomagnesemia in this cohort. We reviewed the files of 53 patients treated for severe osteoporosis with teriparatide for 6 to 24 months between May 2008 and January 2016. Serum magnesium levels were measured at 0, 3, 6, 12, 18, and 24 months. In the full cohort, we observed an average decrease of serum magnesium of 0.075 mmol/L, 0.069 mmol/L, 0.085 mmol/L, 0.086 mmol/L (p < 0.001) at 3, 6, 12 months, and at the end of the treatment, respectively. The cumulative incidence of hypomagnesemia during treatment with teriparatide was 35.9% (19 patients). Patients' older age (71.1 versus 65.1 years; p = 0.05) and lower baseline level of magnesium before teriparatide treatment (0.81 mmol/L versus 0.85 mmol/L; p = 0.03) were significant risk factors for teriparatide-induced hypomagnesemia. The average decrease of serum magnesium was greater in the patients who developed hypomagnesemia compared with normomagnesemic patients at 3 months (0.110 mmol/L versus 0.054 mmol/L; p = 0.02), 6 months (0.139 mmol/L versus 0.036 mmol/L; p < 0.001), and 12 months (0.156 mmol/L versus 0.048 mmol/L; p < 0.001). Serum calcium, creatinine, and parathyroid hormone remained normal throughout the treatment period. We observed a statistically significant decrease in the serum magnesium levels in patients treated with teriparatide for severe osteoporosis. Older age and lower baseline magnesium were significant determinants of hypomagnesemia. Closer monitoring of serum magnesium level should be considered in these patients. © 2018 American Society for Bone and Mineral Research., (© 2018 American Society for Bone and Mineral Research.)

What Is Known and Objective: Nephrotoxicity is a recognized side effect of cisplatin chemotherapy. However, the optimal strategy for preventing cisplatin-induced nephrotoxicity, if any, remains unclear. The primary objective for this study was to determine whether mannitol or furosemide provides better nephroprotection when administered with hydration prior to weekly, low-dose cisplatin concurrently with whole pelvic radiotherapy., Methods: Clinical data were abstracted from all women who underwent chemoradiation for FIGO IB2-IVA cervical cancer at a regional safety net health system between January 2009 and December 2014. Creatinine clearance was estimated using the IDMS-traceable MDRD Study Equation. Descriptive statistics were used to summarize patient demographics. Cox proportional hazard models were used to identify factors associated with hypomagnesemia and survival., Results and Discussion: A total of 133 women received 656 weekly doses of single-agent cisplatin (40 mg/m 2 ) concomitant with whole pelvic radiation. Furosemide (20 mg) was administered intravenously prior to 341 cisplatin doses, whereas mannitol (24 g) was administered prior to 315 doses. Significant magnesium wasting was observed after the second weekly cisplatin infusion regardless of whether furosemide or mannitol was utilized. Repetitive low-dose cisplatin infusion had no impact on measured levels of serum creatinine or estimated glomerular filtration rate. Prior history of hypertension, diabetes mellitus, hepatitis C infection and acute gastrointestinal toxicity were each associated with early onset of hypomagnesemia., What Is New and Conclusions: Repetitive administration of low-dose cisplatin concurrent with whole pelvic radiation is associated with magnesium wasting. However, choice of diuretic with pretreatment hydration had no significant impact on the severity of this adverse effect., (© 2017 John Wiley & Sons Ltd.)

Monoclonal antibody therapies targeting the EGF receptor (EGFR) frequently result in hypomagnesemia in human patients. In contrast, EGFR tyrosine kinase inhibitors do not affect Mg 2+ balance in patients and only have a mild effect on Mg 2+ homeostasis in rodents at elevated doses. EGF has also been shown to affect phosphate (P i ) transport in rat and rabbit proximal convoluted tubules (PCT), but evidence from studies targeting EGFR and looking at P i excretion in whole animals is still missing. Thus, the role of EGF in regulating reabsorption of Mg 2+ and/or P i in the kidney remains controversial. Here, we inject mice with the anti-EGFR monoclonal antibody ME-1 for 2 weeks and observe a significant increase in serum P i and mild hypomagnesemia, but no changes in P i or Mg 2+ excretion. In contrast, a single injection of ME-1 resulted in hyperphosphatemia and a significant reduction in P i excretion 2 days after treatment, while no changes in serum Mg 2+ or Mg 2+ excretion were observed. Dietary Mg 2+ deprivation is known to trigger a rapid Mg 2+ conservation response in addition to hyperphosphatemia and hyperphosphaturia. Interestingly, one dose of ME-1 did not significantly modify the response of mice to 2 days of Mg 2+ deprivation. These data show that EGFR plays a significant role in regulating P i reabsorption in the kidney PCT, but suggest only a minor role in long-term regulation of Mg 2+ transport in the distal convoluted tubule., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Hypomagnesemia is one side effect in patients receiving cisplatin. However, there are few reports of cisplatin-induced hypomagnesemia in Japan. We retrospectively investigated the incidence of hypomagnesemia and nephrotoxicity in patients undergoing radiation therapy who were treated with cisplatin alone (dosage: 40 mg/m 2 , administration interval: 1 week) for cervical cancer. Thirty-two patients undergoing radiation therapy who received cisplatin alone for cervical cancer between January 2012 and May 2016 at Aichi Medical University Hospital were included. We measured patients' serum magnesium and creatinine levels on the day before cisplatin was administered. We utilized the RIFLE criteria (categorized into "risk", "injury", "failure", "loss", and "end-stage kidney disease") to define levels of cisplatin-induced nephrotoxicity, and classified cisplatin-induced nephrotoxicity into "risk" or "injury". Eighteen patients (56.3%) had cisplatin-induced hypomagnesemia, the majority of which occurred after the 4th treatment cycle. The number of patients with moderate renal dysfunction classified as "risk" in the hypomagnesemia group was not significantly higher than in the non-hypomagnesemia group (hypomagnesemia group=27.8%, non-hypomagnesemia group=7.1%; p=0.20). This survey sheds light on the incidence rates of cisplatin-induced hypomagnesemia in patients receiving cisplatin alone. We recommend monitoring the serum magnesium levels during cisplatin administration to prevent hypomagnesemia.

A 39-year-old woman presented with severe, uncontrolled and irreversible hypomagnesaemia, following cisplatin treatment in her childhood. Because high-dose oral magnesium supplementation therapy was insufficient and not tolerated, continuous subcutaneous magnesium supplementation was successfully instituted and continued in the outpatient setting. This case demonstrates that continuous subcutaneous magnesium supplementation is effective in maintaining magnesium levels within the normal range, is well tolerated and may provide a long-term solution for chronic hypomagnesaemia due to intractable renal losses.

Magnesium is the second intracellular cation and the fourth most abundant mineral in the body. Low levels of magnesium have been associated with insulin resistance and type-2 diabetes mellitus, asthma, osteoporosis and chronic kidney disease (CKD). The use of proton pump inhibitors (PPIs) represents the most common cause of hypomagnesemia. The risk of hypomagnesemia, and consequently worsening of the renal function, is increased when diuretics are added to therapy in subjects treated with PPIs. Interestingly, diuretics and PPIs are two of the most used drugs in subjects with CKD. In this review, we described the mechanisms at the basis of the hypomagnesemia and the effect of this electrolyte disturbance in subjects with CKD.

In contrast to other ions, magnesium is treated as an orphan by the body: there are no hormones that have a substantial role in regulating urinary magnesium excretion, and bone, the principal reservoir of magnesium, does not readily exchange with circulating magnesium.The Mg ++ is often overlooked by physicians in the differential diagnosis because it is considered insignificant, but its role is crucial for cells function, first of all neurons and cardiomyocytes. A condition of hypocalcemia associated with hypokalemia, especially in the presence of chronic renal failure, should raise suspicion of a lack of Mg ++.We report the case of an old man of 77 year with kidney transplant for 13 years, treated with cyclosporine, and sodium mycophenolate and steroid who, for about a month, accused impaired balance and walking instability, who fell accidentally down with wrist fracture.Blood tests showed hypocalcemia and hypokalemia, and so we required dosage of serum and urinary magnesium. A significant reduction in the ion plasma concentration was seen, associated to a fraction of excretion inappropriately high in relation to the degree of hypomagnesemia.The cause of this important renal loss is likely attributable to cyclosporine, a drug that has as a side effect the inhibition of the reabsorption of Mg ++ in the distal convoluted tubule. then, oral supplementation was started (244 mg of Mg ++ ion / day), with subsequent normalization, after a few days, not only of magnesiemia, but also in serum calcium and potassium levels, and improvement of neurological symptoms.Hypomagnesaemia is common in patients with renal transplantation in therapy with calcineurin inhibitors ICN, due to the effects of such drugs on the TRPM6 transporter present in the kidney distal convoluted tubule. To prevent complications caused by chronic and severe depletion of magnesium in this particular population, we recommend periodic monitoring of magnesium plasma levels.

Aim: The present study aimed to assess the efficacy of 15 mEq magnesium supplied as part of a prehydration regimen in preventing cisplatin-induced nephrotoxicity in patients undergoing therapy with cisplatin-alone (40 mg/m(2)/week) for cervical cancer., Patients and Methods: We studied 28 patients with cervical cancer. This prospective cohort study compared nephrotoxicity in patients who received hydration with and without magnesium sulfate (Mg-hydration group, n=14; non-Mg-hydration group, n=14)., Results: Baseline characteristics, stage of cervical cancer, cisplatin dose and renal function did not differ significantly between the two groups. The serum creatinine level significantly increased from 0.58 to 0.75 mg/dl, and the estimated glomerular filtration rate significantly decreased from 85.1 to 66.5 ml/min by chemotherapy in the non-Mg-hydration group. In contrast, these levels did not change significantly in the Mg-hydration group., Conclusion: A magnesium dose of 15 mEq was found to provide nephroprotective effects among patients with cervical cancer undergoing chemotherapy with cisplatin alone., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Cetuximab was approved in Japan as the only clinically available molecular targeted drug for the treatment of head and neck cancer. Hypomagnesemia associated with cetuximab is considered one of the most serious adverse events. However, the factors influencing the development of hypomagnesemia are not clear, although the drug was previously approved for the treatment of patients with colorectal cancer. Thus, we studied the factors involved in the development of hypomagnesemia in patients receiving cetuximab therapy for head and neck cancer. Patients' background data and laboratory values before starting cetuximab therapy did not affect the development of hypomagnesemia. Among patients who had never been treated with cisplatin (NT group), 36.4% developed hypomagnesemia. In contrast, all patients who had previously been treated with cisplatin (T group) developed hypomagnesemia (p=0.034). Magnesium is reabsorbed by transient receptor potential subfamily melastatin 6 (TRPM6) in the distal convoluted tubule. The expression level of TRPM6 is controlled by the epidermal growth factor (EGF) pathway. Cetuximab is an EGF receptor inhibitor and reduces the expression of TRPM6. Additionally, recent studies have shown that the expression of TRPM6 is reduced by cisplatin. Therefore, we considered that the serum magnesium level was cumulatively reduced by cetuximab and cisplatin. In conclusion, the T group was more likely to develop hypomagnesemia than the NT group, and therefore the serum magnesium level in the T group requires careful monitoring so that magnesium supplementation can be provided to patients when the level decreases.

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.

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.

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.

Purpose of Review: This review summarizes the recent literature on the potential side-effects of proton pump inhibitors (PPIs) and known interactions with the metabolism/absorption of other drugs., Recent Findings: Data confirm that PPIs are a very well tolerated drug class. Their high safety, efficacy and wide distribution lead to overuse, inappropriate dosage or excessive duration of treatment. Despite the absorption of micronutrients or other plausible effects on the development of bacterial infections linked to PPI-induced hypochlorhydria, it is difficult to demonstrate an association between PPI and specific symptoms. A possible negative effect of PPIs on bone integrity appears weak, but hypomagnesemia is likely a PPI drug class effect. A higher risk of Clostridium difficile infection and other infectious diseases such as small intestinal bacterial overgrowth and spontaneous bacterial peritonitis remain controversial in PPI users. However, the careful use of PPIs in cirrhotic or otherwise fragile patients is mandatory. Short-term or long-term PPI use may trigger microscopic colitis, and the management of this condition may include PPI withdrawal. The effect of PPIs on stimulating exocrine or endocrine gastric cell proliferation is poorly understood. A diagnostic delay or masking of diseases such as gastrinoma is difficult to evaluate., Summary: Short-term standard dose PPI treatment is low risk. Long-term PPI use may complicate health conditions by various mechanisms linked to PPIs and/or to hypochlorhydria.

Introduction: Proton pump inhibitors (PPIs) have been linked to clinically symptomatic hypomagnesemia., Areas Covered: We searched Medline database in all languages using 'proton-pump inhibitors, magnesium, hypomagnesemia and hypomagnesemic hypoparathyroidism' as search terms and other articles were identified through searches of the files of the authors and reference lists from relevant articles. All patients presented with hypomagnesemic hypoparathyroidism, however, they rarely had life-threatening conditions such as malignant ventricular arrhythmias associated with prolonged QT interval, tetany and generalized seizures. Hypomagnesemia was seen with different PPIs, which could suggest a class effect, and was refractory to Mg replacement until PPIs were stopped. Hypomagnesemia may recur after re-challenge with the same or a different PPI and is not clearly dose-related. Mechanisms are poorly understood but PPI-induced hypochlorhydria does not seem involved. Carriers of TRPM6/7 mutations could be at risk., Expert Opinion: Although mechanism and incidence rate remain unclear, there seems little doubt that PPIs may cause hypomagnesemia. We should obtain blood Mg levels prior to initiation of PPIs when patients are expected to be on treatment for long period of time and in those with other potential causes of hypomagnesemia. Use of H2-blockers may be an appropriate alternative.

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.

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.

Background: Recent literature reports of potential adverse effects (AEs) of proton pump inhibitors (PPIs), especially during long-term treatments., Purpose: To present a literature review of major AEs: digestive infections, pneumonia, bone fracture, hypomagnesemia, interstitial nephritis, gastric cancer and neutropenia., Data Sources: The authors used Pubmed; articles in English or French, published between August 2006 and August 2011 were analyzed., Study Selection: Two reviewers analyzed the references of title and summary to retain mainly observational studies, controlled clinical trials, meta-analyzes, case reports., Results: For digestive infections: observational studies have shown a link moderate to high (OR 1.4 to 8.3) with exposure to PPIs. For pneumonia: some case-control studies reported a modest significative risk (OR 1.2 to 1.6), some not. The risk appears dose dependent and greater in subjects at risk. For fractures: the majority of observational studies report a significative increase in low to moderate risk (OR 1.2 to 3.1), correlated with the dose and duration of treatment. For magnesium deficiency: rare but potentially severe, they are described in case reports. Interstitial nephritis are described in case reports and for different PPIs, suggesting a class effect. For the stomach neoplasm: if three observational studies show an increased cancer risk (OR 1.5 to 2, 3), confounding factors make the causal link uncertain. Neutropenia is reported in a clinical observation, a class effect is suggested., Limitations: One can regret the absence of controlled clinical trials; indeed the observational studies have the interest to move closer to "real life", but often have methodological bias., Conclusion: Although AEs PPIs do not call into question the usefulness of this drug class, they show the need to limit their prescribing to indications for which efficacy has been proven. Moreover, PPIs treatment must be regularly reassessed to avoid exposing patients to unnecessary risks., (Copyright © 2012 Elsevier Masson SAS. All rights reserved.)

Introduction: Cisplatin still has a central role in cancer chemotherapy, but is associated with the risk of toxicities, the most common of which is nephrotoxicity. The aim of the present study is evaluation of cisplatin nephrotoxicity in Iranian population of cancer patients., Materials and Methods: All admitted patients to the oncology service who received cisplatin were included in a prospective study from 2004 to 2010. Clinical and laboratory data including kidney function tests were recorded at baseline and during follow-up visits., Results: One hundred patients (56% men) were included. Their mean age was 44 years. Common adverse events were nausea (85%) and vomiting (78%), followed by anorexia and fatigue (20%), taste change (10%), hearing loss (8%), cramping abdominal pain (8%), and tinnitus (5%). The most important finding was normal kidney function, except for mild hypomagnesemia (grade 1 toxicity) in 18%, without any symptoms or other electrolyte abnormalities. None of the patients with hypomagnesemia had significant serum electrolyte imbalances, diarrhea, severe allergic reactions, difficulty in walking, or chest pain., Conclusions: Cisplatin has the potential to produce both mild and severe side effects. Although the neurologic and gastrointestinal toxicities were observed, renal toxicity (rising blood urea and creatinine or electrolyte abnormality) was not observed, and the only toxicity was grade 1 hypomagnesaemia.

Several oral or intravenous drug administrations can cause abnormalities in serum magnesium concentration. Most of drug-induced hypomagnesemia derives from a loss of the mineral in the urine by facilitating renal secretion. Hypermagnesemia can occur by a direct intake of drugs including magnesium, especially in patients with renal insufficiency. Frequent check of serum magnesium concentration will be needed to monitor these abnormalities.

We determined whether the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) N-​(3-​chlorophenyl)-​6,​7-​dimethoxy-​4-​quinazolinamine (tyrphostin AG-1478) causes hypomagnesemia and cardiac dysfunction in rats. Tyrphostin was administered (3 times per week, intraperitoneal injection, to achieve 21.4 mg·(kg body mass)(-1)·day(-1)) to normomagnesemic rats for 5 weeks. Levels of magnesium in the plasma of the tyrphostin-treated rats decreased significantly by the following amount: 17% at week 1, 27% at week 2, and 26%-35% between weeks 3 to 5. Levels of the plasma lipid peroxidation marker 8-isoprostane rose significantly: by 58% at week 1, 168% at week 3, and 113% at week 5. At week 5, blood neutrophils from the tyrphostin-treated group displayed a 2.26-fold higher basal level of O(2)(·-) generation; the ratio of oxidized glutathione (glutathione disulfide; GSSG) to reduced glutathione (GSH) in the red blood cells increased 2.5-fold. At week 5, echocardiography revealed that TKI treatment resulted in significant cardiac systolic dysfunction, with impaired diastolic function and dilated cardiomyopathy. Since hypomagnesemia alone can trigger oxidative stress and cardiac injury, we suggest that inhibition of EGFR-TK caused magnesium wasting, which partly contributed to decreased cardiac contractility.

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.

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.

To evaluate renal side-effects of anti-epileptic medication by valproate (VPA) and carbamazepine (CBZ), we performed a prospective study to assess renal tubular function by measuring N-acetyl-β glucosaminidase (NAG)/Cr activity index in epileptic children. The study was conducted on 112 children who were diagnosed with epilepsy (28 patients were observed before treatment with anti-epileptics, 28 children were administered VPA, 28 children were treated with CBZ, and 28 healthy children were selected age &sex matched for). An especial NAG assay kit was used for quantitative measuring of NAG in patient urine samples. The patients receiving VPA exhibited higher rate of NAG activity compared with the two groups which not receiving anti-epileptic drugs. Measurement of urinary NAG/Cr index in the children who received CBZ also, was significantly higher than those who were not administered anti-epileptic drugs. The measurement of NAG/Cr index in the VPA group was significantly higher than that in the CBZ group (NAG index: 2.75 versus 1.71). Children on anti-epileptic treatment with VPA or CBZ might demonstrate signs of renal tubular dysfunction, reflected by NAG/Cr activity index. This side effect can be potentially more occurred following VPA administration.

Hypouricemia is defined when a serum urate concentration is less than or equal 2.0mg/dl. Differential diagnosis is made by fractional uric acid excretion with the identification of urate transporters and intracellular proteins involved in the tubular transport of uric acid. This review examines current knowledge on uric acid tubular transport and the various clinical situations of hypouricemia.

Purpose: To provide oncology nurses with an overview of the toxicity management associated with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer., Methods: Monoclonal antibodies such as cetuximab and panitumumab that target EGFR have provided patients with metastatic colorectal cancer with effective treatment options. Both antibodies can be used as monotherapy; cetuximab is also approved for use in combination with chemotherapy. We reviewed the literature regarding the signs and symptoms, assessment of severity, and strategies available to prevent and manage adverse events associated with these agents., Key Results: This class of therapeutics is associated with an overall acceptable adverse event profile that is distinctly different from conventional chemotherapeutics. In contrast to cytotoxic chemotherapy, which causes myelosuppression, mucositis, and nausea and vomiting, common toxicities reported for anti-EGFR therapy include the more frequent cutaneous toxicities, electrolyte imbalances, and diarrhoea, as well as the less frequent ocular toxicities. Infusion reactions are also observed with the chimerical monoclonal antibody cetuximab., Conclusions: Oncology nurses play a key role in the administration of multi-agent treatment regimens, especially with respect to the identification and management of toxicities, patient education, and patient support. By reducing the incidence and severity of the adverse events associated with anti-EGFR therapy, oncology nurses have the potential to sustain patient adherence to completion of treatment, identify signs and symptoms early, proactively manage adverse events, and provide appropriate treatment interventions, thereby improving patient quality of life.

Our understanding of magnesium (Mg(2+)) regulation has recently been catapulted forward by the discovery of several disease loci for monogenic disorders of Mg(2+) homeostasis. In this issue of the JCI, Groenestege et al. report that their study of a rare inherited Mg(2+) wasting disorder in consanguineous kindred shows that EGF acts as an autocrine/paracrine magnesiotropic hormone (see the related article beginning on page 2260). EGF stimulates Mg(2+) reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane. These authors show that a point mutation in pro-EGF retains EGF secretion to the apical but not the basolateral membrane, disrupting this cascade and causing renal Mg(2+) wasting. This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology.

Primary hypomagnesemia constitutes a rare heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg(2+)) wasting resulting in generally shared symptoms of Mg(2+) depletion, such as tetany and generalized convulsions, and often including associated disturbances in calcium excretion. However, most of the genes involved in the physiology of Mg(2+) handling are unknown. Through the discovery of a mutation in the EGF gene in isolated autosomal recessive renal hypomagnesemia, we have, for what we believe is the first time, identified a magnesiotropic hormone crucial for total body Mg(2+) balance. The mutation leads to impaired basolateral sorting of pro-EGF. As a consequence, the renal EGFR is inadequately stimulated, resulting in insufficient activation of the epithelial Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) and thereby Mg(2+) loss. Furthermore, we show that colorectal cancer patients treated with cetuximab, an antagonist of the EGFR, develop hypomagnesemia, emphasizing the significance of EGF in maintaining Mg(2+) balance.