Hydrochlorothiazide in CLDN16 mutation

BACKGROUND: Hydrochlorothiazide (HCT) is applied in the therapy of familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) caused by claudin-16 (CLDN16) mutation. However, the short-term efficacy of HCT to reduce hypercalciuria in FHHNC has not yet been demonstrated in a clinical trial. METHODS: Four male and four female patients with FHHNC and CLDN16 mutation, under long-standing HCT therapy (0.4-1.2 mg/kg, median 0.9 mg/kg, dose according to calciuria), aged 0.7-22.4 years, were included in a clinical study to investigate the effect of HCT on calciuria. The study design consisted of three periods: continued therapy for 4 weeks, HCT withdrawal for 6 weeks and restart of therapy at the same dose for 4 weeks. Calciuria and magnesiuria were assessed weekly as Ca/creat and Mg/creat ratio, every 2 weeks in 24 h urine, and serum Mg, K and kaliuria (s-Mg, s-K and K/creat) at weeks 0, 6, 10 and 14. The data of each study period were averaged and analysed by Friedman and Wilcoxon test. RESULTS: Ca/creat was significantly reduced by HCT (median before/at/after withdrawal 0.76/1.24/0.77 mol/mol creat; n = 8, P<0.05). The reduction of Ca/24 h by HCT was not statistically significant (0.13/0.19/0.13 mmol/kg x 24 h; n = 5). Serum Mg (0.51/0.64/0.56 mmol/l; n = 8, P<0.05) and Serum K (3.65/4.35/3.65 mmol/l; n = 8, P<0.05) were significantly higher during withdrawal. However, Mg/creat (0.98/0.90/0.90 mol/mol creat; n = 8), Mg/24 h (0.14/0.12/0.18 mmol/kg x 24h; n = 5) and K/creat (6.3/8.4/6.2 mol/mol creat; n = 8) remained statistically unchanged during withdrawal. CONCLUSIONS: We demonstrated that HCT is effective in reducing hypercalciuria due to CLDN16 mutation on a short-term basis. However, the efficacy of HCT to attenuate disease progression remains to be elucidated.

Impact of proton pump inhibitor use on magnesium homoeostasis: a cross-sectional study in a tertiary emergency department.

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.

The critical dietary potassium concentration for induction of mineral disorders in non-lactating Welsh Mountain sheep

Diets with more than 30 g K/kg DM have previously been associated with hypomagnesaemia in grazing cattle, and to test whether such diets lead to mineral disorders in sheep, the absorption of Mg and other elements was investigated using experimental diets to which KC I had been added to provide 27, 29, 32 or 34 g K/kg DM. The apparent absorption, balance and apparent retention of Mg, and to a lesser extent Ca, were reduced for sheep offered the diets with 32 or 34 g K/kg DM. The absorption and retention of K, Na, P, Zn, Pb and Cd was not affected by treatment. The blood intracellular Ca concentration was reduced by the diets with 29, 32 or 34 g K/kg DM, compared to the diet with 27 g K/kg DM, but the concentration of other elements was unaffected. Blood plasma Ca concentration was increased at the highest level of K inclusion, providing evidence of mild hyperkalaemia and the involvement of Ca homeostatic mechanisms. It is concluded that Mg absorption by sheep will be impaired if the diet contains more than 30 g K/kg DM, equivalent to an intake of approximately 13 g K/d, but that a high K diet may be beneficial before parturition to accustom the sheep to Ca mobilization before lactation. (c) 2005 Elsevier B.V. All rights reserved.

Aminoglycoside-induced changes in the renal handling of cations in the Fischer 344 rat

Disturbances of cation homeostasis, particularly hypomagnesaemia, are a frequent consequence of treatment with aminoglycoside antibiotics. These disturbances are thought to result from renal wasting of cations and administration of gentamicin to rats has been shown to produce hypercalciuria and hypermagnesiuria. The aims of this study were to attempt to elucidate these responses in anaesthetised rats infused with gentamicin and to use this model to investigate the mechanisms of these effects. Fischer 344 rats were anaesthetised and surgically prepared for clearance experiments. Infusion of gentamicin in isotonic saline increased urinary output of calcium and magnesium while sodium and potassium output were unaffected. These elevations in calcium and magnesium excretion were explained by reduced tubular reabsorption of these cations. Both the hypercalciuric and hypermagnesiuric responses to gentamicin were extremely rapid and were sustained during drug infusion; when gentamicin infusion ceased both responses were rapidly reversible. Infusion of another aminoglycoside, tobramycin, produced very similar effects to gentamicin. The hypercalciuria and hypermagnesiuria caused by gentimicin infusion were unaffected by parathyroidectomy. The peak increases in calcium and magnesium output brought about by infusion of gentamicin with frusemide were not significantly different to the increases produced by frusemide alone. The site at which gentamicin interferes with calcium and magnesium reabsorption cannot be firmly deduced from these results. However, the known close association between calcium and sodium reabsorption in the proximal tubule implies that gentamicin is unlikely to change proximal calcium reabsorption without a similar change in proximal sodium reabsorption. The similarity between the hypercalciuric and hypermagnesiuric effects of frusemide alone and the effects of frusemide infused simultaneously with gentamicin suggests that gentamicin may act at the same site as the diuretic, the thick ascending limb of the loop of Henle.

Epirubicin, oxaliplatin, and capecitabine with or without panitumumab for patients with previously untreated advanced oesophagogastric cancer (REAL3): a randomised, open-label phase 3 trial.

BACKGROUND: EGFR overexpression occurs in 27-55% of oesophagogastric adenocarcinomas, and correlates with poor prognosis. We aimed to assess addition of the anti-EGFR antibody panitumumab to epirubicin, oxaliplatin, and capecitabine (EOC) in patients with advanced oesophagogastric adenocarcinoma. METHODS: In this randomised, open-label phase 3 trial (REAL3), we enrolled patients with untreated, metastatic, or locally advanced oesophagogastric adenocarcinoma at 63 centres (tertiary referral centres, teaching hospitals, and district general hospitals) in the UK. Eligible patients were randomly allocated (1:1) to receive up to eight 21-day cycles of open-label EOC (epirubicin 50 mg/m(2) and oxaliplatin 130 mg/m(2) on day 1 and capecitabine 1250 mg/m(2) per day on days 1-21) or modified-dose EOC plus panitumumab (mEOC+P; epirubicin 50 mg/m(2) and oxaliplatin 100 mg/m(2) on day 1, capecitabine 1000 mg/m(2) per day on days 1-21, and panitumumab 9 mg/kg on day 1). Randomisation was blocked and stratified for centre region, extent of disease, and performance status. The primary endpoint was overall survival in the intention-to-treat population. We assessed safety in all patients who received at least one dose of study drug. After a preplanned independent data monitoring committee review in October, 2011, trial recruitment was halted and panitumumab withdrawn. Data for patients on treatment were censored at this timepoint. This study is registered with ClinicalTrials.gov, number NCT00824785. FINDINGS: Between June 2, 2008, and Oct 17, 2011, we enrolled 553 eligible patients. Median overall survival in 275 patients allocated EOC was 11.3 months (95% CI 9.6-13.0) compared with 8.8 months (7.7-9.8) in 278 patients allocated mEOC+P (hazard ratio [HR] 1.37, 95% CI 1.07-1.76; p=0.013). mEOC+P was associated with increased incidence of grade 3-4 diarrhoea (48 [17%] of 276 patients allocated mEOC+P vs 29 [11%] of 266 patients allocated EOC), rash (29 [11%] vs two [1%]), mucositis (14 [5%] vs none), and hypomagnesaemia (13 [5%] vs none) but reduced incidence of haematological toxicity (grade ≥ 3 neutropenia 35 [13%] vs 74 [28%]). INTERPRETATION: Addition of panitumumab to EOC chemotherapy does not increase overall survival and cannot be recommended for use in an unselected population with advanced oesophagogastric adenocarcinoma. FUNDING: Amgen, UK National Institute for Health Research Biomedical Research Centre.