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Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT.
Hochster, HS, Grothey, A, Hart, L, Rowland, K, Ansari, R, Alberts, S, Chowhan, N, Ramanathan, RK, Keaton, M, Hainsworth, JD, et al
Annals of oncology : official journal of the European Society for Medical Oncology. 2014;(6):1172-8
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BACKGROUND Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity. The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and extend the duration of treatment. PATIENTS AND METHODS In this trial involving double randomization, 140 patients were randomized to receive modified FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and Ca/Mg versus placebo (pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF). RESULTS One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP) (HR = 0.533, P = 0.047). CONCLUSIONS An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial despite the very attenuated sample. There was no effect of Ca/Mg on response.
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Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial.
Dorhout Mees, SM, Algra, A, Vandertop, WP, van Kooten, F, Kuijsten, HA, Boiten, J, van Oostenbrugge, RJ, Al-Shahi Salman, R, Lavados, PM, Rinkel, GJ, et al
Lancet (London, England). 2012;(9836):44-9
Abstract
BACKGROUND Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage. METHODS We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome-defined as a score of 4-5 on the modified Rankin Scale-3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36). FINDINGS 1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85-1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86-1·08). INTERPRETATION Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended. FUNDING Netherlands Heart Foundation, UK Medical Research Council.
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Placental secretion of interleukin-1 and interleukin-1 receptor antagonist in preeclampsia: effect of magnesium sulfate.
Amash, A, Holcberg, G, Sapir, O, Huleihel, M
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research. 2012;(9):432-41
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Preeclampsia is a pregnancy-specific disorder characterized by hypertension and systemic endothelial dysfunction. Interleukin (IL)-1β is a possible mediator of maternal endothelial dysfunction in preeclampsia. Serum IL-1β as well as its natural inhibitor IL-1 receptor antagonist (IL-1Ra) were reported to be increased in women with preeclampsia. In the current study, we addressed the role of the placenta in controlling the circulatory levels of IL-1β and its natural inhibitor IL-1Ra in preeclampsia, and the possible effect of magnesium sulfate (MgSO(4)) on these levels. Using an ex vivo placental perfusion system, placentas from preeclamptic (n = 9) and normotensive (n = 6) pregnancies were perfused in presence or absence of MgSO(4). Perfusate samples were collected from the maternal and the fetal circulations of the perfusion system, and IL-1β and IL-1Ra were examined by enzyme-linked immunoassay (ELISA). Preeclamptic placentas secreted higher levels of IL-1β (P < 0.001), and a tendentious higher levels of IL-1Ra, mainly into the maternal circulation, as compared with normotensive placentas, although no differences in IL-1β:IL-1Ra ratio were detected. However, there was only tendentious increase in the secretion levels of IL-1β or IL-1Ra into the fetal circulation of preeclamptic placentas, when compared with normotensive placentas. Administration of MgSO(4) to preeclamptic placentas resulted in an attenuation of the increased secretion of IL-1β into the maternal circulation (P < 0.001), and in a tendentious reduction in IL-1Ra. However, IL-1β:IL-1Ra ratio in preeclamptic placentas was not affected by MgSO(4). Interestingly, exposure of normotensive placenta to MgSO(4) resulted only in increased levels of IL-1Ra in the maternal circulation, without affecting IL-1β levels or IL-1β:IL-1Ra ratio. These findings suggest that the placenta may contribute to the elevation in serum IL-1β and IL-1Ra in preeclampsia by increased secretion of these cytokines into the maternal circulation, and that MgSO(4) is able to attenuate this increased secretion of IL-1β, and possibly IL-1Ra, in preeclampsia.
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Intravenous calcium and magnesium for oxaliplatin-induced sensory neurotoxicity in adjuvant colon cancer: NCCTG N04C7.
Grothey, A, Nikcevich, DA, Sloan, JA, Kugler, JW, Silberstein, PT, Dentchev, T, Wender, DB, Novotny, PJ, Chitaley, U, Alberts, SR, et al
Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2011;(4):421-7
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PURPOSE Cumulative sensory neurotoxicity (sNT) is the dose-limiting toxicity of oxaliplatin, which commonly leads to early discontinuation of oxaliplatin-based therapy in the palliative and adjuvant settings. In a nonrandomized, retrospective study, intravenous (IV) calcium/magnesium (Ca/Mg) was associated with reduced oxaliplatin-induced sNT. METHODS Patients with colon cancer undergoing adjuvant therapy with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) were randomly assigned to Ca/Mg (1g calcium gluconate plus 1g magnesium sulfate pre- and post-oxaliplatin) or placebo, in a double-blinded manner. The primary end point was the percentage of patients with grade 2 or greater sNT at any time during or after oxaliplatin-based therapy by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE; version 3) criteria. An oxaliplatin-specific sNT scale and patient questionnaires were also used to assess sNT. After 104 of 300 planned patients were enrolled, the study was closed. This was due to preliminary reports from another trial that suggested that Ca/Mg decreased treatment efficacy; these data were subsequently found to be incorrect. RESULTS Overall, 102 patients were available for analysis. Ca/Mg decreased the incidence of chronic, cumulative, grade 2 or greater sNT, as measured by NCI CTCAE (P = .038) and also by the oxaliplatin-specific sNT scale (P = .018). In addition, acute muscle spasms associated with oxaliplatin were significantly reduced (P = .01) No effect on acute, cold-induced sNT was found. No substantial differences in adverse effects were noted between Ca/Mg and placebo. CONCLUSION Despite early termination and decreased statistical power, this study supports IV Ca/Mg as an effective neuroprotectant against oxaliplatin-induced cumulative sNT in adjuvant colon cancer.
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Intradermal administration of magnesium sulphate and magnesium chloride produces hypesthesia to mechanical but hyperalgesia to heat stimuli in humans.
Ushida, T, Iwatsu, O, Shimo, K, Tetsunaga, T, Ikeuchi, M, Ikemoto, T, Arai, YC, Suetomi, K, Nishihara, M
Journal of neuroinflammation. 2009;:25
Abstract
BACKGROUND Although magnesium ions (Mg2+) are known to display many similar features to other 2+ charged cations, they seem to have quite an important and unique role in biological settings, such as NMDA blocking effect. However, the role of Mg2+ in the neural transmission system has not been studied as sufficiently as calcium ions (Ca2+). To clarify the sensory effects of Mg2+ in peripheral nervous systems, sensory changes after intradermal injection of Mg2+ were studied in humans. METHODS Magnesium sulphate, magnesium chloride and saline were injected into the skin of the anterior region of forearms in healthy volunteers and injection-induced irritating pain ("irritating pain", for short), tactile sensation, tactile pressure thresholds, pinch-pain changes and intolerable heat pain thresholds of the lesion were monitored. RESULTS Flare formation was observed immediately after magnesium sulphate or magnesium chloride injection. We found that intradermal injections of magnesium sulphate and magnesium chloride transiently caused irritating pain, hypesthesia to noxious and innocuous mechanical stimulations, whereas secondary hyperalgesia due to mechanical stimuli was not observed. In contrast to mechanical stimuli, intolerable heat pain-evoking temperature was significantly decreased at the injection site. In addition to these results, spontaneous pain was immediately attenuated by local cooling. CONCLUSION Membrane-stabilizing effect and peripheral NMDA-blocking effect possibly produced magnesium-induced mechanical hypesthesia, and extracellular cation-induced sensitization of TRPV1 channels was thought to be the primary mechanism of magnesium-induced heat hyperalgesia.
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Magnesium sulfate versus placebo for paroxysmal atrial fibrillation: a randomized clinical trial.
Chu, K, Evans, R, Emerson, G, Greenslade, J, Brown, A
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine. 2009;(4):295-300
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OBJECTIVES The objective was to investigate the efficacy of magnesium sulfate (MgSO4) in decreasing the ventricular rate in emergency department (ED) patients presenting with new-onset, rapid atrial fibrillation (AF). METHODS A double-blinded, placebo-controlled randomized clinical trial was conducted in an adult university hospital. Patients aged > or =18 years with AF onset of less than 48 hours and a sustained ventricular rate of >100 beats/min were randomized to either intravenous (IV) MgSO4 10 mmol or normal saline (NSal). Rhythm and instantaneous heart rate as measured by the monitor were recorded at baseline and every 15 minutes for 2 hours after starting the trial drug. Heart rate and rhythm were compared at 2 hours. A multilevel modeling analysis was performed to adjust for differences in baseline heart rate and any additional treatment and to examine changes in heart rate over time. RESULTS Twenty-four patients were randomized to MgSO4 and 24 to NSal. Baseline heart rate was lower in the MgSO4 group (mean +/- standard deviation [+/-SD] = 125 +/- 24 vs. 140 +/- 21 beats/min]. One and 3 patients in the MgSO4 and NSal groups, respectively, were given another antiarrhythmic or were electrically cardioverted within 2 hours after starting the trial drug. Heart rate (mean +/- SD) at 2 hours in both MgSO4 (116 +/- 30 beats/min) and NSal groups (114 +/- 31 beats/min) decreased below their respective baseline levels. However, the rate of heart rate decrease across time did not differ between groups (p = 0.124). The proportion of patients who converted to sinus rhythm 2 hours post-trial drug did not differ (MgSO4 8.7% vs. NSal 25.0%, p = 0.25). CONCLUSIONS This study was unable to demonstrate a difference between IV MgSO4 10 mmol and saline placebo for reducing heart rate or conversion to sinus rhythm at 2 hours posttreatment in ED patients with AF of less than 48 hours duration.
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A randomized controlled trial of intravenous magnesium sulphate as an adjunct to standard therapy in acute severe asthma.
Singh, AK, Gaur, S, Kumar, R
Iranian journal of allergy, asthma, and immunology. 2008;(4):221-9
Abstract
Though intravenous (IV) Magnesium Sulphate (MgS04) has additive effect to beta-2 agonists, its additive benefit in face of combination therapy with beta-2-agonists and ipratropium (standard therapy of severe acute exacerbation of asthma) remains unaddressed. The aim of this investigation was to evaluate the role of IV MgSO4 when used as an adjunct to standard therapy of severe exacerbations of asthma. Randomized, single blinded, placebo-controlled study was carried out in Emergency Department (ED). Patients aged 18-60 years presenting with acute asthma and FEV1 < 30 % predicted (pred.) were included. All patients received IV Hydrocortisone on arrival. In group1 (controls), patients were nebulised with salbutamol and ipratropium thrice at 20 minutes interval and were given 2g IV MgSO4 at 30 minutes. In group2 patients were nebulised similarly, but were given IV normal saline at 30 minutes for blinding. FEV1 was evaluated at baseline and at 30 minutes intervals. The primary efficacy end point was FEV1%pred. at 120 mins and pooled discharge rate (derived from comparing proportion of groups attaining PEFR > or = 60%pred. and relief in dyspnea at 30, 60, 90, 120 minutes). Both groups of 30 patients each, were matched with respect to demographic and pulmonary parameters (Baseline FEV1% :22.0+/-5.1% in group2 vs.22.07+/-5.2% in group1, p=0.87).At 120 minutes, there was a higher mean FEV1 %pred (62.84+/-4.73% vs. 56.7+/-4.5%) and %improvement from baseline of (40.7+/-9.2%vs34.77+/-7.3%), in group 2 as compared to group1 (Mean Difference= 6.07%, C.I.1.87-10.62., p<0.01).The pooled discharge rate in group2 with respect to group1 was positive and significant (log rank.=6.8, p<0.05). Thus IV MgSO4 improves pulmonary function and discharge rates, when used as an adjunct to standard therapy in severe acute asthma.Magnesium sulfate as an adjunct to standard therapy in patients with severe exacerbation of asthma could cause improvement in pulmonary function and decrease in hospital admission.
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Effects of magnesium sulphate and clonidine on propofol consumption, haemodynamics and postoperative recovery.
Altan, A, Turgut, N, Yildiz, F, Türkmen, A, Ustün, H
British journal of anaesthesia. 2005;(4):438-41
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BACKGROUND This placebo-controlled, double-blind study was designed to assess the effects of magnesium sulphate and clonidine on peroperative haemodynamics, propofol consumption and postoperative recovery. METHODS Sixty ASA I-II patients undergoing spinal surgery were randomized into three groups. Group M received magnesium sulphate 30 mg kg(-1) as a bolus before induction and 10 mg kg(-1) h(-1) by infusion. Group CL received clonidine 3 microg kg(-1) as a bolus before induction and 2 microg kg(-1) h(-1) by infusion during the operation period. The same volume of isotonic solution was administered to the control group (group CT). Anaesthesia was induced with propofol and was maintained with propofol infusion [dose according to the bispectral index (BIS)], fentanyl and cisatracurium. Analysis of variance and the Bonferroni test were used for statistical analysis. RESULTS Induction of anaesthesia with propofol was rapid in the presence of magnesium sulphate and clonidine. The time for BIS to reach 60 was significantly shorter in group M and group CL (P<0.0001) but postoperative recovery was slower with magnesium sulphate compared with the clonidine and control groups (P<0.0001). There was no statistical difference in heart rate and arterial blood pressure between the groups. Propofol requirements for induction and maintenance of anaesthesia were significantly lower with magnesium and clonidine (P<0.0001). CONCLUSION Clonidine caused bradycardia and hypotension and magnesium sulphate caused delayed recovery, but can be used as adjuvant agents with careful management.
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Cardioprotective effects of magnesium sulfate in patients undergoing primary coronary angioplasty for acute myocardial infarction.
Nakashima, H, Katayama, T, Honda, Y, Suzuki, S, Yano, K
Circulation journal : official journal of the Japanese Circulation Society. 2004;(1):23-8
Abstract
BACKGROUND Experimental evidence indicates that magnesium sulfate may have potential cardioprotective properties as an adjunct to coronary reperfusion. The present study was designed to examine the hypothesis that magnesium might have beneficial effects on left ventricular (LV) function and coronary microvascular function in patients with acute myocardial infarction (AMI). METHODS AND RESULTS The study population of 180 consecutive patients with a first AMI (anterior or inferior) underwent successful primary coronary intervention. Patients were randomized to treatment with either intravenous magnesium (magnesium group, n=89) or normal saline (control group, n=91). Pre-discharge left ventriculograms were used to assess LV ejection fraction (LVEF), regional wall motion (RWM) within the infarct-zone and LV end-diastolic volume index. The Doppler guidewire was used to assess coronary flow velocity reserve (CFVR) as an index of coronary microvascular function. Magnesium group subjects showed significantly better LV systolic function (LVEF 63+/-9% vs 55+/-13%, p<0.001; RWM: -1.01+/-1.29 SD/chord vs -1.65+/-1.11 SD/chord, p=0.004), significantly smaller LV end-diastolic volume index (63+/-17 ml/m(2) vs 76+/-20 ml/m(2), p<0.001), and significantly higher CFVR (2.95+/-0.76 vs 2.50+/-0.99, p=0.023) than controls. CONCLUSION Magnesium sulfate as an adjunct to primary coronary intervention shows favorable functional outcomes in patients with AMI.
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A comparison of magnesium sulfate and nimodipine for the prevention of eclampsia.
Belfort, MA, Anthony, J, Saade, GR, Allen, JC, ,
The New England journal of medicine. 2003;(4):304-11
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OBJECTIVE Magnesium sulfate may prevent eclampsia by reducing cerebral vasoconstriction and ischemia. Nimodipine is a calcium-channel blocker with specific cerebral vasodilator activity. Our objective was to determine whether nimodipine is more effective than magnesium sulfate for seizure prophylaxis in women with severe preeclampsia. METHODS We conducted an unblinded, multicenter trial in which 1650 women with severe preeclampsia were randomly assigned to receive either nimodipine (60 mg orally every 4 hours) or intravenous magnesium sulfate (given according to the institutional protocol) from enrollment until 24 hours post partum. High blood pressure was controlled with intravenous hydralazine as needed. The primary outcome measure was the development of eclampsia, as defined by a witnessed tonic-clonic seizure. RESULTS Demographic and clinical characteristics were similar in the two groups. The women who received nimodipine were more likely to have a seizure than those who received magnesium sulfate (21 of 819 [2.6 percent] vs. 7 of 831 [0.8 percent], P=0.01). The adjusted risk ratio for eclampsia associated with nimodipine, as compared with magnesium sulfate, was 3.2 (95 percent confidence interval, 1.1 to 9.1). The antepartum seizure rates did not differ significantly between groups, but the nimodipine group had a higher rate of postpartum seizures (9 of 819 [1.1 percent] vs. 0 of 831, P=0.01). There were no significant differences in neonatal outcome between the two groups. More women in the magnesium sulfate group than in the nimodipine group needed hydralazine to control blood pressure (54.3 percent vs. 45.7 percent, P<0.001). CONCLUSIONS Magnesium sulfate is more effective than nimodipine for prophylaxis against seizures in women with severe preeclampsia.