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Magnesium deficiency may occur for several reasons, such as inadequate intake or increased gastrointestinal or renal loss. A large body of literature suggests a relationship between magnesium deficiency and mild and moderate tension-type headaches and migraines. A number of double-blind randomized placebo-controlled trials have shown that magnesium is efficacious in relieving headaches and have led to the recommendation of oral magnesium for headache relief in several national and international guidelines. Among several magnesium salts available to treat magnesium deficiency, magnesium pidolate may have high bioavailability and good penetration at the intracellular level. Here, we discuss the cellular and molecular effects of magnesium deficiency in the brain and the clinical evidence supporting the use of magnesium for the treatment of headaches and migraines.

The present study evaluated the biochemical profile of horses that received hypotonic electrolyte solutions associated with energy sources by enteral route in continuous flow using a small caliber tube for naso-esophageal administration. Experimental design was a latin square 3 3 with two replicates and three periods. The assays were carried out with “six adult females horses”, divided into three groups submitted to the following treatments each: electrolyte solution containing dextrose (ESDext)d“5 g sodium chloride, 0.5 g potassium chloride”, 1 g of calcium gluconate, 200 mg of magnesium pidolate, and 15 g of dextrose diluted in 1,000 mL of water with measured osmolarity of 264 mOsmol/L; electrolyte solution containing maltodextrine (ESMalt)d5 g of sodium chloride, 0.5 g of potassium chloride, 1 g of calcium gluconate, 200 mg of magnesium pidolate, and 15 g of maltodextrin diluted in 1,000 mL of water with measured osmolarity of 203 mOsmol/L; and electrolyte solution containing sucrose (ESSucr)d“5 g sodium chloride, 0.5 g potassium chloride”, 1 g of calcium gluconate, 200 mg of magnesium pidolate, and 15 g of sugar diluted in 1,000 mL of water with measured osmolarity of 234 mOsmol/L. The electrolyte solutions were administered at the dosage 15 mL/kg/h during 12 hours. Hypotonic enteral electrolyte solutions that contain maltodextrin (ESMalt) and dextrose (ESDext) were effective to increase glycemia in horses without causing any adverse effects, whereas ESSucr presented slight effect on blood glucose, but without causing electrolyte imbalances.

Despite the fact that sickle cell anemia was one of the first diseases to have a demonstrated genetic etiology, to date there is still only one approved therapy for this disease. Recent increases in our understanding of the pathophysiology of the disease should translate into improved and more rapid development of newer therapies. This review will focus on the following current and potential therapeutic strategies to reduce the morbidity of sickle cell anemia. 1) Therapies such as decitabine, hydroxyurea, butyrate, lenalidomide and pomalidomide, which decrease the polymerization rate of HbS by increasing the concentration of Hb F; 2) Drugs that decrease relative intracellular HbS concentration by increasing total cell volume via inhibition of normal membrane ion exchange channels, such as KCL Cotransporter and Gardos Channels. These inhibitors include magnesium pidolate, imidazole antimycotics, arginine and Senicapoc; 3) Treatment of sickle cell vasoocclusion through inhibition of endothelial or cell surface adhesion molecules, such ICAM 4 and alpha(v)beta(3) integrins, by drugs related to the GPII(b)III(a) inhibitors or adhesion molecule modulators, and 4) Attempts to achieve vasodilation by nitric oxide and antioxidant therapy. This review will discuss the status of these emerging therapies in the treatment of sickle cell anemia.

The differing bioavailability of magnesium salts remains an open question, both at the cellular and systemic level. However, this issue is relevant for identifying the most effective magnesium supplement. We compared the effects of three widely used magnesium salts: MgSO4, MgCl2 and Mg pidolate, on the proliferation of four human cell types: promyelocytic leukaemia HL60, osteoblast-like Saos-2 and U-2 OS, and endothelial cells from the umbilical vein. The three magnesium salts had no effect on endothelial and leukemic cell growth, but magnesium pidolate impaired cell growth in osteoblast-like cells. In particular, in Saos-2 cells, 1 mM pidolate induced a slight accumulation of cells in the G0/G1 phase of the cell cycle and, in parallel, an early rise in intracellular calcium and a late decrease in intracellular magnesium content. Interestingly, when cultured in 5 mM magnesium pidolate, Saos-2 cells grew as fast as the controls. Moreover, intracellular magnesium and calcium concentrations did not vary. These results suggest a lower bioavailability of magnesium pidolate in osteoblast-like cells.

Intracellular free magnesium concentration ([Mg2+]i) was measured in enzymatically isolated rat skeletal muscle fibers using the fluorescent dye mag-indo-1. The change in [Mg2+]i produced by a local intracellular microinjection of magnesium pidolate (magnesium pyrrolidone carboxylate) was measured at a given distance from the injection site. In one series of experiments this protocol was tested on isolated fibers that were completely embedded into silicone grease: under these conditions, the injection produced an increase in [Mg2+]i that reached a steady level some time following the injection. The time-course of the [Mg2+]i change could be well accounted for by a model of longitudinal diffusion. The mean apparent Mg2+ diffusion coefficient (D(app)) was 188+/-9 microm2 s(-1) (n = 16), approximately four times lower than the value measured in vitro. This reduction likely results from the effects of cytoplasmic viscosity and of Mg2+ binding to low affinity static sites. Another series of measurements was performed on fibers that were either partially or completely free of silicone: under these conditions, the time course of the change in [Mg2+]i was in many cases more complex than predicted by simple diffusion.

Prevention of erythrocyte dehydration by specific blockade of the transport pathways promoting loss of potassium (K) is a potential therapeutic strategy for sickle cell (SS) disease. Dietary magnesium (Mg) pidolate supplementation over a 4-week period has been shown to inhibit K–Cl co-transport and reduce dehydration. We report here the results in 17 of 20 patients with SS disease treated in an open-label unblinded study of the effects of long-term (6 months) oral Mg pidolate administration (540 mg Mg/d). A significant decrease (P

The effects of oral and intravenous magnesium supplementation on cisplatin (CDDP)-induced hypomagnesemia were investigated in 41 patients treated with 100 mg/m2 CDDP. Patients were randomly allocated to receive no magnesium supplementation, intravenous magnesium supplementation (magnesium sulphate, 3 g before each CDDD administration) or oral magnesium supplementation (magnesium pidolate, 2 g orally every 8 hours on days 2 to 21 of each CDDP course) during the first 4 courses of CDDP treatment. Patients in both supplementation arms showed significantly higher magnesium levels than control patients from the second course on (oral magnesium arm) or from the third course on (intravenous magnesium arm). Three of the 9 patients (33%) in the intravenous magnesium arm and 4 of the 9 (44%) in the oral magnesium arm developed hypomagnesemia after the fourth course of CDDP, compared with 9 of the 10 (90%) unsupplemented patients. There were no magnesium-related side effects in patients on intravenous magnesium supplementation. Two patients treated with oral magnesium developed mild gastrointestinal symptoms (emesis and diarrhea), probably from magnesium therapy. Our study showed that both intravenous and oral magnesium supplementations appear to be safe and efficacious in the prevention of CDDP-induced hypomagnesemia. Since patients were not completely protected, and since the analysis was limited to the first four courses of chemotherapy, additional studies are needed to determine the best schedule of magnesium supplementation, especially in patients who receive more than four courses of CDDP chemotherapy.

The objective was to confirm the long-term utility of magnesium salts treatment on a group of young patients suffering from episodic tension-type headache (ETTH). The study was carried out at the Outpatient Headache Center at the National Neurological Institute “C. Besta,” Milan, Italy, with 45 children/adolescents with ETTH reporting consecutively for treatment. Magnesium pidolate (2.25 g) was given twice per day for three months. Medication was not administered during the year of follow-up. No other treatment was provided at any time. Patients showed significant symptom reduction. Headache days decreased by 69.9%, whereas analgesics consumption was reduced by 65.4%. Overall disability levels improved by the greatest percent − 75.7%. MIDAS subscores improved as well (question A=58.0%; question B=22.5%). Although uncontrolled, these findings are encouraging and suggest that further, better controlled research investigations are warranted.

By inducing physical and mental disorders, human stresses are known to lead to long-term serious consequences and frequent use of more medical resources. Owing to long-term clinical trials, a management algorithm based on the principles of personalized medicine has been elaborated to minimize the consequences of stress, to activate natural adaptation mechanisms and to enhance stress resistance.Известно, что стрессы у людей, вызывая физическое и психическое неблагополучие, приводят к серьезным долгосрочным последствиям и увеличению частоты использования медицинских ресурсов. Благодаря многолетней клинической работе разработан основанный на принципах персонализированной медицины алгоритм ведения пациентов с целью минимизации последствий стресса, а также активизации естественных механизмов адаптации и повышения стрессоустойчивости.

Changes in visual evoked potentials and decreased intracellular magnesium levels have been separately described in patients affected by migraine both during the attacks and in the interictal periods. An inverse correlation between increased P100 amplitude and lowered serum magnesium levels was found in children suffering from migraine with and without aura in a headache-free period. A 20-day treatment with oral magnesium pidolate seemed to normalize the magnesium balance in 90% of patients. After treatment, the reduced P100 amplitude confirmed the inverse correlation with the serum magnesium level. These data seem to suggest the hypothesis that higher visual evoked potential amplitude and low brain magnesium level can both be an expression of neuronal hyperexcitability of the visual pathways related to a lowered threshold for migraine attacks.

The objective was to determine the initial utility of magnesium salt as a treatment for paediatric episodic and chronic tension-type headache (TTH). The study took the form of a clinical replication series in the Outpatient Headache Center at the National Neurological Institute “C. Besta”, Milan, Italy. The patients were five children/adolescents with episodic and four with chronic TTH reporting consecutively for treatment. Magnesium pidolate (2.25 g) was given twice per day for two months, with one year of follow-up. No other treatment was provided. Patients with episodic TTH revealed 76.0% symptom reduction, with 80% of the sample achieving reductions greater than 50%. The patients with chronic TTH revealed 87.5% symptom reduction, with 100% of the sample achieving reductions greater than 50%. Analgesic consumption decreased significantly for chronic TTH. Only one child took medication in the episodic TTH group. No significant changes occurred with respect to depression and anxiety, but these measures were not clinically elevated at the start of treatment. Although uncontrolled, the initial findings are encouraging and suggest that further, better controlled research is warranted.

Article is dedicated to the problem of headache in children. This pathology is being found more frequently in pediatric and children’s neurologic practice. The authors examine headache pathogenesis from the position of magnesium deficiency. Analysis of results of the modern studies on magnesium deficiency and its correction in patients with headache indicates that magnesium metabolism may play an important role both in pathogenesis of different headache types and in its treatment and prevention.

Abstract 819 Background. HbSC is characterized by increased red cell density and clinical complications but has rarely been the target of therapeutic trials. The CHAMPS Trial was a prospective, randomized, double-blinded, multi-center Phase II study of HU and Mg in children and adults with HbSC conducted by the Comprehensive Sickle Cell Centers Clinical Trials Consortium. HU is clinically efficacious in HbSS, but its value has not been demonstrated for HbSC; Mg reduces cation transport activity and improves hydration of HbSS erythrocytes. The primary objective of the trial was to measure the ability of HU and Mg individually and in combination to reduce the density of HbSC erythrocytes. Secondary objectives were to determine the effects of the 2 agents on hematologic parameters and red cell pathobiology, to identify toxicities of HU and Mg, and to record adverse events. Methods. Eligible subjects had HbSC and at least 1 vaso-occlusive event in the previous 12 months (but none in the 4 weeks before study entry) and were ≥ age 5 years. After providing informed consent and baseline evaluations, subjects were randomized to 1 of 4 arms: (A) HU (20 mg/kg/d PO) and Mg (0.6 mEq/kg/d PO in 2 doses), (B) HU and placebo for Mg, (C) HU placebo and Mg, or (D) placebos for both. Subjects were evaluated at 2 or 4 week intervals for 11 months (15 visits). In addition to physical exams, blood counts and chemistry profiles, subjects had central lab evaluations [including measurements of red cell density (by Advia instrument), HbF, red cell cation content, KCl co-transport and Gardos channel activity, cell adhesion to endothelial cells and laminin, and erythrocyte membrane phosphatidyl serine (PS exposure)] at baseline (twice) and weeks 8, 16, 24, and 44. The primary endpoint was red cell density measured at week 8. Results. Forty-four subjects (median age 13.6 years, range 5-53, 73% < age 16) had baseline evaluations and were randomized, 36 reached the primary endpoint and 22 completed 11 months on study drugs. The trial was halted prematurely because of slow enrollment. Subjects in the HU groups (A and B) had increased red cell MCV, cell Hb and HbF compared to baseline and to groups C and D at week 8 (p Conclusions. HU had significant effects on HbSC erythrocytes, including increased HbF and MCV, with increasing response over 6 months. Mg at a dose of 0.6 mEq/kg/d had no measurable effect on red cell properties or endothelial interactions, either alone or in combination with HU. This may have been related to suboptimal dosing, since the maximum tolerated dose was recently found to be 0.9 mEq/kg/d. Differences in acute events, although not significant, suggest a need for studies with larger enrollment. These data provide a basis for performing clinical efficacy trials using HU, perhaps at higher doses, in subjects with HbSC disease. Disclosures: Off Label Use: Hydroxyurea is being tested for its effects on red blood cells in persons with HbSC disease. Magnesium pidolate is being tested for its effects on red blood cells in persons with HbSC disease.

Red blood cells (RBCs) in sickle cell anemia are characterized by increased adhesion to laminin and endothelial cells, due both to increased adhesion receptor expression as well as receptor activation. However, these RBC properties have not been comprehensively evaluated in HbSC disease. In the on-going multi-center CHAMPS trial, all subjects have a diagnosis of HbSC disease and have had at least one significant vaso-occlusive event in the previous 12 months (but none in the previous 4 weeks). All subjects are at least 5 years of age (median 13.4 yr, range = 5.2–53.3 yr) at enrollment. Subjects receive hydroxyurea (HU) and/or magnesium pidolate (Mg) (or their placebos); endpoints include the effect of study drugs on erythrocyte density and RBC-endothelial interactions. To characterize the adhesive properties of RBCs at baseline in these patients, we performed the following analyses on blood samples shipped to a central lab at Duke University from 11 participating sites: adhesion to laminin at 1 dyne/cm2 shear stress; adhesion to endothelial cells after epinephrine (epi) stimulation of RBCs at shear stress of 1 dyne/cm2; and phosphatidylserine exposure, as measured by mean fluorescence intensity after binding of fluoresceinated annexin V. Most subjects had two pre-treatment specimens analyzed. Analysis of the first 83 samples (47 patients) showed that a mean of 1.64% (± 0.15% SEM) of circulating HbSC RBCs expressed phosphatidylserine, or a little less than half as many as in HbSS RBC samples (4.12% positive ± .91% SEM, n = 29) tested as controls (HbSC vs HbSS p=.0009). However HbSC RBCs were also different from HbAA RBCs (1.076% positive, n = 5), and all three sets of values were significantly different by ANOVA (p = .0017) (Figure). The two baseline visits for HbSC subjects resulted in nearly identical means of 1.64% and 1.65%, respectively. Adhesion of HbSC red cells to laminin at baseline was quite variable among patients, with a mean of 36.1 adherent cells/mm2 (range 2–256). This was slightly but not significantly lower than the values obtained using HbSS control RBCs (mean 58.8 cells/mm2, range 0.2–258). After epi stimulation of RBCs, 9.6% of cells adhered to endothelial monolayers at 1 dyne/cm2, whereas 14.8% of HbSS RBCs were adherent (p = .186). HbAA RBCs showed minimal adhesion in both assays (< 5 cells/mm2 and Figure Figure

In sickle cell anaemia, red cell dehydration increases intracellular HbS concentration and promotes sickling. Higher erythrocyte magnesium reduces water loss through negative regulation of membrane transporters. Hydroxycarbamide (also known as hydroxyurea) reduces sickling partly by increasing intracellular HbF. Combining drugs with distinct mechanisms could offer additive effects. A phase I trial combining oral magnesium pidolate and hydroxycarbamide was performed to estimate the maximum tolerated dose (MTD) and toxicity of magnesium. Cohorts of three children with HbSS, who were on a stable dose of hydroxycarbamide (median 28.5 mg/kg/d), received magnesium pidolate for 6 months beginning at 83 mg/kg/d. The dose was escalated by 50% for subsequent cohorts. Laboratory evaluations were performed at 0, 3, 6 and 9 months. Sixteen children (aged 4-12 years) participated. All four dose-limiting toxicities (grade III diarrhoea and abdominal pain) occurred within the first month of starting magnesium. Additionally, diarrhoea grades I (n = 1) and II (n = 3), and abdominal pain grade II (n = 3) occurred. Hydroxycarbamide dose reduction or interruption was not required. The MTD for magnesium pidolate used in combination with hydroxycarbamide was 125 mg/kg/d. KCl co-transporter activity declined after 3 months of magnesium pidolate (P = 0.02). A phase II study is needed to investigate the efficacy of this drug combination.

Red blood cell (RBC) sickling is promoted by increased intracellular deoxygenated Hb S concentration and via cell dehydration. Magnesium (Mg) can reduce RBC water loss through its negative regulation of K-Cl cotransport, a pathway which mediates cell dehydration. Hydroxyurea (HU) reduces sickling in part by increasing intracellular fetal hemoglobin (Hb F). The combination of HU and Mg pidolate, two drugs with distinct mechanisms of action, could offer additive or synergistic effects. We performed a phase I study of treatment with HU and Mg pidolate in children with sickle cell anemia (SCA), to estimate the maximum tolerated dose (MTD) and toxicity of this drug combination, and obtained preliminary data regarding cellular effects of this treatment. Children with SCA who had been treated with HU on a stable dose for a minimum of 6 months, received 6 months of treatment with Mg pidolate in addition to HU. The Mg dose was 0.6 mEq/kg/day for the first cohort of patients and was escalated by 50 % in each subsequent cohort to a maximum of 1.9 mEq/kg/d. HU was continued at the patients’ pre-study dose. Compliance was measured using returned bottles and pills counts for both HU and Mg pidolate. Hematologic studies were performed at baseline, 3, and 6 months, and 3 months after Mg pidolate discontinuation (9 months). In vitro RBC adhesion to immobilized thrombospondin was measured under low shear flow conditions. Sixteen patients participated in the study; 9 were boys, and the median age was 7 years (range 4 – 12 years). All were African American and had Hb SS. The median HU dose was 28.5 mg/kg/day (range 25 to 30 mg/kg/d) and the median pre-study HU treatment duration was 1.9 years (range 0.7 – 8.4 years). The MTD for Mg pidolate used in combination with HU was 0.9 mEq/kg/day. The dose limiting toxicity (DLT) of Mg pidolate was diarrhea. There were 4 cases of grade III toxicity (all in the first 4 weeks of the study), 2 cases of grade II and one case of grade I diarrhea. There also were grade III (2), and grade II (3) abdominal pain events. There were no cases of hematologic toxicity, and no patients required HU dose reduction or interruption. Compliance was above 85 % for both drugs in 95 % of the visits. At baseline, high density RBC and KCl co-transport activity were much lower, and intracellular K was much higher than in untreated Hb SS RBC; these values remained relatively stable on Mg pidolate therapy. Mean RBC adhesion to thrombospondin at baseline was low (323 ± 286 RBCs/mm2) and decreased even further to 245 ± 161 RBCs/mm2 during Mg pidolate use. No significant changes in Hb, WBC, platelets, reticulocytes, Hb F, and MCV occurred. We conclude: The MTD for Mg pidolate when used in combination with HU for children with SCA is 0.9 mEq/kg/d, The most common dose-limiting toxicities from Mg pidolate are diarrhea and abdominal pain, There is no additional hematologic toxicity from HU therapy when Mg pidolate is added, RBC adhesion to endothelium may be further decreased in SCA patients treated with HU when Mg pidolate is added, HU therapy when used at 30 mg/kg/day in fully compliant patients may promote decreased RBC adhesion, higher intracellular K, and lower KCl co-transport activity.

An important characteristic of the Hb SC erythrocyte is its high intracellular Hb concentration, which is due to cell K+ loss and dehydration mediated by an abnormally active K-Cl co-transport. This pathologic state of cellular dehydration raises the intracellular concentration of Hb S, thereby increasing its tendency to polymerize. Previous studies in patients with sickle cell disease have shown that oral Mg supplements can increase erythrocyte Mg content, reduce the activity of K-Cl co-transport and diminish erythrocyte dehydration. We performed a randomized, double blind, placebo-controlled study with crossover design on oral Mg supplementation in children with HbSC disease. Methods: Two major pediatric sickle cell centers participated in this IRB-approved study: Texas Children’s Sickle Cell Center and The Children’s Hospital in Boston. Over 100 eligible patients were contacted and invited to participate. The enrolled patients or their parents/guardians gave informed consent. Patients were randomized to either receive oral Mg pidolate or placebo for 6 months followed by a wash-out period of 2 months, then followed by a 6 month period of the other agent (placebo/Mg pidolate) and 2 months wash-out. Patients were initially followed every 2 weeks, then every 4 weeks. Safety was assessed both by clinical assessment as well as laboratory evaluation, including serum magnesium levels. Results: Between January 2002 and December 2004 we enrolled 12 patients (7 males, 5 female, age range 3.9 to 16.8 years) with HbSC disease and at least one pain crisis within the last year. Only 5 patients are fully evaluable for efficacy assessment. Seven patients came off study for the following reasons: 3 for non-compliance, 2 for study violation (pharmacy dispensed wrong formulation), and 2 withdrew for personal reasons (no longer interested), but all of them were included in the safety assessment. There were 3 events that were considered probably related to study drug (or placebo): diarrhea, grade 2 once and headaches, grade 3, in 2 instances. There were 6 events possibly related to drug (or placebo): diarrhea in three patients (all grade 1) and headaches of grade 2 or 3 in three patients. All adverse events resolved without stopping the drug/placebo. The results of the intracellular Mg concentrations and thus efficacy analysis will be available after unblinding the study in September 2005. Conclusion: Mg pidolate appears to be safe and well-tolerated when used in children with HbSC disease. No serious adverse events occurred that were considered definitively related to the study drug(s). Efficacy results will be available at the time of the meeting. However, despite the fact that study was open at 2 major sickle cell centers and had relatively non-restrictive enrollment criteria, accrual was extremely slow, presumably due to the sporadic and rather low disease intensity of Hb SC disease, and several patients did not complete the study. This should be taken into consideration when designing larger studies for patients with HbSC disease exclusively.

The main objective of this clinical trial was to evaluate the effects of magnesium pidolate (15 mmol/day) on blood pressure at rest and during sympathetic stimulation induced by cold, isometric and tilt test; peripheral blood flow has been evaluated by strain-gauge plethysmography. Fourteen mild to moderate hypertensives (8 males, 6 females, age range 40-60 years) were randomly given magnesium or placebo in a double-blind parallel clinical trial for 6 months. In the actively treated group magnesium urinary excretion increased from 5.3 +/- 2 to 7.7 +/- 2 mmol/24 h, and serum magnesium changed from 0.9 +/- 0.1 to 1.0 +/- 0.2 mmol/l. On magnesium, BP changed at rest from 156/97 +/- 12/4 to 149/90 +/- 8/3 mm Hg, during cold pressor test from 169/105 +/- 9/6 to 174/105 +/- 15/4, during isometric exercise from 170/107 +/- 13/9 to 170/105 +/- 20/6, and during tilt test from 149/96 +/- 11/6 to 153/96 +/- 17/7 mm Hg. Similar changes were observed in the placebo group. Peripheral resistances were 14.7 +/- 4 and 9.8 +/- 2 PRU before and after magnesium, respectively. These data indicate that long-term magnesium pidolate supplementation does not affect blood pressure at rest and during sympathetic stimulation, despite a slight, nonsignificant reduction in forearm peripheral resistance.