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Dihydroxyaluminum aminoacetate, heavy magnesium carbonate, and aspirin tablets is a new combined aspirin preparation, each containing aspirin (81 mg), dihydroxyaluminum aminoacetate (11 mg), and heavy magnesium carbonate (22 mg). This study was conducted to evaluate the pharmacokinetic (PK) and bioequivalence in healthy Chinese subjects. This randomized, open-label, single-dose, 2-sequence, and 2-period crossover study included 78 healthy volunteers (fasting, n = 36; postprandial, n = 42). Blood samples were collected for PK analysis. Aspirin and salicylic acid concentrations in human plasma were determined by liquid chromatography-tandem mass spectrometry. Safety and tolerability were monitored. There were no significant differences between the test and reference formulations in maximum plasma concentration, area under the plasma concentration-time curve (AUC) from time 0 to time t, or AUC from time 0 to infinity. The 90% confidence intervals of the test and reference formulations of maximum plasma concentration, AUC from time 0 to time t, and AUC from time 0 to infinity were within the acceptable range (80%-125%) under fasting and postprandial conditions. All adverse events were mild and no serious adverse events were observed in the study. Both compounds were well tolerated in healthy Chinese volunteers., (© 2024, The American College of Clinical Pharmacology.)

Pelotherapy treatments in thermal spas, which utilize peloids composed of clay minerals mixed with saltwater or mineral-medicinal water, can have various effects on spa users, ranging from therapeutic to potential adverse reactions. Despite the widespread use of peloids, comprehensive information on the penetration and permeation of essential and potentially toxic elements into deeper layers of the skin during pelotherapy is limited. Understanding the concentrations of these elements is crucial for evaluating therapeutic benefits and ensuring safety. This study investigates the in vitro availability and absorption of calcium, magnesium, and potentially toxic elements in two peloids, considering their formulation matrix. To replicate the pelotherapy methodology, an in vitro permeation experiment was conducted using a vertical diffusion chamber (Franz cells) and a biological system with human skin membranes from five Caucasian women, age range between 25 and 51 years. The experiment involved heating the peloids to 45℃. The results emphasize the possible transport properties of chemical elements in peloids, providing valuable information related to potential therapeutic efficacy and safety considerations. Despite no apparent differences between peloids' chemical composition, the method identified permeation variations among chemical elements. The methodology employed in this study adheres to the guidelines outlined by OECD for analyzing skin absorption through an in vitro approach. Furthermore, it aligns with the associated OECD guidance document for conducting skin absorption studies. The replicability of this methodology not only facilitates the analysis of peloids pre-formulation but also provides a robust means to evaluate the effectiveness of therapeutic elements during topical administration, particularly those with potential toxicity concerns., (© 2024. The Author(s).)

The increasing incidence of trauma in medicine brings with it new demands on the materials used for the surgical treatment of bone fractures. Titanium, its alloys, and steel are used worldwide in the treatment of skeletal injuries. These metallic materials, although inert, are often removed after the injured bone has healed. The second-stage procedure-the removal of the plates and screws-can overwhelm patients and overload healthcare systems. The development of suitable absorbable metallic materials would help us to overcome these issues. In this experimental study, we analyzed an extruded Zn-0.8Mg-0.2Sr (wt.%) alloy on a rabbit model. From this alloy we developed screws which were implanted into the rabbit tibia. After 120, 240, and 360 days, we tested the toxicity at the site of implantation and also within the vital organs: the liver, kidneys, and brain. The results were compared with a control group, implanted with a Ti-based screw and sacrificed after 360 days. The samples were analyzed using X-ray, micro-CT, and a scanning electron microscope. Chemical analysis revealed only small concentrations of zinc, strontium, and magnesium in the liver, kidneys, and brain. Histologically, the alloy was verified to possess very good biocompatibility after 360 days, without any signs of toxicity at the site of implantation. We did not observe raised levels of Sr, Zn, or Mg in any of the vital organs when compared with the Ti group at 360 days. The material was found to slowly degrade in vivo, forming solid corrosion products on its surface.

Magnesium (Mg)-based biomaterials hold considerable promise for applications in regenerative medicine. However, the degradation of Mg needs to be reduced to control toxicity caused by its rapid natural corrosion. In the process of developing new Mg alloys with various surface modifications, an efficient assessment of the relevant properties is essential. In the present study, a WE43 Mg alloy with a plasma electrolytic oxidation (PEO)-generated surface was investigated. Surface microstructure, hydrogen gas evolution in immersion tests and cytocompatibility were assessed. In addition, a novel in vitro immunological test using primary human lymphocytes was introduced. On PEO-treated WE43, a larger number of pores and microcracks, as well as increased roughness, were observed compared to untreated WE43. Hydrogen gas evolution after two weeks was reduced by 40.7% through PEO treatment, indicating a significantly reduced corrosion rate. In contrast to untreated WE43, PEO-treated WE43 exhibited excellent cytocompatibility. After incubation for three days, untreated WE43 killed over 90% of lymphocytes while more than 80% of the cells were still vital after incubation with the PEO-treated WE43. PEO-treated WE43 slightly stimulated the activation, proliferation and toxin (perforin and granzyme B) expression of CD8 + T cells. This study demonstrates that the combined assessment of corrosion, cytocompatibility and immunological effects on primary human lymphocytes provide a comprehensive and effective procedure for characterizing Mg variants with tailorable degradation and other features. PEO-treated WE43 is a promising candidate for further development as a degradable biomaterial., Competing Interests: The authors declare no conflict of interest.

The objectives of this study were to describe pharmacokinetic and pharmacodynamic changes as a result of a single intravenous administration of magnesium sulfate (MgSO 4 ) to healthy horses. MgSO 4 is a magnesium salt that has been used to calm horses in equestrian competition and is difficult to regulate because magnesium is an essential constituent of all mammals. Six healthy adult female horses were administered a single intravenous dose of MgSO 4 at 60 mg/kg of body weight over 5 min. Blood, urine, and cerebrospinal fluid (CSF) samples were collected, and cardiovascular parameters were monitored and echocardiograms performed at predetermined times. Noncompartmental pharmacokinetic analysis was applied to plasma concentrations of ionized magnesium (Mg 2+ ). Objective data were analyzed using the Wilcoxon rank-sum test with p < .05 used as a determination for significance. Plasma concentrations of Mg 2+ increased nearly fivefold, ionized calcium (Ca 2+ ) decreased by nearly 10%, and the Ca 2+ to Mg 2+ ratio declined more than 3.5-fold and remained different than baseline until 24 hr (p < .05). Significant changes were seen with urinary fractional excretion of electrolytes, cardiovascular parameters, and echocardiographic measurements. No changes were detected in CSF electrolyte concentrations. The decrease in Ca 2+ result of hypermagnesemia supports the interaction between these cations. Alterations detected in plasma electrolyte concentrations and urinary fractional excretion of electrolytes may serve as biomarkers for regulatory control for the nefarious administration of MgSO 4 ., (© 2020 John Wiley & Sons Ltd.)

Purpose: Micro-arc oxidation (MAO) is a fast and effective method to prepare nanoporous coatings with high biological activity and bonding strength. Simple micro/nano-coatings cannot fully meet the requirements of osteogenesis. To further improve the biological activity of a titanium surface, we successfully added biological magnesium (Mg 2+ ) to a coating by micro-arc oxidation and evaluated the optimal magnesium concentration in the electrolyte, biocompatibility, cell adhesion, proliferation, and osteogenesis in vitro., Methods: Nanoporous titanium coatings with different concentrations of magnesium were prepared by micro-arc oxidation and characterized by scanning electron microscopy (SEM) and energy-dispersive X-ray spectroscopy (EDS). The Mg 2+ release ability of the magnesium-incorporated nanoporous titanium coatings was determined by inductively coupled plasma emission spectrometry (ICP-OES). The cytotoxicity of the magnesium-incorporated nanoporous titanium coatings was detected with live/dead double-staining tests. A CCK-8 assay was employed to evaluate cell proliferation, and FITC-phalloidin was used to determine the structure of the cytoskeleton by staining β-actin. Alkaline phosphatase (ALP) activity was evaluated by alizarin red S (ARS) staining to determine the effect of the coatings on osteogenic differentiation in vitro. The mRNA expression of osteogenic differentiation-related markers was measured using qRT-PCR., Results: EDS analyses revealed the successful addition of magnesium to the microporous coatings. The best magnesium concentration of the electrolyte for preparing the new coating was determined. The results showed that the nano-coatings prepared using the electrolyte with 2 g/L magnesium acetate best promoted the adhesion, proliferation, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs)., Conclusion: These results suggest that the new titanium metal coating with a dual effect of promoting bone morphology and supplying the biological ion Mg 2+ can be beneficial for rapid osseointegration., Competing Interests: The authors report no conflicts of interest in this work., (© 2020 Li et al.)

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.

Primary findings from a recent study reported that magnesium supplementation significantly reduced stress in severely stressed subjects with low magnesemia, and additional vitamin B6 enhanced this effect. The mechanism by which combining magnesium and vitamin B6 leads to reduced stress in these subjects remains to be elucidated. This secondary analysis investigated the impact of magnesium and vitamin B6 supplementation and perceived stress on erythrocyte magnesium levels, as a marker of body magnesium status. This was a secondary analysis from an 8-week randomized controlled trial comparing oral magnesium (300 mg) and magnesium-vitamin B6 (300 mg + 30 mg) supplementation. Stress level and erythrocyte magnesium level at baseline, and change in erythrocyte magnesium and serum vitamin B6 levels at weeks 4 and 8, were analyzed. Overall, 264 subjects were randomized to treatment and had evaluable Depression Anxiety Stress Scale scores (132 in each treatment arm). At baseline, stress scores, and mean serum magnesium, erythrocyte magnesium, and serum vitamin B6 concentrations were similar between arms. Although not significant between groups, a significant increase over time in erythrocyte magnesium levels was observed in the subgroup of subjects with low baseline erythrocyte magnesium levels (<1.6 mmol/L) following treatment with magnesium and magnesium-vitamin B6 (week 4:0.21 mmol/L [95% confidence interval (CI), 0.10 to 0.31], p = 0.0003; and 0.13 mmol/L [95% CI, 0.02 to 0.23], p = 0.0233, respectively). Change from baseline in circulating vitamin B6 levels at weeks 4 and 8 in the magnesium-vitamin B6 supplemented group (314.96 nmol/L [95%CI, 294.61 to 335.31]) was significantly different (p < 0.0001) compared with the magnesium supplemented group (-0.39 nmol/L [95% CI, -20.73 to 19.94]). Magnesium alone and magnesium-vitamin B6 provided statistically significant increases in erythrocyte magnesium in subjects with low magnesium status (<1.6mmol/L). Vitamin B6 supplementation did not further increase magnesium levels.

Osteosarcoma is among the most common cancers in young patients and is responsible for one-tenth of all cancer-related deaths in children. Surgery often leads to bone defects in excised tissue, while residual cancer cells may remain. Degradable magnesium alloys get increasing attention as orthopedic implants, and some studies have reported potential antitumor activity. However, most of the studies do not take the complex interaction between malignant cells and their surrounding stroma into account. Here, we applied a coculture model consisting of green fluorescent osteosarcoma cells and red fluorescent fibroblasts on extruded Mg and Mg-6Ag with a tailored degradation rate. In contrast to non-degrading Ti-based material, both Mg-based materials reduced relative tumor cell numbers. Comparing the influence of the material on a sparse and dense coculture, relative cell numbers were found to be statistically different, thus relevant, while magnesium alloy degradations were observed as cell density-independent. We concluded that the sparse coculture model is a suitable mechanistic system to further study the antitumor effects of Mg-based material.

The coordination chemistry of magnesium (Mg 2+ ) was extensively explored. More recently; magnesium; which plays a role in over 80% of metabolic functions and governs over 350 enzymatic processes; is becoming increasingly linked to chronic disease-predominantly due to magnesium deficiency (hypomagnesemia). Supplemental dietary magnesium utilizing biorelevant chelate ligands is a proven method for counteracting hypomagnesemia. However, the coordination chemistry of such bio-relevant magnesium complexes is yet to be extensively explored or elucidated. It is the aim of this review to comprehensively describe what is currently known about common bio-relevant magnesium complexes from the perspective of coordination chemistry.

Aim: Methotrexate (Mtx) is prescribed to reduce pain and inflammation in arthritis patients; however, improved repair and mobility of joints still are the major concerns. Magnesium oil (MO) improves joint mobility and repair; therefore, MO-assisted transdermal delivery of Mtx was aimed. Methods: MO integrated Mtx nanoemulsion (Mtx-MONE) was prepared with uniform size (175 ± 35.4 nm), pH (6.15 ± 0.3) near to skin pH, and high entrapment efficiency (65 ± 8.6%). Mtx-MONE was transformed to nanogel (Mtx-MONEG) with semisolid consistency (43,408 ± 77.72 cP) and good spreadability (3.63 ± 0.033 mJ). Results: Mtx-MONEG showed significant reduction in oedema, arthritic scores, level of inflammatory cytokines, and improved walking as compared to diseased control. MO offered additional improvements in joints, mobility, and repair. Conclusion: Transdermal delivery of Mtx has been successfully achieved by Mtx-MONEG. Tremendous recovery from inflammation, improved joints mobility and repair, and reduced pain strongly support the use of MO as an adjutant of Mtx for improved transdermal application.

Magnesium (Mg 2+ ) is one of the most frequently supplemented micronutrients. Due to possible gastrointestinal side effects, the European Food Safety Authority and the Institute of Medicine set the upper intake level for Mg 2+ from supplements to 250 and 350 mg, respectively. Nevertheless, systematic data concerning the tolerability of Mg 2+ supplements are scarce. The aim of the study was to directly compare the bioavailability and tolerability of two 500 mg Mg 2+ supplements in a crossover study with duplicate determination. The different release properties were either a direct release (one phase) or a delayed release of the second half (two phases). An open-label, controlled trial with a crossover design, duplicate determination, and one-week washout phases was conducted. The participants ingested the test product after overnight fasting. Blood samples were taken at baseline and after 1, 2, 3, 4, 6, and 8 hours, and urine was collected over a period of 24 hours. The participants were on standardized nutrition during all examination days. There were no significant differences between the test products regarding 24-hour renal Mg 2+ excretion and area under the curve of serum Mg 2+ levels for 8 hours. Both test products were well tolerated with a very low frequency of gastrointestinal adverse effects and no significant differences between the test products. The Mg 2+ bioavailability did not differ between the test products. The supplements examined had the same good tolerability. Both test products are therefore suited to enhance Mg 2+ supply without relevant side effects.

Background High values of endogenous levels of magnesium (Mg) in the body and mechanisms of homeostasis regulation make it difficult to assess the bioavailability of these drugs. The aim of this study was to assess the Mg concentration in blood in volunteers and in erythrocytes in patients with hypomagnesemia. Methods The study included 20 healthy volunteers and 62 patients with chronic heart failure (CHF) I-III functional class (FC) NYHA classification. We studied the composition of Mgorotate and Mgorotate plus potassium (К)orotate. Blood sampling was carried out at 8 a.m. and within 10 h after administering the drugs. Measurement of Mg pharmacokinetic parameters: AUC (concentration of the active substance-time), and Cmax (maximum concentration) in volunteers and measurement of the concentration of Mg in erythrocytes of patients. Results The results indicated that both the AUC in volunteers and concentration of Mg in erythrocytes of patients are comparable, and the differences are not statistically significant. Conclusions The study showed that the standard method of calculating the AUC (total serum Mg) is insufficient for comparative evaluation of Mg absorption due to the high levels of its endogenous content and a small increase in concentration after taking the drugs. It is advisable to assess the concentration of Mg in the red blood cells of patients.

Magnesium is a vital mineral that takes part in hundreds of enzymatic reactions in the human body. In the past several years, new information emerged in regard to the antibacterial effect of magnesium. Here we elaborate on the recent knowledge of its antibacterial effect with emphasis on its ability to impair bacterial adherence and formation complex community of bacterial cells called biofilm. We further talk about its ability to impair biofilm formation in milk that provides opportunity for developing safer and qualitative dairy products. Finally, we describe the pronounced advantages of enrichment of food with magnesium ions, which result in healthier and more efficient food products.

Magnesium (Mg)-based materials have shown great potentials for bioresorbable implant applications. Previous studies showed that Mg with 10 and 20 vol % β-tricalcium phosphate (β-TCP) composites produced by spark plasma sintering, improved mechanical properties when compared with pure Mg. The objectives of this study were to evaluate the degradation behaviors of Mg/10% β-TCP and Mg/20% β-TCP composites in revised stimulated body fluid (rSBF), and to determine their cytocompatibility with bone marrow derived mesenchymal stem cells (BMSCs) using the direct culture method. During the 11 days of immersion in rSBF, Mg/β-TCP composites showed different degradation behaviors at different immersion periods, that is, the initial stage (0-1 hr), the mid-term stage (1 hr to 2 days), and the long-term stage (2-11 days). The counter effects of mass loss due to microgalvanic corrosion and mass gain due to deposition of Ca-P containing layers resulted in slower Mg 2+ ion release for Mg/20% β-TCP than Mg/10% β-TCP in the mid-term, but eventually 16% mass loss for Mg/20% β-TCP and 10% mass loss for Mg/10% β-TCP after 11 days of immersion. The in vitro studies with BMSCs showed the highest cell adhesion density (i.e., 68% of seeding density) on the plate surrounding the Mg/10% β-TCP sample, that is, under the indirect contact condition of direct culture. The β-TCP showed a positive effect on direct adhesion of BMSCs on the surface of Mg/β-TCP composites. This study elucidated the degradation behaviors and the cytocompatibility of Mg/β-TCP composites in vitro; and, further studies on Mg/ceramic composites are needed to determine their potential for clinical applications. © 2019 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 2238-2253, 2019., (© 2019 Wiley Periodicals, Inc.)

The supply of potassium (K) is a strategy to increase the tolerance of plants exposed to Cd toxicity. The aim of this study was to verify the influence of K on the growth and potential of Tanzania guinea grass (Panicum maximum Jacq. cv. Tanzania (syn. Megathyrsus maximus (Jacq.) B.K. Simon & S.W.L. Jacobs)) for Cd phytoextraction as well as to evaluate nutritional attributes of this grass under conditions of Cd stress. The experiment was conducted in a randomized complete block design, using a 3 × 4 factorial arrangement, with three replications. Three rates of K (0.4, 6.0, and 11.6 mmol L -1 ) were combined with four rates of Cd (0.0, 0.5, 1.0, and 1.5 mmol L -1 ) in nutrient solution. Two plant growth periods were evaluated. The increase in K supply to plants exposed to Cd rates of up to 1.0 mmol L -1 caused increase in morphogenic and production attributes, as well as reduction in tiller mortality rate, in the second growth period. K concentrations (in both harvests) increased, while calcium and magnesium concentrations in the second harvest decreased with increasing Cd rates. The high availability of Cd (1.5 mmol L -1 ) in the nutrient solution caused decrease in relative chlorophyll index (RCI) in both harvests. The high supply of K to plants exposed to Cd resulted in high shoot dry mass production, reducing Cd concentration in the photosynthetic tissues (which means great tolerance of the plant) and increasing the accumulation of this metal in the shoots that can be harvested. Therefore, K increases the Cd phytoextraction capacity of Tanzania guinea grass.

Background: Low magnesium (Mg) levels are linked to many diseases. Studies suggest that organic salts of Mg are more readily bioavailable than its oxide or inorganic salts used for supplements production. Unfortunately, the plethora of variables in the previous study designs complicates the making of any clear and reliable conclusions., Methods: 14 healthy males were supplemented for five days with 400 mg Mg to saturate Mg pools before intake of the test products. Bioavailability of 400 mg Mg from Mg citrate (MgC) and Mg oxide (MgO) after single-dose administration was assessed by measuring renal Mg excretion in 24-h urine and blood plasma [Mg] at time points 0, 2, 4, 8, and 24 h., Results: Single-dose MgC supplementation led to a significant (P < 0.05) increase in 24 h urinary Mg excretion, but this was not significant following MgO. Plasma [Mg] was also significantly higher for MgC than for MgO at 4 h (P < 0.05) and 8 h (P < 0.05). Compared with baseline levels, MgC supplementation showed a significant increase in plasma [Mg] at all time points, in contrast to MgO., Conclusions: MgC shows higher bioavailability compared with MgO. Furthermore, urinary Mg excretion should be determined as the primary endpoint of Mg bioavailability studies.

Despite the presumption of the beneficial effects of magnesium supplementation, little is known about the pharmacokinetics of different magnesium formulations. We aimed to investigate the value of two in vitro approaches to predict bioavailability of magnesium and to validate this in subsequent in vivo testing. In vitro assessment of 15 commercially available magnesium formulations was performed by means of a Simulator of the Human Intestinal Microbial Ecosystem (SHIME ® ) and by dissolution tests. Two magnesium formulations with contrasting bioavailability prediction from both in vitro tests (best vs. worst) were selected for in vivo testing in 30 subjects. In vivo bioavailability was compared following one acute ingestion by monitoring blood magnesium concentrations up to 6 h following intake. The in vitro tests showed a very wide variation in absorption and dissolution of the 15 magnesium products. In the in vivo testing, a significant different serum magnesium absorption profile was found up to 4 h following supplement ingestion for the two supplements with opposing in vitro test results. Moreover, maximal serum magnesium increase and total area under the curve were significantly different for both supplements (+6.2% vs. +4.6% and 6.87 vs. 0.31 mM.min, respectively). Collectively, poor bioaccessibility and bioavailability in the SHIME model clearly translated into poor dissolution and poor bioavailability in vivo. This provides a valid methodology for the prediction of in vivo bioavailability and effectiveness of micronutrients by specific in vitro approaches.

Hypomagnesemia (blood Mg 2+ concentration <0.7 mM) is a common electrolyte disorder in patients with type 2 diabetes (T2D), but the etiology remains largely unknown. In patients with T2D, reduced blood Mg 2+ levels are associated with an increased decline in renal function, independent of glycemic control and hypertension. To study the underlying mechanism of this phenomenon, we investigated the renal effects of hypomagnesemia in high-fat-diet (HFD)-fed mice. In mice fed a low dietary Mg 2+ , the HFD resulted in severe hypomagnesemia within 4 wk. Renal or intestinal Mg 2+ wasting was not observed after 16 wk on the diets. Despite the absence of urinary or fecal Mg 2+ loss, the HFD induced a reduction in the mRNA expression transient receptor potential melastatin type 6 in both the kidney and colon. mRNA expression of distal convoluted tubule (DCT)-specific genes was down-regulated by the LowMg-HFD, indicating atrophy of the DCT. The low dietary Mg 2+ resulted in severe HFD-induced proximal tubule phospholipidosis, which was absent in mice on a NormalMg-HFD. This was accompanied by albuminuria, moderate renal damage, and alterations in renal energy metabolism, including enhanced gluconeogenesis and cholesterol synthesis. In conclusion, this study shows that hypomagnesemia is a consequence of diet-induced obesity and insulin resistance. Moreover, hypomagnesemia induces major structural changes in the diabetic kidney, including proximal tubular phospholipidosis, providing a novel mechanism for the increased renal decline in patients with hypomagnesemic T2D.-Kurstjens, S., Smeets, B., Overmars-Bos, C., Dijkman, H. B., den Braanker, D. J. W., de Bel, T., Bindels, R. J. M., Tack, C. J. J., Hoenderop, J. G. J., de Baaij, J. H. F. Renal phospholipidosis and impaired magnesium handling in high-fat-diet-fed mice.

The efficiency of calcium phosphate (CaP) bone substitutes can be improved by tuning their resorption rate. The influence of both crystal orientation and ion doping on resorption is here investigated for beta-tricalcium phosphate (β-TCP). Non-doped and Mg-doped (1 and 6 mol%) sintered β-TCP samples were immersed in acidic solution (pH 4.4) to mimic the environmental conditions found underneath active osteoclasts. The surfaces of β-TCP samples were observed after acid-etching and compared to surfaces after osteoclastic resorption assays. β-TCP grains exhibited similar patterns with characteristic intra-crystalline pillars after acid-etching and after cell-mediated resorption. Electron BackScatter Diffraction analyses, coupled with Scanning Electron Microscopy, Inductively Coupled Plasma-Mass Spectrometry and X-Ray Diffraction, demonstrated the influence of both grain orientation and doping on the process and kinetics of resorption. Grains with c-axis nearly perpendicular to the surface were preferentially etched in non-doped β-TCP samples, whereas all grains with simple axis (a, b or c) nearly normal to the surface were etched in 6 mol% Mg-doped samples. In addition, both the dissolution rate and the percentage of etched surface were lower in Mg-doped specimens. Finally, the alignment direction of the intra-crystalline pillars was correlated with the preferential direction for dissolution. STATEMENT OF SIGNIFICANCE: The present work focuses on the resorption behavior of calcium phosphate bioceramics. A simple and cost-effective alternative to osteoclast culture was implemented to identify which material features drive resorption. For the first time, it was demonstrated that crystal orientation, measured by Electron Backscatter Diffraction, is the discriminating factor between grains, which resorbed first, and grains, which resorbed slower. It also elucidated how resorption kinetics can be tuned by doping β-tricalcium phosphate with ions of interest. Doping with magnesium impacted lattice parameters. Therefore, the crystal orientations, which preferentially resorbed, changed, explaining the solubility decrease. These important findings pave the way for the design of optimized bone graft substitutes with tailored resorption kinetics., (Copyright © 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Magnesium has a very promising adhibition in biomedical field for its excellent mechanical and biodegradable properties, however, the intelligent applications of biomedical magnesium developed difficultly due to its characteristic degradation. A intelligent biomedical magnesium was constructed on magnesium (Mg) surface by incorporating polydopamine (PD) and mechanized hollow mesoporous silica nanoparticles (HMSs) as smart delivery platform nanocontainers. The supramolecular nanovalves of mechanized HMSs consisted of alginate/chitosan multilayers by self-assembly, which are capable of entrapping rhodamine 6G in the mesopores and can release the cargo under the chemical environment of alkali or Mg iron stimuli that correspond to the degradation of biomedical Mg. The alkali/Mg 2+ dual stimuli-responsive release property of the HMSs endows the biodegradable Mg with controlled release potential. The well-designed smart delivery nanocontainers were combined with polydopamine deposited on Mg for excellent adhesion properties and positively charged amino group of PD. Furthermore, when the biomedical Mg with these mechanized HMSs was degraded in the simulated body environment, the alkali/Mg 2+ -triggered release of cargos from this smart delivery platform could bring a more functional application., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A novel bioglass composition (BGMS10), containing strontium and magnesium and characterized by an ultra-high crystallization temperature, is here employed for the first time to produce different composites with the addition of specific amounts of hydroxyapatite. After an investigation of the samples' bioactivity in vitro in a simulated body fluid solution (SBF) - according to a widely used protocol -, the biocompatibility of the new materials was tested with respect to murine fibroblasts both by direct and indirect tests, in order to evaluate possible cytotoxic effects of the materials' eluates. Although none of the samples were cytotoxic and their bioactivity in SBF increased with the increasing amount of the glass in the composite, thus showing the best performance in the case of pure BGMS10 glass, the findings of the biological investigation did not confirm those arising from the SBF assay. Surprisingly, while the composites with the lowest glass amount showed an enhanced biocompatibility in direct tests, on the contrary their biological responsiveness is typically lower in the indirect ones, based on filtered materials' extracts. This fact could be ascribed to the high release of particulate from the composites, which are more porous than the glassy samples: in fact, such pronounced dissolution may affect both the cell viability and the absorbance readings used in the colorimetric assays. The pure BGMS10 glass showed the best biological response only in the cell proliferation test (which is an indirect contact test), being able to stimulate cell proliferation in particular after 24 h. For these reasons, when considering bioactive glasses and bioglass-based composites, the results of direct cell culture assays should be integrated with those obtained by indirect ones, while the findings regarding the in vitro bioactivity in SBF should be interpreted with great care., (Copyright © 2018 Elsevier B.V. All rights reserved.)

While general recommendations are for 300-mg magnesium intake a day, an advanced low-dose formulation of magnesium chloride, ChronoMag®, was designed to provide 100 mg of magnesium element, thus decreasing the risk of gastrointestinal side effects and allowing long-term supplementation in health conditions related to low magnesium levels. The present study aimed to compare magnesium release profile and bioavailability between this patented low-dose continuous-release magnesium chloride tablet (100 mg magnesium element) and a reference tablet at the usually prescribed dose (300 mg magnesium element). Magnesium release profile was determined by dissolving the tablets in solutions simulating the gastrointestinal tract environment. A randomized double-blind crossover controlled trial of ChronoMag® versus reference tablet (3 × 100 mg magnesium element tablets) in 12 normo-magnesemic healthy volunteers was conducted to evaluate the bioavailability of the patented magnesium chloride tablets (two 50 mg magnesium tablets, once-a-day intake). While the reference tablet released 100% of its magnesium within 1 h of dissolution, release from the magnesium chloride formulation was continuous for 6 h. Cumulative urinary magnesium levels compared to those with the reference tablet were 76% (0-5 h), 89% (0-10 h), and 87% (0-24 h). Elimination after 24 h was fairly similar with both supplements. Our results suggest that the new magnesium chloride formulation, providing continuous low-dose magnesium release throughout the gastrointestinal tract, improves absorption and bioavailability. This formulation conforms to the physiological mechanism of magnesium absorption throughout the digestive tract, allowing high absorption, and may improve gastrointestinal tolerance in long-term use.

Effective and compound-sparing methods to evaluate promising drug delivery systems are a prerequisite for successful selection of formulations in early development stages. The aim of the study was to develop a small-scale in situ method to determine drug release and supersaturation in highly concentrated suspensions of enabling formulations. Mesoporous magnesium carbonate (MMC), which delivers the drug in an amorphous form, was selected as a drug carrier. Five model compounds were loaded into the MMC at a 1:10 ratio using a solvent evaporation technique. The μDiss Profiler was used to study the drug release from MMC in fasted-state simulated intestinal fluid. To avoid extensive light scattering previously seen in particle-rich suspensions in the μDiss Profiler, an in-house-designed protective nylon filter was placed on the in situ UV probes. Three types of release experiments were conducted for each compound: micronized crystalline drug with MMC present, drug-loaded MMC, and drug-loaded MMC with 0.01% w/w hydroxypropyl methyl cellulose. The nylon filters effectively diminished interference with the UV absorption; however, the release profiles obtained were heavily compound dependent. For one of the compounds, changes in the UV spectra were detected during the release from the MMC, and these were consistent with degradation of the compound. To conclude, the addition of protective nylon filters to the probes of the μDiss Profiler is a useful contribution to the method, making evaluations of particle-rich suspensions feasible. The method is a valuable addition to the current ones, allowing for fast and effective evaluation of advanced drug delivery systems.

Objective: To assess the absolute bioavailability of 20 mEq magnesium lactate extended-release (ER) caplets and to assess the effect of food on the pharmacokinetics of these ER caplets., Significance: Magnesium in different salt forms is available as over-the-counter oral formulations. The absorption and bioavailability is highly affected by the water solubility of the salt form. A new ER caplet of 10 mEq strength of magnesium L-lactate dihydrate has been developed to increase the bioavailability of magnesium., Methods: An open label, single-dose, randomized, three-period, cross-over study in healthy adults was conducted with three treatments: (a) single oral dose of 20 mEq magnesium L-lactate dehydrate under fasting conditions, (b) single intravenous (IV) infusion of 20 mEq magnesium sulfate, and (c) single oral dose of 20 mEq magnesium L-lactate dehydrate under fed conditions. Urine and blood samples were collected for analysis of urinary and serum magnesium concentrations., Results: Absolute bioavailabilities of the caplets under fasted and fed conditions, compared to IV magnesium sulfate, were 20.26% (fasted) and 12.49% (fed) in serum, based on the geometric mean ratio (GMR) of the baseline-adjusted AUC 0-72 , and 38.11% (fasted) and 40.99% (fed) in urine, based on the GMR of the baseline-adjusted Ae 0-72 . Relative bioavailability of the caplets comparing the fed and fasted states was 61.67% in serum, based on the GMR of the baseline-adjusted AUC 0-72 , and 107.57% in urine, based on the GMR of the baseline-adjusted Ae 0-72 ., Conclusions: This new magnesium formulation has reasonable bioavailability and might be a valuable addition to the currently available magnesium oral products.

Breast cancer is a disease of high mortality, characterized by the progressive accumulation of mutations that contribute to the uncontrolled development of breast tissue cells. Literature shows that disturbances in mineral homeostasis, such as magnesium, may interfere with tumor progression. The objective of this study is to provide updated information about magnesium's role in the pathogenesis of breast cancer. A review of literature was carried out from a search for articles in the PubMed and CAPES Periodicals databases published between 1995 and 2016 with the cross-references of the descriptors "magnesium," "breast neoplasms," and "oxidative stress" and the corresponding words in Portuguese. We included studies on the metabolism and bioavailability of magnesium and studies related to breast cancer and excluded articles in which only the abstract was available, dissertations, theses, articles involving adjuvant and/or neoadjuvant therapies, and supplementation of minerals in breast cancer patients. Magnesium is a mineral that participates in the metabolism of various nutrients and nucleic acids. In the presence of breast cancer, neoplastic cells increase the expression of magnesium transport channels, which raises the intracellular concentration of the mineral, contributing to tumor growth through its function of increasing energy demand. The data obtained in this review illustrates the influence of magnesium on the progression of breast cancer. However, the existing data are scarce and inconsistent, which demonstrates a need for further studies on the subject with a goal to have better control of the disease.

Antidepressant therapy exhibits low clinical efficacy and produces a variety of unwanted side effects. Therefore, the search for more effective antidepressants is still in progress. Antidepressant properties of magnesium and zinc have been demonstrated in animal screen tests/models and clinical studies. Moreover, these bio-elements enhance antidepressant activity of conventional antidepressants in these behavioral paradigms. As for magnesium, clinical studies demonstrated equivocal results concerning its supplementary effectiveness in the treatment of depression. Generally, some depressed patients with hypomagnesemia responded very well to such supplementation, whereas response of other patients was weaker. Clinical data on the effectiveness of zinc supplementation in the therapy of depression are much more robust. A number of studies demonstrated enhancement of the efficacy of pharmacotherapy by zinc supplementation in major depression. What is important, recent studies demonstrate that zinc supplementation augments efficacy of antidepressants also in treatment-resistant patients. All the available data indicate the importance of magnesium and zinc in the therapy of depression.

Magnesium (Mg2+) is an essential mineral without known specific regulatory mechanisms. In ruminants, plasma Mg2+ concentration depends primarily on the balance between Mg2+ absorption and Mg2+ excretion. The primary site of Mg2+ absorption is the rumen, where Mg2+ is apically absorbed by both potential-dependent and potential-independent uptake mechanisms, reflecting involvement of ion channels and electroneutral transporters, respectively. Transport is energised in a secondary active manner by a basolateral Na+/Mg2+ exchanger. Ruminal transport of Mg2+ is significantly influenced by a variety of factors such as high K+ concentration, sudden increases of ammonia, pH, and the concentration of SCFA. Impaired Mg2+ absorption in the rumen is not compensated for by increased transport in the small or large intestine. While renal excretion can be adjusted to compensate precisely for any surplus in Mg2+ uptake, a shortage in dietary Mg2+ cannot be compensated for either via skeletal mobilisation of Mg2+ or via up-regulation of ruminal absorption. In such situations, hypomagnesaemia will lead to decrease of a Mg2+ in the cerebrospinal fluid and clinical manifestations of tetany. Improved knowledge concerning the factors governing Mg2+ homeostasis will allow reliable recommendations for an adequate Mg2+ intake and for the avoidance of possible disturbances. Future research should clarify the molecular identity of the suggested Mg2+ transport proteins and the regulatory mechanisms controlling renal Mg excretion as parameters influencing Mg2+ homeostasis.

Objective: To investigate the pharmacokinetics of a 20 mmol magnesium bolus in regards to serum and urinary magnesium concentration, volume of distribution, and half-life., Design: Prospective, experimental study., Setting: A university-affiliated teaching hospital., Participants: Twenty consecutive cardiac surgery patients treated with magnesium bolus therapy for prevention of arrhythmia., Interventions: A 20-mmol bolus of magnesium sulfate was administered intravenously., Measurements and Main Results: Median magnesium levels increased from 1.04 (interquartile range 0.94-1.23) mmol/L to 1.72 (1.57-2.14) mmol/L after 60 minutes of magnesium infusion (p < 0.001) but decreased to 1.27 (1.21-1.36) and 1.16 (1.11-1.21) mmol/L after 6 and 12 hours, respectively. Urinary magnesium concentration increased from 6.3 (4.2-14.5) mmol/L to 19.1 (7.4-34.5) mmol/L after 60 minutes (p < 0.001), followed by 22.7 (18.4-36.7) and 15 (8.4-19.7) mmol/L after 6 and 12 hours, respectively. Over the 12-hour observation period, the cumulative urinary magnesium excretion was 19.1 mmol (95.5% of the dose given). The median magnesium clearance was 10 (4.7-15.8) mL/min and increased to 14.9 (3.8-20.7; p = 0.934) mL/min at 60 minutes. The estimated volume of distribution was 0.31 (0.28-0.34) L/kg., Conclusion: Magnesium bolus therapy after cardiac surgery leads to a significant but short-lived increase of magnesium serum concentration due to renal excretion and distribution, and the magnesium balance is neutral after 12 hours., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Suboptimal magnesium status is likely widespread in the United States and increasing evidence links it to many chronic diseases. Therapeutically addressing magnesium status can be challenging, as higher supplementation often leads to bowel intolerance. This study evaluated the absorption, cellular uptake, and clinical effectiveness of a timed-release formulation containing dimagnesium malate with vitamins B6, B12, and folate (MagSRT™) in a standard clinical population., Methods: A standard clinical population of 91 adults participated in a placebo-controlled study carried out at two clinics; 53 individuals received MagSRT™, containing 500 mg dimagnesium malate and vitamins B6, B12, and folate, while the remaining individuals received a placebo. Baseline serum magnesium, red blood cell (RBC) magnesium, and magnesium status questionnaire scores were collected prior to trial initiation. Serum magnesium was measured 4 and 8 hours after participants ingested 2 supplemental tablets (250 mg magnesium) or 2 placebo tablets. After 30 days, RBC magnesium was evaluated and participants completed the magnesium status questionnaire. A subset of MagSRT™ participants (24) continued the trial for 90 days. Both RBC magnesium and the magnesium status questionnaire were evaluated at 90 days., Results: More than 75% of trial participants presented with suboptimal serum and RBC magnesium status at baseline, while the magnesium status questionnaire predicted 100% of participants to have suboptimal magnesium status. MagSRT™ was well tolerated by 91% of magnesium intervention participants. RBC magnesium increased 6% and 30% over 30 and 90 days, respectively, suggesting magnesium absorption and uptake into red blood cells over time. Overall symptomatology, assessed through a magnesium status questionnaire, improved 28% over 30 days and 63% over 90 days., Conclusion: A standard adult clinical population presented with both qualitative and quantitative evidence of compromised magnesium status at the beginning of the trial. Supplementation with MagSRT™, a timed-release dimagnesium malate supplement containing vitamins B6, B12, and folate, for at least 30 days significantly improved magnesium status symptoms and increased RBC magnesium with minimal gastrointestinal symptoms.

Mg-based stent is a promising candidate of the next generation fully degradable vascular stents. The latest progress includes the CE approval of the Magmaris ® WE43 based drug eluting stent. However, so far, the long term (more than 1 year implantation) in vivo degradation and the physiological effects caused by the degradation products were still unclear. In this study, a 20 month observation was carried out after the bare Mg-Nd-Zn-Zr (abbr. JDBM) stent prototype was implanted into the common carotid artery of New Zealand white rabbit in order to evaluate its safety, efficacy and especially degradation behavior. The degradation of the main second phase Mg 12 Nd was also studied. Results showed that the bare JDBM stent had good safety and efficacy with a complete re-endothelialization within 28 days. The JDBM stent struts were mostly replaced in situ by degradation products in 4 month. The important finding was that the volume and Ca concentration of the degradation products decreased in the long term, eliminating the clinicians' concern of possible vessel calcification. In addition, the alloying elements Mg and Zn in the stent could be safely metabolized as continuous enrichment in any of the main organs were not detected although Nd and Zr showed an abrupt increase in spleen and liver after 1 month implantation. Collectively, the long term in vivo results showed the rapid re-endothelialization of JDBM stent and the long term safety of the degradation products, indicating its great potential as the backbone of the fully degradable vascular stent., Statement of Significance: Mg-based stent is a promising candidate of the next generation fully degradable stents, especially after the recent market launch of one of its kind (Magmaris). However the fundamental question about the long term degradation and metabolic mechanism of Mg-based stent and its degradation products remain unanswered. We implanted our patented Mg-Nd-Zn-Zr bare stent into the common carotid artery of rabbits and conducted a 20 months observation. We found that the Ca containing degradation products could be further degraded in vivo. All the alloying elements showed no continuous enrichment in the main organs of rabbits. These findings eliminate the clinicians' concern of possible vessel calcification and element enrichment after the implantation of Mg alloy based stents to some extent., (Copyright © 2018 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Magnesium (Mg) alloys are considered promising materials for biodegradable medical devices; however, the initial effects and distribution of released Mg 2+ ions following implantation are unclear. This is addressed in the present study, using two types of Mg alloys implanted into rats. An in vitro immersion test was first carried out to quantify Mg 2+ ions released from the alloys at early stages. Based on these data, we performed an in vivo experiment in which large amounts of alloys were subcutaneously implanted into the backs of rats for 1, 5, 10, and 25 h. Mg 2+ accumulation in organs was measured by inductively coupled plasma mass spectrometry. In vivo, blood and urine Mg 2+ concentrations were higher in rats receiving the implants than in controls after 1 h; however, the levels were within clinically accepted guidelines. The Mg 2+ concentration in bone was significantly higher in the 25 h implanted group than in the other groups. Our results suggest that homeostasis is maintained by urinary excretion and bone accumulation of released Mg 2+ ions in response to sudden changes in Mg 2+ ion concentration in the body fluid in a large number of Mg alloy implants at the early stages.

The aim of this study was to measure the content of calcium, magnesium, iron, zinc, and copper and determine the bioavailability of these ingredients in gluten-free breads fortified with milk and selected seeds. Due to the increasing prevalence of celiac disease and mineral deficiencies, it has become necessary to produce food with higher nutritional values which maintains the appropriate product characteristics. This study was designed for gluten-free breads fortified with milk and seeds such as flax, poppy, sunflower seeds, pumpkin seeds or nuts, and flour with amaranth. Subsequently, digestion was performed in vitro and the potential bioavailability of the minerals was measured. In the case of calcium, magnesium, iron, and copper, higher bioavailability was observed in rice bread, and, in the case of copper and zinc, in buckwheat bread. This demonstrated a clear increase in bioavailability of all the minerals when the bread were enriched. However, satisfactory results are obtained only for the individual micronutrients.

Objective: We conducted an ex-vivo analysis and a study in healthy subjects to compare magnesium bioavailability after administration of Sucrosomial® magnesium or commercially available preparations of magnesium citrate, magnesium oxide and magnesium bisglycinate., Materials and Methods: In the ex-vivo study we simulated magnesium intestinal absorption after digestion through sections of intestinal mucosa isolated from rats. We compared the absorption of magnesium oxide and Sucrosomial® magnesium at two different concentrations: 32.9 mg/ml and 329 mg/ml. The human study was a single day double-blinded repeated crossover study in healthy subjects. Each subject was administered 350 mg magnesium in different formulations (Sucrosomial® magnesium, magnesium citrate, magnesium oxide or magnesium bisglycinate) after 1 week of washout. We collected blood and urine samples to measure magnesium concentration in blood, urine and red blood cells., Results: The ex-vivo evaluation showed that magnesium absorption after administration of Sucrosomial® magnesium was faster and with higher rates compared to a standard formulation of magnesium oxide. This finding was further confirmed by the results of the study in healthy subjects, that showed a more evident increase in magnesium concentration after administration of Sucrosomial® magnesium compared to the other formulations. In particular, the increase in magnesium concentration from baseline to 24 h was statistically higher in blood and in urine for Sucrosomial® magnesium compared to magnesium oxide, while in red blood cells Sucrosomial® magnesium had a statistically significant advantage compared to magnesium bisglycinate., Conclusions: Our findings suggest that Sucrosomial® magnesium leads to an increased bioavailability of magnesium compared to other formulations. Further studies are needed to investigate if this advantage turns into more evident clinical efficacy.

Hydrogels are appealing biomaterials for applications in regenerative medicine due to their tunable physical and bioactive properties. Meanwhile, therapeutic metal ions, such as magnesium ion (Mg 2+ ), not only regulate the cellular behaviors but also stimulate local bone formation and healing. However, the effective delivery and tailored release of Mg 2+ remains a challenge, with few reports on hydrogels being used for Mg 2+ delivery. Bisphosphonate exhibits a variety of specific bioactivities and excellent binding affinity to multivalent cations such as Mg 2+ . Herein, we describe a nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. These nanoparticles bearing acrylate groups on the surface not only function as effective multivalent crosslinkers to strengthen the hydrogel network structure, but also promote the mineralization of hydrogels and mediate sustained release of Mg 2+ . The released Mg 2+ ions facilitate stem cell adhesion and spreading on the hydrogel substrates in the absence of cell adhesion ligands, and promote osteogenesis of the seeded hMSCs in vitro. Furthermore, the acellular porous hydrogels alone can support in situ bone regeneration without using exogenous cells and inductive agents, thereby greatly simplifying the approaches of bone regeneration therapy., Statement of Significance: In this study, we developed a novel bioactive nanocomposite hydrogel based on hyaluronic acid and self-assembled bisphosphonate-magnesium (BP-Mg) nanoparticles. Such hydrogels are stabilized by the multivalent crosslinking domains formed by the aggregation of Ac-BP-Mg NPs, and therefore show enhanced mechanical properties, improved capacity for mineralization, and controlled release kinetics of Mg 2+ . Moreover, the released Mg 2+ can enhance cell adhesion and spreading, and further promote the osteogenic differentiation of hMSCs. Owing to these unique properties, these acellular hydrogels alone can well facilitate the in vivo bone regeneration at the intended sites. We believe that the strategy reported in this work opens up a new route to develop biopolymer-based nanocomposite hydrogels with enhanced physical and biological functionalities for regenerative medicine., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Site-specific controlled release of exogenous angiogenic growth factors, such as recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. Here, we have developed an implant composed of spiral magnesium (Mg) and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The encapsulated protein could release continually for 4weeks with well preserved bioactivity. We compared the angiogenic effect produced by Mg-PLGA-rhbFGF with that of a PLGA implant loaded with rhbFGF (PLGA-rhbFGF). The incorporation of Mg in the implant raised the microclimate pH in the polymer, which preserved the stability of rhbFGF. Mg-PLGA-rhbFGF exhibited advantages over PLGA-rhbFGF implant in terms of a cytocompatibility evaluation. An in vivo angiogenesis test further confirmed the efficacy of released rhbFGF. HE, CD31 and α-SMA staining revealed that the controlled release of rhbFGF from the Mg-PLGA-rhbFGF implant was superior in promoting angiogenesis compared with that of the PLGA-rhbFGF implant. Four weeks post-implantation, the capillary density of the Mg-PLGA-rhbFGF group was significantly higher than that of the PLGA-rhbFGF, control and the normal group (p<0.05, p<0.01 and p<0.01, respectively). Furthermore, the limb blood perfusion ratios of the Mg-PLGA-rhbFGF and PLGA-rhbFGF groups were dramatically increased, at 99.1±2.9% and 80.7±3.2%, respectively, whereas the ischemic limb did not recover in the control group. The biocompatibility of the implants was also evaluated. In conclusion, Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery. The results suggest potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia., Statement of Significance: Magnesium (Mg)-based implant has been already used in patients with critical limb ischemia. Site-specific controlled release of recombinant human basic fibroblast growth factor (rhbFGF), has become a promising approach to improve peripheral vascular disease. We report here on a novel combination implant composed of spiral magnesium and a coating made using poly(lactic-co-glycolic acid) (PLGA) with encapsulated rhbFGF (Mg-PLGA-rhbFGF). The preparation method does not involve any complex processes and results in a high encapsulation efficiency (approximately 100%). The degradation of metal Mg raise the microclimate pH in the PLGA polymer, which could well preserve the bioactivity of rhbFGF incorporated in the implant. Mg-PLGA-based, sustained local delivery of rhbFGF promotes post-ischemic angiogenesis and blood flow recovery in rat limb ischemic model. This work marks the first report for controlled release of rhbFGF in combination with metal Mg, and suggests potential therapeutic usefulness of Mg-PLGA-rhbFGF for tissue ischemia., (Copyright © 2017 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Objectives: The release of magnesium ions (Mg 2+ ) from titanium surfaces has been shown to boost the initial biological response of peri-implant bone and to increase the biomechanical strength of osseointegration. The objective of the present paper was to investigate if the initial improvement in osseointegration would influence the bone remodeling also during the maturation stage of bone healing., Methods: Titanium implants were coated with mesoporous titania layers and either loaded with Mg 2+ (test group) or left untreated (control group). The implants were inserted in the tibiae of 10 New Zealand White rabbits. Osseointegration was assessed after 6 weeks by means of biomechanical testing (RTQ), non-decalcified histology and histomorphometry (BIC%, BA%, NBA%). The expression of genes involved in the bone formation and remodeling was quantified using qPCR., Results: Mg 2+ releasing mesoporous titania coatings showed, on average, higher removal torques and histomorphometrical outcomes (RTQ: 17.2 Ncm vs. 15 Ncm; BIC: 38.8% vs. 32.1%; BA%: 71.6% vs. 64%; NBA% 62.5% vs. 54% for the tests vs the controls); however, the differences were not statistically significant. Three osteogenic markers, osteocalcin (OC), collagen 1 alpha 1 (COL1A1), and alkalin phosphatase (ALPL), were respectively 2-fold, 1.53-fold, and 1.13-fold up-regulated in the control group compared to the test. The expression of COL1A1 was particularly high in both groups, while the biomarkers for remodeling and inflammation showed a low expression in both groups., Significance: The results suggested that the initial enhancement in osseointegration induced by magnesium release from mesoporous titania coatings has no detrimental effects during bone maturation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 2118-2125, 2017., (© 2016 Wiley Periodicals, Inc.)

The influence of frequently used buffer system 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) compared to CO 2 /HCO3- on the corrosion of magnesium is investigated. Samples were immersed in simulated body fluid (m-SBF) while monitored by electrochemical impedance spectroscopy (EIS) for up to 30 days. In CO 2 /HCO3- the initial corrosion rate was 0.11 mm yr -1 . An inner protective layer of magnesium oxide was formed within the first 30 min exposure and subsequently covered by an outer layer of apatite within 24 h . The corrosion mechanism thereafter is best described as passive pitting with a porosity of ∼10%. Using HEPES as buffer agent increased the corrosion rate to 3.37 mm yr -1 . Cross sectional microscopy show a porous outer corrosion layer allowing rapid diffusion of aggressive ions through the film. Here the EIS results are best described by an active pitting model with an inner layer 5 to 10 times less protective compared to the inner layer formed without HEPES. Further the suitability of human whole blood and plasma as in vitro models for Mg degradation was evaluated. Mg corrosion caused coagulation after 24 h in both biological fluids. The corrosion during the first 24 h is similar to the corrosion in m-SBF with HEPES. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 1490-1502, 2017., (© 2016 Wiley Periodicals, Inc.)

In the present study, the tube well water quality and the associated health risks, emphasizing on arsenic contamination, were investigated in rural and urban samples from Tehsil Mailsi located in Punjab, Pakistan. Arsenic concentrations (μg/L) were ranged from 12 to 448.5 and which exceeded the WHO recommended limit (10 μg/L) in all cases. The calculated average daily dose (3.3 × 10 -0.4 to 1.2 × 10 -0.2  mg/kg day) and hazard quotient (1.1-40) reflected the potential health risk to local population due to tube well water consumption as drinking purpose. Sodium percent (Na%), sodium absorption ratio, residual sodium carbonate, Kelly's index and magnesium absorption ratio were also determined to assess the suitability of tube well water for irrigation purpose. The resulting piper plot revealed the Na-Ca-HCO 3 type water chemistry of the area and generally alkaline environment. The spatial distribution of arsenic in the tube well waters pinpoints the significant contribution of anthropogenic activities to arsenic pollution. Nevertheless, different statistical tools, including principal component analysis, hierarchical cluster analysis and correlation matrices, revealed the contribution of both natural and anthropogenic activities and alkaline type of aquifers toward the high level of arsenic contamination.

Biomedical Mg alloy is promising for its widespread use clinically. In vitro and in vivo studies showed that the degradation products of biomedical Mg alloy were composed of O, P, Ca, Mg and other alloying elements. However, little is known about the metabolism of the degradation products. In this study, the in vitro macrophage phagocytosis of the degradation products of a biomedical Mg-Nd-Zn-Zr alloy was directly observed. This result affirms the necessity to investigate the long-term fate of Mg alloy degradation products in physiological environments. Besides, an electrochemical method was proposed to prepare enough amount of degradation products in vitro efficiently., (Copyright © 2017 Elsevier B.V. All rights reserved.)

A material that rapidly absorbs molecular oxygen (known as an oxygen scavenger or deoxygenation agent (DOA)) has various industrial applications, such as in food preservation, anticorrosion of metal and coal deoxidation. Given that oxygen is vital to cancer growth, to starve tumours through the consumption of intratumoral oxygen is a potentially useful strategy in fighting cancer. Here we show that an injectable polymer-modified magnesium silicide (Mg 2 Si) nanoparticle can act as a DOA by scavenging oxygen in tumours and form by-products that block tumour capillaries from being reoxygenated. The nanoparticles are prepared by a self-propagating high-temperature synthesis strategy. In the acidic tumour microenvironment, the Mg 2 Si releases silane, which efficiently reacts with both tissue-dissolved and haemoglobin-bound oxygen to form silicon oxide (SiO 2 ) aggregates. This in situ formation of SiO 2 blocks the tumour blood capillaries and prevents tumours from receiving new supplies of oxygen and nutrients.

Background: Oral magnesium supplementation is commonly used to support a low magnesium diet. This investigation set out to determine whether magnesium in a cream could be absorbed transdermally in humans to improve magnesium status., Methods and Findings: In this single blind, parallel designed pilot study, n = 25 participants (aged 34.3+/-14.8y, height 171.5+/-11cm, weight 75.9 +/-14 Kg) were randomly assigned to either a 56mg/day magnesium cream or placebo cream group for two weeks. Magnesium serum and 24hour urinary excretion were measured at baseline and at 14 days intervention. Food diaries were recorded for 8 days during this period. Mg test and placebo groups' serum and urinary Mg did not differ at baseline. After the Mg2+ cream intervention there was a clinically relevant increase in serum magnesium (0.82 to 0.89 mmol/l,p = 0.29) that was not seen in the placebo group (0.77 to 0.79 mmol/L), but was only statistically significant (p = 0.02)) in a subgroup of non-athletes. Magnesium urinary excretion increased from baseline slightly in the Mg2+ group but with no statistical significance (p = 0.48). The Mg2+ group showed an 8.54% increase in serum Mg2+ and a 9.1% increase in urinary Mg2+ while these figures for the placebo group were smaller, i.e. +2.6% for serum Mg2+ and -32% for urinary Mg2+. In the placebo group, both serum and urine concentrations showed no statistically significant change after the application of the placebo cream., Conclusion: No previous studies have looked at transdermal absorbency of Mg2+ in human subjects. In this pilot study, transdermal delivery of 56 mg Mg/day (a low dose compared with commercial transdermal Mg2+ products available) showed a larger percentage rise in both serum and urinary markers from pre to post intervention compared with subjects using the placebo cream, but statistical significance was achieved only for serum Mg2+ in a subgroup of non-athletes. Future studies should look at higher dosage of magnesium cream for longer durations., Trial Registration: ISRCTN registry ID No. ISRTN15136969.

Magnesium alloys are presently under investigation as promising biodegradable implant materials with osteoconductive properties. To study the molecular mechanisms involved, the potential contribution of soluble magnesium corrosion products to the stimulation of osteoblastic cell differentiation was examined. However, no evidence for the stimulation of osteoblast differentiation could be obtained when cultured mesenchymal precursor cells were differentiated in the presence of metallic magnesium or in cell culture medium containing elevated magnesium ion levels. Similarly, in soft tissue no bone induction by metallic magnesium or by the corrosion product magnesium hydroxide could be observed in a mouse model. Motivated by the comparatively rapid accumulation solid corrosion products physicochemical processes were examined as an alternative mechanism to explain the stimulation of bone growth by magnesium-based implants. During exposure to physiological solutions a structured corrosion coat formed on magnesium whereby the elements calcium and phosphate were enriched in the outermost layer which could play a role in the established biocompatible behavior of magnesium implants. When magnesium pins were inserted into avital bones, corrosion lead to increases in the pull out force, suggesting that the expanding corrosion layer was interlocking with the surrounding bone. Since mechanical stress is a well-established inducer of bone growth, volume increases caused by the rapid accumulation of corrosion products and the resulting force development could be a key mechanism and provide an explanation for the observed stimulatory effects of magnesium-based implants in hard tissue. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 105A: 697-709, 2017., (© 2016 Wiley Periodicals, Inc.)

The aim of this study was to assess the relationship between magnesium status and oxidative stress in obese and nonobese women. This cross-sectional study included 83 women, aged between 20 and 50 years, who were divided into two groups: the obese group (n = 31) and the control group (n = 52). The control group was age-matched with the obese group. Magnesium intake was monitored using 3-day food records and NutWin software version 1.5. The plasma and erythrocyte magnesium concentrations were determined by flame atomic absorption spectrophotometry. Plasma levels of thiobarbituric acid reactive substances (TBARS) were determined as biomarkers for lipid peroxidation and therefore of oxidative stress. The mean values of the magnesium content in the diet were found to be lower than those recommended, though there was no significant difference between groups (p > 0.05). The mean concentrations of plasma and erythrocyte magnesium were within the normal range, with no significant difference between groups (p > 0.05). The mean concentration of plasma TBARS was higher in obese woman, and the difference between the groups was statistically different (p < 0.05). There was a positive correlation between erythrocyte magnesium and plasma TBARS in the obese group (p = 0.021). Obese patients ingest low dietary magnesium content, which does not seem to affect the plasma and erythrocyte concentrations of the mineral. The study showed a negative correlation between erythrocyte magnesium concentrations and plasma TBARS, suggesting the influence of magnesium status on the parameters of oxidative stress in obese women.

Introduction: During growth, protein deprivation impairs epiphyseal growth plate (EGP) height, bone volume (BV) and endochondral ossification. During catch-up growth, Ca availability becomes essential to ensure the extra amount needed to achieve optimal peak bone mass and strength. GOS and FOS improve mineral absorption in the colon., Purpose: The effect of a mixture of GOS/FOS ® 9:1 added to a 0.5 %Ca (NCa) and a 0.3 %Ca (LCa) diets on Ca, P and Mg absorptions and bone mineralization, density and structure using an experimental model of growing rats recovering from early protein malnutrition was investigated., Methods: To induce protein malnutrition, rats were fed a low protein diet: 4 % (LPD) during 1 week and then were randomly assigned to recovery groups (R) until day 50 (T = 50) as follows: R0.5 %: NCa; RP0.5 %: NCa + 5.3 % GOS/FOS ® ; R0.3 %: LCa and RP0.3 %: LCa + 5.3 % GOS/FOS ® . Control groups received the 0.5 %Ca or 0.3 %Ca diet from weaning until day 40 or 50., Results: Body weight and length increased in C groups throughout the study; both were arrested in all R during LPD consumption and increased immediately after re-feeding. Independently of dietary Ca content, LS counts, β-glucosidase and Ca, P and Mg absorption increased, whereas cecum pH, β-glucuronidase, urease and tryptophanase decreased in RP0.5 %: and RP0.3 %: as compared to the other studied groups (p < 0.01). Prebiotic consumption decreased CTX levels and increased femur Ca, Mg and P contents, total skeleton bone mineral content, proximal tibia and spine BMD, BV, EGP height and hypertrophic zone thickness, stiffness and elastic modulus as compared to recovery groups fed the prebiotic-free diets., Conclusion: Under the present experimental conditions, GOS/FOS ® mixture induced colonic positive effects, which increased Ca, P and Mg absorption. Thus, consuming the prebiotic-containing diet resulted in an extra amount of minerals that improved bone development in growing rats recovering from protein malnutrition.

The aim of this work was preparation, characterization, bioactivity and biocompatibility evaluation of Mg-substituted fluorapatite (Mg-FA) nanopowders. Mg-FA nanopowders with a chemical composition of Ca10-xMgx(PO4)6F2, with x=0, 0.5, 1, and 2 were prepared by mechanically activated method. The in vitro bioactivity was investigated by soaking the powders in simulated body fluid (SBF) for various time periods to analyze the nucleation and growth of bone-like apatite on the surface of the samples. Cell viability and cell attachment were studied by MTT assay. Results indicated that the bioactivity of all of samples with different Mg content was improved compared with the pure FA. However, the mechanism of bioactivity is different and depends on the amount of Mg substitution. Finally, cell culture suggested that the addition of Mg(2+) has no adverse effect and Mg-FA samples have good biocompatibility. The Mg-FA material shows potential in satisfying the requirements of biomedical applications., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: AST-120 is used to decrease the abundance of serum uremic toxins in treatment of chronic kidney disease; however, it could also adsorb concomitantly administered drugs. This study aimed to develop a prediction method for drug interaction between AST-120 and concomitantly administered drugs based on in vitro dissolution and in vivo absorption behavior., Methods: Sixty-eight drugs were selected for the analysis. For each drug, theoretical dissolution (R d ) and absorption (R a ) rates at estimated dosing intervals (1, 30, 60, 90, 120, and 240 min) were calculated using the Noyes-Whitney formula and compartment analysis, respectively. The optimal thresholds for R d and R a (R dth and R ath ) were estimated by comparing the results with those of previous drug interaction studies for six drugs. Four drug interaction risk categories for 68 drugs at each dose interval were defined according to the indices of dissolution and absorption against their thresholds., Results: The in vitro dissolution and in vivo absorption behavior of the selected drugs were well fitted to the Noyes-Whitney formula and one- or two-compartment models. The optimal R dth and R ath that gave the highest value of consistency with the equivalence of drug interaction studies were 90 and 30 %, respectively. As the dosing intervals were lengthened, the number of drugs classified into the low-risk categories increased., Conclusion: A new drug interaction prediction method based on the pharmacokinetic parameters of drugs was developed. The new model is useful for estimating the risk of drug interaction in clinical practice when AST-120 is used in combination with other drugs., Competing Interests: Shinya Uchida and Tsutomu Kotegawa have received advisory fees from KUREHA CORPORATION.

The aim of this study was to investigate the effect of magnesium (Mg) on the photosynthetic gas exchange parameters ([net CO 2 assimilation rate (A), stomatal conductance (g s ), and internal CO 2 concentration (C i )], chlorophyll (Chl) fluorescence a parameters {minimal fluorescence (F 0 ), maximum fluorescence (F m ), maximum quantum yield of photosystem II (F v /F m ), photochemical quenching coefficient (q p ), yield of photochemistry [Y(II)], yield of regulated energy dissipation [Y(NPQ)] and yield of non-regulated dissipation losses [Y(NO)]} as well as on the concentrations of chloroplastidic pigments in rice plants grown in a nutrient solution containing 0.5 or 1.5 mM of Mg (-Mg or + Mg plants, respectively) and non-inoculated or inoculated with Monographella albescens. A higher Mg supply decreased the leaf scald symptoms in addition to partially preserving the photosynthetic performance of rice leaves challenged with M. albescens. Photosynthetic impairments were associated with photochemical and biochemical dysfunctions at the chloroplast level. The images of Chl a fluorescence evidenced increases in both the Y(II) and q p coupled with decreases in Y(NPQ) associated with a higher Mg supply regardless of inoculation, suggesting increased electron transport rates and lower energy dissipation as heat. Notably, as the leaf scald developed, the use of light energy through photochemical reactions was continuously lost, especially for the inoculated -Mg plants. Interestingly, the lower values for F 0 , F m , and F v /F m for -Mg plants were associated with greater photochemical dysfunctions and a progressive loss of photosynthetic pigments during the infection process of M. albescens. The underlying mechanism through which Mg can affect rice resistance against M. albescens remains to be fully elucidated., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Pure Mg and a Mg-6wt.% Zn alloy were investigated as potential candidates for biodegradable implants for the urinary system. The in vitro corrosion behavior was studied by potentiodynamic polarization and immersion tests in simulated body fluid (SBF) at 37°C. The in vivo degradation and histocompatibility were examined through implantation into the bladders of Wistar rats. The alloying element Zn elevated the passivation potential and increased the cathodic current density. Both in vitro and in vivo degradation tests showed a faster corrosion rate for the Mg-6Zn alloy. Tissues stained with hematoxylin and eosin (HE) suggested that both pure Mg and Mg-6Zn alloy exhibited good histocompatibility in the bladder indwelling implantation and no differences between pure Mg and Mg-6Zn groups were found in bladder, liver and kidney tissues during the 2weeks implantation. Overall, this work presented instructive information on the degradation properties and histocompatibility of pure Mg and the Mg-6Zn alloy in the urinary system., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Magnetic resonance imaging (MRI) contrast agents are categorised according to the following specific features: chemical composition including the presence or absence of metal atoms, route of administration, magnetic properties, effect on the magnetic resonance image, biodistribution and imaging applications. The majority of these agents are either paramagnetic ion complexes or superparamagnetic magnetite particles and contain lanthanide elements such as gadolinium (Gd3+) or transition metal manganese (Mn2+). These elements shorten the T1 or T2 relaxation time, thereby causing increased signal intensity on T1-weighted images or reduced signal intensity on T2-weighted images. Most paramagnetic contrast agents are positive agents. These agents shorten the T1, so the enhanced parts appear bright on T1-weighted images. Dysprosium, superparamagnetic agents and ferromagnetic agents are negative contrast agents. The enhanced parts appear darker on T2-weighted images. MRI contrast agents incorporating chelating agents reduces storage in the human body, enhances excretion and reduces toxicity. MRI contrast agents may be administered orally or intravenously. According to biodistribution and applications, MRI contrast agents may be categorised into three types: extracellular fluid, blood pool and target/organ-specific agents. A number of contrast agents have been developed to selectively distinguish liver pathologies. Some agents are also capable of targeting other organs, inflammation as well as specific tumors.