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Aluminum and silicon are contaminants found in formulations used to prepare parenteral nutrition. Both elements are leached from glass containers, mainly during the heating cycle for sterilization. Insoluble and biologically inactive species of hydroxyaluminosilicates have been shown to form in solutions containing Al and Si. Therefore, this interaction may play an important role in protecting the body against Al toxicity. In this study, the bioavailability of Al in the presence of Si, calcium gluconate (Gluc.), and potassium phosphate (Phosf.) was investigated in rats. The rats were divided into 10 groups of 5 animals each: control, Al, Si, Al + Si, Gluc, Gluc + Al, Gluc + Al + Si, Phosf, Phosf + Al, and Phosf + Al + Si. The doses, consisting of 0.5 mg/kg/day Al and 2 mg/kg/day Si in the presence or absence of Gluc. or Phosf., were intraperitoneally administered for 3 months. Tissues were analyzed for Al and Si content. Al accumulated in the liver, kidneys, and bones, and the simultaneous administration of Si decreased Al accumulation in these tissues. The presence of Si reduced the amount of Al present by 72% in the liver, by 45% in the kidneys, and by 16% in bone. This effect was lees pronounced in the presence of parenteral nutrition compounds though. Si tissue accumulation was also observed, mainly when administered together with phosphate. These results suggest that Si may act as a protector against Al toxicity, by either reducing Al absorption or increasing its excretion, probably through hydroxyaluminosilicates formation. The presence of calcium gluconate and potassium phosphate decreases or inhibits this effect., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aluminium (Al) is soluble in acidic waters and may become toxic to organisms. In this study, the acute effects of two Al concentrations were evaluated in the Amazonian fish Bryconops caudomaculatus. Antioxidant responses and lipid damage were assessed in gills, liver and muscle, along with the electrocardiography (ECG) and characterization of cardiac complex and wave intervals. Fish were essayed as follows: two control groups at neutral and acidic pH and two exposure groups at acidic pH (0.3 mg/L and 3.0 mg/L Al). Water samples were collected at 0h, 24h and 48h, for chloride (Cl - ), fluoride (F - ) and sulphate (SO 4 2- ) ion analyses, while total Al was quantified in muscle. Concentrations of Cl - and SO 4 2- were constant over time whereas F - was not detected. Total Al concentrations in water and muscle were concentration-dependent. Antioxidant responses, total antioxidant capacity against peroxyl radicals (ACAP) and glutathione S-transferase were not triggered in fish tissues exposed to 0.3 mg/L Al; however, fish exposed to 3.0 mg/L Al presented increased and reduced ACAP in gills and liver, respectively. No changes in lipoperoxidation levels occurred among groups. Fish exposed to 0.3 mg/L Al showed prolonged intervals in ECG as a reflection of low heart rate (HR), with sinus bradycardia. Moreover, there was a marked prolongation of the PQ interval (time between the atrial activity and the start of ventricular activity), indicating interference on the cardiac cell automaticity. Fish exposed to the highest concentration of Al showed reduced wave intervals as a consequence of increased HR, with sinus arrhythmia, while ECG tracings did not present P waves (atrial contraction), indicating an atrioventricular blockade. In conclusion, 48h exposure sufficed to cause cardiotoxicity in B. caudomaculatus at either Al concentration. However, as oxidative stress was not observed, such cardiac alterations seem to be reversible under the experimental conditions established herein., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Erythropoietin (EPO) formulations may comprise aluminum (Al) as a contaminant. Due to the toxicity of Al in chronic kidney disease patients, possible sources of Al were investigated. Since EPO formulations are stored in container-closure systems made of glass and rubber, and both contain Al, formulation ingredients may enable its leaching into the solution during shelf-life., Methods: Individual solutions of formulation ingredients were stored in new glass vials and in contact with the rubber stopper and kept at 4 ± 2 °C. For 12 months, aliquots of each solution were collected for analysis. Fifteen commercial samples of EPO were analyzed for their Al content. Aluminum was determined by atomic absorption spectrometry., Results: Glass and rubber are sources of Al for EPO formulations. Storage assay showed that citrate and phosphate (used as buffers) extracted high amounts of Al from the container/closure parts. The most important difference, however, was found when comparing liquid and lyophilized samples. While in liquid forms the Al level reached 943 μg/L, in lyophilized forms the level did not exceed 20 μg/L. The container system was also confirmed as a source of Al in reconstituted lyophilized samples. Al in reconstituted samples stored in their own vials increased 19-fold in 12 months. Lyophilized powders stored for 2 years in glass vials contained less Al than in 1 month after dissolution., Conclusion: The difference in the Al measured in liquid forms of EPO and in lyophilized powders suggests that the latter would be the best pharmaceutical form for CKD patients.

Erythropoietin (EPO) is a glycoprotein that stimulates erythropoiesis and is clinically used for treating anemia during chronic renal failure and for anemia in preterm infants. EPO formulations usually have elevated rates of contamination due to aluminum (Al), which is toxic to both types of patients. Size-exclusion chromatography (SEC) coupled with graphite furnace atomic absorption spectrometry (GF AAS) was employed to separate proteins and to quantify the amount of aluminum present in the elution volume corresponding to EPO and, therefore, to evaluate possible binding. Because EPO formulations contain human serum albumin (HSA), a chromatographic method was optimized for the separation of these proteins. Subsequent to the chromatographic separation, 1-mL fractions of the column effluent were collected, and the Al content in these aliquots was measured by GF AAS. EPO and HSA samples were incubated with Al for 4h at 4°C and 37°C as well as for 16 h at 4°C and 37°C. Afterwards, they were injected into the chromatographic system. These samples were also submitted to ultrafiltration (10 and 50 kDa membranes), and Al was measured in the ultrafiltrates. The results showed that Al was present in the eluent volume corresponding to the EPO peak but not in the HSA peak in the chromatograms. Temperature strengthened the interaction because the Al present in the EPO fraction was 3 times higher at 37°C compared to 4°C. Thirty-eight percent of the Al present in a 2.4 μg/mL EPO standard solution, and approximately 50% of the Al in formulation samples containing approximately 11 μg/mL EPO and either citrate or phosphate, were non-ultrafiltrable, which suggests that EPO is an effective Al acceptor in vitro., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Silicate (Si) and aluminum (Al) may be concomitant impurities in solutions for parenteral nutrition (PN). Silicate can bind to Al to form stable hydroxyaluminosilicates (HAS), thus reducing Al availability. This possibility is investigated by heating solutions containing constituents of PN in glass containers to promote the release of Si and Al., Methods: The total amount of Si and Al in solution is measured by atomic absorption spectrometry, and the Al not bound to Si is evaluated by reaction with morin., Results: When the Si:Al molar ratio is >5, no free Al is found in solution. For ratios <5, it is found that the lower the ratio, the higher the free Al fraction. However, in solutions of some amino acids, even with a low Si:Al ratio (<2), the amount of free Al is lower than that found in other solutions. The same tendency is observed among commercial formulations. Although in salt solutions the free fraction of Al reaches almost 100% when the Si concentration is low, in amino acid formulations the free fraction of Al does not surpass 50%. Moreover, even for Si:Al ratios >5, there is a "residual" fraction of free Al in amino acid formulations., Conclusions: The concomitant presence of Al and Si in solutions for PN reduces the amount of Al available attributable to the formation of HAS. In amino acid formulations this effect may be slightly reduced given the affinity of certain amino acids for Al. Therefore, amino acids may behave in the same fashion as silicate.

Background: Although dialysis facilities provide high-quality water, abnormal aluminium levels among patients on haemodialysis have still been reported. Since patients with chronic kidney disease are often on multiple medications, medicines may be an extra source of aluminium for them. The degree to which ingesting contaminated medication influenced the level of aluminium in the patients' blood was investigated., Methods: All medications consumed by a group of patients on regular dialysis treatment were analysed and the total aluminium ingested by each patient was calculated. At the same time, the patients' blood was collected and aluminium was measured. The analyses were carried out by atomic absorption spectrometry., Results: For all drugs consumed, the amount of aluminium ingested versus the blood aluminium level presented no correlation. Since a high level of contamination was presented by injectable iron, insulin and erythropoietin (EPO), another group of patients that received a reduced amount of oral medication was selected. Among them, eight did not receive any injectable drug, five received only EPO and seven injectable iron, EPO and insulin. With these restricted groups, it was possible to show that the injectable administration of contaminated medication increased the Al level in the patients' blood, mainly in relation to iron formulations., Conclusion: Among the medications investigated, the injectables are the most significant source of aluminium for patients with renal insufficiency. This extra aluminium intake is reflected in higher aluminium levels in the patients' blood.

Four different procedures for the determination of aluminum in tissues by atomic absorption spectrometry (AAS) were investigated. They consisted of conventional acid digestion carried out before and after sample drying, associated or not with fat extraction. Drying was carried out in a conventional oven at 65 degrees C for 24 h. For fat extraction, different solvents and solvent mixtures were investigated considering both extraction yield and sample adequacy for further AAS measurement. Acid digestion was carried out with pure HNO3 or with its mixture with HClO4. After digestion, aluminum was measured by graphite furnace atomic absorption spectrometry. Tissues were collected from Al-exposed and nonexposed mice. The results indicated that drying the sample prior to digestion is advantageous as the amount of acid necessary can be significantly reduced. This procedure does not contribute to increase the aluminum level in the samples providing that careful measures to avoid contamination are taken, as the same procedures carried out without taking any precautions to avoid contamination produced imprecise results. Finally, aluminum was not found in the fatty fraction of any sample, even in exposed mice, demonstrating that aluminum does not accumulate in this part of the tissues.

The interaction between aluminium and cysteine and cystine was evaluated by means of ion-exchange experiments and potentiometry. Ion-exchange experiments included other ligands with affinity for aluminium and two kinds of resins, either a Na+ -form or an Al3+ -form exchanger. The ability of the ligands to keep aluminium in solution in the presence of the Na+ exchanger or to withdraw it from the Al3+ -form resin was evaluated. Aluminium quantification was carried out by either graphite-furnace or flame atomic absorption spectrometry. Aluminium extraction isotherms were linearised using the Scatchard plot, and stability constants were obtained from the curves' slopes. The experiments showed that the ability of the ligands to withdraw aluminium from the Al3+ -form resin increased following the order cysteine < oxalate < citrate = cystine < nitrilotriacetic acid < ethylenediaminetetraacetic acid. Potentiometric titrations, carried out in aqueous solution with constant ionic strength and temperature, showed that the predominant species in solution have a metal-ligand proportion of 1:1 for both amino acids. The main species are Al(OH)3L, with log K of 6.2 for cysteine, and AlL and Al(OH)L, with log K of 10.3 and 1.7, respectively, for cystine. Stability constants obtained from the Scatchard plots showed a linear correlation with the stability constants obtained by potentiometry for cystine and cysteine in this work and those collected from the literature for the other ligands. These results show that cysteine and cystine extract and maintain aluminium in solution, which may explain elevated concentrations of aluminium in parenteral nutrition solutions containing these amino acids.

The interaction of aluminium with some amino acids present in human blood was studied combining ion-chromatography (IC), atomic absorption spectrometry (AAS) and ultrafiltration (UF) techniques. An IC system for simultaneous determination of ornithine, lysine, glutamic acid, aspartic acid and tyrosine was developed. By adding aluminium to standard solutions of the amino acids and keeping the pH at 6 and 7 it was possible to verify that aluminium caused a reduction on the amino acid chromatographic signals. Similar experiment, carried out for copper showed the same behaviour (with different percentage of signal reductions) and validated the results for aluminium, considering that the interaction Cu-amino acid is well-established. The AAS analysis of sample fractions (500 microl) after the IC separation showed that aluminium (as copper as well) is not present in the fractions in which the amino acid peaks appear in the chromatogram. These approaches carried out with serum samples after UF showed that part of the "free" fraction of serum aluminium is distributed, besides other ligands, among these amino acids. It was found that in serum the affinity for aluminium followed the sequence Lys>Orn>Tyr>Glu approximately Asp.