Simone Noremberg

Aluminum Content in Intravenous Solutions for Administration to Neonates: Role of Product Preparation and Administration Methods

BACKGROUND Aluminum loading can reach toxic levels depending on the amount of aluminum intake in intravenous solutions (IV). Premature infants are at a higher risk of aluminum toxicity because of their reduced urinary aluminum elimination. All steps involved in the preparation of intravenous solutions for premature neonates in intensive care units were evaluated to determine to what degree, if any, they increased the aluminum load and should be considered when assessing the daily aluminum intake (<5 mcg/kg) established by the U.S. Food and Drug Administration (FDA). METHODS Products and medical devices used for the IV administration of solutions to preterm neonates were analyzed for their aluminum content. Commercial formulations, bags after compounding, and medications before and after their preparation, as well as infusion sets (including burettes) and syringes, were evaluated for their contribution to the aluminum levels in the final solution. The determination was carried out by atomic absorption spectrometry. RESULTS Currently available products used to prepare parenteral nutrition solutions as well as injectable medications usually administered to premature neonates present aluminum contamination. Bags, burettes, and syringes were also contaminated by aluminum to some degree, which may be leached during use. CONCLUSIONS Commercial products are the main source of aluminum in parenteral nutrition; nevertheless, manipulation, containers, and administration sets increased aluminum levels by about 40%. Because this is a significant rate, these sources should be taken into account when calculating the amount of aluminum delivered to the patient in order to comply with FDA standards.

Seleno- and Telluro-xylofuranosides attenuate Mn-induced toxicity in C. elegans via the DAF-16/FOXO pathway

Organochalcogens are promising pharmacological agents that possess significant biological activities. Nevertheless, because of the complexity of mammalian models, it has been difficult to determine the molecular pathways and specific proteins that are modulated in response to treatments with these compounds. The nematode worm Caenorhabditis elegans is an alternative experimental model that affords easy genetic manipulations, green fluorescent protein tagging and in vivo live analysis of toxicity. Abundant evidence points to oxidative stress in mediating manganese (Mn)-induced toxicity. In this study we challenged worms with Mn, and investigated the efficacy of inedited selenium- and tellurium-xylofuranosides in reversing and/or protecting the worms from Mn-induced toxicity. In addition, we investigated their putative mechanism of action. First, we determined the lethal dose 50% (LD50) and the effects of the xylofuranosides on various toxic parameters. This was followed by studies on the ability of xylofuranosides to afford protection against Mn-induced toxicity. Both Se- and Te-xylofuranosides increased the expression of superoxide dismutase (SOD-3). Furthermore, we observed that the xylofuranosides induced nuclear translocation of the transcription factor DAF-16/FOXO, which in the worm is known to regulate stress responsiveness, aging and metabolism. These findings suggest that xylofuranosides attenuate toxicity Mn-induced, by regulating the DAF-16/FOXO signaling pathway.

Determination of aluminum and silicon in bovine liver by graphite furnace atomic absorption spectrometry after dissolution with tetramethylammonium hydroxide

Studies suggest that silicic acid or silica can reduce the oral absorption and increase the excretion of aluminum thus protecting the organism against the adverse effects induced by this metal. Therefore, the simultaneous or concomitant determination of Al and Si in biological samples is of significance. In this study a method for sample treatment and the determination of both Al and Si by graphite furnace atomic absorption spectrometry (GFAAS) in animal tissue was developed. Sample dissolution with tetramethylammonium hydroxide (TMAH) proved to be suitable for the determination of both elements. Because Si enhances the Al signal during atomization, this element acted as a chemical modifier for the determination of Al. For the determination of Si, palladium nitrate was the most suitable modifier. The use of Zr as a permanent modifier minimized the tube degradation caused by TMAH. The limits of detection were 5.8 μg L−1 for Al and 29.0 μg L−1 for Si, and the recoveries in spiked samples were between 97 and 112%. The method was validated against bovine liver standard reference materials (SRM 1577b and 1577c), and the obtained concentrations agreed with the certified values.

Evidence for aluminum-binding erythropoietin by size-exclusion chromatography coupled to electrothermal absorption atomic spectrometry

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.

Blueberry (Vaccinium ashei Reade) extract ameliorates ovarian damage induced by subchronic cadmium exposure in mice: Potential δ‐ALA‐D involvement

Females are born with a finite number of oocyte‐containing follicles and ovary damage results in reduced fertility. Cadmium accumulates in the reproductive system, damaging it, and the cigarette smoke is a potential exposure route. Natural therapies are relevant to health benefits and disease prevention. This study verified the effect of cadmium exposure on the ovaries of mice and the blueberry extract as a potential therapy. Blueberry therapy was effective in restoring reactive species levels and δ‐aminolevulinate dehydratase activity, and partially improved the viability of cadmium‐disrupted follicles. This therapy was not able to restore the 17 β‐hydroxysteroid dehydrogenase activity. Extract HPLC evaluation indicated the presence of quercetin, quercitrin, isoquercetin, and ascorbic acid. Ascorbic acid was the major substance and its concentration was 620.24 µg/mL. Thus, cadmium accumulates in the ovaries of mice after subchronic exposure, inducing cellular damage, and the blueberry extract possesses antioxidant properties that could protect, at least in part, the ovarian tissue from cadmium toxicity.

Aluminum in Erythropoietin Formulations: Lyophilized versus Liquid Forms

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.