High particle counts in neonatal parenteral nutrition solutions with added cysteine: Relationship to crystal formation and effect of filtration on cysteine content.

BACKGROUND: Parenteral nutrition(PN) solutions containing calcium gluconate and cysteine have elevated particle counts when analyzed using laser light obscuration (LO) as recommended by the United States Pharmacopeia. It is unclear whether increased particle formation in these solutions results in decreased availability of cysteine to neonatal patients due to filtration. OBJECTIVE: The purpose of this study was to measure cysteine concentrations in neonatal PN solutions before and after filtration as well as analyze precipitates on filters. METHODS: Solutions of PN containing amino acids with and without cysteine that were compounded with calcium chloride or calcium gluconate plus potassium phosphate were analyzed using LO. Concentrations of cysteine were measured before and after filtration. The effect on particle formation of magnesium sulfate (MgSO4 ) and D70 was also evaluated. RESULTS: Multiple additives including the specific calcium or D70 additive, cysteine, and MgSO4 influenced particle formation of particles detected using LO. There was no significant decrease in cysteine concentration because of filtering and there was no difference in the amount of calcium on filters of various solutions after filtration regardless of LO particle counts. Scanning electron micrographic (SEM) analysis found no significant differences in crystal composition. Light microscopic and SEM examination did not show evidence of high particle counts on filters. CONCLUSION: The increased particle counts detected in neonatal PN solutions containing cysteine added at the time of compounding does not appear to result in increased precipitate or crystal formation. It is not associated witha decrease in cysteine delivery to patients.

Disposition of Fluorine on New Firefighter Turnout Gear.

Firefighter turnout gear is essential for reducing occupational exposure to hazardous chemicals during training and fire events. Per-and polyfluoroalkyl substances (PFASs) are observed in firefighter serum, and possible occupational sources include the air and dust of fires, aqueous film-forming foam, and turnout gear. Limited data exist for nonvolatile and volatile PFASs on firefighter turnout gear and the disposition of fluorine on the individual layers of turnout gear. Further implications for exposure to fluorine on turnout gear are not well understood. Three unused turnout garments purchased in 2019 and one purchased in 2008, were analyzed for 50 nonvolatile and 15 volatile PFASs by liquid chromatography quadrupole time-of-flight mass spectrometry (LC-qTOF-MS) and gas chromatography-mass spectrometry (GC-MS), respectively. Particle-induced gamma ray emission (PIGE), a surface technique, and instrumental neutron activation analysis (INAA), a bulk technique, were used to measure total fluorine. Bulk characterization of the layers by pyrolysis-GC/MS (py-GC/MS) was used to differentiate fluoropolymer (e.g., PTFE) films from textile layers finished with side-chain polymers. The outer layer, moisture barrier, and thermal layers of the turnout gear all yielded measured concentrations of volatile PFASs that exceeded nonvolatile PFAS concentrations, but the summed molar concentrations made up only a small fraction of total fluorine (0.0016-6.7%). Moisture barrier layers comprised a PTFE film, as determined by py-GC-MS, and gave the highest individual nonvolatile (0.159 mg F/kg) and volatile PFAS (20.7 mg F/kg) as well as total fluorine (122,000 mg F/kg) concentrations. Outer and thermal layers comprised aromatic polyamide-based fibers (aramid) treated with side-chain fluoropolymers and had lower levels of individual nonvolatile and volatile PFASs. Equal concentrations of total fluorine by both PIGE and INAA on the outer and thermal layers is consistent with treatment with a side-chain fluoropolymer coating. New turnout gear should be examined as a potential source of firefighter occupational exposure to nonvolatile and volatile PFASs in future assessments.

Aluminum Content of Neonatal Parenteral Nutrition Solutions: Options for Reducing Aluminum Exposure.

INTRODUCTION: Calcium chloride (CaCl2 ) has been the only calcium additive available in the United States that has a low aluminum (Al) content. Calcium gluconate in glass vials (CaGluc-Gl) has a high Al content while calcium gluconate in plastic vials (CaGluc-Pl) has a low Al content. The purpose of this study was to measure Al concentrations in neonatal parenteral nutrition (PN) solutions prepared using various calcium additives. METHODS: Samples of solutions compounded with CaCl2 or CaGluc-Gl and sodium phosphate (NaPhos) as well as CaGluc-Pl and sodium glycerophosphate (NaGP) with and without cysteine were analyzed for Al content. Samples of the cysteine and calcium gluconate additives were also sent for analysis. RESULTS: Solutions containing CaCl2 and CaGlu-Pl had mean Al concentrations of 1.2-2.3 mcg/dL, while those with CaGlu-Gl had mean concentrations of 14.6-15.1 mcg/dL. Solutions made with NaGP were low in Al content. The measured Al content of 2 lots of the cysteine additive were 168 ± 23 mcg/L and 126 ± 5 mcg/L. The Al concentration equalled 2730 ± 20 mcg/L for the CaGlu-Gl additive and 310 ± 80 mcg/L for the CaGlu-Pl additive. CONCLUSION: The study indicates that solutions containing CaCl2 or CaGluc-Pl and NaPhos or NaGP are low in Al content. Using these options for calcium and phosphate additives can limit aluminum intake from neonatal PN to levels within the Food and Drug Administration guideline of ≤5 mcg/kg/d.

Aluminum Content of Neonatal Parenteral Nutrition Solutions.

INTRODUCTION: Calcium chloride (CaCl2) has been the only calcium additive available in the United States that has a low aluminum (Al) content. Calcium gluconate in glass vials (CaGluc-Gl) has a high Al content while calcium gluconate in plastic vials (CaGluc-Pl) has a low Al content. The purpose of this study was to measure Al concentrations in neonatal parenteral nutrition (PN) solutions prepared using various calcium additives. METHODS: Samples of solutions compounded with CaCl2 or CaGluc-Gl and sodium phosphate (NaPhos) as well as CaGluc-Pl and sodium glycerophosphate (NaGP) with and without cysteine were analyzed for Al content. Samples of the cysteine and calcium gluconate additives were also sent for analysis. RESULTS: Solutions containing CaCl2 and CaGlu-Pl had mean Al concentrations of 1.2-2.3 mcg/dL, while those with CaGlu-Gl had mean concentrations of 14.6-15.1 mcg/dL. Solutions made with NaGP were low in Al content. The measured Al content of 2 lots of the cysteine additive were 168 ± 23 mcg/L and 126 ± 5 mcg/L. The Al concentration equalled 2730 ± 20 mcg/L for the CaGlu-Gl additive and 310 ± 80 mcg/L for the CaGlu-Pl additive. CONCLUSION: The study indicates that solutions containing CaCl2 or CaGluc-Pl and NaPhos or NaGP are low in Al content. Using these options for calcium and phosphate additives can limit aluminum intake from neonatal PN to levels within the Food and Drug Administration guideline of ≤5 mcg/kg/d.

Physiologically based pharmacokinetic model for composite nanodevices: effect of charge and size on in vivo disposition.

PURPOSE: To characterize temporal exposure and elimination of 5 gold/dendrimer composite nanodevices (CNDs) (5 nm positive, negative, and neutral, 11 nm negative, 22 nm positive) in mice using a physiologically based mathematical model. METHODS: 400 ug of CNDs is injected intravenously to mice bearing melanoma cell lines. Gold content is determined from plasma and tissue samples using neutron activation analysis. A physiologically based pharmacokinetic (PBPK) model is developed for 5 nm positive, negative, and neutral and 11 nm negative nanoparticles and extrapolated to 22 nm positive particles. A global sensitivity analysis is performed for estimated model parameters. RESULTS: Negative and neutral particles exhibited similar distribution profiles. Unique model parameter estimates and distribution profiles explain similarities and differences relative to positive particles. The model also explains mechanisms of elimination by kidney and reticuloendothelial uptake in liver and spleen, which varies with particle size and charge. CONCLUSION: Since the PBPK model can capture the diverse temporal profiles of non-targeted nanoparticles, we propose that when specific binding ligands are lacking, size and charge of nanodevices govern most of their in vivo interactions.

Fabrication of {198Au0} radioactive composite nanodevices and their use for nanobrachytherapy.

We describe the simple fabrication of poly({198Au}) radioactive gold-dendrimer composite nanodevices in distinct sizes (diameter between 10 nm and 29 nm) for targeted radiopharmaceutical dose delivery to tumors in vivo. Irradiation of aqueous solutions of 197Au containing poly(amidoamine) dendrimer tetrachloroaurate salts or {197Au0} gold-dendrimer nanocomposites in a nuclear reactor resulted in the formation of positively charged and soluble poly{198Au0} radioactive composite nanodevices (CNDs). A mouse melanoma tumor model was used to test whether the poly{198Au0} CNDs can deliver a therapeutic dose. A single intratumoral injection of poly{198Au0}(d=22nm) CNDs in phosphate-buffered saline delivering a dose of 74 muCi resulted after 8 days in a statistically significant 45% reduction in tumor volume, when compared with untreated groups and those injected with the "cold" nanodevice. No clinical toxicity was observed during the experiments. This study provides the first proof of principle that radioactive CNDs can deliver therapeutic doses to tumors.

Significant effect of size on the in vivo biodistribution of gold composite nanodevices in mouse tumor models.

There is growing interest in developing tissue-specific multifunctional drug delivery systems with the ability to diagnose or treat several diseases. One class of such agents, composite nanodevices (CNDs), is multifunctional nanomaterials with several potential medical uses, including cancer imaging and therapy. Nanosized metal-dendrimer CNDs consist of poly(amidoamine) dendrimers (in various sizes, surface substituents, and net charges) and inorganic nanoparticles, properties of both of which can be individually modified and optimized. In this study we examine effects of size and surface charge on the behavior of Au-dendrimer CNDs in mouse tumor models. Quantitative biodistribution and excretion analyses including 5-nm and 22-nm positive surface, 5-nm and 11-nm negative surface, and a 5-nm neutral surface CNDs were carried out in the B16 mouse melanoma tumor model system. Results seen with the 22-nm CND in the B16 melanoma model were corroborated in a prostate cancer mouse tumor model system. Quantitative in vivo studies confirm the importance of charge and show for the first time the importance of size in affecting CND biodistribution and excretion. Interestingly, CNDs of different size and/or surface charge had high levels of uptake ("selective targeting") to certain organs without specific targeting moieties placed on their surfaces. We conclude that size and charge greatly affect biodistribution of CNDs. These findings have significance for the design of all particle-based nanodevices for medical uses. The observed organ selectivity may make these nanodevices exciting for several targeted medical applications.

In vivo biodistribution of dendrimers and dendrimer nanocomposites -- implications for cancer imaging and therapy.

Our results indicate that the surface chemistry, composition, and 3-D structure of nanoparticles are critical in determining their in vivo biodistribution, and therefore the efficacy of nanodevice imaging and therapies. We demonstrate that gold/dendrimer nanocomposites in vivo, present biodistribution characteristics different from PAMAM dendrimers in a B16 mouse tumor model system. We review important chemical and biologic uses of these nanodevices and discuss the potential of nanocomposite devices to greatly improve cancer imaging and therapy, in particular radiation therapy. We also discuss major issues confronting the use of nanoparticles in the near future, with consideration of toxicity analysis and whether biodegradable devices are needed or even desirable.