Background: Quaternary ammonium compounds are a large class of chemicals used for their antimicrobial and antistatic properties. Two common quaternary ammonium compounds, alkyldimethylbenzyl ammonium chloride (ADBAC) and didecyldimethyl ammonium chloride (DDAC), are combined in common cleaners and disinfectants. Introduction of a cleaner containing ADBAC1DDAC in the vivarium caused neural tube defects (NTDs) in mice and rats. Methods: To further evaluate this finding, male and female mice were dosed in the feed at 60 or 120 mg/kg/day, or by oral gavage at 7.5, 15, or 30 mg/kg ADBAC1DDAC. Mice also received ambient exposure to ADBAC1DDAC from the disinfectant used in the mouse room. Embryos were evaluated on gestational day 10 for NTDs, and fetuses were evaluated on gestational day 18 for gross and skeletal malformations. Results: We found increased NTDs with exposure to ADBAC1DDAC in both rats and mice. The NTDs persisted for two generations after cessation of exposure. Notably, male exposure alone was sufficient to cause NTDs. Equally significant, ambient exposure from disinfectant use in the vivarium, influenced the levels of NTDs to a greater extent than oral dosing. No gross or significant axial skeletal malformations were observed in late gestation fetuses. Placental abnormalities and late gestation fetal deaths were increased at 120 mg/kg/day, which might explain the lack of malformations observed in late gestation fetuses.Conclusion: These results demonstrate that ADBAC1DDAC in combination are teratogenic to rodents. Given the increased use of these disinfectants, further evaluation of their safety in humans and their contribution to health and disease is essential.
Adsorption of organic molecules from aqueous solution to the surface of carbon nanotubes or graphene is an important process in many applications of these materials. Here we use molecular dynamics simulation, supplemented by analytical chemistry, to explore in detail the adsorption thermodynamics of a diverse set of aromatic compounds on graphenic materials, elucidating the effects of the solvent, surface coverage, surface curvature, defects, and functionalization by hydroxy groups. We decompose the adsorption free energies into entropic and enthalpic components and find that different classes of compoundssuch as phenols, benzoates, and alkylbenzenescan easily be distinguished by the relative contributions of entropy and enthalpy to their adsorption free energies. Overall, entropy dominates for the more hydrophobic compounds, while enthalpy plays the greatest role for more hydrophilic compounds. Experiments and independent simulations using two different force field frameworks (CHARMM and Amber) support the robustness of these conclusions. We determine that concave curvature is generally associated with greater adsorption affinity, more favorable enthalpy, and greater contact area, while convex curvature reduces both adsorption enthalpy and contact area. Defects on the graphene surfaces can create concave curvature, resulting in localized binding sites. As the graphene surface becomes covered with aromatic solutes, the affinity for adsorbing an additional solute increases until a complete monolayer is formed, driven by more favorable enthalpy and partially canceled by less favorable entropy. Similarly, hydroxylation of the surface leads to preferential adsorption of the aromatic solutes to remaining regions of bare graphene, resulting in less favorable adsorption entropy, but compensated by an increase in favorable enthalpic interactions.
Cannabinoid production for medicinal purposes has renewed interest in utilizing byproducts of industrial hemp (IH) as a feed source for livestock. However, the presence of bioactive residues in animal tissues may pose a risk to consumers. The purpose of this study was to characterize the plasma pharmacokinetics (PK) of cannabinoids and their metabolites in cattle after a single oral exposure to IH. Eight castrated male Holstein calves received a single oral dose of 35 g of IH to achieve a target dose of 5.4 mg/kg cannabidiolic acid (CBDA). Blood samples were collected for 96 h after dosing. Plasma cannabinoid concentrations were profiled using liquid chromatography coupled with mass-spectroscopy (UPLC) and PK parameters were calculated using noncompartmental methods. The cannabinoids CBDA, tetrahydrocannabinolic acid-A (THCA-A), cannabidivarinic acid (CBDVA), and cannabichromenic acid (CBCA) were detected in all cattle after IH dosing. The geometric mean maximum concentration of CBDA of 72.7 ng/mL was observed at 14 h after administration. The geometric mean half-life of CBDA was 14.1 h. No changes in serum biochemistry analysis were observed following IH dosing compared to baseline values. These results show acidic cannabinoids, especially CBDA, are readily absorbed from the rumen and available for distribution throughout the body.
Studies have demonstrated that smokers have lower levels of brain monoamine oxidase (MAO) A and B activity and lower MAO-B platelet activity than non-smokers. Recent speculations suggest that in addition to nicotine, tobacco components which are MAO inhibitors, may contribute to some tobacco related psychopharmacological effects. Furthermore, epidemiological evidence indicates a lower incidence of Parkinson's disease in smokers than in non-smokers. This relationship also might be linked to MAO inhibition. These intriguing observations prompted studies on the effects of tobacco leaf and tobacco smoke constituents on MAO activity. Studies reported here demonstrate that crude hexane tobacco leaf and hexane and aqueous leaf extracts have MAO inhibitory properties. Rat brain mitochondrial MAO-A and MAO-B activity are not altered following continuous 28 day exposure to (osmotic minipump) to two tobacco alkaloids, (S)-nicotine or (R,S)-N-methylanatabine. However, earlier studies in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) treated parkinsonian C57BL/6 mouse model have provided indirect evidence that the tobacco derived 2,3,6-trimethyl-1,4-naphthoquinone (an MAO-A and B inhibitor) is effective in inhibiting MAO-B in vivo and is neuroprotective. Results reported here from more extensive tobacco leaf extractions provide evidence for three additional compounds with MAO-B inhibitory properties. One contains a chromone system, another a polyunsaturated macro-cycle and the third we have identified as farnesylacetone. These findings provide support to the thesis that components of tobacco smoke may be responsible for the inhibition of brain MAO-A and brain and platelet MAO-B in human smokers.
The aim of this study was to determine the pharmacokinetics and prostaglandin E2 (PGE2) synthesis inhibiting effects of intravenous (IV) and transdermal (TD) flunixin meglumine in eight adult female Boer goats. A dose of 2.2 mg/kg was administered intravenously (IV) and 3.3 mg/kg administered TD using a cross‐over design. Plasma flunixin concentrations were measured by LC‐MS/MS. Prostaglandin E2 concentrations were determined using a commercially available ELISA. Pharmacokinetic (PK) analysis was performed using noncompartmental methods. Plasma PGE2 concentrations decreased after flunixin meglumine for both routes of administration. Mean λz‐HL after IV administration was 6.032 hr (range 4.735–9.244 hr) resulting from a mean Vz of 584.1 ml/kg (range, 357.1–1,092 ml/kg) and plasma clearance of 67.11 ml kg−1 hr−1 (range, 45.57–82.35 ml kg−1 hr−1). The mean Cmax, Tmax, and λz‐HL for flunixin following TD administration was 0.134 μg/ml (range, 0.050–0.188 μg/ml), 11.41 hr (range, 6.00–36.00 hr), and 43.12 hr (15.98–62.49 hr), respectively. The mean bioavailability for TD flunixin was calculated as 24.76%. The mean 80% inhibitory concentration (IC80) of PGE2 by flunixin meglumine was 0.28 μg/ml (range, 0.08–0.69 μg/ml) and was only achieved with IV formulation of flunixin in this study. The PK results support clinical studies to examine the efficacy of TD flunixin in goats. Determining the systemic effects of flunixin‐mediated PGE2 suppression in goats is also warranted.
Toxicity and integrity disruption in response to transport through the blood-brain barrier (BBB) of the organophosphates malathion and malaoxon and heavy metal lead acetate were assessed in two in vitro barrier systems. One system was constructed using bovine brain microvascular endothelial cells (BMEC), while the other system was constructed with rat brain microvascular endothelial cells (RBE4); both were cocultured with rat astrocytes. We hypothesized that these models would respond differently to neurotoxic compounds. Concentrations of malathion, malaoxon, and lead acetate between 0.01 microM and 1 mM were assessed for their capacity to cause cytotoxicity to the astrocytes and endothelial cells utilized to construct the BBB systems, with the least cytotoxic concentrations chosen for transfer assessments of neurotoxicants through the barrier systems. Concentrations of malathion at 10 microM, malaoxon at 1 microM, and lead acetate at 1 and 10 microM were selected. Lead concentrations were measured in media of the abluminal and luminal sides of both systems using graphite furnace atomic absorption at the beginning of the treatment (T0) and 14 h later (T14). Passage of organophosphate compounds was determined utilizing inhibition of acetylcholinesterase enzyme in a neuroblastoma cell line (SH-SY5Y) localized below the barrier system. Transendothelial electrical resistance was assessed as a measurement of integrity of the barrier systems, with baseline values higher with the RBE4-astrocyte system than with the BMEC-astrocyte system. Metabolic capability, as measured by esterase activity, was higher in BMECs, which were more likely to retain lead than RBE4 cells. Results suggest that differences in endothelial cell source can affect the outcome of studies on toxicant transfer through in vitro BBB systems.
Background: Urinary catecholamines and metanephrines have been proposed as a diagnostic tool for identifying canine pheochromocytomas, but the effects of critical illness on urine concentrations of catecholamines and metanephrines currently are unknown.Objectives: To examine the effects of illness on urine concentrations of catecholamines and metanephrines in dogs. Animals: Twenty-five critically ill dogs and 25 healthy age-and sex-matched control dogs. Methods: Prospective observational study. Urine was collected from healthy and critically ill dogs, and urine concentrations of epinephrine, norepinephrine, metanephrine, and normetanephrine were measured by high-performance liquid chromatography with electrochemical detection. Urinary catecholamine and metanephrine : creatinine ratios were calculated and compared between groups.Results: Urinary epinephrine, norepinephrine, metanephrine, and normetanephrine : creatinine ratios were higher in critically ill dogs when compared with a healthy control population (P 5 .0009, P o 0.0001, P o 0.0001, and P o 0.0001, respectively).Conclusions and Clinical Importance: Illness has a significant impact on urinary catecholamines and their metabolites in dogs. Further investigation of catecholamine and metanephrine concentrations in dogs with pheochromocytomas is warranted to fully evaluate this test as a diagnostic tool; however, the findings of this study suggest that the results may be difficult to interpret in dogs with concurrent illness.
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