Pharmacokinetic Disposition of Amiodarone When Given with an Intralipid Rescue Strategy.

While the antiarrhythmic drug amiodarone is commonly used in clinical practice, it has a narrow therapeutic index that can lead to acute overdose. One proposed method to deal with this toxicity is lipid emulsion therapy, which may potentially quench the free amiodarone in blood and prevent its further distribution to target organs and tissues. In this study, we utilize an established swine model to examine the effects of Intralipid™ (IL) administration for acute amiodarone toxicity. A total of 14 pigs received an overdose of intravenous amiodarone. After twenty minutes, half of the pigs (n = 7) received IL while the control group (n = 7) received normal saline. Serum concentrations of amiodarone were then analyzed using a validated high-performance liquid chromatography (HPLC) method. Noncompartmental pharmacokinetic analyses were performed on the observed concentrations. There were no statistical differences in the area under the concentration time curve (6 h) or clearance, but there was a difference in the half-life between the two groups (3.12 vs. 0.85 h, p = 0.01). The administration of IL did not statistically change the overall exposure of amiodarone in the blood in the first 6 h; however, trends toward prolonged blood retention in the IL group were seen.

Analysis of HETEs in human whole blood by chiral UHPLC-ECAPCI/HRMS.

The biosynthesis of eicosanoids occurs enzymatically via lipoxygenases, cyclooxygenases, and cytochrome P450, or through nonenzymatic free radical reactions. The enzymatic routes are highly enantiospecific. Chiral separation and high-sensitivity detection methods are required to differentiate and quantify enantioselective HETEs in complex biological fluids. We report here a targeted chiral lipidomics analysis of human blood using ultra-HPLC-electron capture (EC) atmospheric pressure chemical ionization/high-resolution MS. Monitoring the high-resolution ions formed by the fragmentation of pentafluorobenzyl derivatives of oxidized lipids during the dissociative EC, followed by in-trap fragmentation, increased sensitivity by an order of magnitude when compared with the unit resolution MS. The 12(S)-HETE, 12(S)-hydroxy-(5Z,8E,10E)-heptadecatrienoic acid [12(S)-HHT], and 15(S)-HETE were the major hydroxylated nonesterified chiral lipids in serum. Stimulation of whole blood with zymosan and lipopolysaccharide (LPS) resulted in stimulus- and time-dependent effects. An acute exposure to zymosan induced ∼80% of the chiral plasma lipids, including 12(S)-HHT, 5(S)-HETE, 15(R)-HETE, and 15(S)-HETE, while a maximum response to LPS was achieved after a long-term stimulation. The reported method allows for a rapid quantification with high sensitivity and specificity of enantiospecific responses to in vitro stimulation or coagulation of human blood.

Siderophore-mediated iron removal from chrysotile: Implications for asbestos toxicity reduction and bioremediation.

Asbestos fibers are highly toxic (Group 1 carcinogen) due to their high aspect ratio, durability, and the presence of iron. In nature, plants, fungi, and microorganisms release exudates, which can alter the physical and chemical properties of soil minerals including asbestos minerals. We examined whether exudates from bacteria and fungi at environmentally relevant concentrations can alter chrysotile, the most widely used asbestos mineral, and lower its toxicity. We monitored the release of iron from chrysotile in the presence of organic acid ligands and iron-specific siderophores derived from bacteria and fungi and measured any change in fiber toxicity toward peritoneal macrophages harvested from mice. Both fungal and bacterial siderophores increased the removal of iron from asbestos fibers. In contrast, organic acid ligands at environmentally relevant concentrations neither released iron from fibers nor helped in siderophore-mediated iron removal. Removal of plant-available or exchangeable iron did not diminish iron dissolution by both types of siderophores, which indicates that siderophores can effectively remove structural iron from chrysotile fibers. Removal of iron by siderophore lowered the fiber toxicity; fungal siderophore appears to be more effective than bacterial siderophore in lowering the toxicity. These results indicate that prolonged exposure to siderophores, not organic acids, in the soil environment decreases asbestos fiber toxicity and possibly lowers the health risks. Thus, bioremediation should be explored as a viable strategy to manage asbestos-contaminated sites such as Brownfield sites, which are currently left untreated despite dangers to surrounding communities.

Asbestos Fiber Preparation Methods Affect Fiber Toxicity.

To measure the toxic potential of asbestos fibers-a known cause of asbestosis, lung cancer, and malignant mesothelioma-asbestos minerals are generally first ground down to small fibers, but it is unknown whether the grinding condition itself changes the fiber toxicity. To evaluate this, we ground chrysotile ore with or without water for 5-30 min and quantified asbestos-induced reactive oxygen species generation in elicited murine peritoneal macrophages as an indicator of fiber toxicity. The toxicity of dry-ground fibers was higher than the toxicity of wet-ground fibers. Grinding with or without water did not materially alter the mineralogical properties. However, dry-ground fibers contained at least 7 times more iron than wet-ground fibers. These results indicate that grinding methods significantly affect the surface concentration of iron, resulting in changes in fiber-induced reactive oxygen species generation or toxicity. Therefore, fiber preparation conditions should be accounted for when comparing the toxicity of asbestos fibers between reported studies.