scholarly journals Modeling the interactions of particulates with epithelial lining fluid antioxidants

1999 ◽  
Vol 277 (4) ◽  
pp. L719-L726 ◽  
Author(s):  
Henryk Zielinski ◽  
Ian S. Mudway ◽  
Kelly A. Bérubé ◽  
Samantha Murphy ◽  
Roy Richards ◽  
...  

Oxidative stress may be a fundamental mode of injury associated with inspired particles. To examine this, we determined the ability of three carbon black particles (CBPs; M120, M880, and R250) and two forms of silicon dioxide, amorphous (Cabosil) and crystalline (DQ12) quartz, to deplete epithelium lining fluid antioxidant defenses. Single and composite antioxidant solutions of uric acid, ascorbic acid (AA), and reduced glutathione (GSH) were examined in the presence of particle concentrations of 150 μg/ml. Uric acid was not depleted by any particle considered. AA was depleted in a near-linear fashion with time by the three different CBPs; however, AA depletion rates varied markedly with CBP type and decreased in the presence of metal chelators. An initially high GSH depletion rate was noted with all CBPs, and this was always accompanied by the appearance of oxidized glutathione. Exposure to Cabosil or DQ12 did not result in the loss of GSH. Together, these data demonstrate that particle type, size, and surface area are all important factors when considering particle-antioxidant interactions in the airways.

1993 ◽  
Vol 75 (2) ◽  
pp. 825-832 ◽  
Author(s):  
A. Gillissen ◽  
P. Birrer ◽  
N. G. McElvaney ◽  
R. Buhl ◽  
C. Vogelmeier ◽  
...  

Secretory leukoprotease inhibitor (SLPI), a 12-kDa serine antiprotease, serves as the major inhibitor of neutrophil elastase (NE) on the epithelial surface of the upper airways. As a control for studies to evaluate the aerosol administration of recombinant SLPI (rSLPI) to augment the anti-NE defenses of the lung, the status of antioxidants in respiratory epithelial lining fluid (ELF) was evaluated. Unexpectedly, aerosol administration of rSLPI caused an elevation in ELF glutathione, a major component of the epithelial antioxidant screen; i.e., rSLPI may provide not only augmentation of anti-NE defenses but also antioxidant defenses. To evaluate this concept, rSLPI (100 mg) was aerosolized to sheep, and SLPI, glutathione, anti-NE capacity, and anti-H2O2 capacity were evaluated in respiratory ELF over a 30-h period. As expected, aerosolization of rSLPI increased ELF SLPI levels and anti-NE capacity. Strikingly, postaerosol levels of glutathione in ELF were also increased (5-fold 24 h after aerosol), with a concomitant increase in ELF anti-H2O2 capacity; i.e., the rSLPI augmented the antioxidant screen of ELF. This suggests that rSLPI may be particularly well suited for therapy in lung diseases characterized by excess of both serine proteases and oxidants on the respiratory epithelial surface.


2004 ◽  
Vol 48 (4) ◽  
pp. 1215-1221 ◽  
Author(s):  
Naomi R. Florea ◽  
Pamela R. Tessier ◽  
Cuilian Zhang ◽  
Charles H. Nightingale ◽  
David P. Nicolau

ABSTRACT Recent clinical failures associated with levofloxacin treatment for Streptococcus pneumoniae infections and growing evidence of frequent mutations in the isolate population have led to increased concerns regarding fluoroquinolone resistance. Our objective was to characterize the efficacies of levofloxacin and moxifloxacin against various genotypes of S. pneumoniae after simulated bronchopulmonary exposures. An in vitro model was used to simulate a levofloxacin concentration of 500 mg and a moxifloxacin concentration of 400 mg, which were previously determined to be the concentrations in the epithelial lining fluid of older adults receiving once-daily dosing. The effects of the drugs were tested against six S. pneumoniae containing various mutations. Bacterial density and resistance were quantitatively assessed over 48 h. The S. pneumoniae isolate with no mutation displayed a 4-log reduction in CFU after treatment with both agents and did not develop resistance. Isolates containing the parC or parE mutation or both mutations regrew and developed resistance when they were exposed to levofloxacin, despite an unbound area under the concentration-time curve (AUC):MIC ratio of ∼100. When the isolate containing the parC and gyrA mutations was exposed to levofloxacin, there was a half-log reduction in the number of CFU compared to that for the control, but the isolate subsequently regrew. Likewise, levofloxacin did not kill the isolate containing the parC, gyrA, and parE mutations. Moxifloxacin sustained the killing of all bacterial isolates tested without the development of resistance. Levofloxacin did not sustain bacterial killing and did not prevent the emergence of further resistance in mutants with the parC or parE mutation or both mutations, even though an unbound AUC:MIC ratio for exposure well above the breakpoint of 30 to 40 established in the literature for S. pneumoniae was maintained. Moxifloxacin was effective against all isolates tested, despite the presence of isolates with two- and three-step mutations, for which the MICs were increased.


2016 ◽  
Vol 60 (8) ◽  
pp. 5085-5087 ◽  
Author(s):  
Danilo Cesar Galindo Bedor ◽  
Sandrine Marchand ◽  
Isabelle Lamarche ◽  
Julian Laroche ◽  
Davi Pereira de Santana ◽  
...  

ABSTRACTThe aim of this study was to determine the biopharmaceutical characteristics of oseltamivir carboxylate (OC) after pulmonary delivery. After OC bolus and intratracheal nebulization (NEB) in rats, blood was collected and bronchoalveolar lavages (BALs) were performed. Epithelial lining fluid (ELF) concentrations were estimated from BAL fluid. The area under the curve (AUC) ratio for ELF to plasma was 842 times higher after NEB than after intravenous (i.v.) administration, indicating that OC nebulization offers a biopharmaceutical advantage over i.v. administration.


Respirology ◽  
2007 ◽  
Vol 12 (5) ◽  
pp. 740-743 ◽  
Author(s):  
Yasushi NAKANO ◽  
Sadatomo TASAKA ◽  
Fumitake SAITO ◽  
Wakako YAMADA ◽  
Yoshiki SHIRAISHI ◽  
...  

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Sandrine Marchand ◽  
Matthieu Boisson ◽  
Shachi Mehta ◽  
Christophe Adier ◽  
Olivier Mimoz ◽  
...  

ABSTRACT Amikacin and gentamicin pharmacokinetic behaviors after nebulization were determined by comparing plasma and pulmonary epithelial lining fluid (ELF) concentrations in rats after intratracheal and intravenous administrations. ELF areas under concentration-time curve were 874 and 162 times higher after nebulization than after intravenous administration for amikacin and gentamicin, respectively. Even if both molecules appear to be good candidates for nebulization, these results demonstrate a much higher targeting advantage of nebulization for amikacin than for gentamicin.


2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.


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