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Keith A. Rodvold - One of the best experts on this subject based on the ideXlab platform.

  • comparison of omadacycline and tigecycline pharmacokinetics in the plasma Epithelial Lining Fluid and alveolar cells of healthy adult subjects
    Antimicrobial Agents and Chemotherapy, 2017
    Co-Authors: Mark H Gotfried, Karolyn S Horn, Lynne Garrityryan, Stephen Villano, Evan Tzanis, Surya Chitra, Amy Manley, Ken S Tanaka, Keith A. Rodvold
    Abstract:

    The steady-state concentrations of omadacycline and tigecycline in the plasma, Epithelial Lining Fluid (ELF), and alveolar cells (AC) of 58 healthy adult subjects were obtained. Subjects were administered either omadacycline at 100 mg intravenously (i.v.) every 12 h for two doses followed by 100 mg i.v. every 24 h for three doses or tigecycline at an initial dose of 100 mg i.v. followed by 50 mg i.v. every 12 h for six doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject following the start of the fifth dose of omadacycline at 0.5, 1, 2, 4, 8, 12, or 24 h and after the start of the seventh dose of tigecycline at 2, 4, 6, or 12 h. The value of the area under the concentration-time curve (AUC) from time zero to 24 h postdosing (AUC0-24) (based on mean concentrations) in ELF and the ratio of the ELF to total plasma omadacycline concentration based on AUC0-24 values were 17.23 mg · h/liter and 1.47, respectively. The AUC0-24 value in AC was 302.46 mg · h/liter, and the ratio of the AC to total plasma omadacycline concentration was 25.8. In comparison, the values of the AUC from time zero to 12 h postdosing (AUC0-12) based on the mean concentrations of tigecycline in ELF and AC were 3.16 and 38.50 mg · h/liter, respectively. The ratio of the ELF and AC to total plasma concentrations of tigecycline based on AUC0-12 values were 1.71 and 20.8, respectively. The pharmacokinetic advantages of higher and sustained concentrations of omadacycline compared to those of tigecycline in plasma, ELF, and AC suggest that omadacycline is a promising antibacterial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens.

  • meropenem rpx7009 concentrations in plasma Epithelial Lining Fluid and alveolar macrophages of healthy adult subjects
    Antimicrobial Agents and Chemotherapy, 2015
    Co-Authors: Eric Wenzler, Mark H Gotfried, Jeffrey S Loutit, Stephanie Durso, David C Griffith, Michael N Dudley, Keith A. Rodvold
    Abstract:

    The steady-state concentrations of meropenem and the β-lactamase inhibitor RPX7009 in plasma, Epithelial Lining Fluid (ELF), and alveolar macrophage (AM) concentrations were obtained in 25 healthy, nonsmoking adult subjects. Subjects received a fixed combination of meropenem (2 g) and RPX7009 (2 g) administered every 8 h, as a 3-h intravenous infusion, for a total of three doses. A bronchoscopy and bronchoalveolar lavage were performed once in each subject at 1.5, 3.25, 4, 6, or 8 h after the start of the last infusion. Meropenem and RPX7009 achieved a similar time course and magnitude of concentrations in plasma and ELF. The mean pharmacokinetic parameters ± the standard deviations of meropenem and RPX7009 determined from serial plasma concentrations were as follows: Cmax = 58.2 ± 10.8 and 59.0 ± 8.4 μg/ml, Vss = 16.3 ± 2.6 and 17.6 ± 2.6 liters; CL = 11.1 ± 2.1 and 10.1 ± 1.9 liters/h, and t1/2 = 1.03 ± 0.15 and 1.27 ± 0.21 h, respectively. The intrapulmonary penetrations of meropenem and RPX7009 were ca. 63 and 53%, respectively, based on the area under the concentration-time curve from 0 to 8 h (AUC0-8) values of ELF and total plasma concentrations. When unbound plasma concentrations were considered, ELF penetrations were 65 and 79% for meropenem and RPX7009, respectively. Meropenem concentrations in AMs were below the quantitative limit of detection, whereas median concentrations of RPX7009 in AMs ranged from 2.35 to 6.94 μg/ml. The results from the present study lend support to exploring a fixed combination of meropenem (2 g) and RPX7009 (2 g) for the treatment of lower respiratory tract infections caused by meropenem-resistant Gram-negative pathogens susceptible to the combination of meropenem-RPX7009.

  • penetration of gsk1322322 into Epithelial Lining Fluid and alveolar macrophages as determined by bronchoalveolar lavage
    Antimicrobial Agents and Chemotherapy, 2014
    Co-Authors: Odin J Naderer, Keith A. Rodvold, Lori S. Jones, John Zhu, Chester L Bowen, Liangfu Chen, Etienne Dumont
    Abstract:

    GSK1322322 is a potent peptide deformylase inhibitor with in vitro and in vivo activity against multidrug-resistant skin and respiratory pathogens. This report provides plasma and intrapulmonary pharmacokinetics, safety, and tolerability of GSK1322322 after repeat (twice daily intravenous dosing for 4 days) dosing at 1,500 mg. Plasma samples were collected over the last 12-hour dosing interval of repeat dosing following the day 4 morning dose (the last dose). Bronchoalveolar lavage samples were collected once in each subject, either before or at 2 or 6 h after the last intravenous dose. Plasma area under the concentration-time curve (AUC0-τ) was 66.7 μg · h/ml, and maximum concentration of drug in serum (Cmax) was 25.4 μg/ml following repeat doses of intravenous GSK1322322. The time course of Epithelial Lining Fluid (ELF) and alveolar macrophages (AM) mirrored the plasma concentration-time profile. The AUC0-τ for ELF and AM were 78.9 μg · h/ml and 169 μg · h/ml, respectively. The AUC0-τ ratios of ELF and AM to total plasma were 1.2 and 2.5, respectively. These ratios increased to 3.5 and 7.4, respectively, when unbound plasma was considered. These results are supportive of GSK1322322 as a potential antimicrobial agent for the treatment of lower respiratory tract bacterial infections caused by susceptible pathogens. (This study has been registered at ClinicalTrials.gov under registration number NCT01610388.).

  • comparison of plasma Epithelial Lining Fluid and alveolar macrophage concentrations of solithromycin cem 101 in healthy adult subjects
    Antimicrobial Agents and Chemotherapy, 2012
    Co-Authors: Keith A. Rodvold, Mark H Gotfried, Gordon J Still, Kay Clark, Prabhavathi Fernandes
    Abstract:

    The 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 (AUC0–24 values) 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 AUC0–24 values were 10.3 and 10.0, respectively. The AUC0–24 values 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 AUC0–24 values 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.

  • penetration of vancomycin into Epithelial Lining Fluid in healthy volunteers
    Antimicrobial Agents and Chemotherapy, 2011
    Co-Authors: Thomas P Lodise, George L Drusano, Jill M Butterfield, Joshua Scoville, Mark H Gotfried, Keith A. Rodvold
    Abstract:

    ABSTRACT Although vancomycin is often regarded as an agent that concentrates poorly in the lower respiratory tract, as determined from concentrations in Epithelial Lining Fluid (ELF), few data are available. This study sought to determine the profile of vancomycin exposure in the ELF relative to plasma. Population modeling and Monte Carlo simulation were employed to estimate the penetration of vancomycin into ELF. Plasma and ELF pharmacokinetic (PK) data were obtained from 10 healthy volunteers. Concentration-time profiles in plasma and ELF were simultaneously modeled using a three-compartment model with zero-order infusion and first-order elimination and transfer using the big nonparametric adaptive grid (BigNPAG) program. Monte Carlo simulation with 9,999 subjects was performed to calculate the ELF/plasma penetration ratios by estimating the area under the concentration-time curve (AUC) in ELF (AUC ELF ) and plasma (AUC plasma ) after a single simulated 1,000-mg dose. The mean (standard deviation) AUC ELF /AUC plasma penetration ratio was 0.675 (0.677), and the 25th, 50th, and 75th percentile penetration ratios were 0.265, 0.474, and 0.842, respectively. Our results indicate that vancomycin penetrates ELF at approximately 50% of plasma levels. To properly judge the adequacy of current doses and schedules employed in practice, future studies are needed to delineate the PK/PD (pharmacodynamics) target for vancomycin in ELF. If the PK/PD target in ELF is found to be consistent with the currently proposed target of an AUC/MIC of ≥400, suboptimal probability of target attainment would be expected when vancomycin is utilized for pneumonias due to MRSA (methicillin-resistant Staphylococcus aureus) with MICs in excess of 1 mg/liter.

Akitoshi Ishizaka - One of the best experts on this subject based on the ideXlab platform.

  • gene expression analysis of endobronchial Epithelial Lining Fluid in the evaluation of indeterminate pulmonary nodules
    The Journal of Thoracic and Cardiovascular Surgery, 2009
    Co-Authors: Nicolas Kahn, Akitoshi Ishizaka, Ruprecht Kuner, Ralf Eberhardt, Michael Meister, Thomas Muley, Susanne Winteroll, Philipp A Schnabel, Felix J F Herth, Annemarie Poustka
    Abstract:

    Objective Making a definitive preoperative diagnosis in patients with indeterminate pulmonary nodules is still a challenge. Gene expression profiling may be a useful adjunctive diagnostic utility in this regard. We investigated the feasibility of bronchoscopic microsampling to collect endobronchial Epithelial Lining Fluid to obtain RNA as a starting point for gene expression profiling. Methods In 15 patients, Epithelial Lining Fluid was collected in triplicate from subsegmental bronchi close to the pulmonary nodules and from contralateral lungs. Diagnosis was confirmed by transbronchial biopsy or surgery (non–small cell lung cancer, n=11; benign or other lesions, n=4). Total RNA was isolated from the samples and evaluated concerning quantity and quality. The complementary DNA was generated and analyzed by quantitative real-time polymerase chain reaction for potential lung cancer associated genes like matrix metalloprotinase (MMP9) . Results Total RNA of adequate amount (>0.8 μg) and sufficient quality was obtained in 13 (86%) of the 15 patients. In patients with lung cancer, normalized MMP9 gene expression levels in endobronchial Lining Fluid samples collected close to the lesions were in median 12 times higher than levels in the matching contralateral samples. MMP9 expression levels were particularly high in endobronchial Lining Fluid samples collected from patients with squamous cell carcinoma but not elevated in the case of benign lesions. Conclusions Our results show that quantitative gene expression analysis of endobronchial Lining Fluid collected by bronchoscopic microsampling is both feasible and reliable and may therefore be a useful additional diagnostic method in patients with indeterminate pulmonary nodules.

  • comparison of the pharmacodynamics of biapenem in bronchial Epithelial Lining Fluid in healthy volunteers given half hour and three hour intravenous infusions
    Antimicrobial Agents and Chemotherapy, 2009
    Co-Authors: Eiki Kikuchi, Akitoshi Ishizaka, Junko Kikuchi, Yasuyuki Nasuhara, Satoshi Oizumi, Masaharu Nishimura
    Abstract:

    The time above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) parameter that correlates with the therapeutic efficacy of beta-lactam antibiotics. A prolonged infusion can provide plasma drug concentrations that remain above the MIC for a long period. The objective of this study was to compare the PK/PD parameters in bronchial Epithelial Lining Fluid (ELF) of biapenem given as 0.5-h and 3-h infusions by using bronchoscopic microsampling (BMS). Six healthy adult volunteers received 0.5-h and 3-h infusions of 0.3 g of biapenem with a washout interval. BMS was performed repeatedly from 0.5 to 24 h after biapenem administration in order to determine the pharmacokinetics in bronchial ELF. The subjects received intravenous biapenem with the same regimens again and then underwent bronchoalveolar lavage (BAL) at the end of infusion in order to determine the concentration of the drug in alveolar ELF. The percentages (means +/- standard deviations) of T>MIC in bronchial ELF at MICs from 0.25 to 4 microg/ml ranged from zero to 34.6% +/- 5.2% after the 0.5-h infusion and from 5.1% +/- 5.6% to 52.2% +/- 17.0% after the 3-h infusion. The percentage of T>MIC in bronchial ELF after the 3-h infusion tended to be higher than that after the 0.5-h infusion. The concentrations of the drug in alveolar ELF after 0.5-h and 3-h infusions were 3.5 +/- 1.2 microg/ml and 1.3 +/- 0.3 microg/ml, respectively. The present results support the use of prolonged infusions of beta-lactam antibiotics and may provide critical information for successful treatment of lower respiratory tract infections based on PK/PD parameters in bronchial ELF.

  • concentrations of clarithromycin and active metabolite in the Epithelial Lining Fluid of patients with mycobacterium avium complex pulmonary disease
    Pulmonary Pharmacology & Therapeutics, 2009
    Co-Authors: Naoki Hasegawa, Koichi Yamazaki, Sadatomo Tasaka, Satoru Hashimoto, Yasushi Nakano, Tomoyasu Nishimura, Masazumi Watabnabe, Masahiro Nishimura, Akitoshi Ishizaka
    Abstract:

    Abstract Objectives Clarithromycin (CAM) is widely accepted for the treatment of Mycobacterium avium complex (MAC) pulmonary diseases. This study measured (a) the concentrations of CAM and its active metabolite (14OH-CAM) in bronchial Epithelial Lining Fluid (ELF) obtained by bronchoscopic microsampling (BMS), and (b) the minimal inhibitory concentrations (MIC) of CAM for each MAC isolate. Methods We studied eight patients with MAC pulmonary disease treated with oral CAM, 400 ( n  = 4) or 800 ( n  = 4) mg/day. BMS was performed 3 h after the last CAM dose, and the concentrations of CAM and 14OH-CAM were measured in ELF collected from the diseased and normal contralateral pulmonary segments, and in serum. Results The mean ± SEM ELF concentrations of CAM (23.85 ± 7.64 μg/ml) and CAM + 14OH-CAM (28.71 ± 8.37 μg/ml) in the 800 mg/day treatment group were significantly higher than in the 400 mg/day group (7.48 ± 2.58 μg/ml and 9.63 ± 2.99 μg/ml, respectively; both p M. avium recommended by the Clinical Laboratories Standards Institute), while the mean concentration in the 800 mg/day treatment group was >8 μg/ml. Conclusion These observations suggest that CAM, 800 mg/day, is an appropriate dose to treat MAC pulmonary disease, and prevent its spread from diseased to non-diseased lung segments.

  • Comparison of the Pharmacodynamics of Biapenem in Bronchial Epithelial Lining Fluid in Healthy Volunteers Given Half-Hour and Three-Hour Intravenous Infusions
    2009
    Co-Authors: Akitoshi Ishizaka, Masaharu Nishimura
    Abstract:

    The time above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic (PK/PD) parameter that correlates with the therapeutic efficacy of beta-lactam antibiotics. A prolonged infusion can provide plasma drug concentrations that remain above the MIC for a long period. The objective of this study was to compare the PK/PD parameters in bronchial Epithelial Lining Fluid (ELF) of biapenem given as 0.5-h and 3-h infusions by using bronchoscopic microsampling (BMS). Six healthy adult volunteers received 0.5-h and 3-h infusions of 0.3 g of biapenem with a washout interval. BMS was performed repeatedly from 0.5 to 24 h after biapenem administration in order to determine the pharmacokinetics in bronchial ELF. The subjects received intrave-nous biapenem with the same regimens again and then underwent bronchoalveolar lavage (BAL) at the end of infusion in order to determine the concentration of the drug in alveolar ELF. The percentages (means standard deviations) of T>MIC in bronchial ELF at MICs from 0.25 to 4 g/ml ranged from zero to 34.6 % 5.2 % after the 0.5-h infusion and from 5.1 % 5.6 % to 52.2 % 17.0 % after the 3-h infusion. The percentag

  • proteomic analysis of undiluted lung Epithelial Lining Fluid
    Chest, 2008
    Co-Authors: Eric Kipnis, Akitoshi Ishizaka, Kirk C Hansen, Teiji Sawa, Kiyoshi Moriyama, Ashley Zurawel, Jeanine P Wienerkronish
    Abstract:

    Background Proteomics is increasingly leading to biomarker discovery in human disease. Epithelial Lining Fluid (ELF), until now only recovered indirectly, diluted in BAL Fluid, is an attractive sample for lung disease proteomics. The direct recovery of undiluted ELF is now possible using a bronchoscopic microsampling (BMS) probe. In this preliminary study of anesthetized ventilated rabbits, we applied this probe to recover ELF and to analyze the resulting samples with the aim of determining their potential in lung disease biomarker discovery. Methods In order to do so, a method was devised and evaluated in preliminary experiments both for nonbronchoscopic use of the probe and for recovering undiluted ELF from probe tips. To verify the proteomic potential of the sample, the recovered ELF was separated by one-dimensional polyacrylamide gel electrophoresis, and the resulting lane was cut into multiple fractions, each of which was digested and analyzed by liquid chromatography tandem mass spectrometry. The identified proteins were then searched against Medline for association with broad categories of lung disease. Results Nonbronchoscopic use of the probe allowed successful ELF sampling and the recovery of undiluted ELF from probe tips. Proteomic analysis showed that ELF contains many proteins that have already been reported as being associated with lung disease as well as proteins potentially correlated with lung disease. Conclusions This preliminary study of undiluted ELF, as recovered by the BMS probe, shows that it may be an ideal sample for lung proteomics. The potential application of this sampling technique in various lung diseases will need to be confirmed by future studies.

Naoki Hasegawa - One of the best experts on this subject based on the ideXlab platform.

  • pharmacokinetics of arbekacin in bronchial Epithelial Lining Fluid of healthy volunteers
    Journal of Infection and Chemotherapy, 2014
    Co-Authors: Yohei Funatsu, Naoki Hasegawa, Hiroshi Fujiwara, Ho Namkoong, Takahiro Asami, Sadatomo Tasaka, Yoshifumi Kimizuka, Hirofumi Kamata, Makoto Ishii, Osamu Iketani
    Abstract:

    Abstract Introduction Arbekacin is a unique aminoglycoside antibiotic with anti-methicillin-resistant Staphylococcus aureus activity. The efficacy of aminoglycosides is related to their serum maximum concentration. Local concentration of antibiotics in pulmonary Epithelial Lining Fluid, rather than its serum concentration, can help determine its clinical efficacy more precisely for treatment of respiratory infectious disease. The objective of this study was to sequentially measure arbekacin concentration in Epithelial Lining Fluid after infusion of a single clinically available dose. Method After the initial blood sampling, arbekacin was intravenously infused into 6 healthy volunteers over 1 h. Epithelial Lining Fluid and serum samples were collected by bronchoscopic microsampling 1, 1.5, 2, 2.5, 3, 4, 5, and 6 h after the start of 200 mg arbekacin infusion. Results Each probe sampled 10.1 ± 5.2 μl bronchial Epithelial Lining Fluid. The sample dilution factor was 266.7 ± 157.1. Drug concentration was successfully measured in all but 2 of the Epithelial Lining Fluid samples. The maximum concentration of arbekacin in Epithelial Lining Fluid and serum was 10.4 ± 1.9 μg/ml and 26.0 ± 12.2 μg/ml, respectively. The ratio of the maximum drug concentration in the Epithelial Lining Fluid to that in the serum was 0.47 ± 0.19. Conclusions The maximum concentration of Epithelial Lining Fluid reached levels that would effectively treat most clinical strains of methicillin-resistant S. aureus .

  • concentrations of clarithromycin and active metabolite in the Epithelial Lining Fluid of patients with mycobacterium avium complex pulmonary disease
    Pulmonary Pharmacology & Therapeutics, 2009
    Co-Authors: Naoki Hasegawa, Koichi Yamazaki, Sadatomo Tasaka, Satoru Hashimoto, Yasushi Nakano, Tomoyasu Nishimura, Masazumi Watabnabe, Masahiro Nishimura, Akitoshi Ishizaka
    Abstract:

    Abstract Objectives Clarithromycin (CAM) is widely accepted for the treatment of Mycobacterium avium complex (MAC) pulmonary diseases. This study measured (a) the concentrations of CAM and its active metabolite (14OH-CAM) in bronchial Epithelial Lining Fluid (ELF) obtained by bronchoscopic microsampling (BMS), and (b) the minimal inhibitory concentrations (MIC) of CAM for each MAC isolate. Methods We studied eight patients with MAC pulmonary disease treated with oral CAM, 400 ( n  = 4) or 800 ( n  = 4) mg/day. BMS was performed 3 h after the last CAM dose, and the concentrations of CAM and 14OH-CAM were measured in ELF collected from the diseased and normal contralateral pulmonary segments, and in serum. Results The mean ± SEM ELF concentrations of CAM (23.85 ± 7.64 μg/ml) and CAM + 14OH-CAM (28.71 ± 8.37 μg/ml) in the 800 mg/day treatment group were significantly higher than in the 400 mg/day group (7.48 ± 2.58 μg/ml and 9.63 ± 2.99 μg/ml, respectively; both p M. avium recommended by the Clinical Laboratories Standards Institute), while the mean concentration in the 800 mg/day treatment group was >8 μg/ml. Conclusion These observations suggest that CAM, 800 mg/day, is an appropriate dose to treat MAC pulmonary disease, and prevent its spread from diseased to non-diseased lung segments.

  • pharmacokinetics of clarithromycin in bronchial Epithelial Lining Fluid
    Respirology, 2008
    Co-Authors: Eiki Kikuchi, Akitoshi Ishizaka, Junko Kikuchi, Koichi Yamazaki, Naoki Hasegawa, Satoru Hashimoto, Masaharu Nishimura
    Abstract:

    Background and objective:  BAL is an established technique for measuring antibiotic concentrations in the Epithelial Lining Fluid (ELF) of the bronchiolar-alveolar regions. However, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique for repeated sampling of bronchial ELF. The objective of the present study was to determine the time versus concentration profile of clarithromycin and its active metabolite, 14-hydroxy-clarithromycin, in bronchial ELF, as determined by BMS. Methods:  BMS was performed at 1, 2, 3, 5 and 10 h after a single oral administration of 200 mg clarithromycin in five healthy volunteers. BAL was performed 3 h after administration to determine clarithromycin concentrations in alveolar ELF and alveolar macrophages (AM). Results:  The maximum concentration (Cmax) of clarithromycin was 0.36 ± 0.07 mg/L in serum and 1.44 ± 0.49 mg/L in bronchial ELF (P < 0.01). Cmax for 14-hydroxy-clarithromycin was 0.34 ± 0.13 mg/L in serum and 0.68 ± 0.34 mg/L in bronchial ELF. The area under the concentration–time curve from 0 to 10 h (AUC0-10) for clarithromycin was 2.10 ± 0.49 mg·h/L for serum and 7.37 ± 2.07 mg·h/L for bronchial ELF (P < 0.01). The concentrations of clarithromycin in alveolar ELF and AM, 3 h after oral administration, were 4.84 ± 3.39 mg/L and 10.7 ± 8.7 mg/L, respectively. Conclusions:  A single oral dose of clarithromycin produces a significantly higher Cmax and AUC0-10 for clarithromycin in bronchial ELF than in serum, and higher concentrations in alveolar ELF and AM than in serum. BMS might be useful for measuring the pharmacokinetic profile of clarithromycin in bronchial ELF.

  • vascular endothelial growth factor in Epithelial Lining Fluid of patients with acute respiratory distress syndrome
    Respirology, 2008
    Co-Authors: Hidefumi Koh, Naoki Hasegawa, Sadatomo Tasaka, Tomoyuki Matsuda, Toru Kotani, Hiroshi Morisaki, Junzo Takeda, Koichiro Asano, Seitaro Fujishima, Satoru Hashimoto
    Abstract:

    Background and objective:  Vascular endothelial growth factor (VEGF) is known to contribute to the development of pulmonary oedema, and has been suggested to have a protective role against lung injury. To determine the role of VEGF in acute lung injury (ALI) and ARDS, VEGF levels were measured in lung Epithelial Lining Fluid (ELF) collected from patients with ALI/ARDS. Methods:  Forty patients with ALI/ARDS underwent bronchoscopic microsampling to collect ELF on days 0 (onset of ALI/ARDS), 1, 3, 5, 7 and 10, unless the patient was extubated or had died. Twelve patients, who underwent bronchoscopy for examination of small, peripheral pulmonary nodules, served as controls. Results:  The initial (day 0) levels of VEGF in ELF of the ALI/ARDS patients who survived and those who did not were 5.5 ng/mL (IQR: 2.3–19.7) and 1.7 ng/mL (IQR: 0.0–6.4), respectively. On days 0, 5, 7 and 10, the VEGF levels in ELF were significantly greater in survivors than in non-survivors (P < 0.05). VEGF levels on days 1 and 3 did not differ between survivors and non-survivors. There was no significant difference in ELF VEGF levels between control subjects and patients with ALI/ARDS at any time point. Lung injury score was inversely correlated with VEGF concentration in ELF (P < 0.001). Conclusions:  In patients with ALI/ARDS, elevated VEGF levels in ELF may predict a better outcome. Increased production of VEGF in the injured lung may contribute to resolution of inflammation in the lung.

  • endothelin 1 level in Epithelial Lining Fluid of patients with acute respiratory distress syndrome
    Respirology, 2007
    Co-Authors: Yasushi Nakano, Naoki Hasegawa, Sadatomo Tasaka, Hidefumi Koh, Fumitake Saito, Wakako Yamada, Yoshiki Shiraishi, Yuko Ogawa, Seitaro Fujishima, Satoru Hashimoto
    Abstract:

    Background and objectives:  Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells, has been implicated in the dysfunction of various organs. To determine the role of ET-1 in acute lung injury (ALI) and ARDS, ET-1 levels were measured in Epithelial Lining Fluid (ELF) and plasma obtained from patients with ALI/ARDS. Methods:  A cross-sectional study of patients with ALI/ARDS in the intensive care unit of two university hospitals was performed. Patients with ALI/ARDS underwent bronchoscopic microsampling to collect ELF on the day of onset of the disease. Patients who underwent bronchoscopy to examine a small peripheral pulmonary nodule served as controls. Results:  In the 23 patients with ALI/ARDS, the ET-1 level in ELF was significantly greater than that in plasma (P < 0.001). In contrast, ET-1 was not detectable in the ELF from six of the seven control subjects. The albumin concentration of ELF, used as a marker of endothelial and Epithelial permeability, correlated with the ET-1 level in ELF (P < 0.001). The oxygenation index (PaO2/FiO2) was also correlated with ET-1 concentration in ELF (P < 0.001). Conclusion:  In patients with ALI/ARDS, ET-1 is produced mainly in the lung and is associated not only with pulmonary vasoconstriction but also the development of permeability oedema, leading to the impairment of oxygenation.

J. M. Andrews - One of the best experts on this subject based on the ideXlab platform.

  • concentrations of garenoxacin in plasma bronchial mucosa alveolar macrophages and Epithelial Lining Fluid following a single oral 600 mg dose in healthy adult subjects
    Journal of Antimicrobial Chemotherapy, 2003
    Co-Authors: J. M. Andrews, G Jevons, M Boyce, D Honeybourne, A Bello, R. Wise, D Gajjar
    Abstract:

    A microbiological assay was used to measure concentrations of garenoxacin (BMS-284756) in plasma, bronchial mucosa (BM), alveolar macrophages (AM) and Epithelial Lining Fluid (ELF), following a single 600 mg oral dose. Twenty-four healthy subjects were allocated into four nominal time intervals after the dose, 2.5-3.5, 4.5-5.5, 10.5-11.5 and 23.5-24.5 h. Mean concentrations in plasma, BM, AM and ELF, respectively, for the four nominal time windows were for 2.5-3.5 h 10.0 mg/L (S.D. 2.8), 7.0 mg/kg (S.D. 1.3), 106.1 mg/L (S.D. 60.3) and 9.2 mg/L (S.D. 3.6); 4.5-5.5 h 8.7 mg/L (S.D. 2.2), 6.0 mg/kg (S.D. 1.9), 158.6 mg/L (S.D. 137.4) and 14.3 mg/L (S.D. 8.2); 10.5-11.5 h 6.1 mg/L (S.D. 1.9), 4.0 mg/kg (S.D. 1.4), 76.0 mg/L (S.D. 47.7) and 7.9 mg/L (S.D. 4.6); and 23.5-24.5 h 2.1 mg/L (S.D. 0.5), 1.7 mg/kg (S.D. 0.7), 30.7 mg/L (S.D. 12.9) and 3.3 mg/L (S.D. 2.3). Concentrations at all sites exceeded MIC 90 s for the common respiratory pathogens Haemophilus influenzae (0.03 mg/L), Moraxella catarrhalis (0.015 mg/L) and Streptococcus pneumoniae (0.06 mg/L). These data suggest that garenoxacin should be effective in the treatment of community-acquired pneumonia and chronic obstructive pulmonary disease.

  • rifampicin concentrations in bronchial mucosa Epithelial Lining Fluid alveolar macrophages and serum following a single 600 mg oral dose in patients undergoing fibre optic bronchoscopy
    Journal of Antimicrobial Chemotherapy, 2002
    Co-Authors: Hisham M Ziglam, J. M. Andrews, David R Baldwin, Ian Daniels, R G Finch
    Abstract:

    The concentrations of rifampicin in Epithelial Lining Fluid (ELF), human alveolar macrophages (AM), bronchial mucosal biopsies and serum were measured after a single oral dose of 600 mg rifampicin from 15 patients undergoing fibre-optic bronchoscopy. The samples of ELF, AM, the bronchial mucosal biopsies and serum were obtained approximately 2-5 h after dosing. The mean concentrations (mean +/- standard error) were 5.25 mg/L (+/-0.67) in ELF, 7.93 mg/kg (+/-1.61) in bronchial biopsies, 15.48 mg/L (+/-1.41) in serum and 251.8 mg/L (+/-65.92) in alveolar macrophages. These site concentrations exceeded the MIC90 for common respiratory pathogens including Mycobacterium tuberculosis and support the observed clinical efficacy of rifampicin in the treatment of a wide range of respiratory tract infections.

  • concentrations of trovafloxacin in bronchial mucosa Epithelial Lining Fluid alveolar macrophages and serum after administration of single or multiple oral doses to patients undergoing fibre optic bronchoscopy
    Journal of Antimicrobial Chemotherapy, 1997
    Co-Authors: J. M. Andrews, D Honeybourne, N Brenwald, D Bannerjee, M Iredale, B Cunningham, R. Wise
    Abstract:

    Concentrations of trovafloxacin were measured in serum, alveolar macrophages, Epithelial Lining Fluid and bronchial mucosa following single and multiple oral doses. Concentrations were determined using a microbiological assay method. There were 18 subjects in the single dose and nine subjects in the multiple dose groups. After single dosing, mean concentrations in serum, alveolar macrophages, Epithelial Lining Fluid and bronchial mucosa at 6, 12 and 24 h were as follows: 6 h, 1.41 mg/L, 19.06 mg/L, 3.01 mg/L and 1.52 mg/kg; 12 h, 0.85 mg/L, 16.22 mg/L, 4.8 mg/L and 1.01 mg/kg; 24 h, 0.37 mg/L, 10.23 mg/L, 0.93 mg/L, and no measurable concentration, respectively. After multiple dosing (approximately 6 h post-dose) the corresponding concentrations were 1.47 mg/L, 34.3 mg/L, 10.21 mg/L and 1.67 mg/kg, respectively. These concentrations exceed the MIC 90 s for the common respiratory pathogens, Haemophilus influenzae 0.06 mg/L, Moraxella catarrhalis 0.008 mg/L and Streptococcus pneumoniae 0.12 mg/L and suggest that trovafloxacin should be efficacious in the treatment of community- and hospital-acquired respiratory infections.

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  • concentrations of clarithromycin and active metabolite in the Epithelial Lining Fluid of patients with mycobacterium avium complex pulmonary disease
    Pulmonary Pharmacology & Therapeutics, 2009
    Co-Authors: Naoki Hasegawa, Koichi Yamazaki, Sadatomo Tasaka, Satoru Hashimoto, Yasushi Nakano, Tomoyasu Nishimura, Masazumi Watabnabe, Masahiro Nishimura, Akitoshi Ishizaka
    Abstract:

    Abstract Objectives Clarithromycin (CAM) is widely accepted for the treatment of Mycobacterium avium complex (MAC) pulmonary diseases. This study measured (a) the concentrations of CAM and its active metabolite (14OH-CAM) in bronchial Epithelial Lining Fluid (ELF) obtained by bronchoscopic microsampling (BMS), and (b) the minimal inhibitory concentrations (MIC) of CAM for each MAC isolate. Methods We studied eight patients with MAC pulmonary disease treated with oral CAM, 400 ( n  = 4) or 800 ( n  = 4) mg/day. BMS was performed 3 h after the last CAM dose, and the concentrations of CAM and 14OH-CAM were measured in ELF collected from the diseased and normal contralateral pulmonary segments, and in serum. Results The mean ± SEM ELF concentrations of CAM (23.85 ± 7.64 μg/ml) and CAM + 14OH-CAM (28.71 ± 8.37 μg/ml) in the 800 mg/day treatment group were significantly higher than in the 400 mg/day group (7.48 ± 2.58 μg/ml and 9.63 ± 2.99 μg/ml, respectively; both p M. avium recommended by the Clinical Laboratories Standards Institute), while the mean concentration in the 800 mg/day treatment group was >8 μg/ml. Conclusion These observations suggest that CAM, 800 mg/day, is an appropriate dose to treat MAC pulmonary disease, and prevent its spread from diseased to non-diseased lung segments.

  • pharmacokinetics of clarithromycin in bronchial Epithelial Lining Fluid
    Respirology, 2008
    Co-Authors: Eiki Kikuchi, Akitoshi Ishizaka, Junko Kikuchi, Koichi Yamazaki, Naoki Hasegawa, Satoru Hashimoto, Masaharu Nishimura
    Abstract:

    Background and objective:  BAL is an established technique for measuring antibiotic concentrations in the Epithelial Lining Fluid (ELF) of the bronchiolar-alveolar regions. However, the results may not reflect concentrations in bronchial regions. Bronchoscopic microsampling (BMS) is a technique for repeated sampling of bronchial ELF. The objective of the present study was to determine the time versus concentration profile of clarithromycin and its active metabolite, 14-hydroxy-clarithromycin, in bronchial ELF, as determined by BMS. Methods:  BMS was performed at 1, 2, 3, 5 and 10 h after a single oral administration of 200 mg clarithromycin in five healthy volunteers. BAL was performed 3 h after administration to determine clarithromycin concentrations in alveolar ELF and alveolar macrophages (AM). Results:  The maximum concentration (Cmax) of clarithromycin was 0.36 ± 0.07 mg/L in serum and 1.44 ± 0.49 mg/L in bronchial ELF (P < 0.01). Cmax for 14-hydroxy-clarithromycin was 0.34 ± 0.13 mg/L in serum and 0.68 ± 0.34 mg/L in bronchial ELF. The area under the concentration–time curve from 0 to 10 h (AUC0-10) for clarithromycin was 2.10 ± 0.49 mg·h/L for serum and 7.37 ± 2.07 mg·h/L for bronchial ELF (P < 0.01). The concentrations of clarithromycin in alveolar ELF and AM, 3 h after oral administration, were 4.84 ± 3.39 mg/L and 10.7 ± 8.7 mg/L, respectively. Conclusions:  A single oral dose of clarithromycin produces a significantly higher Cmax and AUC0-10 for clarithromycin in bronchial ELF than in serum, and higher concentrations in alveolar ELF and AM than in serum. BMS might be useful for measuring the pharmacokinetic profile of clarithromycin in bronchial ELF.

  • vascular endothelial growth factor in Epithelial Lining Fluid of patients with acute respiratory distress syndrome
    Respirology, 2008
    Co-Authors: Hidefumi Koh, Naoki Hasegawa, Sadatomo Tasaka, Tomoyuki Matsuda, Toru Kotani, Hiroshi Morisaki, Junzo Takeda, Koichiro Asano, Seitaro Fujishima, Satoru Hashimoto
    Abstract:

    Background and objective:  Vascular endothelial growth factor (VEGF) is known to contribute to the development of pulmonary oedema, and has been suggested to have a protective role against lung injury. To determine the role of VEGF in acute lung injury (ALI) and ARDS, VEGF levels were measured in lung Epithelial Lining Fluid (ELF) collected from patients with ALI/ARDS. Methods:  Forty patients with ALI/ARDS underwent bronchoscopic microsampling to collect ELF on days 0 (onset of ALI/ARDS), 1, 3, 5, 7 and 10, unless the patient was extubated or had died. Twelve patients, who underwent bronchoscopy for examination of small, peripheral pulmonary nodules, served as controls. Results:  The initial (day 0) levels of VEGF in ELF of the ALI/ARDS patients who survived and those who did not were 5.5 ng/mL (IQR: 2.3–19.7) and 1.7 ng/mL (IQR: 0.0–6.4), respectively. On days 0, 5, 7 and 10, the VEGF levels in ELF were significantly greater in survivors than in non-survivors (P < 0.05). VEGF levels on days 1 and 3 did not differ between survivors and non-survivors. There was no significant difference in ELF VEGF levels between control subjects and patients with ALI/ARDS at any time point. Lung injury score was inversely correlated with VEGF concentration in ELF (P < 0.001). Conclusions:  In patients with ALI/ARDS, elevated VEGF levels in ELF may predict a better outcome. Increased production of VEGF in the injured lung may contribute to resolution of inflammation in the lung.

  • endothelin 1 level in Epithelial Lining Fluid of patients with acute respiratory distress syndrome
    Respirology, 2007
    Co-Authors: Yasushi Nakano, Naoki Hasegawa, Sadatomo Tasaka, Hidefumi Koh, Fumitake Saito, Wakako Yamada, Yoshiki Shiraishi, Yuko Ogawa, Seitaro Fujishima, Satoru Hashimoto
    Abstract:

    Background and objectives:  Endothelin-1 (ET-1), a potent vasoconstrictor peptide produced by endothelial cells, has been implicated in the dysfunction of various organs. To determine the role of ET-1 in acute lung injury (ALI) and ARDS, ET-1 levels were measured in Epithelial Lining Fluid (ELF) and plasma obtained from patients with ALI/ARDS. Methods:  A cross-sectional study of patients with ALI/ARDS in the intensive care unit of two university hospitals was performed. Patients with ALI/ARDS underwent bronchoscopic microsampling to collect ELF on the day of onset of the disease. Patients who underwent bronchoscopy to examine a small peripheral pulmonary nodule served as controls. Results:  In the 23 patients with ALI/ARDS, the ET-1 level in ELF was significantly greater than that in plasma (P < 0.001). In contrast, ET-1 was not detectable in the ELF from six of the seven control subjects. The albumin concentration of ELF, used as a marker of endothelial and Epithelial permeability, correlated with the ET-1 level in ELF (P < 0.001). The oxygenation index (PaO2/FiO2) was also correlated with ET-1 concentration in ELF (P < 0.001). Conclusion:  In patients with ALI/ARDS, ET-1 is produced mainly in the lung and is associated not only with pulmonary vasoconstriction but also the development of permeability oedema, leading to the impairment of oxygenation.