Inhibition of endotoxin- and antigen-induced airway inflammation by fudosteine, a mucoactive agent

Komatsu, Hidetada; Yamaguchi, S; Komorita, Naruyasu; Goto, Kumiko; Takagi, Shun; Ochi, Hirono; Okumoto, Takeki

doi:10.1016/j.pupt.2004.11.002

Cited by 22 publications

(17 citation statements)

References 22 publications

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“…In the present study, fudosteine had no inhibitory effect on CINC-1, in contrast to results reported previously [2]. CINC-1 is known to increase within a relatively short time period (4-24 h) following LPS stimulation, so the assay time-points of 48 and 96 h used in the present study may have been too late to detect an inhibitory effect.…”

Section: Discussioncontrasting

confidence: 99%

“…LPS and TNF-a are well-known stimulants of goblet cell hyperplasia and mucus hypersecretion [2,13]. The present experiments with rats and NCI-H292 cells revealed that, after stimulation with LPS or TNF-a, goblet cell hyperplasia and increased expression of the MUC5AC gene occur, followed by mucus hypersecretion.…”

Section: Discussionsupporting

confidence: 47%

“…In addition, inhibition of CINC-1 production may not be an essential target of fudosteine. The possibility that CINC-1 inhibition is due to other pharmacological effects cannot be ruled out, since fudosteine does not inhibit LPS-induced CINC-1 production by rat alveolar macrophages in vitro [2]. Therefore, although there was no inhibition of CINC-1 at 48 and 96 h after LPS stimulation, fudosteine significantly inhibited LPS-induced neutrophil migration and showed efficacy in reducing mucin hypersecretion in rats.…”

Section: Discussionmentioning

confidence: 95%

“…TAKAHASHI et al [18] showed that isoproterenol increases the number of goblet cells in the tracheal epithelium, and that fudosteine inhibits this increase. KOMATSU et al [2] showed that fudosteine inhibits endotoxininduced goblet cell hyperplasia by inhibiting CINC-1 production and/or neutrophil migration, and that it also inhibits ovalbumin-induced eosinophil infiltration. However, to date, no studies have been published regarding the signal pathways involved in the inhibitory effects of fudosteine.…”

Section: Discussionmentioning

confidence: 99%

“…In 2001, fudosteine ((-)-(R)-2-amino-3-(3-hydroxypropylthio)propionic acid) was approved in Japan for use as a new mucoactive agent with indications for chronic respiratory diseases, such as bronchial asthma, chronic bronchitis, pulmonary emphysema, bronchiectasis, pulmonary tuberculosis, pneumoconiosis, atypical mycobacterial disease and diffuse panbronchiolitis [2]. In a clinical trial, fudosteine showed efficacy in improving the sense of discomfort in the chests of patients with a variety of chronic respiratory diseases [3].…”

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confidence: 99%

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Effect of fudosteine on mucin production

Rhee

Kang²,

You³

et al. 2008

European Respiratory Journal

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Fudosteine is a novel mucoactive agent, although little is known about how fudosteine decreases mucin production. The present study examined the effects of fudosteine on MUC5AC mucin synthesis and cellular signalling.An animal model of lipopolysaccharide (LPS)-induced inflammation and a bronchial epithelial cell line model of tumour necrosis factor (TNF)-a-induced inflammation were used. Fudosteine was administered before stimulation with LPS or TNF-a. The MUC5AC mucin levels were assayed and the expression of the MUC5AC gene was measured. Western blotting was carried out for the detection of phosphorylated epidermal growth factor receptor (p-EGFR), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK) and phosphorylated extracellular signal-related kinase (p-ERK).MUC5AC mucin synthesis and the expression of the MUC5AC gene were increased by LPS in rats or TNF-a in NCI-H292 cells; these effects were inhibited by fudosteine treatment. After stimulation with LPS or TNF-a, the expression of p-EGFR, p-p38 MAPK and p-ERK were detected. Fudosteine treatment reduced the expression levels of p-p38 MAPK and p-ERK in vivo and of p-ERK in vitro.The present results suggest fudosteine inhibits MUC5AC mucin hypersecretion by reducing MUC5AC gene expression and the effects of fudosteine are associated with the inhibition of extracellular signal-related kinase and p38 mitogen-activated protein kinase in vivo and extracellular signal-related kinase in vitro.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Effect of fudosteine on mucin production

Rhee

Kang²,

You³

et al. 2008

European Respiratory Journal

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Quantification of fudosteine in human plasma by high‐performance liquid chromatography‐electrospray ionization mass spectrometry employing precolumn derivatization with 9‐fluorenylmethyl chloroformate

Zhang

Jiao

et al. 2006

J. Mass Spectrom.

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This paper describes a novel method for the sensitive and selective determination of fudosteine in human plasma. The method involves a derivatization step with 9-fluorenylmethyl chloroformate (FMOC-Cl) in borate buffer and detection based on high-performance liquid chromatography-electrospray ionization mass spectrometry (LC/ESI/MS). After acetonitrile-induced protein precipitation of plasma samples, fudosteine was derivatized with FMOC-Cl, then extracted by ethyl acetate, evaporated, reconstituted and injected using an LC/ESI/MS instrument. Separation was achieved using an ODS column and isocratic elution. Excellent linearity was obtained for the entire calibration range from 0.05 to 20 microg/ml. Validation assays of the lower limit of quantification (LLOQ) as well as for the intra- and inter-batch precision and accuracy met the international acceptance criteria for bioanalytical method validation. Using the developed analytical method, fudosteine could be detected for the first time in human plasma with a low limit of detection (LLOD) of 0.03 microg/ml. The proposed method has been successfully applied to study the pharmacokinetics of fudosteine in healthy Chinese volunteers after single and multiple oral administration.

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The pharmacokinetics of orally administered fudosteine in healthy Chinese volunteers

Jiao

Zhang

et al. 2006

European Journal of Drug Metabolism and Pharmacokinetics

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The pharmacokinetics of fudosteine in healthy Chinese volunteers was investigated for the first time after single- and multiple-dose administration. Five male and five female volunteers were enrolled in this study. Each subject received 400 mg fudosteine capsules (the therapeutic dose) on day 1 after overnight fasting for the single-dose study and three times daily oral administration (400 mg) for 5 consecutive days until the sixth morning for the multiple-dose study. Serial blood samples were collected at specified time intervals up to 16 hours following the first and last doses of fudosteine. Plasma harvested from the blood was separated and analyzed for fudosteine levels by a validated high-performance liquid chromatography-electrospray ionization mass spectrometry (HPLC/ESI/MS) method employing percolumn derivatization with 9-fluorenylmethyl chloroformate (FMOC-Cl). Noncompartmental analysis was used for the calculation of the total area under the plasma concentration-time curve (AUC) from time zero to time infinity and the terminal half-life (t1/2) of fudosteine. The pharmacokinetic parameters for single- and multiple-dose administration were estimated as follows: Cmax amounted to 10.13+/-4.39 microg/mL and 11.75+/-6.51 microg/mL, tmax to 0.69+/-0.36 h and 0.53+/-0.12 h and t1/2 to 2.33+/-0.63 h and 2.40+/-0.37 h, respectively. No significant differences were found between single- and multiple-dose oral administration, although gender differences were observed.

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Inhibition of endotoxin- and antigen-induced airway inflammation by fudosteine, a mucoactive agent

Cited by 22 publications

References 22 publications

Effect of fudosteine on mucin production

Effect of fudosteine on mucin production

Quantification of fudosteine in human plasma by high‐performance liquid chromatography‐electrospray ionization mass spectrometry employing precolumn derivatization with 9‐fluorenylmethyl chloroformate

The pharmacokinetics of orally administered fudosteine in healthy Chinese volunteers

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