title: An inhaled phosphodiesterase 4 inhibitor E6005 suppresses pulmonary inflammation in mice.
abstract: Chronic obstructive pulmonary disease (COPD) is a progressive lung disease associated with significant morbidity and mortality. Although several oral phosphodiesterase 4 (PDE4) inhibitors have been developed for the treatment of COPD, their use has been restricted because of side effects including nausea and emesis. We hypothesized that delivery of a dry powdered PDE4 inhibitor by inhalation would minimize systemic absorption and enable local PDE4 inhibition to suppress inflammation within the lung. Neutrophilic pulmonary inflammation was induced in mice by intratracheal administration of lipopolysaccharide. Mice were treated intratracheally with a new dry powder PDE4 inhibitor, E6005 (methyl 4-[({3-[6,7-dimethoxy-2-(methylamino)quinazolin-4-yl]phenyl}amino) carbonyl] benzoate). The pharmacokinetics, cell profiles and levels of cytokines, chemokines, and lipid mediators in bronchoalveolar lavage fluid (BALF), and lung histology were assessed. Intratracheal administration of E6005 to mice resulted in high concentrations of the compound in the lungs. Histological analysis of E6005-treated mice demonstrated reduced inflammation of lung tissue that correlated with a decrease in BALF levels of neutrophils, proinflammatory cytokines, chemokines, and cysteinyl leukotrienes. Thus, intratracheal administration of E6005 effectively suppresses neutrophilic pulmonary inflammation, suggesting that the new inhaled dry powder PDE4 inhibitor represents an alternative to the conventional oral formulation for treating COPD.
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Eisai Co. Ltd., Tsukuba Research Laboratories, 34 Miyukigaoka, Tsukuba, Ibaraki 305-8501, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Shirato
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Okuno
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Ikkou
authors.initials: I
authors.lastname: Higashimoto
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Machida
authors.affiliation: Department of Biochemistry, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan. Electronic address: inoue-pulm@umin.net.
authors.forename: Hiromasa
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D018925:Chemokines / Q000378:metabolism; D005260:Female; D050356:Lipid Metabolism / Q000187:drug effects; D008070:Lipopolysaccharides / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D058988:Phosphodiesterase 4 Inhibitors / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D010795:Phthalic Acids / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011014:Pneumonia / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011799:Quinazolines / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D018925:Chemokines; D008070:Lipopolysaccharides; D058988:Phosphodiesterase 4 Inhibitors; D010795:Phthalic Acids; D011799:Quinazolines; C583128:methyl 4-(((3-(6,7-dimethoxy-2-(methylamino)quinazolin-4-yl)phenyl)amino)carbonyl)benzoate
keywords: E6005; Inhalation; Phosphodiesterase 4 inhibitor; Pulmonary inflammation