title: Preferential inhibition of human phosphodiesterase 4 by ibudilast.
abstract: Ibudilast ophthalmic solution exhibited an improved clinical efficacy over cromoglycate in the treatment of allergic conjunctivitis. To further characterize its principal mode of action, the phosphodiesterase (PDE) inhibitory profile of ibudilast has been examined using human recombinant enzymes. Ibudilast, but not the other commonly used anti-allergic ophthalmic solutions including cromoglycate, ketotifen, tranilast and levocabastine, potently inhibits purified human PDE4A, 4B, 4C and 4D with IC50 values at 54, 65, 239 and 166 nM, respectively. Ibudilast effectively blocks lipopolysaccharide (LPS)-induced tumor necrosis factor (TNFalpha, IC50 = 6.2 microM) and N-formyl-Met-Leu-Phe (fMLP)-induced leukotriene (LT) B4 biosynthesis (IC50 = 2.5 microM) in human whole blood, which are 3 and 6-fold more potent than cilomilast, respectively. The attenuated inflammatory and allergic responses from the potent and preferential PDE4 inhibition of ibudilast may have contributed significantly to its beneficial pharmacological responses and distinguishes ibudilast from the other ophthalmic solutions in the treatment of ocular allergy.
authors.affiliation: Merck Frosst Centre for Therapeutic Research, Kirkland, Quebec, Canada. zheng_huang@merck.com
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Susana
authors.initials: S
authors.lastname: Liu
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Myriam
authors.initials: M
authors.lastname: Salem
authors.forename: Gillian M
authors.initials: GM
authors.lastname: Greig
authors.forename: Chi Chung
authors.initials: CC
authors.lastname: Chan
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Natsumeda
authors.forename: Kazuhito
authors.initials: K
authors.lastname: Noguchi
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D002460:Cell Line; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007975:Leukotriene B4 / Q000096:biosynthesis / Q000097:blood; D008070:Lipopolysaccharides / Q000494:pharmacology; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D009883:Ophthalmic Solutions / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000096:biosynthesis; D007212:Indolizines; D011720:Pyrazoles
chemical_list: D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D007975:Leukotriene B4; D008070:Lipopolysaccharides; D009240:N-Formylmethionine Leucyl-Phenylalanine; D009883:Ophthalmic Solutions; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; C517355:PDE4A protein, human; C038366:ibudilast; D007212:Indolizines; D011720:Pyrazoles