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The inhibitory effect of TMK688, a novel anti‐allergic drug having both 5‐lipoxygenase inhibitory activity and anti‐histamine activity, against bronchoconstriction, leukotriene production and inflammatory cell infiltration in sensitized guinea pigs
Author(s) -
TOHDA Y.,
NAKAJIMA S.,
SHIZAWA T.,
MAEDA KAZUHA,
OHMORI S.,
SATOH H.,
ISHII T.,
KAMITANI T.
Publication year - 1997
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/j.1365-2222.1997.tb00680.x
Subject(s) - bronchoconstriction , azelastine , antihistamine , leukotriene , histamine , leukotriene d4 , pharmacology , ketotifen , leukotriene c4 , inhibitory postsynaptic potential , arachidonate 5 lipoxygenase , immunology , guinea pig , chemistry , medicine , asthma , arachidonic acid , biochemistry , enzyme
Summary Background TMK688 is being developed as ati anti‐allergic drug having both 5‐lipoxygenasc inhibitory activity atid anti‐histaminc activity. Method We compared the inhibition ol the late asthmatic rcsponses by TMK688 with that by other anti‐allergic agents in actively sensitized guinea pigs, and examined the relationship between 5‐lipoxygetiase inhibition and the late asthmatic responses Results At 1–3.2 mg/kg, TMK688 inhibited the increases in respiratory resistance, leukotriene (LT) B 4 and C 4 production in the lungs and eosinophil infiltralion into the alveoli during the late asthmatic response, whereas the eliects tended to lessen at the dose of 10mg/kg. These effects are thought to be caused by the 5‐lipoxygenase inhibitory activity of TMK688 because Azelastine. an anti‐allergic drug having potent antihistamine activity, exhibited no effect. ONO‐1078. a peptide LT antagonist. inhibited the late‐phase bronchoconstriction at a dose of 100mg/kg p.o., but not the increase in the infiltration of inflammatory cells into the alveoli, suggesting that the late‐phase bronchoconstriction is induced, in part, by peptide LTs, i.e. LT C 4 , D 4 and E 4 atid that the inflammatory cell infiltration may be caused by LTB 4 , TMK688 inhibited the immediate bronchoconstriction dose‐dependently, and the effect was significant at a dose of 10mg/kg orally. Since Azelastine, Ketotifen and Oxatomide suppressed the bronchoconstriction at far lower doses than did TMK688, the inhibitory effect was mainly caused by its antihistamine activity. Conclusions TMK688 appears to be a novel anti‐allergic drug having inhibitory effects on both the bronchoconstriction and the infiltration of inflatnmutory cells during late asthmatic responses.