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.
BACKGROUND
TMK688 is being developed as an anti-allergic drug having both 5-lipoxygenase inhibitory activity and anti-histamine activity.


METHODS
We compared the inhibition of the late asthmatic responses by TMK688 with that by other anti-allergic agents in actively sensitized guinea pigs, and examined the relationship between 5-lipoxygenase inhibition and the late asthmatic responses.


RESULTS
At 1-3.2 mg/kg, TMK688 inhibited the increases in respiratory resistance, leukotriene (LT) B4 and C4 production in the lungs and eosinophil infiltration into the alveoli during the late asthmatic response, whereas the effects tended to lessen at the dose of 10 mg/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 100 mg/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 C4, D4 and E4 and that the inflammatory cell infiltration may be caused by LTB4. TMK688 inhibited the immediate bronchoconstriction dose-dependently, and the effect was significant at a dose of 10 mg/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 inflammatory cells during late asthmatic responses.
Tohda
Y
Y
Fourth Department of Internal Medicine, School of Medicine, Kinki University, Oosaka, Japan.
Nakajima
S
S
Shizawa
T
T
Maeda
K
K
Ohmori
S
S
Satoh
H
H
Ishii
T
T
Kamitani
T
T
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D001249:Asthma / Q000139:chemically induced / Q000378:metabolism; D016084:Bronchoconstriction / Q000187:drug effects* / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004804:Eosinophils / Q000502:physiology*; D006098:Granulocytes; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D010047:Ovalbumin; D010880:Piperidines / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors
D018926:Anti-Allergic Agents; D006633:Histamine Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010880:Piperidines; D015842:Serine Proteinase Inhibitors; C087493:TMK 688; D010047:Ovalbumin