EFFECTS OF TMK688, A NOVEL ANTIALLERGIC DRUG, ON ALLERGIC NASAL OBSTRUCTION AND EXUDATIVE RESPONSES IN SENSITIZED GUINEA-PIGS

TMK688 -[{5'-(3''-methoxy-4''-ethoxycarbonyloxyphenyl)-2' ,4'-pentadie noyl} aminoethyl]-4-diphenylmethoxypiperidine) is being developed as a n orally effective antiallergic drug having both 5-lipoxygenase inhibi tory activity and anti-histamine activity (Shizawa et al. 1996; Tohda et al. 1997). The efficacy of TMK688 against allergic rhinitis was exa mined in passively sensitized guinea pigs. TMK688 inhibited the increa se in intranasal resistance following antigen challenge at doses of 1 and 3.2 mg/kg p.o. The allergic nasal obstruction was also suppressed by 10 mg/kg i.v. of FPL-55712, a peptide leukotriene receptor antagoni st, but not by 3.2 mg/kg i.v. pyrilarnine, a histamine H-1 receptor an tagonist, or by 10 mg/kg p.o. of ketotifen, an anti-allergic drug havi ng anti-histamine ac tivity, suggesting that the nasal obstruction was caused by leukotrienes. Following antigen challenge, the intranasal r elease of leukotrienes B-4 and C-4, and histamine increased in passive ly sensitized guinea pigs. TMK688 tended to suppress the increase in i mmunoreactive leukotrienes B-4 and C-4 in the nasal lavage fluid at a dose of 1 mg/kg p.o., and significantly inhibited the increase at 3.2 mg/kg. The brilliant blue dye leakage following antigen challenge from the blood stream into the nasal cavities was significantly inhibited by not only TMK688 and FPL-55712 but also pyrilamine, suggesting that the allergic dye leakage was caused cooperatively by leukotrienes and histamine. However, ketotifen showed no significant suppression of the dye leakage even at 10 mg/kg p.o., although this drug inhibited the h istamine-induced dye leakage at far lower doses (0.1 mg/kg p.o. or hig her) in unsensitized guinea pigs. Therefore, histamine is not necessar ily the major mediator of allergic dye leakage in our experiment. Thes e findings demonstrate that TMK688 may be superior to antihistamines a s a therapeutic agent for allergic rhinitis.