Effects of TMK688, a novel anti-allergic drug, on allergic nasal obstruction and exudative responses in sensitized guinea pigs

Abstract

TMK688 (1-[[5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadien oyl] aminoethyl]-4-diphenylmethoxypiperidine) is being developed as an orally effective antiallergic drug having both 5-lipoxygenase inhibitory activity and anti-histamine activity (Shizawa et al. 1996; Tohda et al. 1997). The efficacy of TMK688 against allergic rhinitis was examined in passively sensitized guinea pigs. TMK688 inhibited the increase 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 antagonist, but not by 3.2 mg/kg i.v. pyrilamine, a histamine H1 receptor antagonist, or by 10 mg/kg p.o. of ketotifen, an anti-allergic drug having anti-histamine activity, suggesting that the nasal obstruction was caused by leukotrienes. Following antigen challenge, the intranasal release of leukotrienes B4 and C4, and histamine increased in passively sensitized guinea pigs. TMK688 tended to suppress the increase in immunoreactive leukotrienes B4 and C4 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 histamine-induced dye leakage at far lower doses (0.1 mg/kg p.o. or higher) in unsensitized guinea pigs. Therefore, histamine is not necessarily the major mediator of allergic dye leakage in our experiment. These findings demonstrate that TMK688 may be superior to antihistamines as a therapeutic agent for allergic rhinitis.

Elevated Nasal Mucosal G Protein Levels and Histamine Receptor Affinity in a Guinea Pig Model of Nasal Hyperresponsiveness

“…Intranasal pressure was measured as an index of intranasal resistance by the method described in previous papers [14, 15]with minor modifications. Briefly, guinea pigs were anesthetized with urethane (1.6 g/kg, i.p.)…”

Effects of Fexofenadine Hydrochloride in a Guinea Pig Model of Antigen-Induced Rhinitis

“…That is, the experimental animals also exhibit sneezing [6][7][8][9][10] , nasal secretion [9] and nasal obstruction [6][7][8][9][10][11][12][13][14][15][16][17] . It has been demonstrated that histamine [10,12,14,16] , leukotrienes [9,10,12,13,16] , and thromboxane [6,10,12,14,15,17,18] are involved in the mechanism of development of the pathology in these models. Accordingly, these guinea pig models have come to be widely used for evaluation of the pharmacological effects of drugs being developed for the treatment of allergic rhinitis.…”