ovalbumin and enofelast

The 5-lipoxygenase (5-LO) inhibitors BI-L-239 and A-64077 were compared with the 5-LO translocation inhibitor MK-886 for the ability to inhibit leukotriene B4 (LTB4) biosynthesis by chopped (1 mm3) guinea pig lung. LTB4 synthesis by ovalbumin-sensitized chopped lung tissue was determined after stimulation with either calcium ionophore (A23187) or antigen. With A23187 stimulation, MK-886 was more potent (IC50 = 0.39 +/- 0.23 microM, mean +/- SEM, p < 0.01) than BI-L-239 (IC50 = 2.48 +/- 0.46 microM) or A-64077 (IC50 = 4.68 +/- 0.70 microM) and BI-L-239 was more potent than A64077 (p < 0.02). Thus, the order of potency was MK-886 > BI-L-239 > A-64077 for inhibition of calcium ionophore-induced LTB4 generation. There was no significant differences in potency of the compounds in chopped lung stimulated with antigen: IC50 for LTB4 synthesis by A-64077 = 3.31 +/- 1.70 microM, for BI-L-239 = 9.06 +/- 4.94 microM, and for MK-886 = 13.33 +/- 7.91 microM. The ability of these compounds to inhibit contraction of tracheal tissue from actively sensitized guinea pigs in response to antigen was also determined in the presence of indomethacin (15 micrograms/ml), mepyramine, and atropine (5 micrograms each/ml). Both 5-LO inhibitors inhibited antigen-induced contraction, with IC50 values for BI-L-239 and A-64077 of 1.58 and 4.35 microM respectively. MK-886 was ineffective at inhibiting antigen-induced tracheal contraction in vitro at concentrations up to 30 microM. In summary, these compounds inhibit antigen-induced and A23187-induced leukotriene biosynthesis in guinea pig tissue. These 5-LO inhibitors were similarly effective at inhibiting antigen-induced tracheal contraction where MK-886 was ineffective.

Topics: Animals; Guinea Pigs; Hydroxyurea; In Vitro Techniques; Indoles; Leukotriene B4; Lipoxygenase Inhibitors; Lung; Male; Muscle Contraction; Muscle, Smooth; Ovalbumin; Phenols; Trachea

Male Hartley guinea pigs were actively sensitized to ovalbumin (OA). Respiratory system resistance (Rrs) was measured by forced oscillations superimposed on tidal breathing. Airway responsiveness (inhaled methacholine PC100) was determined three days prior and three days after (day 10) three alternate day inhalations of OA. Airway cell composition was assessed on day 10 by lung lavage. Three groups (n = 5-6) were studied: A) vehicle challenged, B) OA challenged/placebo treated, C) OA challenged/BI-L-239 (2,6-dimethyl-4-[2-(4-fluorophenyl)ethenyl]phenol) treated (10 x 0.75 mg/actuation, 10 minutes prior to each OA challenge). Animals were treated with pyrilamine and indomethacin (10 mg/kg i.p.) 30 minutes prior to each OA challenge. OA induced acute increases in Rrs of 143 +/- 29%, 238 +/- 73% and 102 +/- 43% in placebo and 86 +/- 34%, 45 +/- 35% (p, 0.05 vs. placebo) and 102 +/- 31% in BI-L-239 treated. OA induced a significant (p less than 0.05) increase in airway leukocytes in placebo (487 +/- 36 to 1615 +/- 421 x 10(3)/ml) but not BI-L-239 treated (to 881 +/- 155 x 10(3)/ml) and decrease in methacholine PC100 in placebo (1.487 +/- 0.49 to 0.39 +/- 0.18 mg/ml) but not BI-L-239 treated (0.99 +/- 34 to 1.04 +/- 0.39 mg/ml). We conclude that BI-L-239 attenuates the airway constriction, inflammation and hyperresponsiveness induced by repeated antigen inhalations in conscious guinea pigs.

Topics: Administration, Inhalation; Airway Resistance; Animals; Antigens; Bronchoconstriction; Guinea Pigs; Indomethacin; Lipoxygenase Inhibitors; Male; Methacholine Compounds; Ovalbumin; Phenols; Pyrilamine; Respiratory Hypersensitivity