MCI-826

In this report, the in vitro and in vivo pharmacological profile of MCI-826 ((E)-2,2-diethyl-3'-[2-[2-(4-isopropyl) thiazolyl]ethenyl]succinanilic acid, CAS 121230-22-6) is described. In isolated guinea pig ileum, MCI-826 inhibited LTD4 (a peptide leukotriene, 10(-9) mol/l)-induced contraction in a concentration-dependent manner with an IC50 of 6.8 x 10(-12) mol/l. It had no effect on histamine (10(-5) mol/l)-, serotonin (2.5 x 10(-5) mol/l)-, or acetylcholine (5.5 x 10(-6) mol/l)- induced contractions in isolated guinea pig ileum. In isolated guinea pig trachea, MCI-826 demonstrated competitive antagonism of the contractile activity of LTD4 and LTE4 with pA2 values of 9.0 and 8.8, respectively. MCI-826 inhibited LTC4-induced contraction in a concentration-dependent manner. However, in the presence of an inhibitor of the metabolism of LTC4 to LTD4, MCI-826 (10(-6) mol/l) produced no effect on LTC4 concentration-response curves in guinea pig trachea. In the in vivo study, the oral administration of MCI-826 caused a dose-dependent inhibition of LTC4- and LTD4-induced bronchoconstrictions in guinea pigs with an ED50 of 0.049 and 0.013 mg/kg, respectively. However, MCI-826 (3 mg/kg p.o.) showed no effect on histamine-induced bronchoconstriction in guinea pigs. The pharmacological half-life of orally administered MCI-826 as assessed by LTD4-induced bronchoconstriction was more than 12 h in guinea pigs. MCI-826 also inhibited antigen-induced bronchoconstriction in a dose-dependent manner with a MID (minimum dose that causes significant inhibition) of 0.1 mg/kg p.o. in guinea pigs.(ABSTRACT TRUNCATED AT 250 WORDS)

Combined treatment with propranolol and reserpine enhanced acetylcholine-induced dose-response curves for bronchoconstriction in guinea pigs in vivo. This airway hyperreactivity model was investigated pharmacologically. (1) Increased capillary permeability and increases in leukocytes in bronchoalveolar lavage fluid (BALF) were not observed after this combined treatment. (2) The increased airway sensitivity to acetylcholine produced by propranolol and reserpine was inhibited by ketotifen and theophylline, reported in clinical studies to inhibit airway hyperreactivity. (3) Two leukotriene (LT) receptor antagonists, MCI-826 and FPL-55712, clearly inhibited this increased airway reactivity. (4) A thromboxane A2 (TXA2) receptor antagonist, ONO-3708, and TXA2 synthetase inhibitor, OKY-046, also inhibited this increased airway reactivity. These results suggest that the airway hyperreactivity model produced by propranolol and reserpine in guinea pigs is a valuable pharmacological tool for investigating a remedy and LT and TXA2 may be involved in the onset of this airway hyperreactivity.