ABSTRACT
1. The novel leukotriene antagonist Bay x7195, has been evaluated against bronchoconstriction induced by leukotriene D4 (LTD4), the thromboxane A2 (TXA2) mimetic U46619, histamine and antigen, in the guinea-pig in vivo by use of a modified Konzett-Rössler preparation. 2. LTD4, given intravenously (i.v.) at 1 or 3 microg kg(-1) in the presence of indomethacin and sotalol, caused a 50-70% maximal bronchoconstriction in most animals. 3. BAY x7195, given i.v., orally (p.o.), by aerosol or dry powder insufflation, in lactose, reduced LTD4-induced bronchoconstriction dose-dependently. The approximate ID50 values were 83 microg kg(-1), 3 mg kg(-1), 0.0003% w/v for 20 breaths and 20 microg respectively. 4. The action of BAY x7195 (10 mg kg(-1), p.o.) was long lasting, causing significant inhibition of the LTD4-induced response (88% reduction) 8 h after dosing. 5. When given intravenously, in the presence of selected antagonists, BAY x7195 caused a dose-related reduction in the antigen-induced response, with an approximate ID50 of 2 mg kg(-1). 6. At 3 mg kg(-1), i.v., a dose which abolished the response to LTD4, BAY x7195 had no effect on U46619- or histamine-induced bronchoconstriction. 7. BAY x7195 is a potent, selective and long acting antagonist of LTD4-induced bronchoconstriction, in an anaesthetized, ventilated guinea-pig model. It is therefore worthy of clinical evaluation in diseases believed to involve the sulphidopeptide leukotrienes, such as asthma.
Subject(s)
Bronchoconstriction/drug effects , Bronchodilator Agents/pharmacology , Hydroxy Acids/pharmacology , Leukotriene Antagonists , Administration, Oral , Aerosols , Anesthesia, General , Animals , Antigens/immunology , Guinea Pigs , Injections, Intravenous , Leukotriene D4/administration & dosage , Leukotriene D4/pharmacology , Lung Volume Measurements , Male , Powders , Thromboxane A2/administration & dosage , Thromboxane A2/pharmacologyABSTRACT
BAY x1005 ((R)-2-[4-quinolin-2-yl-methoxy)phenyl]-2-cyclopentyl acetic acid), an inhibitor of leukotriene synthesis, was evaluated, both in vitro and in vivo, for inhibition of antigen-induced airway contraction in the sensitised guinea-pig. Antigen (ovalbumin 0.001-10 micrograms/ml) challenge of tracheae in the presence of pyrilamine and indomethacin induced contractile responses which were inhibited by BAY x1005 with an IC50 value of 0.36 (0.2-0.8) microM. Using the same test system BAY x1005 (1 microM), ICI D2138 (0.3 microM) or AA 861 (1 microM) had similar inhibitory activities, whereas MK 886, MK 591, and Zileuton (A64077) all tested at 1 microM and REV 5901 (10 microM) had no significant effect. Using tracheae from non-sensitised (control) guinea-pigs the calcium ionophore A23187 (1 microM) induced a maximal contraction which was significantly inhibited by BAY x1005 at 1 microM, whereas MK 886 was only active at 3 microM. BAY x1005 tested at 10 microM and 3 microM had no effect against leukotriene D4- or KCl-induced contractions of guinea-pig tracheae respectively. In the anaesthetised ovalbumin sensitised guinea-pig BAY x1005 caused a dose-related inhibition of ovalbumin-induced bronchoconstriction, with approximate ID50 values of 0.85 mg/kg i.v. and 6.3 mg/kg p.o. In the same model MK 886, MK 591, AA 861 and ICI D2138 each given at 10 mg/kg p.o. had no significant inhibitory activity against antigen challenge. Six hours after administration BAY x1005 (10 mg/kg p.o.) was still effective against the antigen-induced response.(ABSTRACT TRUNCATED AT 250 WORDS)
