Hilary P Dr Francis

BAY u3405 an antagonist of thromboxane A2‐ and prostaglandin D2‐induced bronchoconstriction in the guinea‐pig

1 The novel thromboxane (TX) antagonist, BAY u3405, has been evaluated against bronchoconstriction induced by the TXA2 mimetic U‐46619, prostaglandin D2 (PGD2), 5‐hydroxytryptamine (5‐HT), leukotriene D4 (LTD4) and histamine in the guinea‐pig in vivo by use of a modification of the model described by Konzett & Rössler. 2 When given intravenously (i.v.) at 30 or 100 μg kg−1, U‐46619 caused 80% maximal bronchoconstriction in most animals. In contrast, PGD2 caused a smaller 40%‐50% maximal bronchoconstriction at the highest dose tested (300 μg kg−1, i.v.). 3 BAY u3405, given intravenously, orally (p.o.) or by aerosol antagonized U‐46619‐induced bronchoconstriction in a dose‐related manner. The approximate ID50 values were 600 μg kg−1, i.v., 1.7 mg kg−1 p.o. and 0.1% w/v 20 breaths by aerosol. 4 BAY u3405 had similar inhibitory activities against U‐46619‐induced bronchoconstriction and hypertension suggesting that it had no preferential activity on the airways. 5 When given intravenously BAY u3405 antagonized the bronchoconstrictor effect of intravenous PGD2 with ID50 values between 30–100 μg kg−1. 6 The action of BAY u3405 (10 mg kg−1, p.o.) was long lasting, causing significant inhibition of U‐46619‐induced bronchoconstriction 7 h after dosing. 7 At 1 mg kg−1, i.v., a dose that abolished the response to U‐46619 and PGD2, BAY u3405 had no effect on histamine‐, 5‐HT‐ or LTD4‐induced bronchoconstriction. 8 BAY u3405 potently and selectively antagonized U‐46619‐ or PGD2‐induced bronchoconstriction in the Konzett‐Rössler model of guinea‐pig lung function. It should therefore prove to be a useful tool for defining the role of TXA2 and PGD2 in airway diseases such as asthma.

Inhibition of antigen-induced contraction of guinea-pig airways by a leukotriene synthesis inhibitor, BAY x1005

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)

A new structural analogue antagonist of peptido-leukotrienes. The discovery of bay x7195

Abstract Systematic modification of LTD4 has led to the discovery of BAY x7195, a potent, selective, orally-active peptido-leukotriene antagonist.

The effects of a novel sulphidopeptide leukotriene antagonist, BAY x7195, against elicited bronchoconstriction in the anaesthetized guinea‐pig

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. LTD4, given intravenously (i.v.) at 1 or 3 μg kg−1 in the presence of indomethacin and sotalol, caused a 50–70% maximal bronchoconstriction in most animals. 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 μg kg−1, 3 mg kg−1, 0.0003 % w/v for 20 breaths and 20 μg respectively. 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. 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. 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. 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.