ABSTRACT-We evaluated the antagonist activity of ONO-1078 against peptide leukotrienes (LTs) by a radioligand binding assay and functional experiments in guinea pigs. In the radioligand binding assay, ONO-1078 inhibited [3H]LTD4 and [3H]LTE4 bindings to lung membranes (K; = 0.99 and 0.63 nM, re spectively) and was 2,000 to 3,000-fold more potent than FPL55712. Antagonism of ONO-1078 against [3H]LTC4 binding (K; = 5640 nM) was approximately twofold more potent than that of FPL55712. The antagonism of ONO-1078 against [3H]LTD4 binding was competitive. In functional experiments, ONO 1078 showed competitive antagonism against the LTC4 and LTD4-induced contractions of guinea pig trachea and lung parenchymal strips with a pA2 range of 7.70 to 10.71 and was approximately 400 to 3,300-fold more potent than FPL55712. Interestingly, in the presence of an inhibitor of the bioconver sion of LTC4 to LTD4, ONO-1078 also antagonized the LTC4-induced contraction of guinea pig trachea (pA2 = 7.78). ONO-1078 significantly reversed the LTD4-induced prolonged contraction without effect on the KCl and BaC12-induced contractions of guinea pig trachea. Furthermore, ONO-1078 antago nized the antigen-induced SRS-A mediated contraction of guinea pig trachea. On the other hand, ONO-1078 showed no antagonism against histamine, acetylcholine, 5-hydroxytryptamine, prostaglandin D2 and U-46619. In addition, ONO-1078 showed little or no effect on the activities of cyclooxygenase, 5-lipoxygenase and thromboxane synthetase. These in vitro studies indicate that ONO-1078 is a highly potent, selective and competitive antagonist of peptide leukotrienes that acts with higher affinity at LTD4 and LTE4 receptors than LTC4 receptors.
The inhibitory effect of ONO-1078, a novel leukotriene (LT) receptor antagonist, was investigatedon guinea pig lung anaphylaxis in vitro and in vivo. It was demonstrated that this compound could inhibit thelate phase of contractile responses in Schultz-Dale reactions and endogenous LT-mediated bronchoconstrictions in passively sensitized guinea pigs, in a dose-dependent fashion, implying its clinical usefulness in thetreatment of human bronchial asthma.
Abstract-We examined the effect of thromboxane A2 (TXA2) synthetase inhibitor, OKY-046, on bronchoconstriction induced by antigen and various spasmogenic mediators in guinea pigs in vivo. Further, inhibitory activities of OKY-046 on contractions of isolated tracheae and lung parenchymal strips induced by various contractile agents were also investigated in vitro. OKY-046, but not indomethacin, significantly inhibited antigen-induced bronchoconstriction in a dose-dependent manner. Moreover, OKY-046 attenuated bronchoconstrictions induced by peptide leukotrienes (LTs) and platelet activating factor (PAF), but not those by histamine, prostaglandin D2 (PGD2) and STA2 (a stable TXA2 mimetic agent). Although contractile responses induced by spasmogens such as peptide LTs, PAF and hista mine were not influenced by OKY-046 in isolated tracheae, OKY-046 elicited significant and concentration-dependent inhibitions against contractile responses induced by peptide LTs and PAF in isolated lung parenchymal strips. These results suggest the possible involvement of TXA2 in the development of anaphylactic bronchoconstriction in sensitized guinea pigs.
The effect of the leukotriene receptor antagonist ONO-1078 on experimental and clinical bronchial asthma was evaluated. It was found that this compound could inhibit antigen-induced bronchoconstriction in passively sensitized guinea pigs and leukotriene D4- and allergen-induced bronchial responses in normal and in asthmatic subjects. Clinical trials in patients with chronic bronchial asthma demonstrated its effectiveness in reducing hazardous symptoms like wheezing and dyspneic attacks.
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