The actions of GR32191B, a thromboxane receptor antagonist, on the effects of inhaled PAF on human airways

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Abstract
We investigated acute bronchoconstriction and changes in airway responsiveness to methacholine following the inhalation of platelet activating factor (PAF) in an open study of 12 non-asthmatic subjects. Ventilatory function was monitored using a flow rate at 30% of vital capacity (.ovrhdot.V30) and airway responsiveness was measured as PD40 .ovrhdot.V30, i.e. the dose of metacholine causing a 40% fall in .ovrhdot.V30. PAF (3-422 .mu.g) resulted in dose-related acute bronchoconstriction in 10 of the 12 subjects. There was no association between the airway responsiveness to PAF and to methacholine. Ten subjects showed some increase in airway responsiveness to methacholine 1 or 3 days following PAF. Overall, these changes were statistically significant (P < 0.05) but were of small magnitude (geometric mean PD40 .ovrhdot.V30 pre-PAF = 457 .mu.g; 24 hr after PAF = 259 .mu.g; 72 hr after PAF = 258 .mu.g) and variable: only seven subjects showing increased airway responsiveness on both day 1 and day 3 after PAF. Six subjects who appeared to show increases in airway responsiveness following PAF were re-studied with the inhaled PAF pre-medicated by either placebo or a specific thromboxane receptor antagonist (GR32191B) in a double-blind fashion. GR32191B did not reduce the acute bronchoconstriction due to PAF. In this part of the study, these six subjects did not show significant increases in airway responsiveness following the placebo pre-medicated PAF challenge and so no effect of the drug on airway responsiveness could be shown. We conclude that PAF-induced bronchoconstriction in normal individuals is not mediated by thromboxane and that any increases in airway responsiveness following PAF are frequently poorly sustained, are poorly reproducible, and are not readily detectable.