vapiprost and Asthma

Thromboxane sensitive (TP)-receptors are widely distributed in the airways smooth muscle of various species. In man they mediate constrictor responses, not only to TxA2 but also to other prostanoids such as PGD2 and PGF2 alpha. The evidence for the involvement of these TP-receptors in human asthma is equivocal; however, the recent development of potent, selective TP-receptor blocking drugs such as GR32191 has provided the opportunity to answer this question. GR32191 (80mg p.o.) caused a marked inhibition of PGD2 but not methacholine-induced bronchospasm in asthmatic subjects, and also caused a modest reduction in allergen-induced bronchospasm. However, it had no inhibitory effect against the bronchoconstriction resulting from inhaled PAF or from exercise. Finally, GR32191 was tested in moderate to severe asthmatics for its ability to reduce symptom scores. At a dose of 40mg four times a day for three weeks, GR32191 had no effect upon morning or evening peak expiratory flow rates, on subjective symptom score, on bronchodilator usage or on occurrence of nocturnal dyspnoea. These results do not support a key role for prostanoids acting through TP-receptors in the aetiology of asthma.

Topics: Animals; Asthma; Biphenyl Compounds; Bronchial Provocation Tests; Bronchoconstriction; Forced Expiratory Volume; Heptanoic Acids; Humans; Thromboxane A2

Airway responsiveness to methacholine was measured in nine subjects (22-53 years, seven male) with chronic stable asthma. All subjects were taking inhaled beclomethasone (less than 1000 micrograms daily). The mean baseline FEV1 was 2.841 (77% of predicted) and the geometric mean PD20FEV1 was 31 micrograms. After a run-in period, the subjects were randomly allocated to two treatment periods with the specific thromboxane receptor antagonist GR32191, 40 mg four times daily for 3 weeks, and identical placebo capsules. A double-blind, placebo-controlled, cross-over design was employed with 4 weeks between the two treatment periods. Treatment with GR32191 did not result in any significant improvement in mean FEV1 (2.941 after placebo and 2.861 after GR3219; F7.71 = 1.02, P greater than 0.1) or PD20FEV1 (24.3 micrograms after placebo and 38.5 micrograms after GR32191; F7.71 = 0.59, P greater than 0.1). We conclude that thromboxane is not important in the maintenance of airway hyperresponsiveness in chronic asthma and that thromboxane receptor antagonists are unlikely to provide effective treatment for this group of patients.

Topics: Adult; Asthma; Biphenyl Compounds; Bronchial Hyperreactivity; Double-Blind Method; Female; Forced Expiratory Volume; Heptanoic Acids; Humans; Male; Methacholine Chloride; Middle Aged; Receptors, Thromboxane; Thromboxane A2

Thromboxane sensitive (TP)-receptors are widely distributed in the airways smooth muscle of various species. In man they mediate constrictor responses, not only to TxA2 but also to other prostanoids such as PGD2 and PGF2 alpha. The evidence for the involvement of these TP-receptors in human asthma is equivocal; however, the recent development of potent, selective TP-receptor blocking drugs such as GR32191 has provided the opportunity to answer this question. GR32191 (80mg p.o.) caused a marked inhibition of PGD2 but not methacholine-induced bronchospasm in asthmatic subjects, and also caused a modest reduction in allergen-induced bronchospasm. However, it had no inhibitory effect against the bronchoconstriction resulting from inhaled PAF or from exercise. Finally, GR32191 was tested in moderate to severe asthmatics for its ability to reduce symptom scores. At a dose of 40mg four times a day for three weeks, GR32191 had no effect upon morning or evening peak expiratory flow rates, on subjective symptom score, on bronchodilator usage or on occurrence of nocturnal dyspnoea. These results do not support a key role for prostanoids acting through TP-receptors in the aetiology of asthma.

Topics: Animals; Asthma; Biphenyl Compounds; Bronchial Provocation Tests; Bronchoconstriction; Forced Expiratory Volume; Heptanoic Acids; Humans; Thromboxane A2

In this study we investigated the effect of the selective and potent thromboxane A2 (TxA2) receptor antagonist GR32191 on smooth muscle contraction induced by the TxA2 analogue U46619, prostaglandin (PG) D2, PGF2 alpha, and methacholine (MCh) in guinea pig airways in vitro and the airways response provoked by inhaled PGD2 and MCh in asthmatic subjects in vivo. GR32191 antagonized competitively the contractile responses of all three prostanoids to a similar degree but had no effect on MCh-induced contractions. In asthmatic subjects GR32191, in a single oral dose of 80 mg, did not affect base-line airway caliber or MCh-induced broncho-constriction but caused significant inhibition of PGD2-induced bronchoconstriction, displacing the concentration-response curves to the right by greater than 10-fold. The effect of the same oral dose of GR32191 on allergen-induced immediate bronchoconstriction was subsequently investigated in allergic asthmatic subjects. In individual subjects, GR32191 inhibited to varying degrees the overall bronchoconstrictor response, with the maximum effect occurring between 10 and 30 min after allergen challenge. These studies suggest that prostanoids contribute to the immediate bronchoconstriction induced by inhaled allergen in allergic asthmatics, and that this effect is mediated by stimulation of a thromboxane receptor.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Adolescent; Adult; Animals; Asthma; Biphenyl Compounds; Bronchi; Dinoprost; Guinea Pigs; Heptanoic Acids; Histamine; Humans; Male; Methacholine Compounds; Prostaglandin D2; Prostaglandin Endoperoxides, Synthetic; Receptors, Prostaglandin; Receptors, Thromboxane; Thromboxane A2