GR32191 and the role of thromboxane A2 in asthma--preclinical and clinical findings

Abstract

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.