PICUMETEROL - DISSOCIATION OF IMPROVEMENT IN LUNG-FUNCTION AND REDUCTION OF AIRWAYS HYPERRESPONSIVENESS IN ASTHMATICS

Aims The new potent and selective beta(2)-adrenoceptor agonist, GR 114 297A (picumeterol) is the R-enantiomer of the racemic form, GR 63411B. Picumeterol has been shown to produce long-lasting relaxation of airw ays smooth muscle both in vitro and in vivo. We assessed the intrinsic activity of picumeterol by increasing intracellular levels of c-AMP a nd compared this with isoprenaline and salbutamol. Methods In human at opic asthmatics, we have investigated the duration of action and effic acy of picumeterol and GR 63411B with regard to improvement in resting lung function (i.e. FEV(1)) and airways responsiveness (i.e. PC20) to methacholine (MCh). The study design consists of two clinical parts e ach for one drug. Different asthmatics participated in the two studies , seven in the first part and eight in the second part. In human bronc hial smooth muscle cells in vitro, we have investigated the intrinsic activity of picumeterol in increasing intracellular levels of cyclic A MP and compared it with isoprenaline and salbutamol. Results In vivo, both drugs caused bronchodilatation with similar potency, but, their e ffects were short-lasting. Despite their bronchodilator activity, neit her drug improved PC20, when compared with placebo. lit vitro, picumet erol was found have intrinsic activity lower than the other beta(2)-ad renoceptor agonists tested. Conclusions In the clinical studies, the b ronchodilator potencies of picumeterol and GR 63411B were similar. How ever, both drugs were short-acting, which is at odds with their activi ty in vitro. Our data suggest that these compounds display dissociatio n between bronchodilator activity and protection against MCh-induced b ronchoconstriction. These findings may be explained by low intrinsic a ctivity and need further conformation.