Picumeterol: dissociation of improvement in lung function and reduction of airways hyperresponsiveness in asthmatics.
OBJECTIVE
The new potent and selective beta 2-adrenoceptor agonist, GR 114297A (picumeterol) is the R-enantiomer of the racemic form, GR 63411B. Picumeterol has been shown to produce long-lasting relaxation of airways smooth muscle both in vitro and in vivo. We assessed the intrinsic activity of picumeterol by increasing intracellular levels of c-AMP and compared this with isoprenaline and salbutamol.


METHODS
In human atopic asthmatics, we have investigated the duration of action and efficacy of picumeterol and GR 63411B with regard to improvement in resting lung function (i.e. FEV1) and airways responsiveness (i.e. PC20) to methacholine (MCh). The study design consists of two clinical parts each for one drug. Different asthmatics participated in the two studies, seven in the first part and eight in the second part. In human bronchial smooth muscle cells in vitro, we have investigated the intrinsic activity of picumeterol in increasing intracellular levels of cyclic AMP and compared it with isoprenaline and salbutamol.


RESULTS
In vivo, both drugs caused bronchodilatation with similar potency, but, their effects were short-lasting. Despite their bronchodilator activity, neither drug improved PC20, when compared with placebo. In vitro, picumeterol was found have intrinsic activity lower than the other beta 2-adrenoceptor agonists tested.


CONCLUSIONS
In the clinical studies, the bronchodilator potencies of picumeterol and GR 63411B were similar. However, both drugs were short-acting, which is at odds with their activity in vitro. Our data suggest that these compounds display dissociation between bronchodilator activity and protection against MCh-induced bronchoconstriction. These findings may be explained by low intrinsic activity and need further conformation.
Weersink
E J
EJ
Department of Pulmonology, University Hospital Groningen, The Netherlands.
Postma
D S
DS
Koëter
G H
GH
Man
Y
Y
Nials
A T
AT
Coleman
R A
RA
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000420:Albuterol / Q000494:pharmacology; D019540:Area Under Curve; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004311:Double-Blind Method; D006801:Humans; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009130:Muscle, Smooth / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012129:Respiratory Function Tests
D058666:Adrenergic beta-2 Receptor Agonists; D000318:Adrenergic beta-Agonists; D011725:Pyridines; C097635:picumeterol; D000242:Cyclic AMP; D007545:Isoproterenol; D000420:Albuterol