ABSTRACT
The single-dose effect of formoterol racemate and enantiomers on bronchodilatation up to 24 h was determined. Forty-six reversible asthmatic patients were randomised to this double blind, crossover study. Formoterol was inhaled by nebulizer (HaloLite); 4.5 and 36 microg of the racemate (rac-formoterol), 2.25 and 18 microg of (R;R)-formoterol, 18 mirog of (S;S)-formoterol, or placebo. Airway and systemic effects were assessed by serial measurements of forced expiratory volume during the first second, FEV1 (24 h), and heart rate (4 h). Rac- and (R;R)-formoterol significantly and dose-dependently increased FEV1 with similar mean maximal effect. (S;S)-formoterol was without significant effects on FEV1 and heart rate. (R;R)- and rac-formoterol were still effective 22-24 h after single high doses, but this was associated with some systemic side effect (increased heart rate) initially. Average 22-24 h FEV1 was 8% (rac-formoterol 36 microg) and 11% ((R;R)-formoterol 18 microg) over placebo, respectively. No significant differences in effects were observed between rac- and (R;R)-formoterol. Thus, the single dose bronchodilatating effect of formoterol resides in (R;R)-formoterol. This study does not indicate a clinically important advantage of (R;R)-formoterol as acute bronchodilator compared to the racemate.
Subject(s)
Adrenergic beta-Agonists/pharmacology , Asthma/drug therapy , Ethanolamines/pharmacology , Adrenergic beta-Agonists/chemistry , Adult , Aged , Aged, 80 and over , Asthma/physiopathology , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Ethanolamines/chemistry , Forced Expiratory Volume/drug effects , Forced Expiratory Volume/physiology , Formoterol Fumarate , Heart Rate/drug effects , Heart Rate/physiology , Humans , Middle Aged , Nebulizers and Vaporizers , Stereoisomerism , Treatment OutcomeABSTRACT
OBJECTIVE: To quantify the relation between local and systemic magnitudes of effects of inhaled formoterol and salbutamol. METHODS: Twenty-eight stable asthmatic patients completed this double-blind, randomised crossover study. Pre-drug administration FEV1 (mean 2.08 L) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutanmol. Patients inhaled three single doses of formoterol fumarate dihydrate (Oxis) (delivered doses of 4.5, 18 and 54 microg) via Turbuhaler, two single doses of salbutamol (200 and 1800 microg) via a pressurised metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. A classic sigmoid model of log-dose response was used to discriminate pharmacologically between formoterol and salbutamol. Relative local (maximum FEV1) and systemic (minimum S-KC) dose potencies, and their ratio, the relative therapeutic index, were estimated using an on-linear mixed effect model. RESULTS: The drug effects were well tolerated and dose dependent The bronchodilating effect was on a part of the dose response curve that could be well approximated by a log-linear function, the serum potassium suppressing effect sometimes was not (the lowest doses differed only marginally from placebo). Thus, a log-linear approximation was used to describe bronchodilation, whereas a sigmoid approximation was more apt to describe the decrease in serum potassium concentration. A bivariate dose-response model based on these principles was fitted simultaneously to all data. The mean relative therapeutic index was estimated to be 2.5 (95%confidence interval: 0.9-6.5). CONCLUSIONS: The mean relative therapeutic index between formoterol (Oxis) 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to 2.5 in favour of formoterol; this trend was not statistically significant.
