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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.

A double-blind, randomized crossover study in 28 asthmatic patients assessed the relative therapeutic index for inhaled formoterol and salbutamol. Pre-drug administration FEV1 (mean 2.08 l) was 49-93% of predicted and reversibility 16-82% after inhalation of salbutamol. Patients inhaled single doses of formoterol (Oxis) (4.5,18 and 54 microg, delivered doses) via Turbuhaler, salbutamol (Ventolin) (200 and 1800 microg) via pressurized metered dose inhaler (pMDI) and placebo at intervals of 48 h or more. Individual maximum FEV1 and minimum S-K+ were calculated. Relative local (maximum FEV1) and systemic (minimum S-K+) dose potencies, and their ratio, the relative therapeutic index, were estimated using a non-linear mixed effect model. The drug effects were well tolerated and dose dependent. A log-linear approximation was used to describe the bronchodilatory effect, 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 between formoterol 4.5-54 microg given via Turbuhaler and salbutamol 200-1800 microg given via pMDI was estimated to be 2.5 in favour of formoterol; this trend was not statistically significant.

Objectives: To compare the relative systemic dose potency and tolerability of inhaled formoterol and salbutamol and to describe elimination of formoterol, particularly any enantioselectivity., Methods: Twelve healthy subjects, aged 18-28 years, completed three open study days, and eleven asthmatic patients, aged 20-56 years, completed four double-blind study days in randomised, placebo-controlled and crossover fashions. The healthy subjects inhaled 13.5 + 13.5 + 27 microg formoterol (Oxis) via Turbuhaler and 300 + 300 + 600 microg salbutamol (Ventoline) via a pressurised metered dose inhaler (pMDI). The asthmatics, being on formoterol 9 microg twice daily via Turbuhaler during the study, inhaled the same single doses as the healthy subjects plus 900 + 900 + 1800 microg salbutamol via pMDI. Doses were given cumulatively 30 min apart on separate study days. Placebo was a day of no treatment in the healthy subjects. Double dummies were used for the asthmatics. Cardiovascular and metabolic effects were evaluated. Elimination of formoterol was addressed in the healthy subjects., Results: Formoterol was estimated to be 28-109 times as potent as salbutamol, depending on the systemic effect variable. The duration of systemic action seemed to differ marginally at approximately equieffective doses of formoterol and salbutamol. Systemic effects were well tolerated and tended to be more pronounced in the healthy subjects than in the asthmatic patients. The half-life of the pharmacologically more active (R;R)-formoterol was longer than that of (S;S)-formoterol., Conclusions: Systemically, formoterol was shown to be 28-109 times as potent as salbutamol. Equieffective doses seemed to have a similar duration of effect. Formoterol and salbutamol were well tolerated by healthy subjects up to the tested total doses of 54 microg and 1200 microg, respectively, and by asthmatic patients up to the tested total doses of 54 microg and 3600 microg, respectively. Elimination of formoterol was enantioselective.

Salmeterol and formoterol are two long-acting beta2-agonists for inhalation, currently being used in clinical practice. The aim of the present study was to investigate the onset of action, duration of effect and potency of these two beta2-agonists in asthmatic patients. Patients (n=28) were included on the basis of salbutamol stepwise reversibility (100, 100 and 200 microg, given cumulatively; total reversibility > or =15%). In a double-blind placebo-controlled crossover study, the bronchodilating properties of formoterol 6, 12 and 24 microg were compared with the effects of salmeterol 50 microg. Formoterol was given via Turbuhaler and salmeterol via Diskhaler, and forced expiratory volume in one second (FEV1) was monitored during 12 h. Formoterol at all doses had a more rapid onset than salmeterol as judged from bronchodilation at 3 min after the dose. Formoterol at all doses had a similar duration of effect to salmeterol 50 microg, as judged from bronchodilation at 12 h after dose administration. When the relative potency of the two drugs was compared, salmeterol 50 microg was estimated to correspond to formoterol 9 microg (95% confidence interval: 3-19 microg). We confirm that formoterol and salmeterol are both long-acting beta2-agonists, but with some differences in effect profile. We confirm the more rapid onset of action of formoterol compared with salmeterol, and furthermore, no difference in duration of effect is evident.