Over 12 Hours: DISCUSSION

Early studies with formoterol oral formulation in a dosage of 80 |xg indicated a long duration of action of 8 hours; one should take into account, however, that a substantial part of studies performed with this oral formulation took place in Japan with measurements only up to 8 hours. Multiple dose trials with the oral formulation administered twice daily showed equipo- tency or slight superiority over salbutamol 4 mg three times daily. Based on the Japanese results, it is suggested that white patients take formoterol, 80 |xg twice or three time daily.

The early studies with the metered dose aerosol formulation also showed a duration of action of at least 8 hours. For the design of single-dose crossover studies with this long acting compound, one should take into consideration the wash-out period between the ex­amination days. The wash-out period between study days in this trial was merely based on previous clinical experience with formoterol aerosol, as well as on the consideration that climatologic influence on the asthma patients should be avoided as much as possible by performing the tests within a short interval. Also, the short half life was taken into account, which was in the range of 1.7 to 2.3 hours, obtained by measuring the urinary excretion rates and cumulative urinary excretion of the drug. In pharmacokinetic studies in man, it appeared that even with highly sensitive methods, the detection of nonradioactive labelled formoterol in plasma was impossible at an oral dosage below 200 |xg. From studies with H-formoterol, it appeared that about 60 percent of the drug was absorbed from the digestive tract and serum peak levels were measured after 1.5 to 2.0 hours.
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At the end of each examination day, an additional reversibility test with 200 ug salbutamol metered dose aerosol was performed. In both groups, the results appeared to be compatible with those obtained on the selection day in respect to maximum bronchodilator effect 15 minutes after administration. This might be an indication that despite the “rest effect” of formo- terol 12 hours after administration, no desensitization on the receptor site occurred. The mechanism of action, however, especially on the receptor site, of this inhaled long acting beta^-agonist is not yet clear; further studies are therefore recommended.

The results of this study on the efficacy and tolera- bility of 12 |xg formoterol metered-dose aerosol in comparison with 200 ug salbutamol confirm the ex­perience of previous investigators in their conclu­sions a 12 ug dose of formoterol being both clinically very efficacious and safe in patients with stable and reversible asthma. The bronchospasmolytic capacity and duration of the effect after inhalation of formoterol in this study were quite compatible with earlier investigations; the maximum bronchodilator effect (40 percent above baseline) was reached in 1 to 2 hours, which lasted until 6 hours after administration, where­after a gradual decrease could be observed, leading to still a mean improvement of 20 percent above baseline 12 hours after administration. This “rest effect” of 20 percent was considered to be clinically relevant and was also statistically significantly better than 200 ug salbutamol, a dosage which is considered worldwide to be therapeutic and safe. Beside this, the broncho­spasmolytic effect of formoterol was statistically sig­nificantly better than salbutamol from 2 hours onward after administration. suhagra

The significantly higher therapeutic “rest-effect” 12 hours after administration of formoterol brings new perspectives for the treatment of patients with a so- called “morning dip” in their lung function, which cannot be prevented by the oral or inhaled betas- agonists at present on the market (salbutamol, feno- terol, terbutalin, etc). For this reason, further investi­gations with formoterol administered at 22:00 hours followed by nightly registrations of lung function parameters over 12 hours are recommended.