The therapeutic effects of inhaled long-acting beta2-adrenergics (LABA) and corticosteroids (ICS) are not affected by their inhalation sequence in moderate/persistent asthma.
Bronchial asthma is defined as "a chronic inflammatory disease of the airways involving many cells" and inhaled corticosteroids have therefore become the fundamental drugs for the long-term management of the disease. In moderate and severe persistent asthma the use of a long-acting bronchodilator is recommended in order to control symptoms and to enhance the efficacy of corticosteroids. Although not based on scientific evidence, it has been assumed that the, 2 adrenergic and the inhaled steroid should be administered in a strict inhalation sequence: the bronchodilatator first and then the steroid. The aim of the study was to assess the effects of this assumption experimentally, common indeed since long ago.


METHODS
Twelve subjects with moderate-persistent asthma (7 males, aged 18-64, basal FEV1 = 65.59% pred. +/- 7.59 ds; reversibility = + 14.8% +/- 8.3 ds from baseline after Salbutamol 200mg), symptomatic despite the regular home treatment with Fluticasone p. 250mg bid and beta 2 short-acting prn for over 6 weeks, were initially treated with combined SM/FP 50/250mg bid from an unique Diskus" device, for 6 weeks. After this initial phase, the treatment continued according to a randomised, double-blind, cross-over design: all subjects received the same drugs, from two different Diskus" inhalers, and according to two different sequences of administration: 1) SM first and FP 20' later for 4 weeks, and then FP first and SM 20' later for a further 4 weeks; 2) vice versa. No wash-out period was included between these two phases of cross-over treatment. FEV1 (% pred.); morning PEF (L/min), the use of short-acting beta 2 as required (n/week); the number of awakenings at night (n/week), and the daytime asthma symptom score were measured.


METHODS
The t paired test and anova (Duncan test) were used for statistical comparisons: a p<0.05 was accepted as the minimum level of significance.


RESULTS
After the first six weeks of treatment with combined Salmeterol/Fluticasone, 50/250 mg FEV1 changed from 69.6% pred. +/- 7.59 ds to 79.8% pred. +/- 10.1 ds (p>0.005), whilst the morning PEF changed from 282.2 l/min : 64.1 ds to 333.4 l/min +/- 55.5 ds (p<0.02). Furthermore, the consumption of beta 2 adrenergic prn dropped from 4.4 (no./week) +/- 7.3 ds to 1.2 +/- 0.9 ds (p<0.001); the number of night-time awakenings decreased from 1.6 (no./week) +/- 0.2 ds to 0.2 +/- 0.3 ds (p<0.001), and the daytime symptom score changed from 3.4 +/- ds 0.8 to 1.9 +/- 0.7 ds (p<0.001). This therapeutic performance was maintained over the two subsequent 4-week periods of treatment from two distinct devices independently of the inhalation sequence. In particular, by both using salmeterol first or using fluticasone first, the therapeutic effects proved quite identical: FEV1: 80.7 % pred. +/- 9.5 ds and 80.3 +/- 7.4 ds; morning PEF: 336.5 l/min +/- 55.4 ds and 338.6 l/min +/- 67.1 ds; consumption of beta 2 adrenergic as required: 0.9 (no./week) +/- 0.6 ds and 0.9 (no./week) +/- 0.8 ds; number of awakenings: 0.3 (no./week) +/- 0.3 and 0.2 (no./week) +/- 0.3 ds; day-time/night-time symptom score: 1.7 +/- 0.5 ds and 1.8 +/- 0.6 ds, respectively (anova = ns).


CONCLUSIONS
Both in terms of lung function and of clinical outcomes the efficacy of SM and FP administration proved completely independent of the particular sequence for their separate inhalation and quite superimposable to thatachieved b y their combined inhalation from an unique device.
Dal Negro
R W
RW
Lung Dept., Orlandi Gen. Hospital, Bussolengo, Verona, Italy.
Micheletto
C
C
Tognella
S
S
Trevisan
F
F
Guerriero
M
M
D000280:Administration, Inhalation; D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage* / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D000420:Albuterol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000730:Androstadienes / Q000627:therapeutic use*; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D000068298:Fluticasone; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010366:Peak Expiratory Flow Rate / Q000187:drug effects; D000068299:Salmeterol Xinafoate; D013147:Spirometry; D016896:Treatment Outcome
D058672:Adrenergic beta-2 Receptor Antagonists; D000319:Adrenergic beta-Antagonists; D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D000068299:Salmeterol Xinafoate; D000068298:Fluticasone; D000420:Albuterol