title: Systemic and bronchodilator effects of inhaled rac-formoterol in subjects with chronic obstructive pulmonary disease: a dose-response study.
abstract: BACKGROUND
  The long-acting inhaled beta(2)-agonist formoterol has systemic effects when taken in high doses. It can be used as relief medication in asthma and there is interest in this approach in chronic obstructive pulmonary disease (COPD). Relief medication can involve high doses, and in subjects with COPD who have limited ability to bronchodilate the adverse effects can outweigh the benefits. There are concerns with the overall safety of high-dose beta(2)-agonists in subjects with COPD, and this study looks at the balance of beneficial and adverse effects of a range of doses of inhaled formoterol.
  
  
  CONCLUSIONS
  Among subjects with COPD, high-dose inhaled formoterol produced a dose-related increase in forced expiratory volume in 1 s without a corresponding reduction in dyspnoea or increase in walk distance. Systemic effects were modest, however, and high doses did not appear to reduce patient satisfaction. Although further safety data are needed, inhaled formoterol may have a role as relief medication in COPD. AIMS Rac-formoterol is effective as maintenance treatment for both asthma and chronic obstructive pulmonary disease (COPD) and is now used as relief therapy in asthma. Using rac-formoterol for relief and maintenance treatment could involve inhalation of high doses, and whether this is of benefit in COPD is uncertain. Our aim was to determine whether higher doses of inhaled rac-formoterol produce systemic adverse effects that outweigh the limited bronchodilator benefit seen in subjects with COPD.
  
  
  METHODS
  We examined airway and systemic effects of 6, 12, 24 and 48 microg rac-formoterol and placebo on separate days in 20 subjects with symptomatic COPD [forced expiratory volume in 1 s (FEV(1)) 47% predicted]. FEV(1), oxygen saturation, dyspnoea, 6-min walk distance, patient satisfaction and systemic effects were measured and treatment was assessed against placebo and for dose-response effects.
  
  
  RESULTS
  FEV(1)[area under the time-response curve (AUC)] and satisfaction scores increased with all formoterol doses compared with placebo, as did AUC tremor with the 24- and 48-microg doses and AUC heart rate with the 48-microg dose. A dose-response relationship was seen with FEV(1) and tremor, but not with satisfaction scores. There was no difference between placebo and rac-formoterol for other variables.
  
  
  CONCLUSIONS
  Our results show that in patients with COPD rac-formoterol improves FEV(1) and patient satisfaction without a corresponding reduction in dyspnoea. Since the systemic effects from a relatively high dose were minimal, its use as relief medication in COPD merits further evaluation.
authors.affiliation: Division of Respiratory Medicine, University of Nottingham, City Hospital, Nottingham, UK. chris.whale@btinternet.com
authors.forename: Christopher I
authors.initials: CI
authors.lastname: Whale
authors.forename: Milind P
authors.initials: MP
authors.lastname: Sovani
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Mortimer
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Harrison
authors.forename: Anne E
authors.initials: AE
authors.lastname: Tattersfield
mesh_terms: D000280:Administration, Inhalation; D000368:Aged; D019540:Area Under Curve; D001993:Bronchodilator Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004983:Ethanolamines / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D005541:Forced Expiratory Volume; D000068759:Formoterol Fumarate; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy*
chemical_list: D001993:Bronchodilator Agents; D004983:Ethanolamines; D000068759:Formoterol Fumarate