Combination bronchodilator therapy for chronic obstructive pulmonary disease (COPD) potentially can provide increased benefit over single-agent therapy. The objective of this double-blind, randomized, positive-control trial was to determine the effectiveness of an albuterol-ipratropium solution aerosol combination (Dey combination solution, Dey LP, Napa, Calif., USA) compared with solution aerosols of both component medications administered alone in patients with COPD. The trial consisted of a 6-week, 3-period crossover phase followed by a 6-week parallel phase during which patients self-administered study medications by inhalation from a nebulizer. A total of 863 patients were initially randomized to each of the six possible treatment sequences of the three study medications in the crossover phase and received each study medication in turn for a 2-week period. Patients continued to receive the same treatment administered during the last 2-week period of the crossover phase for an additional 6 weeks in the parallel phase. Assessment of 1-second forced expiratory volume (FEV₁) curves before and after dosing on the last day of each 2-week period indicated that the combination was superior to either single agent in peak effect and area under the curve up to 8 h after dosing (FEV₁-AUC_0–8), in both phases of the trial. The use of Dey combination during the crossover phase resulted in 24% more improvement in peak FEV₁ than was seen with albuterol alone (p < 0.001), and 37% more than was seen with ipratropium alone (p < 0.001). Similarly, when examining FEV₁-AUC_0–8, Dey combination resulted in 30% more improvement than was seen with albuterol alone (p < 0.001), and 32% more than was seen with ipratropium alone (p < 0.001). The combination affords a convenient dosing regimen and incorporates enhanced benefit without compromising the safety profile of either component agent.

The demonstration of bronchodilator effects of ß2-adrenergic agonists delivered by metered dose inhalation (MDI) devices can be useful in the development of new therapies for asthma or assessing the effects of a formulation. MDI formulations of hydroiluoroalkanc (HFA)-134a (a chlorofluorocarbon [CFC]-free propellant), salbutamol in the HFA-134a propellant, CFC-P11/P12 propellant, and salbutamol and formoterol in the CFC propellant were evaluated for their ability to reduce leukotriene D4 (LTD4)-induced bronchoconstriction in guinea pigs using the Konzett-Rossler method. LTD4 challenges were made at various times up to 6 hours after MDI treatment. Neither the placebo vehicle propellants nor the drug formulations affected basal airflow. Only the salbutamol/CFC, formoterol/CFC, and salbutamol/HFA MDI formulations inhibited LTD4-induced bronchoconstriction. One actuation of the MDI device containing salbutamol or formoterol in the CFC propellant produced -100% inhibition of LTD4-induced effects following a 5-minute pretreatment period at doses greater than or equal to 10 pg per actuation. A single actuation of salbutamol (100 fig per actuation) was required to show significant inhibition 30 minutes after aerosol drug delivery (-50% inhibition) and was inactive 1 hour after drug delivery. Inhibition with formoterol was observed at 30 minutes after aerosol delivery at 25 fig per actuation and for up to 6 hours at 100 fig per actuation. Results 41 HAMMERBECK ET AL.of this study indicate that the bronchodilator activity of MDI-delivered /^-adrenergic agonists could be demonstrated using either CFC or HFA propellants in a standard preclinical animal model.