THE DEMONSTRATION OF BRONCHODILATOR EFFECTS OF SALBUTAMOL FORMULATED IN CHLOROFLUOROCARBON AND HYDROFLUOROALKANE-134A METERED-DOSE INHALATION DEVICES ON LEUKOTRIENE D-4-INDUCED PULMONARY RESPONSES IN THE GUINEA-PIG

The demonstration of bronchodilator effects of beta(2)-adrenergic agon ists delivered by metered dose inhalation (MDI) devices can be useful in the development of new therapies for asthma or assessing the effect s of a formulation. MDI formulations of hydrofluoroalkane (HFA)-134a ( a chlorofluorocarbon [CFC]-free propellant), salbutamol in the HFA-134 a propellant, CFC-P11/P12 propellant, and salbutamol and formoterol in the CFC propellant were evaluated for their ability to reduce leukotr iene D-4 (LTD(4))-induced bronchoconstriction in guinea pigs using the Konzett-Rossler method. LTD(4) challenges were made at various times up to 6 hours after MDI treatment. Neither the placebo vehicle propell ants nor the drug formulations affected basal airflow. Only the salbut amol/CFC, formoterol/CFC, and salbutamol/HFA MDI formulations inhibite d LTD(4)-induced bronchoconstriction. One actuation of the MDI device containing salbutamol or formoterol in the CFC propellant produced sim ilar to 100% inhibition of LTD(4)-induced effects following a 5-minute pretreatment period at doses greater than or equal to 10 mu g per act uation. A single actuation of salbutamol (100 mu g per actuation) was required to show significant inhibition 30 minutes after aerosol drug delivery (similar to 50% inhibition) and was inactive 1 hour after dru g delivery. Inhibition with formoterol was observed at 30 minutes afte r aerosol delivery at 25 mu g per actuation and for up to 6 hours at 1 00 mu g per actuation. Results of this study indicate that the broncho dilator activity of MDI-delivered beta(2)-adrenergic agonists could be demonstrated using either CFC or HFA propellants in a standard precli nical animal model.