EFFECT OF THEOPHYLLINE ADMINISTERED INTRATRACHEALLY AS A DRY POWDER FORMULATION ON BRONCHOSPASM AND AIRWAY MICROVASCULAR LEAKAGE IN THE ANESTHETIZED GUINEA-PIG

The effect of theophylline (a non-selective phosphodiesterase (PDE) inhibitor), dosed intratracheally (it) as a dry powder, on histamine- and platelet activating factor (Paf)-induced bronchospasm and antigen (ovalbumin, OA)-, histamine- and Paf-induced microvascular leakage (MVL) in the airways, was studied in the anaesthetized guinea-pig. Bronchospasm was measured as the increase in pulmonary inflation pressure (PIP). MVL was assessed by fluorometric assay of fluorescein isothiocyanate dextran (FITC-dextran) content in airway tissues and tracheobronchial lavage fluid. OA (200 mu g), histamine (60 nmol) and Paf (4 nmol), all given it, significantly increased MVL by up to 350% over levels in undosed unchallenged animals. Theophylline (50-500 mu g it, n=5-6) inhibited histamine-induced bronchospasm (30% inhibitory dose, ID30: 258+/-30 mu g) and Paf-induced bronchospasm (ID30: 190+/-80 mu g). An inhibition of 40-50% of maximal bronchospasm was the largest attained. Theophylline, at approximately the bronchospasm ID30 dose (200 mu g it, n=4-8), inhibited MVL induced by all agents by 30-80% in airway tissues and in lavage fluid samples. Theophylline (50-500 mu g it, n=3) produced plasma drug levels of 0.13+/-0.07 to 0.83+/-0.39 mu g/ml 10 min after dosing. Plasma levels were the same 60 min after dosing, suggesting retention of theophylline in the airways. The local concentration of theophylline retained in the airways should be sufficient to inhibit PDE activity. Direct application of theophylline (arguably by inhibition of the PDE isoforms PDE III, PDE IV and PDE V) thus has significant antiinflammatory and some bronchodilator effects at very low doses which should have no systemic toxicity. Theophylline applied as a dry powder locally in the airways may thus improve its documented usefulness in the treatment of asthma.