Theophylline does not inhibit allergen-induced increase in airway responsiveness to methacholine

Allergen-induced increase in airway hyperresponsiveness can be used as a model of airway inflammation for assessing antiasthma pharmacologic agents. Steroids and cromolyn, but not βn-agonists, inhibit this increase; theophylline, recently suggested as having anti-inflammatory effects, has not been evaluated in this model. Six atopic subjects with asthma and with late asthmatic responses (N = 5) and postallergen reduction in a provocative concentration of methacholine causing a 20% fall in FEV₁ (PC₂₀) (N = 6) were studied. Sustained-release theophylline (Theo-Dur; Astra Pharmaceuticals Canada, Ltd., Mississauga, Canada), 300 mg, and placebo were administered single-blind twice daily for eight doses up to 1 hour before allergen inhalation; cromolyn sodium, 10 mg, was administered in a single dose 10 minutes before allergen inhalation on another day as a "positive control." Mean theophylline levels were in the low therapeutic range, 57 ± 17 and 58 ± 13 μmol/L 1 and 8 hours after the last tablet. The FEV₁ was 7% and 9% greater after the seventh and eighth doses of theophylline versus placebo (p < 0.05). Theophylline also produced a significant (p < 0.05) twofold increase in methacholine PC₂₀. There was a 40% (p = 0.06) reduction in early asthmatic fall in FEV₁ and a 25% (not significant) reduction in late FEV₁ fall when theophylline was compared to placebo. Theophylline did not influence the geometric mean allergen-induced fall in methacholine PC₂₀ Δ log PC₂₀; this was true individually in five of the six subjects. By contrast, cromolyn sodium inhibited all aspects of the allergen response completely. When FEV₁ had returned to baseline, the cromolyn sodium Δ log PC₂₀ (-0.02 ± 0.06) was significantly less than the theophylline Δ log PC₂₀ (0.42 ± 0.27) (p = 0.016). These data fail to provide evidence for an anti-inflammtory effect of theophylline in this in vivo human model. Theophylline appears to have primarily a bronchodilator effect.