Theophylline Has a Dose-related Effect on the Airway Response to Inhaled Histamine and Methacholine in Asthmatics

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Abstract
To study whether theophylline inhibits airway hyperresponsiveness in a dose-dependent fashion, we performed inhalation challenges with histamine and methacholine in 9 asthmatic patients. On 4 separate days, 3 consecutive histamine or methacholine tests were carried out, each of them 20 min after saline (placebo) and after 100, 100, and 200 mg intravenous theophylline ethylenediamine given in a cumulative fashion. Airway responsiveness was expressed as the provocative dosage of histamine or methacholine necessary to increase specific airway resistance by 100% (PD100SRaw). After placebo PD100SRaw for histamine showed a small but significant (p < 0.01) increase not observed after methacholine. Theophylline markedly attenuated airway reactivity in a dose-dependent manner. At a mean (SD) serum concentration of 6.14 (0.30) mg/L, theophylline increased geometric mean PD100SRaw for histamine from 2.76 to 6.07 units (p < 0.01) and for methacholine from 1.52 to 2.60 units (p < 0.05). At a mean (SD) serum concentration of 12.9 (0.70) mg/L, theophylline increased geometric mean PD100SRaw for histamine for 2.70 to 17.1 units (p < 0.01) and for methacholine from 1.28 to 4.89 units (p < 0.01). Thus, there was a protective effect of theophylline on histamine and methacholine responsiveness in patients with bronchial asthma at "subtherapeutic" serum theophylline concentrations with increasing efficacy at higher serum theophylline concentrations. These observations may have therapeutic implications in the treatment of patients with mild asthma.