Am. J. Respir. Crit. Care Med., Volume 158, Number 3, September 1998, 792-796

Effects of Theophylline on Tolerance to the Bronchoprotective Actions of Salmeterol in Asthmatics In Vivo

DAVID CHEUNG, ANTON M. J. WEVER, JAAP A. de GOEIJ, CASPER S. de GRAAFF, HERMAN STEEN, and PETER J. STERK

Department of Pulmonology, Leiden University Medical Centre; Red Cross Hospital, The Hague; Schieland Hospital, Schiedam; Medical Centre Alkmaar; and Byk, Zwanenburg, The Netherlands

Long-term treatment with salmeterol produces tolerance for its protective effects against bronchoconstrictor stimuli in patients with asthma. There is human in vitro evidence that theophylline may prevent ₂-adrenoceptor downregulation. Therefore, we investigated the effect of theophylline on the tolerance to the protective effect of salmeterol against histamine challenge in asthma in vivo. In a parallel 6-wk study, 25 asthmatics were treated with theophylline (mean serum level ± SEM: 9.9 ± 1.1 mg/L, Days 1 to 40) or placebo, combined with inhaled salmeterol (50 µg twice daily, Days 8 to 36). Histamine challenges were carried out by tidal breathing method at entry, and at Days 4, 8, 22, 36, and 40. The response was measured by PC₂₀. There was no significant change in PC₂₀ after 4 d monotherapy with theophylline or placebo (mean difference ± SEM: 0.54 ± 0.39 and 0.02 ± 0.41 doubling dose [DD], respectively; p > 0.15). One hour after the first dose, salmeterol afforded significant protection against histamine, as shown by an increase in PC₂₀ in both the theophylline and placebo group (by 3.49 ± 0.28 and 3.36 ± 0.32 DD, respectively; p < 0.001). However, after 2 and 4 wk salmeterol treatment, the improvements in PC₂₀ by salmeterol were significantly reduced to 1.80 ± 0.35 and 1.69 ± 0.36 DD, respectively, in the theophylline group (p < 0.001), and to 1.55 ± 0.47 and 1.52 ± 0.56 DD, respectively, in the placebo group (p < 0.002). These changes were not significantly different between the groups (p > 0.80). After cessation of salmeterol treatment, PC₂₀ was not significantly different from the values at entry in either group (p > 0.90). We conclude that regular theophylline treatment neither prevents, nor worsens, the development of tolerance to the bronchoprotective effect of salmeterol in asthmatics in vivo.

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