EFFECTS OF THEOPHYLLINE ON TOLERANCE TO THE BRONCHOPROTECTIVE ACTIONSOF SALMETEROL IN ASTHMATICS IN-VIVO

Long-term treatment with salmeterol produces tolerance for its protect ive effects against bronchoconstrictor stimuli in patients with asthma . There is human in vitro evidence that theophylline may prevent beta( 2)-adrenoceptor downregulation. Therefore, we investigated the effect of theophylline on the tolerance to the protective effect of salmetero l against histamine challenge in asthma in vivo. In a parallel 6-wk st udy, 25 asthmatics were treated with theophylline (mean serum level +/ - SEM: 9.9 +/- 1.1 mg/L, Days 1 to 40) or placebo, combined with inhal ed salmeterol (50 mu g twice daily, Days 8 to 36). Histamine challenge s 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 sig nificant change in PC20 after 4 d monotherapy with theophylline or pla cebo (mean difference +/- SEM: 0.54 +/- 0.39 and -0.02 +/- 0.41 doubli ng 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 s almeterol were significantly reduced to 1.80 +/- 0.35 and 1.69 +/- 0.3 6 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 g roups (p > 0.80). After cessation of salmeterol treatment, PC20, was n ot significantly different from the values at entry in either group (p > 0.90). We conclude that regular theophylline treatment neither prev ents, nor worsens, the development of tolerance to the bronchoprotecti ve effect of salmeterol in asthmatics in vivo.