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

Abstract

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 beta2-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 microgram 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.

Prevention of asthma in genetically susceptible children: A multifaceted intervention trial focussed on feasibility in general practice

“…Thereafter, a histamine challenge test was performed. An aerosol of buffered saline was inhaled, followed by aerosols of histamine acid phosphate in doubling concentrations from 0.03 to 16 mg/ml at 5‐min intervals (26). Dynamic spirometry was repeated once after 30 and after 90 sec following each inhalation.…”

Effect of oral prednisolone on the bronchoprotective effect of formoterol in patients with persistent asthma

“…Longacting b 2 -agonists are indicated in the treatment of patients with moderate and severe persistent asthma for relief of symptoms [1]. With continued use of longacting b 2 -agonists, these patients develop tolerance to the bronchoprotective effect of these drugs [7], which is not prevented by concomitant treatment with inhaled corticosteroids [10 -13], oral theophylline [23], or oral glucocorticoids. Furthermore, exposure to allergens may result in b 2 -receptor dysfunction [24], possibly on top of the existing downregulated b 2 -receptor numbers [17].…”

Effects of Salmeterol in Patients with Persistent Asthma Receiving Inhaled Corticosteroid plus Theophylline

“…In patients with chronic obstructive pulmonary disease, a combination therapy with salmeterol and theophylline provided significantly greater physiological and clinical improvements than a monotherapy with either agent alone [18, 19]. It has been reported that adding theophylline to regular salmeterol treatment neither prevents nor worsens the development of tolerance to the bronchoprotective effect of salmeterol in asthma [20]. The interaction between LABA and theophylline has been uncertain in severe asthma.…”