Cheung D, Wever A M, de GOEIJ J A, de GRAAFF C S, Steen H, Sterk P J
Department of Pulmonology, Leiden University Medical Centre, Red Cross Hospital, The Hague, The Netherlands.
Am J Respir Crit Care Med. 1998 Sep;158(3):792-6. doi: 10.1164/ajrccm.158.3.9801036.
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.
沙美特罗长期治疗会使哮喘患者对其针对支气管收缩刺激的保护作用产生耐受性。有体外人体证据表明,茶碱可能预防β2 -肾上腺素能受体下调。因此,我们研究了茶碱对哮喘患者体内沙美特罗针对组胺激发的保护作用耐受性的影响。在一项为期6周的平行研究中,25名哮喘患者接受茶碱治疗(平均血清水平±标准误:9.9±1.1 mg/L,第1至40天)或安慰剂治疗,并联合吸入沙美特罗(每日两次,每次50微克,第8至36天)。在入组时以及第4、8、22、36和40天通过潮气呼吸法进行组胺激发试验。通过PC20测量反应。茶碱或安慰剂单药治疗4天后,PC20无显著变化(平均差异±标准误:分别为0.54±0.39和 -0.02±0.41倍剂量增加[DD];p>0.15)。首次给药1小时后,沙美特罗对组胺提供显著保护,茶碱组和安慰剂组的PC20均增加(分别增加3.49±0.28和3.36±0.32 DD;p<0.001)。然而,沙美特罗治疗2周和4周后,茶碱组中沙美特罗使PC20的改善分别显著降低至1.80±0.35和1.69±0.36 DD(p<0.001),安慰剂组分别降低至1.55±0.47和1.52±0.56 DD(p<0.002)。两组之间这些变化无显著差异(p>0.80)。停止沙美特罗治疗后,两组的PC20与入组时的值均无显著差异(p>0.90)。我们得出结论,在体内,常规茶碱治疗既不能预防也不会加重哮喘患者对沙美特罗支气管保护作用耐受性的发展。