Mieke C. Timmers

Long-term effects of a long-acting beta 2-adrenoceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma

BACKGROUND Asthma is characterized by hyperresponsiveness of the airways to bronchoconstrictive stimuli. Long-acting beta 2-adrenoceptor agonists have been introduced as a new therapeutic approach, but there is growing concern about whether control of asthma may deteriorate with the regular use of these agents. We investigated the long-term effects of the beta 2 agonist salmeterol on bronchodilation and on airway hyperresponsiveness to the bronchoconstrictive agent methacholine in mild asthma. METHODS In a parallel, double-blind study, 24 patients with mild asthma were randomly assigned to treatment with either inhaled salmeterol (50 micrograms, twice daily) (n = 12) or placebo (n = 12) during an eight-week trial. Methacholine challenge was performed before, during, and after the treatment period. Methacholine responsiveness was measured as the provocative concentration (PC20) that caused a 20 percent decrease in the forced expiratory volume in one second (FEV1). RESULTS There was a significant increase in FEV1 one hour after the inhalation of salmeterol (P = 0.006), which did not differ significantly on days 0, 28, and 56 of the treatment period (increase, 9.8, 9.4, and 8.8 percent of predicted FEV1, respectively; P = 0.91). On the first treatment day, salmeterol afforded significant protection against methacholine-induced bronchoconstriction, as shown by a 10-fold increase in the PC20 as compared with the value at entry (P less than 0.001). After four and eight weeks of treatment, however, the salmeterol-induced change in the PC20 was significantly attenuated (P less than 0.001) to only a twofold increase. Two and four days after treatment ended, the PC20 was not significantly different from the value before treatment (P = 0.15). CONCLUSIONS Regular treatment of patients with mild asthma with salmeterol leads to tolerance to its protective effects against a bronchoconstrictor stimulus, in this case inhaled methacholine, despite well-maintained bronchodilation. This finding raises concern about the effectiveness of prolonged therapy with long-acting beta 2-adrenoceptor agonists in asthma.

Effect of experimental rhinovirus 16 colds on airway hyperresponsiveness to histamine and interleukin‐8 in nasal lavage in asthmatic subjects in vivo

Background Asthma exacerbations are closely associated with respiratory virus infections. However, the pathophysiological consequences of such infections in asthma are largely unclear.

The protective effect of a beta 2 agonist against excessive airway narrowing in response to bronchoconstrictor stimuli in asthma and chronic obstructive lung disease.

Beta 2 agonists reduce airway hypersensitivity to bronchoconstrictor stimuli acutely in patients with asthma and chronic obstructive lung disease. To determine whether these drugs also protect against excessive airway narrowing, the effect of inhaled salbutamol on the position and shape of the dose-response curves for histamine or methacholine was investigated in 12 patients with asthma and 11 with chronic obstructive lung disease. After pretreatment with salbutamol (200 or 400 micrograms) or placebo in a double blind manner dose-response curves for inhaled histamine and methacholine were obtained by a standard method on six days in random order. Airway sensitivity was defined as the concentration of histamine or methacholine causing a 20% fall in FEV1 (PC20). A maximal response plateau on the log dose-response curve was considered to be present if two or more data points for FEV1 fell within a 5% response range. In the absence of a plateau, the test was continued until a predetermined level of severe bronchoconstriction was reached. Salbutamol caused an acute increase in FEV1 (mean increase 11.5% predicted in asthma, 7.2% in chronic obstructive lung disease), and increase in PC20 (mean 15 fold in asthma, fivefold in chronic obstructive lung disease), and an increase in the slope of the dose-response curves in both groups. In subjects in whom a plateau of FEV1 response could be measured salbutamol did not change the level of the plateau. In subjects without a plateau salbutamol did not lead to the development of a plateau, despite achieving a median FEV1 of 44% predicted in asthma and 39% in chronic obstructive lung disease. These results show that, although beta 2 agonists acutely reduce the airway response to a given strength of bronchoconstrictor stimulus, they do not protect against excessive airflow obstruction if there is exposure to relatively strong stimuli. This, together with the steepening of the dose-response curve, could be a disadvantage of beta 2 agonists in the treatment of moderate and severe asthma or chronic obstructive lung disease.

Small airways function and molecular markers in exhaled air in mild asthma

Background: Several studies suggest that the periphery of the lung is the major site of inflammation in asthma. Fractional exhaled nitric oxide (Feno) and 8-isoprostane have been proposed as biomarkers of inflammation and oxidative stress. We therefore hypothesised that small airway dysfunction in asthma is of inflammatory origin that can be detected by molecular markers in exhaled air. To test this hypothesis, we examined the relationship of Feno and 8-isoprostane in exhaled air with small airways function as assessed by the single breath nitrogen test. Methods: Sixteen patients (14 women) with mild atopic asthma (forced expiratory volume in 1 second >80% predicted) of mean (SD) age 23.0 (5.5) years participated in a cross sectional study. Feno was recorded by chemiluminescence and 8-isoprostane was measured by ELISA in concentrated exhaled breath condensate. The slope of phase III (δN2) and the closing volume (CV) were assessed from the single breath washout curve. Results: The median Feno level was 30.4 ppb (range 10.1–82.8), the median 8-isoprostane concentration in exhaled breath condensate was 2.2 pg/ml (range 1.6–2.7), and the mean (SD) δN2 value was 1.1 (0.4)% N2/l. Feno was positively associated with δN2 (rs = 0.54, p = 0.032) while 8-isoprostane was inversely correlated with FEV1% predicted (rs = −0.58; p = 0.017) and CV as a percentage of vital capacity (rs = 0.58; p = 0.019). Conclusions: Feno and 8-isoprostane in exhaled air are associated with small airways function in mild asthma. This suggests that these markers reflect small airway inflammation and favours a role for them as disease markers that is complementary to spirometry in the monitoring of patients with asthma.

The effect of an inhaled leukotriene antagonist, L-648,051, on early and late asthmatic reactions and subsequent increase in airway responsiveness in man.

We have investigated the protective effects of the inhaled cysteinyl leukotriene antagonist, L-648,051, on allergen-induced early asthmatic response (EAR) and late asthmatic response (LAR) and the subsequent changes in bronchial responsiveness to methacholine. Ten atopic men with asthma participated in a double-blind, crossover, placebo-controlled trial. All subjects had documented EAR and LAR to house dust-mite extract. Responsiveness to methacholine was measured the day before and the day after a standardized allergen-challenge test. L-648,051 was inhaled in two doses of 12 mg 20 minutes before and 3 hours after the allergen challenge. The response was obtained from FEV1 and flows from maximal (V40m) and partial (V40p) expiratory flow-volume curves. All subjects had an EAR and LAR during placebo therapy, but only a minority demonstrated an increase in methacholine responsiveness of more than one doubling dose. The ratio of V40m to V40p during methacholine challenge was higher than during both EAR and LAR (p less than 0.05). There was no difference between drug- and placebo-therapy periods in baseline function, EAR, LAR, ratio of V40m to V40p, and the allergen-induced hyperresponsiveness (p greater than 0.1). These results indicate that an effective aerosolized leukotriene antagonist in man does not protect against allergen-induced airflow obstruction, despite the evidence of an inflammatory response to allergen challenge. This suggests that either the potency or duration of activity of L-648,051 is limited or that leukotrienes C4 and D4 do not play a causative role in human allergic asthma.

Protective effect of inhaled budesonide against unlimited airway narrowing to methacholine in atopic patients with asthma

BACKGROUND Patients with asthma who have moderate to severe airway hyperresponsiveness often demonstrate progressive, unlimited airway narrowing in response to inhaled bronchoconstrictor stimuli, which is likely to be due to inflammatory changes within the airway wall. It is unknown whether regular therapy with inhaled steroids can limit this excessive response. OBJECTIVE We investigated the effect of inhaled budesonide on the development of a plateau on the dose-response curve to methacholine in patients with asthma who did not show such a plateau before the study. METHODS Thirty-one atopic patients with asthma (age, 19 to 31 years; FEV1 > 70% of predicted value; PC20 < 8 mg/ml) with documented absence of a maximal-response plateau to methacholine on two occasions during the run-in period, participated in a double-blind, placebo-controlled, parallel study. Standardized methacholine challenges were performed at -1, 0, 4, 8, and 12 weeks of treatment with inhaled budesonide, 800 microg two times a day, or corresponding placebo, and after a 2-week washout period. Airway response was measured by FEV1 (percent fall from baseline). A maximal-response plateau was considered if three or more consecutive data points fell within a 5% response range. RESULTS Thirty patients completed the study. There was a steady increase in the number of budesonide-treated patients exhibiting a maximal-response plateau on the dose-response curve from zero of 15 patients at run-in to nine of 14 patients at week 12, as compared with four of 16 patients in the placebo group (p = 0.03, chi square test). This was accompanied by a significant improvement in PC20 in the budesonide group as compared with the placebo group (p < 0.01 at week 12), whereas the changes in FEV1 were not significantly different between the groups (p = 0.77 at week 12). CONCLUSION Regular treatment with the inhaled corticosteroid budesonide limits maximal airway narrowing in response to methacholine by introducing a plateau on the dose-response curve in patients with asthma, who were initially characterized by the absence of a plateau. This indicates that inhaled steroids are likely to reduce the hazard of unlimited airway narrowing in asthma.