Effect of chronic theophylline treatment on the methacholine dose-response curve in allergic asthmatic subjects

Abstract

Theophylline is a bronchodilator and immunomodulator drug which has recently been demonstrated to attenuate the recruitment and activation of inflammatory cells into lungs of asthmatics. This study investigated the effect of chronic treatment with theophylline for its ability to alter airway responsiveness, as indicated by changes in airway sensitivity and reactivity to inhaled methacholine. The subjects studied were mild asthmatics who relied on beta-agonist medication only and who were randomized into two groups, one receiving theophylline (median dose 250 mg twice daily; range 250-375 mg twice daily) and the other placebo. A number of parameters was measured before and after treatment, including baseline forced expiratory volume in one second (FEV1), the provocative concentration of methacholine causing a 20% fall in FEV1 (PC20; sensitivity), dose-response slope (reactivity) and percentage eosinophils, eosinophil cationic protein and T-cell markers in peripheral blood (by flow cytometry). After 2 months of treatment with theophylline there was a significant lowering of airway reactivity (slope) to methacholine and improvement in methacholine sensitivity (PC20). However, such changes were not associated with any significant change in the number or activation status of eosinophils and lymphocytes in peripheral blood. In conclusion, chronic treatment with theophylline reduces the reactivity of the airways to methacholine, which might be beneficial in the treatment of persistent asthma. The cellular mechanisms of this improvement remain to be clarified.

A molecular mechanism of action of theophylline: Induction of histone deacetylase activity to decrease inflammatory gene expression

“…Several studies have shown that low doses of theophylline have an anti-inflammatory or immunomodulatory effect in vivo (3,4,(6)(7)(8)(9)(10)(11)(12)29). In our current study we did not find any significant effect of theophylline on lung function or airway hyperresponsiveness (5).…”

“…In asthmatic patients low-dose theophylline reduces eosinophils and other inflammatory markers (5-7), inhibits the eosinophilia induced by an inhaled allergen (8), and reduces the expression of cytokines, such as interleukin (IL)-5 (9). Long-term treatment with theophylline reduces airway hyperresponsiveness to methacholine challenge (10). In addition, in patients with severe asthma who are withdrawn from theophylline, there is a deterioration of asthma control, despite the fact that patients are maintained on high does of inhaled corticosteroids (11,12).…”

Outpatient treatment of chronic obstructive pulmonary disease: Comparisons with asthma

“…89 The use of low-dose theophylline appears to reduce the number of activated lymphocytes in the peripheral blood after allergen challenge, 90 and in subjects with nocturnal asthma, theophylline results in significant reductions in the percentage of bronchoalveolar lavage neutrophils and eosinophils at 4 AM. 91 Theophylline also protects against airway responsiveness in asthma, 92,93 but despite the antiinflammatory effects of theophylline, the results from multiple clinical trials indicate that methyl xanthines are inferior to inhaled corticosteroids in the treatment of chronic asthma.…”

Performing a Lung Disability Evaluation

“…(48-60) In one study, patients with asthma with the minimum medication needed to control symptoms were divided into four groups: (1) those who required no medication; (2) those who required short-acting β 2 agonist occasionally, but not daily; (3) those who required daily short-acting β 2 agonist; and (4) those who required additional inhaled corticosteroid dosing. The mean PC 20 value was highest in group 1 and lowest in group 4; the differences between each group were significant.…”