Efficacy as Maintenance Therapy for Chronic Asthma

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Theophylline has been repeatedly demonstrated to be effective as a single maintenance medication in the management of chronic asthma. The first studies of this in the early 1970s demonstrated that symptoms were markedly diminished, and need for intervention with measures to treat acute symptoms were virtually eliminated for most patients (14,15). Subsequent studies compared theophylline with alternative medications. Theophylline was associated with more asymptomatic days than cromolyn sodium (disodium cromoglycate) when both were used as monotherapy in patients with severe chronic asthma (16), although efficacy appeared similar in patients with milder asthma (62-64).

Comparison with oral p2-agonists have shown clinical advantage for theophylline, especially for nocturnal symptoms (65,66). Although inhaled albuterol is far more potent for acute bronchodilatation than theophylline, a controlled clinical trial demonstrated that theophylline nonetheless provided more stable clinical effect (19). In contrast, longer acting |b2-agonists, salme-terol and formoterol, are used as twice-daily maintenance medications for chronic asthma. In a two-week comparison study with theophylline (67), salmeterol was more effective than theophylline, but only 98 of 141 patients (median age 51) completed the trial, and over half the patients had serum theophylline concentrations below the 10-20 mg/mL range despite initially determined dosage that attained serum concentrations of 10-20 mg/mL, where maximal efficacy is most likely (14,34,35). Other large-scale multicenter trials have suffered from the same problem with most patients having serum concentrations consistently below 10 mg/mL during the trial (68,69). A study of 15 patients reported little difference between salmeterol and theophylline on nocturnal asthma during a two-week study with a range of serum theophylline concentrations from less than 8 to greater than 15 mg/mL (median 11 mg/mL) (70). Although several large trials have reported sustained bronchodilatation and clinical efficacy with long-term use of salmeterol (71), there is concern regarding loss ofbronchoprotective effect against challenge with methacholine (72), exercise (73,74), and allergen inhalation (75) after as little as two weeks. The effect from continuous use of p2-agonists may be particularly important for certain genetic polymorphisms of the p2-receptor (76). In contrast, attenuation of airway responsiveness to exercise is sustained with theophylline (77).

Theophylline has substantial additive effect with inhaled (17,20,22) or alternate morning oral corticosteroids (17), reducing symptoms (Fig. 1), improving exercise tolerance, and decreasing requirements for inhaled bronchodilator and the need for short courses of corticosteroids because of bronchodilator subresponsiveness (17). Moreover, abrupt discontinuation of theophylline in patients with severe asthma results in precipitous deterioration even though other drugs such as cromolyn, inhaled steroids, and p2-agonists are continued (20). This has been observed even among patients receiving a mean of 1500 mg/day of beclomethasone (22). In contrast, cromolyn sodium (disodium cromoglycate) has not shown additive effect with either theophylline (16) or inhaled corticosteroids in three placebo-controlled studies (78-80). Trials of nedocromil in adults at doses of 4mg (81) and 8mg (82) four times daily showed only a small additive effect with inhaled corticosteroids. A small additive effect with inhaled cor-ticosteroids has been observed for a leukotriene antagonist, montelukast (83), but this appears to be less than is seen from adding salmeterol (84). Of currently marketed non-steroidal medications, only salmeterol has had additive benefit of a magnitude similar to theophylline for patients already receiving an inhaled corticosteroid (85,86).

The degree of clinical effect from theophylline described above is most readily apparent when serum concentrations are maintained between 10 and 20 mg/mL (14,33-35), and the magnitude of effect can be demonstrated to relate to serum concentration (26,35,87,88). Measures of effect on airway hyper-responsiveness to histamine (23), methacholine (23,89), or exercise (26) relate closely to serum concentration. Inhibition of exercise-induced bronchospasm relates to serum concentration, with clinically important

Figure 1 Mean frequency of symptoms in 21 children with asthma receiving a constant dose of beclomethasone dipropionate (mean of 550 mg/day, 11 puffs per day) and treated in randomized sequence for four weeks with each of placebo (p) or theophylline at dosage previously individualized to achieve a peak serum concentration of 10-20 mg/mL (t). Nocturnal symptoms of cough, wheeze, or dyspnea that disturbed sleep were recorded each morning, and interference with activity, cough, and wheeze during the day were recorded each evening as absent, transient, repeated, or continuous. In addition to significantly fewer symptoms, theophylline was also associated with significantly less airway responsiveness to exercise and significantly fewer interventions with both inhaled b2-adrenergic agonists and short courses of oral corticosteroids. Source: From Ref. 17.

Figure 1 Mean frequency of symptoms in 21 children with asthma receiving a constant dose of beclomethasone dipropionate (mean of 550 mg/day, 11 puffs per day) and treated in randomized sequence for four weeks with each of placebo (p) or theophylline at dosage previously individualized to achieve a peak serum concentration of 10-20 mg/mL (t). Nocturnal symptoms of cough, wheeze, or dyspnea that disturbed sleep were recorded each morning, and interference with activity, cough, and wheeze during the day were recorded each evening as absent, transient, repeated, or continuous. In addition to significantly fewer symptoms, theophylline was also associated with significantly less airway responsiveness to exercise and significantly fewer interventions with both inhaled b2-adrenergic agonists and short courses of oral corticosteroids. Source: From Ref. 17.

effects most apparent above 10 mg/mL and even greater effects above 15 mg/ mL (26). At these concentrations theophylline is more effective than cromo-lyn in attenuating exercise-induced bronchospasm (26), although it generally does not match the acute benefits from an inhaled |b2-receptor agonist.

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