Fluticasone propionate versus zafirlukast: effect in patients previously receiving inhaled corticosteroid therapy.

BACKGROUND: The use of inhaled corticosteroids compared with leukotriene modifying drugs in the treatment of persistent asthma has not been extensively studied. OBJECTIVE: To compare the efficacy and safety of a low dose of fluticasone propionate (FP) and zafirlukast in patients previously maintained on inhaled corticosteroids. METHODS: Patients (> or = 12 years old; FEV1 = 60% to 85% of predicted) with persistent asthma who were previously treated with low doses of triamcinolone acetonide (TAA) 400 to 800 microg/day or beclomethasone dipropionate (BDP) 168 to 336 microg/day were randomized to treatment with FP aerosol 88 microg BID (FP, n = 221) or zafirlukast 20 mg BID (n = 216) over 6 weeks. RESULTS: Treatment with FP significantly increased the mean change at endpoint (the last post-baseline observation) in FEV1 (0.22 L versus 0.03 L, P < .001), morning PEF (17.8 versus 3.1 L/min, P = .004), evening PEF (16.7 versus 2.6 L/min, P = .002), the percentage of symptom-free days (16.2 versus 7.1%, P = .007), and the percentage of rescue-free days (23.4 versus 9.3%, P < .001), and significantly decreased rescue albuterol use (-0.66 puffs/day versus an increase of 0.27 puffs/day, P < .001) and combined symptom scores (-0.13 versus an increase of 0.08, P < .001) compared with zafirlukast. Treatment with FP maintained the percentage of awakening-free nights (-1.0 +/- 1.0); in contrast, treatment with zafirlukast reduced the percentage of awakening-free nights (-9.0 +/- 1.6, P < .001). A clinically meaningful difference (change of > or = 0.5; P < .001) was observed between FP and zafirlukast in the Asthma Quality of Life Questionnaire (AQLQ) global score and for each domain score except activity limitation (change of 0.3, P < .001). Significantly more patients in the zafirlukast group experienced an asthma exacerbation (n = 14) compared with FP-treated patients (n = 5, P = .035). Patients in the zafirlukast group were significantly more likely to be withdrawn due to lack of efficacy (P < .001). CONCLUSION: Switching patients from low doses of inhaled corticosteroids to a lower total microgram dose of FP improves pulmonary function, asthma symptoms, and quality of life, while switching to the leukotriene receptor antagonist zafirlukast may result in worsening of asthma control. This was indicated by the significant number of zafirlukast-treated patients who were dropped from the study due to lack of efficacy within 6 weeks of discontinuing inhaled corticosteroids.

A multicenter, placebo-controlled study of twice daily triamcinolone acetonide (800 microg per day) for the treatment of patients with mild-to-moderate asthma.

BACKGROUND: National and international guidelines recommend the use of inhaled antiinflammatory medications in patients with all but the mildest forms of asthma. Twice daily dosing may increase compliance with therapy. OBJECTIVE: We sought to evaluate the safety and efficacy of 400 microg twice daily triamcinolone acetonide (TAA) compared with placebo in adult patients with mild-to-moderate asthma who were poorly controlled by beta2-agonist therapy. METHODS: We performed a multicenter, randomized, double-blind, placebo-controlled study, including a screening visit, a 7- to 21-day pretreatment baseline phase, and a 6-week double-blind treatment phase. Efficacy was measured by weekly spirometry and daily diary recordings of peak flow rates, asthma symptom scores, and albuterol use. Eligible patients used albuterol four or more times per day, had total asthma symptom scores of 15 or greater (possible total, 60) over 5 of 7 baseline days, and had FEV1 measurements of 60% of predicted value or greater. RESULTS: One hundred twenty-one patients were randomized to treatment. TAA was superior to placebo for all efficacy measures, with significant improvements in asthma symptoms, albuterol use, morning and evening peak flow rates, and forced vital capacity evident at Treatment Week 1. Significant improvements in other pulmonary function measurements were observed after 2 or more weeks. All efficacy variables improved progressively throughout the study. CONCLUSIONS: Twice daily TAA (400 microg) decreased asthma symptoms and improved lung function in patients with mild-to-moderate asthma compared with placebo. Therapeutic benefit was evident within 1 week and increased throughout treatment.

Dose-dependent kinetics of theophylline disposition in asthmatic children.

Prior assumptions of first-order elimination for theophylline were tested by administering theophylline by intravenous infusion at two dosage levels to 20 children with chronic asthma. The resulting steady-state serum concentrations increased to a greater degree than would have been predicted if increases in serum concentration were proportional to changes in dose, and the subsequent calculation of clearance revealed values of 1.37 +/- 0.09 ml/kg/minute (mean +/- SE of the mean) at the lower infusion rate and of 1.21 +/- 0.06 ml/kg/minute at the higher infusion rate (p less than 0.02). Even greater differences in clearance were present among ten of these children whose higher infusion rates were at least two times greater than the lower rate. An additional child was observed who experienced a seizure following a medication error that resulted in a 50% increase in daily dosage and a greater than threefold increase of serum concentration. The nonlinear nature of the relationship between dose and serum concentration suggests that theophylline dosage adjustment should be performed cautiously using small increments.

Relationship of theophylline clearance to oral dosage in children with chronic asthma.

Theophylline clearance was examined in 23 children with chronic asthma by administering constant intravenous infusions of theophylline until steady-state serum concentrations were documented. Clearance was subsequently related to peak and trough serum concentrations during a multiple-dose oral theophylline regimen. Although theophylline clearances tended to decrease with age, considerable interpatient variability was observed. Clearances correlated inversely with a standardized index of serum concentration response to oral dosage resulting in a wide range of dosage requirements to maintain therapeutic serum concentrations of 10 to 20 microgram/ml. Intrapatient variability over an interval up to seven months, however, was acceptably small, suggesting that dosage requirements, once established for an individual, should remain relatively stable under normal conditions. Differences in serum theophylline values during a 6-hour dosing interval among children who were receiving theophylline on a continuous basis correlated with clearance and averaged 9 +/- 3 microgram/ml (mean +/- SD), exceeding to 10 microgram/ml interval width of the therapeutic range among 40% of the children. This observation supports the clinical need for reliable sustained-release preparations of theophylline for children who are receiving continuous therapy in order to avoid unrealistically short dosing intervals.

Terbutaline and ephedrine in asthmatic children.

The effects of terbutaline, ephedrine, and placebo on the cardiovascular and pulmonary systems have been compared in 24 asthmatic children. Ephedrine and terbutaline were both found to be effective bronchodilators, with onset of action within 30 minutes. The bronchodilator effect of ephedrine was maintained for three hours, while terbutaline was active for five hours. Terbutaline caused significantly greater improvement in pulmonary functions than did ephedrine. Both terbutaline and ephedrine were associated with clinically insignificant changes in blood pressure and pulse rate. The only significant side effect observed was hand tremor in children receiving terbutaline and this appeared only early in the course of drug treatment. There was no evidence of tolerance to the bronchodilator effect of ephedrine or terbutaline after eight weeks of therapy.

Comparison of cromoglycate (cromolyn) and theophylline in controlling symptoms of chronic asthma. A collaborative study.

28 children with chronic asthma (15 in Denver and 13 in London) completed a 12 wk double-blind trial of treatment with sodium cromoglycate (cromolyn sodium), theophylline, and a combination of both. The three regimens were administered, each for 4 wk, in random sequence as part of a collaborative investigation of the relative efficacy of the two antiasthmatic agents. Cromoglycate was administered by inhalation in standard doses of 20 mg q.i.d. Theophylline dosage was individualized with the assistance of serum-theophylline measurements and averaged 6 mg/kg/dose q.i.d. (range 3-8--8-5 mg/kg/dose). Peak expiratory-flow rates measured twice daily on all patients averaged 75% of that predicted during cromoglycate administration, 79% during theophylline, and 81% during the combined-drug regimen (P less than 0.05). Patients had an average of 59% of days free of symptoms while on cromoglycate and 71% of days symptom-free when on both the theophylline and the combination regimens (P less than 0.025). None of the 13 patients whose asthmatic symptoms were previously controlled with cromoglycate was unable to complete the 4 wk trial with theophylline alone; 1 patient whose symptoms had been previously controlled with theophylline twice developed severe asthmatic symptoms while receiving cromoglycate, and he had to be withdrawn from that study period. No significant differences in adverse effects of the medication were observed during the 12 wk trial.

Intravenous aminophylline dosage. Use of serum theophylline measurement for guidance.

A practical method for monitoring serum theophylline concentrations has been used to investigate intravenous aminophylline dosage requirements. Initial serum theophylline concentrations were found to vary widely and correlate poorly with drug history. Aminophylline loading doses determined from these values more frequently resulted in drug concentrations in the therapeutic range (10 mug to 20 mug/ml) than when therapy was given without knowledge of serum theophylline concentrations. Continuous intravenous aminophylline therapy administered in a standardized dosage (0.9 mg/kg/hr in adults and 1.0 mg/kg/hr in children) produced variable and often excessive serum concentrations. This resulted from variable drug clearance rates, which in adults averaged 0.64 +/- 0.38 ml/kg/min (mean +/- SD), only half that previously reported. These observations suggest that it is not possible to achieve optimal therapeutic aminophylline dosage without monitoring serum theophylline concentrations.