Long-Term Xanthine Therapy of Asthma: Enprofylline and Theophylline Compared

Abstract

Enprofylline is a new xanthine derivative that shares theophylline's bronchodilator properties but is free of theophylline's adenosine receptor antagonist activity. We compared the long-term efficacy and tolerability of enprofylline and theophylline given over a 1-year period to adults with asthma.Patients were recruited from 18 centers and 4 countries to participate in a 1-month double-blind comparison of enprofylline or theophylline in the treatment of asthma and were subsequently maintained on a regimen with the assigned medication for a further 11 months. The dosage of each xanthine was incremented from 150 mg twice daily at initiation to 300 and later 450 mg twice daily depending on the patient's tolerance and, in the case of theophylline, the rapidly assayed serum theophylline level. Patients kept a diary in which they recorded peak expiratory flow rate (PEFR) measured morning and evening, asthma symptom score, and the number of beta 2-agonists taken. Spirometry was checked at clinic visits at 3, 6, 9, and 12 months following randomization.Three-hundred forty-eight patients (174 enprofylline, 174 theophylline) participated in the trial. For both drugs there were significant improvements in PEFR and FEV1 during the first month of treatment with no significant difference between drugs (0.25 L for enprofylline vs 0.30 L for theophylline). Similarly, there were no differences in clinical outcome such as asthma exacerbations or beta 2-agonist usage between the two groups over follow-up. However, inhaled steroid dosage was more likely to have been incremented in theophylline-treated than enprofylline-treated patients (18% vs 8%, p = 0.025). Both drugs produced a modest increase in heart rate throughout the trial (approximately 5 beats/min). In 31 patients (26 enprofylline, 5 theophylline), asymptomatic elevations in aspartate aminotransferase and/or alanine aminotransferase occurred at least once during the study. In five patients (four enprofylline, one theophylline), the increase exceeded three times the upper limit of the normal range. In some subjects receiving enprofylline, serum enprofylline levels rose progressively despite constant oral dosage of the drug.Long-term xanthine therapy is well-tolerated by most adult asthmatics. However, long-term enprofylline administration may be associated with elevation in liver enzyme levels and unpredictable blood levels, thereby limiting its clinical usefulness.