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Background 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. Methods 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 β 2 -agonists taken. Spirometry was checked at clinic visits at 3, 6, 9, and 12 months following randomization. Results Three-hundred forty-eight patients (174 enprofylline, 174 theophylline) participated in the trial. For both drugs there were significant improvements in PEFR and FEV 1 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 β 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. Conclusions: 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.

The acute cardiovascular effects of a new xanthine, enprofylline, were studied in patients with chronic lung disease. The studies were done during cardiac catheterization (n = 12) and by radionuclide ventriculography (n = 6). Enprofylline was given intravenously, 2 mg/kg, and measurements were done after ten and 30 min. Enprofylline reduced the mean pulmonary artery pressure from 30 ± 10 to 26 ± 7 mm Hg (p

Long-term ambulatory Holter-monitoring was used to evaluate the arrhythmogenic effects of beta 2 -agonist therapy, alone and in combination with a xanthine derivative, theophylline or enprofylline. Twenty patients (mean age 51 years) with mild-to-moderate obstructive lung disease (bronchial asthma or chronic bronchitis), but without concomitant ischemic heart disease were studied. Compared with beta 2 -agonist therapy alone, both combined regimens were associated with a small but significant increase in the frequency of ventricular arrhythmias. Few serious arrhythmias were observed, however, and the clinical significance of these findings is thought to be minor. Although adenosine has been suggested to have an antiarrhythmic effect, a difference between theophylline and enprofylline in the effect on adenosine (theophylline but not enprofylline being an adenosine antagonist) would appear to be of less cardiac relevance in patients without ischemic heart disease.

Twenty-four patients (five women) aged 53-72 yr with both ischemic heart disease and asthma or chronic bronchitis receiving oral beta 2-agonists also received additional bronchodilating therapy with theophylline (600 mg daily), enprofylline (600 mg daily) or placebo. The study was double-blind, randomized, triple-crossover with each regimen given for two weeks. Holter monitoring was used during 48 consecutive hours in each period. Compared with placebo, addition of theophylline and enprofylline were associated with an increased mean hourly heart rate of 6 bpm (p less than 0.001). A small, but statistically significant (p less than 0.05) increase in mean hourly frequency of premature ventricular beats (PVBs) occurred with enprofylline as compared with placebo. However, in only two patients with enprofylline (and one patient with theophylline) the increase in PVBs was such that a clinically relevant proarrhythmic effect seems possible. Furthermore, ventricular tachycardia was not more frequently observed with any xanthine than with placebo. Thus, combined oral bronchodilator therapy is not contraindicated in patients with obstructive lung disease and concomitant ischemic heart disease. Holter monitoring is recommended to assess the individual patient's response to such therapy.

We compared the bronchodilating effects of intravenously administered enprofylline (2 mg/kg) with nebulized terbutaline (10 mg) in patients presenting to hospital with acute asthma in a multicenter double-blind parallel study. One hundred twenty three patients were randomized into the study, and 69 of these fulfilled the inclusion criteria and a retrospective time to study entry criterion; 34 received enprofylline and 35 received terbutaline. There was no significant difference in maximum increase in forced expired volume in 1 second (FEV1) between the enprofylline group (0.24 +/- 0.33 L) and the terbutaline group (0.25 +/- 0.28 L) (p greater than 0.05), nor for the increase in FEV1 over the 1-hour study period. Tremor was reported more in the group receiving terbutaline, and nausea was reported more in the group receiving enprofylline. Two patients experienced hypotension and one patient had a vasovagal episode with enprofylline treatment. Both agents acted as bronchodilators with similar efficacy in patients with acute asthma in this study.