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In 6 asthmatic patients, the possibility of obtaining a steady state plasma level of 5 mg/l of enprofylline by administration of two constant rate infusions was examined. The simulated plasma concentration curves, based on information from preassessment of individual pharmacokinetic parameters, were in good agreement with the plasma levels obtained. The side-effects and bronchodilatation produced by enprofylline were compared to those obtained with theophylline at a steady state level of 15 mg/l. Enprofylline and theophylline caused a mean maximal increase in FEV1.0 of 14% and 2.6% per mg/l in plasma, respectively. Side-effects, headache, nausea and vomiting, became pronounced in 2 patients in whom the plasma enprofylline level was about 6 mg/l. No other serious adverse reaction was seen. It is suggested that enprofylline should be further evaluated as a possible anti-asthmatic drug.

The bronchodilator activity and side-effects of treatment for 4 days with either 0.085, 0.170 or 0.34 mg/kg bambuterol b.i.d. (a prodrug of terbutaline) or 0.071 mg/kg terbutaline t.i.d. have been evaluated over 12 h, in a double-blind, randomized crossover trial in 19 asthmatic out-patients. Plasma terbutaline concentrations after bambuterol administration were smoother, with a ratio between the maximum and minimum values of about 1.4 compared to 2.6 for terbutaline. The plasma terbutaline level rose with dose, but by less than the increase in dose. The bronchodilator effect was related to the plasma terbutaline concentration in each treatment group, so bambuterol produced more prolonged bronchodilatation than treatment with terbutaline. Tremor and cardiac side-effects were most pronounced after administration of bambuterol 0.34 mg/kg. No severe side-effects were seen. Bambuterol produced stable plasma levels of terbutaline, indicating that as a prodrug of terbutaline it might possibly be administered once daily with good antiasthmatic effect.

The bronchodilator effect and side-effects of a single oral dose of enprofylline were compared with the corresponding actions of a therapeutic dose of theophylline in 20 asthmatic patients, in a randomized cross-over clinical trial. Enprofylline 4 mg/kg and theophylline 8 mg/kg produced mean maximum plasma levels of 4.40 +/- 0.91 micrograms/ml and 16.5 +/- 2.58 micrograms/ml and mean maximum increases in FEV1.0 of 38.5% and 34.8%, respectively. The degree of headache and nausea was estimated by a scoring system. Enprofylline produced significantly higher scores for headache than theophylline, and both drugs produced s light nausea. No other side-effects were seen. Enprofylline seems to have bronchodilating properties comparable to those of theophylline without producing severe side-effects.

Twenty-seven asthmatic outpatients were randomly treated with bambuterol 30 mg administered once daily before going to bed and sustained release terbutaline 10 mg twice daily in a 14 day, double blind cross over study. On all the parameters of bronchodilator effects, namely peak expiratory flow rate (PEF), use of extra beta-agonist puffs, asthma symptom score, and patient preference for one of the treatments, no statistically or clinically significant difference between the two treatments was found. No significant difference between treatments was observed in the number or severity of side-effects. Bambuterol administered once daily appears to be an effective anti-asthmatic treatment.

In patients requiring a high or low dose of theophylline the pharmacokinetics of theophylline and enprofylline were studied. The low-dose group took an average daily dose of 8.91 mg/kg body wt. and the high-dose group 24.75 mg/kg body wt. The average half-life of theophylline in the former was 7.11 h and in the latter 4.72 h. The average clearances (CL) of theophylline were 2.83 and 4.58 l/h, respectively. The daily oral intake of theophylline was negatively correlated with the theophylline t1/2 (r = -0.63). While the t1/2 of enprofylline was similar in the two groups, CL and volume of distribution (Vc) were slightly (about 30%) but significantly higher in patients requiring a high dose of theophylline. CL of enprofylline did not correlate with CL of theophylline, nor was the Vc of the two drugs correlated. Interindividual variability in t1/2 and CL was considerably lower for enprofylline than for theophylline.