Effects of enprofylline and theophylline on exercise-induced asthma.

Eight asthmatic out-patients with a history of exercise-induced asthma (EIA) were randomly treated with intravenously administered enprofylline 1.5 mg/kg b.wt., theophylline 5 mg/kg b.wt., and placebo immediately prior to a 6-min exercise provocation in this double-blind crossover comparison. A reduction in peak flow of more than 20% was seen in all patients after placebo pre-treatment. Mean plasma concentrations at the start of the exercise test were 3.3 mg/l and 13.2 mg/l after 20 min infusion of enprofylline and theophylline, respectively. The corresponding figures 25 min later were 2.3 and 11.7, respectively. Maximal fall in peak expiratory flow (PEF) after exercise in percent of pre-exercise PEF was 49% +/- 6% (mean +/- SEM), 39% +/- 6% and 24% +/- 5% after infusion of placebo, enprofylline, and theophylline, respectively. Theophylline produced a statistically significant better protection against EIA compared to enprofylline and placebo. Enprofylline produced a slight protection from EIA not statistically significantly different from placebo.

The effect of theophylline and enprofylline on allergen-induced bronchoconstriction.

The effect on the allergen-induced immediate and late bronchoconstriction of theophylline and enprofylline (3-propylxanthine), a new xanthine derivative with negligible ability to antagonize adenosine, was studied in nine patients with asthma. The patients were challenged three times at weekly intervals with the same dose of allergen. FEV1 and SGaw were followed up to 6 hours after challenge. The drugs were administered intravenously. Placebo was always administered on the first occasion. Theophylline and enprofylline were administered on test days 2 and 3 with a double-blind, randomized crossover technique. One hour before the allergen challenge, a loading dose was administered during 60 minutes followed by a constant infusion during 6 hours. The loading infusion was 7.2 mg/kg of theophylline and 2.7 mg/kg of enprofylline. The maintenance dose was 74 mg/hr and 71 mg/hr, respectively. Both theophylline and enprofylline caused a minor initial bronchodilatation. Theophylline and enprofylline slightly but significantly attenuated the immediate bronchoconstricting reaction after allergen inhalation. Theophylline and enprofylline had a significant attenuating effect on the late bronchial reaction. The mean plasma level of theophylline was 0, 10.8, 10.5, and 10.5 mg/L at 0, 1, 4, and 7 hours after the start of the loading infusion, respectively. The corresponding mean plasma levels of enprofylline were 0, 2.6, 2.7, and 2.7 mg/L. Theophylline and enprofylline caused headache in one patient. Two patients developed nausea and vomiting during the enprofylline infusion. The present data suggest that adenosine receptor antagonism may not be the main mode of action of xanthines in inhibiting bronchoconstriction after single dose antigen challenge.

Relaxation of lower esophageal sphincter and stimulation of gastric secretion and diuresis by antiasthmatic xanthines. Role of adenosine antagonism.

The study was designed to obtain information on selected extrapulmonary effects of enprofylline, an adenosine-non-blocking alkylxanthine that is about 5 times more potent as a bronchodilator than the adenosine receptor antagonist theophylline. Effects of theophylline (5.0 mg/kg) on lower esophageal sphincter pressure (LESP), gastric secretion, and diuresis and of enprofylline (1.5 mg/kg intravenously producing about 2 micrograms/ml plasma) were examined in 8 healthy volunteers. Enprofylline and theophylline decreased LESP (by 5.0 +/- 2.6 mm Hg, mean +/- SD, p less than 0.001, and by 5.8 +/- 2.7 mmHg, p less than 0.001, respectively), but only theophylline stimulated gastric secretion (volume p less than 0.01 and acidity p less than 0.01) and urine production (volume p less than 0.01 and sodium chloride excretion p less than 0.01). Neither xanthine affected plasma gastrin. Enprofylline and theophylline can be expected to have a similar ability to reduce the barrier to gastroesophageal reflux, but only the latter would have additional stimulant effects on gastric secretion and diuresis. These findings may have clinical significance and suggest a role for adenosine in regulating gastric secretion (and diuresis) but not LESP.

Pharmacokinetics of theophylline and enprofylline in patients requiring a high or low dose of theophylline.

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.

Continuous treatment of asthmatic patients with enprofylline and theophylline.

Twenty-five asthmatic outpatients were treated for 3 one-week periods with either enprofylline slowly eroding 300 mg tablets t.i.d., theophylline 300 mg tablets (Theo-Dur) t.i.d., or placebo in a double-blind, cross-over, randomized trial. Sixteen patients were able to complete 2 or 3 one-week periods. Evaluation of bronchodilating properties by home recordings of peak expiratory flow (PEF) and side effects suggested that enprofylline was an effective antiasthmatic xanthine derivative for continuous treatment, as it improved mean morning PEF significantly. Continuous treatment with the 2 xanthine derivatives resulted in mean steady state plasma levels within therapeutic range for theophylline, and 3-4 times lower mean plasma levels for enprofylline. Enprofylline induced headache in 13 of 16 patients, theophylline in 9 of 19 patients, and placebo in 2 of 18 patients. No serious side effects were seen.

Maximally effective plasma concentrations of enprofylline and theophylline during constant infusion.

Bronchodilating effects produced by increasing intravenously administered doses of enprofylline and theophylline compared to placebo were evaluated in 20 asthmatic outpatients. Three mean plasma plateaux of enprofylline of 1.5, 2.9 and 4.0 micrograms/ml produced a mean increase in forced expiratory volume in the first second (FEV1.0) as a percentage of baseline, of 12.8%, 18.8% and 30.1%, respectively. Comparable plasma plateaux of theophylline i.e. 5.5, 10.8 and 15.2 micrograms/ml produced a mean increase of FEV1.0 in percent of basal values of 12.4%, 21.6% and 28.2%, respectively. Enprofylline at plasma concentrations above 2.9 micrograms/ml induced more headache and slightly more nausea than theophylline and placebo. Theophylline infusion produced more tremor (finger oscillation) than enprofylline and placebo. Intravenously administered enprofylline produces bronchodilation comparable to theophylline in a mean dose ratio of 3.8.

Increase in plasma free fatty acids and natriuresis by xanthines may reflect adenosine antagonism.

The hypothesis has been examined that adenosine is involved in the diuretic and free fatty acid (FFA) - releasing action of xanthines. The effects of theophylline (T), a potent adenosine antagonist, were compared with those of enprofylline (3-propyl xanthine, E), which exerts negligible antagonism of adenosine. Eight healthy male volunteers were given E 1.5 mg/kg, T 5.0 mg/kg or placebo 0.9% saline (P) intravenously in a double-blind, randomized, cross-over investigation. Blood samples were analyzed for E, T, catecholamines (CA: adrenaline, noradrenaline and dopamine), FFA, renin, glucose, glucagon and insulin, and urine was collected at 2-h intervals. T (plasma concentration 53 +/- 8 mumol/l) but not E (11 +/- 2 mumol/l) caused an increase in FFA from 0.42 to 0.86 mmol/l after 90 min. Without affecting the urinary excretion of potassium, T doubled natriuresis and the urine volume as compared to E and P. Neither T nor E had any effect on plasma CA, or on any other of the metabolic parameters studied. E, but not T, produced a small but statistically significant decrease in diastolic blood pressure (5 mmHg) and an increase in heart rate (3 beats/min). It is suggested that the difference between E and T in terms of stimulation of FFA-release and natriuresis may be related to their different ability to antagonize adenosine.

Comparison of oral enprofylline and theophylline in asthmatic patients.

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.

Absorption of enprofylline from the gastrointestinal tract in healthy subjects.

Enprofylline, a new potent bronchodilator xanthine drug, was given orally as an aqueous solution to 6 healthy subjects in single doses of 2, 4 and 6 mg/kg. The two lower doses produced plasma concentrations in the range 1-4 mg/l, i.e. in the assumed "therapeutic interval" according to previous animal studies. A high 24 h urine recovery of unchanged drug, with mean values for the three dose levels ranging from 85 to 91% of the given dose, indicated good absorption and little metabolism. The dose-corrected area under the plasma concentration-time curve rose with dose as the latter was increased from 2 to 6 mg/kg. This indicates that the elimination of enprofylline is capacity-limited at high doses. Double peaks in the plasma concentration-time curves at the higher dose levels suggested intermittent and delayed gastric emptying as a possible explanation. This hypothesis was confirmed by studies in 6 other healthy subjects, who received the drug solution by three different routes; by mouth, via a catheter in the duodenum, and rectally via a catheter in the colon. The corresponding time to peak values (mean +/- SEM) were 32.5 +/- 8.7, 13.3 +/- 2.5, and 157 +/- 23 min.

Enprofylline--effects of a new bronchodilating xanthine derivative in asthmatic patients.

The bronchodilating effect of two doses of peroral enprofylline was compared with placebo in 24 asthmatic patients. Enprofylline produced significantly greater bronchodilatation than placebo. A dose of 2 mg/kg b.wt. and 4 mg/kg b.wt. caused a mean maximal increase in FEV1 of 26% and 35%, respectively. The degree and the incidence of headache and nausea were estimated by means of a scoring system. Dose-related effects on both parameters were observed. Other side effects were negligible. In seven patients the mean plasma half-life of enprofylline was found to be 113 min. It is suggested that enprofylline should be studied further in patients suffering from obstructive lung disease.

Intravenous administration of enprofylline to asthmatic patients.

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.