A placebo-controlled comparison between the bronchodilatory effects of ipratropium bromide inhaled as a dry powder and by metered dose inhaler in chronic obstructive pulmonary disease.

A placebo-controlled study was performed to compare the effect of the inhalation of ipratropium bromide as a powder (capsule = 40 micrograms) and by pressurized aerosol (two puffs of 20 micrograms; ie, 40 micrograms). Fifteen patients (nine males and six females) with chronic obstructive pulmonary disease were studied in a double-blind crossover comparison of the two different modes of administration. The VC, FEV1 and viscous work of breathing time-response curves were almost identical, indicating bronchodilation. We conclude that in patients with chronic obstructive pulmonary disease, the powder inhalation was not more effective than the pressurized aerosol. It could, however, be offered as an alternative to patients with poor hand-lung coordination. The patients tolerated the two modes of administration without difficulties: no local irritation or coughing was observed.

Comparison of disodium cromoglycate, terbutaline and thiazinamium in the prevention of exercise-induced asthma and its relation to non-specific bronchial responsiveness.

The protective effect of pre-exercise treatment with disodium cromoglycate (DC), terbutaline sulphate (TS) and thiazinamium methylsulphate (TM) on exercise-induced asthma (EIA) was investigated. Thirty-one adults each exercised for over 6 min on a bicycle ergometer. Each subject performed five tests. The first and last exercise tests served as controls. A profile of bronchial reactivity based on the combination of hyperreactivity - as measured by acetylcholine (a), histamine (h) and propranolol (p) - was drawn up. The following combinations and frequencies were based on the response (+ or -) in hyperreactivity studies: group (h+, a+, p+) was present in 21 of the 31 patients studied, group (h-, a+, p+) in 6 patients, group (h+, a+, p-) in 2 patients and group (h-, a+, p-) in 2 patients. The proportion of patients effectively protected from their EIA was 80% for TS, 60% for DC and 40% for TM. These findings suggest that there exists a consistent heterogeneity in the patients' response to exercise, possibly related to the individual distribution of receptors leading to bronchial hyperreactivity.

Urinary excretion of histamine and some of its metabolites in man: influence of the diet.

Urinary excretions of histamine, N tau-methylhistamine and N tau-methylimidazoleacetic acid have been determined in 10 normal subjects on 3 different diets, containing a very low protein, a low protein and a high protein amount. Foodstuffs which could contain histamine were excluded. The mean excretion of N tau-methylhistamine on the second day of each diet amounted to 0.861 mumol/24 h, 1.051 mumol/24 h and 1.378 mumol/24 h, respectively. The excretions of histamine and N tau-methylimidazoleacetic acid were not affected. In 6 normal persons on a protein low diet, the excretions of histamine, N tau-methylhistamine and N tau-methylimidazoleacetic acid have been determined for 10 days. On the fifth day, to 3 persons 200 mumol of histamine was given orally, the other 3 persons received a high protein diet. The persons receiving histamine showed a strongly enhanced excretion of N tau-methylimidazoleacetic acid, corresponding to 36.1% of the administered histamine, whereas the urinary excretions of histamine and N tau-methylhistamine were only slightly elevated. On the high protein diet, only the excretion of N tau-methylhistamine was slightly elevated. The urinary excretions of histamine in the female subjects sometimes showed unexpectedly high values. Most probably, this phenomenon is attributable to bacterial histamine production in the urogenital tract.

Disposition and clinical pharmacokinetics of microcrystalline theophylline.

Variation in the systemic disposition of theophylline after ingestion of a new microcrystalline product (Theolair) has been investigated in 7 hospitalized patients with generalized obstructive lung disease. Disposition (absolute bioavailability) was determined by comparing in the same patients the areas under the serum concentration-time curves after a single oral dose of microcrystalline theophylline and after an intravenous infusion of aminophylline. Oral absorption appeared to be fast. The half-life of absorption was 19 +/- 9 min (mean +/- SD). Maximal serum concentrations reached after 100 +/- 30 min were found to be in a rather narrow range: 9.8 +/- 2.5 mg x 1(-1). The absolute bioavailability of the microcrystalline preparation was high and it showed only small variation: 102.7 +/- 10.2% of the dose. Relevant pharmacokinetic parameters (half-life of elimination, volume of distribution and total body clearance) were determined after both routes of administration. Individual dosage regimens required to obtain a therapeutic serum concentration were calculated for each individual patient on the basis of the observed pharmacokinetic parameters.

Disposition and clinical pharmacokinetics of theophylline after administration of a new sustained release tablet.

The systemic disposition of theophylline after taking a new, sustained release tablet (Theolair Retard 250 mg, Theolair S.R., Riker Laboratories) has been studied in 8 hospitalized patients. Absolute bioavailability was determined from the ratios of the areas under the serum concentration-time curves after intake of the tablet and after intravenous infusion of aminophylline in the same patient. The absolute bioavailability of Theolair Retard 250 mg was 110.9 +/- 20.8% (mean +/-SD). Maximal serum concentrations were reached after 7.3 +/- 3.5 h, the large intersubject variation being due to differences in gastric emptying time. The tablets appear to release theophylline slowly in acid conditions, but more rapidly in an alkaline medium. Invasion was found to be either monophasic with a rate constant of about 0.8 h-1 (intestine), or biphasic with rate constants of 0.2 h-1 (stomach) and 0.8 h-1 (intestine). The peak levels accounted for 7.9 +/- 2.2 mg . 1-1. The profiles of the serum concentration-time curves were such that the concentrations remained above 80% of cmax for 6.5 +/- 3.3 h. The relevant pharmacokinetic parameters (half-life of elimination, total body clearance and volume of distribution) were determined and were used to calculate the individual dosage regimens required to obtain therapeutic serum concentrations. The optimal dosing interval to obtain an average steady state serum concentration of 12.5 mg . l-1 was 9.8 +/- 3.1 h.

Chronopharmacodynamics and kinetics after symmetric and asymmetric multiple theophylline doses in patients with chronic obstructive pulmonary disease.

In a randomized double-blind crossover study, the effects of 4 days of symmetric or asymmetric dosing with sustained-release theophylline (Sabidal-SR) were compared with placebo in ten patients with chronic obstructive pulmonary disease in a stable state. The doses were 450 mg b.i.d. and 270 mg plus 630 mg, respectively. Special attention was paid to circadian rhythms in pharmacokinetics and pharmacodynamic effects, during 24 h of measuring. The peak plasma theophylline concentrations at night with a symmetric dosage were lower than with an asymmetric dosage: 11.5 mg/l (+/- 3.8) and 13.6 mg/l (+/- 4.4), respectively. Both theophylline regimens caused a significant increase in vital capacity (8%) and in forced expiratory volume in one second (15%), and also a decrease of specific viscous work of breathing (49%). There were no significant differences in pharmacodynamic effects between the symmetric and asymmetric dosing regimen. An exception was the heart rate, that increased significantly only with an asymmetric dose. We found no correlation between the theophylline plasma concentration and the changes in lung function and heart rate. Theophylline had no influence on subjective findings of the patients, nor on the oxygen saturation of the blood during sleep.