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.

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.

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 · 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.

Gimeno, F., Berg, W. Chr., Steenhuis, E. J., de Vries, K., Peset, R., and Sluiter, H. J. (1974).Thorax,29, 16-20. Exercise-induced airway obstruction in relation to chronic obstructive lung disease. Forty-two patients with chronic obstructive lung disease and clinically suspected exercise-induced airway obstruction were studied to ascertain whether those with proven exercise-induced airway obstruction had specific distinguishing features. Exercise-induced airway obstruction (defined as a fall of FEV1 of at least 10% of the pre-exercise values) was detected in 20 of the 42 patients. These 20 were found to have a lower elastic recoil but were otherwise identical with the remainder as regards clinical and physiological abnormality. It is postulated that exercise-induced airway obstruction can be a manifestation of chronic obstructive lung disease.

A patient is described in whom exercise-induced airway obstruction was the first symptom of obstructive lung disease. Administration of a variety of drugs before exercise afforded no protection against postexercise airway obstruction. Studies demonstrated that the phenomenon was not due to cholinergic efferent impulses, histamine release, hypocapnia, or hypoxemia.

In 14 patients with chronic obstructive lung disease, spirometry-induced airway obstruction was observed. In 2 patients, esophageal pressure was recorded simultaneously with the spirogram. In one of these patients, there was evidence that the inspiratory part of the vital capacity was the maneuver inducing the change, particularly when inspiration occurred through the mouth. Spirometry-induced bronchial obstruction was completely blocked by administration of thiazinamium, a drug with antihistaminic and anticholinergic properties. Further research is required to investigate whether this type of bronchial obstruction is due to a reflex mechanism or to local reaction of the peripheral bronchi to the inspired gas or to both.

In a group of 187 patients with various types of obstructive lung disease, the transpulmonary pressure at full inspiration (Ptlc) was correlated with other lung function variables and with symptoms. Measurements were made before and after bronchodilation. In a number of patients, the effect of bronchoconstriction on the volume-pressure curves was assessed. As estimated from the Ptlc, the lungs were abnormally compliant in most patients. This abnormality was most pronounced in the younger subjects, in whom reduced elastic recoil occurred without signs of airway obstruction during forced expiration and without increased total lung capacity. The findings suggested that lung structures determining elastic recoil were at least partly independent of those determining mechanical stability of the airways. Statistical analysis revealed that the clinical value of Ptlc measurement was limited to the differentiation of patients with asthma from those with emphysema. Because these subjects constituted less than 10 per...

The efficacy of the new antiallergic drug, disodium cromoglycate, has been studied with protection tests on bronchial allergen challenge in 17 patients with reversible obstructive lung disease. There was, in general, a markedly protective effect on the immediate allergic reaction without concomitant bronchodilitation. Thiazinamium also produced a very good protective effect, probably the result of the combination of bronchodilation and a specific antihistaminic activity.