Theophylline in maintenance treatment of chronic asthma: concentration-dependent additional effect to beta 2-agonist therapy.

The effect of long-term treatment with theophylline was studied in 20 chronic asthmatic patients receiving oral and inhaled beta 2-agonists. In a double-blind, randomized cross-over fashion during three consecutive 6-week periods, the patients received theophylline in individually adjusted dosages or placebo to obtain plasma concentrations of 25-45 mumol/l, 50-85 mumol/l and 0, respectively. PEF, beta 2-aerosol consumption, symptom scores and side-effects were recorded daily. The addition of theophylline caused a significant further bronchodilating effect. There was, however, a large interindividual variation in response to additional theophylline and only half of the subjects were responders. Those responding had increased therapeutic efficacy from a steady-state concentration in the range of 50-85 mumol/l compared to the lower concentration. The responders had, on average, more pronounced air-flow obstruction. The incidence of adverse reactions increased with increasing concentrations of theophylline.

Rectal administration of choline theophyllinate in adult asthmatics on theophylline maintenance therapy.

The relief of bronchial obstruction from theophylline administered intravenously and as retention enema was compared in a controlled double-blind cross-over study in 21 adult patients with reversible bronchial obstruction, who were on continuous treatment with an individually adjusted maintenance dose of oral theophylline. In two sessions the patients received in random order a 10 ml aminophylline infusion intravenously (180 mg theophylline) and the equivalent of 400 mg theophylline rectally in the form of choline theophyllinate, followed by serial determinations of ventilatory function and plasma theophylline levels during the next 8 h. Significant improvement of FEV1 within 1 h was recorded with both treatments and the duration of the effect was very similar for the two routes of administration. The patients were in stable state while taking part in the experiment but the similarity in the outcome suggests that choline theophyllinate administered as retention enema, although slower acting, represents a useful alternative to intravenous aminophylline also in the management of acute episodes of bronchial obstruction.

Dextromethorphan and codeine: comparison of plasma kinetics and antitussive effects.

Plasma kinetics of dextromethorphan (as dextrorphan ) and codeine were investigated after acute oral doses in 8 patients with pathological cough; after which the patients participated in an acute dose-response study of the antitussive effects of each drug administered as syrups. Maximum plasma codeine concentrations averaged 384 ng.ml-1 (s.d. +/- 78.3) occurring between 0.75 and 2h after ingestion of 60 mg codeine phosphate; in comparison mean peak plasma dextrorphan levels were 386 ng.ml-1 (s.d. +/- 107.2) and 388 ng.ml-1 (s.d. +/- 101.3) respectively, after administration of 60 mg dextromethorphan syrup and tablet formulations. Bioavailability of dextromethorphan tablets was comparable to syrup. No correlation emerged between instantaneous plasma concentrations of either dextrorphan or codeine and antitussive responses; however, peak antitussive effect was significantly related to log dose with both drugs. Antitussive effects of 30 mg codeine phosphate and 60 mg dextromethorphan hydrobromide did not differ significantly; both were superior to 30 mg dextromethorphan hydrobromide and placebo.

Effect of ritodrine on labor after premature rupture of the membranes.

The effect on labor of administering ritodrine after a premature rupture of the membranes (PROM) was studied in a double-blind trial in 30 patients. The patients were selected according to the following criteria: 28 to 36 weeks' gestation, only 1 fetus, cervix dilated 4 cm or less, and absence of pyrexia or other signs of uterine infection. Fourteen patients received ritodrine and 16 received a placebo. The 2 groups were statistically comparable. None of the patients receiving ritodrine delivered within 24 hours. The difference between the 2 groups was statistically significant with respect to the number of patients delivered within 24 hours (P less than 0.05). However, after 24 hours, there was no difference between the groups as regards the length of pregnancy. The infections registered in the mothers of infants were few and easily controlled. The incidence of idiopathic respiratory distress syndrome (IRDS) was low in the study and allows no conclusions concerning the benefit of prolonging the pregnancy for more than 24 hours after PROM.

Hexoprenaline and terbutaline administered by inhalation. A comparison between two beta2-adrenoreceptor agonists with respect to effect on bronchial obstruction, heart rate, blood pressure and muscle tremor.

In a controlled double-blind cross-over study in 15 patients with reversible bronchial obstruction hexoprenaline (Ipradol, 0.20 mg/puff) and terbutaline (Bricanyl, 0.25 mg/puff) when administered as metered aerosol in a dosage of one puff followed by two puffs 30 min later produced the same maximum improvement of ventilatory function. However, after inhalation of terbutaline a more sustained broncholytic effect was obtained than after hexoprenaline. Similar results were obtained in six patients after doubling the dose of each agent. The influence on pulse rate and blood pressure was negligible with either agent. The amplitude of finger tremor was measured after 2 + 4 puffs. No significant changes in mean values occurred after either of the two agents although after hexoprenaline an increase in amplitude of more than 100% was recorded in two out of six patients 30 min after the second dose.

Plasma level and broncholytic effect of choline theophyllinate after a single dose of a press-coated tablet formulation.

The broncholytic effect and plasma concentrations of theophylline in 10 asthmatic patients were studied for 8 hours after a single dose of 600 mg choline theophyllinate in press-coated 200 mg tablets. Therapeutic concentrations of theophylline were rapidly achieved and the plasma peak averaged 10.4 mug/ml after 2 hours. The broncholytic effect was closely related to the plasma level of theophylline. The largest change was in FEV1, which was significantly increased 1 to 6 hours after the dose. No patient complained of adverse effects. A theophylline concentration of 7 mug/ml plasma was adequate for a broncholytic effect, but a higher level was required for a maximal response. The results provide a basis for further studies to establish a dosage schedule suitable for prolonged therapy.

Plasma theophylline level and ventilatory function in chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate.

Plasma levels of theophylline and broncholytic activity have been studied in 12 patients with chronic obstructive pulmonary disease during prolonged oral treatment with choline theophyllinate, administered as a press-coated tablet (BrondaxinR). The plasma levels determined immediately before and 80 minutes after each dose showed very good agreement with those calculated on the basis of data from a previous single dose study. The plasma concentration and improvement in ventilatory function were closely correlated throughout the 48 hours of the study. A tendency towards further reduction of bronchial obstruction was observed during the second day, despite essentially unchanged plasma levels of theophylline. The results provide a rational basis for determination of an optimal dose schedule for oral treatment with choline theophyllinate to reduce the symptoms of obstructive bronchial disease.