In a double-blind controlled trial 14 chronic asthmatic patients with regular nocturnal exacerbations took 16 mg slow-release oral salbutamol (two Ventolin spandets), 450 mg slow-release aminophylline (two Phyllocontin Continus tablets), or placebo at midnight. Mean peak expiratory flow rates on waking were significantly higher on the active drugs than on placebo (p<001 for salbutamol; p < 005 for aminophylline) but neither drug abolished the overnight fall in PEFR. Plasma drug levels at 0600 hr were 17-3 ng/ml (+5 3 ng/ml SD) for salbutamol, and 7-1 ig/ml (±3 1 ig/ml SD) for theophylline. Steady-state data derived from plasma levels of salbutamol during intravenous infusion indicated that the morning salbutamol levels were probably in a therapeutic range for asthma. The morning theophylline levels, however, were suboptimal when aminophylline was given only at night.Early morning wheezing is a common symptom of asthma for which sustained release bronchodilator tablets are frequently prescribed. In normal people a diurnal variation of peak expiratory flow (PEFR) of up to 10% has been obs,erved.1 However, in asthma much larger variations frequently occur, and may sometimes pass unnoticed by the patient.2 These overnight falls in PEFR may continue apparently harmlessly foTr many years or may be associated with deterioration in the overall control of the subject's asthma.3 4Although slow-release bronchodi-lator preparations are widely prescribed to prevent nocturnal symptoms of asthma, there are few data to suggest the correct dose based on measurement of drug plasma levels. Information is available on the therapeutically effective range of plasma levels of theophylline for acute and chronic asthma, but there is no such information for salibuta,mol. This study was undertaken to investigate the plasma levels of salbutamol and theophylline produced by slow-release oral preparations, and to relate these to the degree of control achieved in chronic nocturnal asthma and

A 3-month double-blind group comparative trial of nedocromil sodium (4 mg twice daily) and placebo was carried out in 30 adult asthmatic patients maintained on bronchodilator therapy. Fifteen patients received each treatment. Subjective (asthma symptoms and severity) and objective (lung function and use of concomitant medication) variables were measured to monitor the response to trial treatments. Significant differences in favour of nedocromil sodium for night-time asthma, daytime asthma, cough, daytime bronchodilator use and clinic assessment of forced expiratory volume during the first second of expiration were observed by week 4 of the trial. The diurnal variation in peak expiratory flow rate was reduced in the nedocromil sodium treated patients. There were no serious adverse reactions and no treatment related changes in haematological findings, blood biochemistry or urinalysis.

1 The time course of changes in plasma cyclic AMP, heart rate and bronchial tone after inhalation of fenoterol or isoprenaline from a dose-metered aerosol are reported in a group of normal subjects. 2 After isoprenaline, plasma cyclic AMP increased rapidly reaching a peak by 10 min and returned to basal levels within 60 min. A rapid, transient rise in heart rate occurred that was maximal by 5 min and returned to a basal level by 45 min. 3 After fenoterol, the changes in cyclic AMP and heart rate were of much longer duration. The rise in plasma cyclic AMP was slower in onset and of greater magnitude than for isoprenaline, reaching a peak by 20 min and remaining above basal level for more than 6 h. The maximum increase in heart rate after fenoterol was less than that observed with isoprenaline but an elevated rate persisted for 4 h after inhalation of fenoterol. 4 Fenoterol is known to have a longer duration of action as a bronchodilator in comparison with isoprenaline. The prolonged rise in plasma cyclic AMP in normal subjects given inhaled fenoterol may reflect this long duration of action. The concomitant rise in heart rate, however, suggests that the duration of plasma cyclic AMP response may in part be due to the systemic effect of the fraction of inhaled fenoterol known to be absorbed via the buccal and intestinal routes.

A total of 104 asthmatic patients with symptoms of asthma and/or a 'morning dip' in the peak expiratory flow rate (PEFR) who were receiving multiple therapies, including inhaled or oral steroids, were treated in addition once nightly with controlled-release theophylline in an 8-week double-blind, placebo-controlled cross-over study. Theophylline produced an improvement in symptoms of cough, wheeze, sleep disturbance and PEFR in the 73 completing patients compared to run-in and placebo treatment. Theophylline also produced an improvement in the forced expiratory volume in 1 s and forced vital capacity relative to baseline, and in the difference between actual and predicted PEFR values. Nausea was the most frequent side-effect but both patients' and investigator's global impressions of the effect of study medication were in favour of theophylline.

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