As many as 80 percent of asthmatics experience nighttime or early-morning episodes, which are difficult to treat and potentially fatal. The greater-than-normal amplitude of circadian airflow variation in many asthmatics contributes heavily to the genesis of the early 'morning dip'. Beta-agonists and corticosteroids are of limited usefulness in nocturnal asthma, and slow-release theophylline drugs, while potentially effective, vary in 24-hr blood profile and hence their influence on nocturnal episodes. Traditional 12-hr 'symmetric' theophylline regimens, instead of meeting increased nocturnal demands, may actually produce lower night- than daytime blood levels. On the other hand, appropriately timed administration of a once-daily theophylline drug might provide maximum blood levels when needed and help stabilize 24-hr airflow. Accumulated data, summarized in this review, demonstrate the chronotherapeutic potential of single-daily evening doses of a controlled-release theophylline preparation (Uniphyl 400-mg tablets) in nocturnal and early morning asthma. Nighttime blood concentrations with this regimen were higher than were those with Theo-Dur tablets, B.I.D., in the same total daily doses, or with once-daily morning Uniphyl administration. In fed and fasted subjects, evening administration of Uniphyl 400-mg tablets was well tolerated and did not lead to 'dose dumping.' Clinically, this treatment demonstrated advantages over B.I.D. theophylline, over single-daily morning regimens, and over prior theophylline therapy. Advantages of the evening regimen included better early-morning airflow (without significant decline later in the day), more effective symptom control, better patient acceptance, fewer night awakenings, and the obvious convenience of once-daily dosing. In addition, lung function showed greater stability, throughout the day, with once-daily evening therapy than with traditional 12 hr dosing. Uniphyl 400-mg tablets may be administered once daily to provide maximum blood levels at the time of peak bronchoconstriction, whether at night or during the day.
1. Asthma and COPD worsen at night and in the early morning, due to various circadian influences. 2. Uninterrupted sleep, stable lung function over 24 h, and reduced and stable airways responsiveness are primary therapeutic goals in asthma and COPD. 3. Once-daily evening theophylline chronotherapy meets these goals, providing rising blood levels at night and in the early morning, when most needed. 4. This regimen is now indicated for morning and evening dosing for reversible airway obstruction, in the United States and Canada, and marks the first available treatment for these diseases to include dosing time in the therapeutic strategy. It reflects increasing recognition by the medical community of the need to consider the individual patient's timing of symptoms in relation to the kinetics of the drug. 5. Theophylline chronotherapy is as well tolerated as more frequently administered methylxanthine preparations despite the relatively large single doses required by the prolonged dosing interval. The convenience of once-daily administration favors drug-taking compliance. 6. Theophylline chronotherapy does not provide constant blood levels over the 24-h day. Indeed, by improving lung function by means of a larger peak-to-trough difference than associated with twice-daily theophylline, once-daily chronotherapy has altered our thinking about theophylline pharmacodynamics.
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