Double-blind randomized cross-over trial of nocturnal elixir theophylline supplementation of a twice-daily sustained-release theophylline tablet formulation in asthmatic patients.

Sixteen asthmatic patients with normal diurnal activity between 05:00 and 23:00 h participated in this randomized, multiple-dose, double-blind, placebo-controlled, crossover study of the pharmacokinetics and efficacy of evening supplementation of a 12-hourly sustained-release theophylline (SRT) regimen with a nonsustained-release theophylline (NSRT) formulation. The treatments were Nuelin SA (SRT) every 12 h plus, in the evening, either placebo or an additional dose of Nuelin liquid (NSRT), determined to raise the early morning (0300) plasma theophylline concentration (PTC) to 18 micrograms/ml by using the dose-concentration prediction equation established in a study conducted on healthy volunteers and reported in this journal. The 11-day trial included two 24-h inpatient periods during which PTCs and lung functions (PEF, FEV1, FEF25-75, and FVC) were determined every 2 h. The value of the prediction equation was confirmed when the early morning PTC, after evening supplementation with Nuelin Liquid, was raised nearly to the targeted 18 micrograms/ml. The nocturnal peak-to-trough fluctuation in PTC was larger during additional treatment with Nuelin liquid, but the nocturnal peak-to-trough fluctuation in lung function parameters decreased. Overall, airflow during the early morning hours (0100-0500) significantly improved during this chronotherapeutically optimized treatment of adding an NSRT product to the evening dose of a 12-hourly SRT regimen.