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 μ/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 inpa-tient periods during which PTCs and lung functions (PEF, FEV, FEF_25-75, 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 μg/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. Key Words: Nocturnal asthma—Chronotherapy—Sustained-release theophylline—Nonsustained-release theophylline—Forced vital capacity—Forced expiratory volume— Forced expiratory flow—Peak expiratory flow—Area under the maximum expiratory flow-volume curve.