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-bli nd, placebo-controlled, crossover study of the pharmacokinetics and ef ficacy of evening supplementation of a 12-hourly sustained-release the ophylline (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 (N SRT), determined to raise the early morning (0300) plasma theophylline concentration (PTC) to 18 mug/ml by using the dose-concentration pred iction 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, FEV1, FEF25-7 5, and FVC) were determined every 2 h. The value of the prediction equ ation was confirmed when the early morning PTC, after evening suppleme ntation with Nuelin Liquid, was raised nearly to the targeted 18 mug/m l. The nocturnal peak-to-trough fluctuation in PTC was larger during a dditional treatment with Nuelin liquid, but the nocturnal peak-to-trou gh fluctuation in lung function parameters decreased. Overall, airflow during the early morning hours (0100-0500) significantly improved dur ing this chronotherapeutically optimized treatment of adding an NSRT p roduct to the evening dose of a 12-hourly SRT regimen.