Comparison of Once-Daily Evening Versus Morning Sustained-Release Theophylline Dosing For Nocturnal Asthma

Abstract

Eight diurnally active (approximately 0730-1100 hr) adults (41-61 yr) suffering from nocturnal asthma volunteered for a double-blind, cross-over randomized study of a once-daily dosing (600-900 mg/24 hr) of Armophylline (Rorer s.a., France), a sustained-release theophylline given either at 0800 hr or 2000 hr for 8-day durations. Study variables monitored daily were: (a) self-measured peak expiratory flow (PEF), heart rate, oral temperature and self-rated fatigue checked every 2 hr during the waking span as well as upon spontaneous nocturnal awakenings and (b) duration and subjective characteristics of sleep rated every morning. In addition, serum theophylline concentration (STC) plus the variables in (a) were sampled every 2 hr during the 24 hr of the eighth day of each timed treatment span. Rx at 0800 hr was associated with a nocturnal dip in PEF of 20 +/- 2.8% (X +/- S.E.M.) from the level achieved at the time of the diurnal crest; Rx at 2000 hr moderated the nocturnal fall; it was only 10 +/- 2.1% and within the physiologic limits of non-asthmatic persons. The STC peak height (Cmax) was greater (P less than 0.05) and time-to-peak (Tmax) shorter (P less than 0.005) with Rx at 0800 hr than at 2000 hr. With Rx at 2000 hr an STC plateau of approximately 12 hr resulted. A statistically significant correlation (r = 0.86; P less than 0.01) between PEF and the corresponding-in-time STC was observed with Rx at 2000 hr but not with Rx at 0800 hr. A small, but statistically significant, higher heart rate resulted from 2000 hr dosings in five out of eight subjects relative to the 0800 hr dosing. There were no differences in the sleep characteristics nor in oral temperature between dosing times. Once-daily (600-900 mg) SRT dosing at 2000 hr controlled the nocturnal dip of bronchial patency with no major side-effects in diurnally active adult patients with nocturnal allergic asthma.

Role of School Schedule, Age, and Parental Socioeconomic Status on Sleep Duration and Sleepiness of Parisian Children

“…In the past, sleep logs and VAS have been useful successfully to quantify subjective variables in adults such as fatigue, attention, and drowsiness, for example, in field studies of shift workers (11,12) and patients with nocturnal asthma (13). These methods also have been successfully applied in studies of children as young as 7 years of age to investigate circadian changes in subjective variables (14)(15)(16)(17)(18).…”

Bedtime administration of long-acting antihypertensive drugs restores normal nocturnal blood pressure fall in nondippers with essential hypertension

“…Although medication has been recommended after breakfast, the validity of this has not been proved. Knowledge of the circadian rhythms in symptom intensity of chronic disease, along with the chronopharmacology of medications, has been used to optimize conventional once-a-day H2-receptor antagonists for peptic ulcer disease [10], theophylline for nocturnal asthma [11], cholesterol-lowering agents [12], and even cancer medications to lessen their toxicity and enhance therapeutic outcome [13]. However, many doctors and patients are unaware that the effects of certain antihypertensive drugs differ significantly according to the time of day they are ingested.…”

Influence of the Circadian System on Disease Severity

“…The recommended daily pattern of dosing is either a single evening dose, or one-third of the daily dose in the morning and two-thirds in the evening. Several studies have shown that the bioavailability of Theophylline is greater if administered in the evening than in the morning, and that such chronotherapy is more effective in preventing the nighttime dip in FEV1 than the conventional Theophylline administration (equally divided daily dose between morning and evening administration)99-101, although this effect may be concentration dependent102. Kraft et al have also shown that administration of Theophylline to subjects with asthma in the evening improved the inflammatory profile of the distal airways, and this was correlated with improved nocturnal FEV1103.…”