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Study of the chronobiology of allergic rhinitis (AR) and bronchial asthma (BA) and the chronopharmacology and chronotherapy of the medications used in their treatment began five decades ago. AR is an inflammatory disease of the upper airway tissue with hypersensitivity to specific environmental antigens, resulting in further local inflammation, vasomotor changes, and mucus hypersecretion. Symptoms include sneezing, nasal congestion, and runny and itchy nose. Approximately 25% of children and 40% of adults in USA are affected by AR during one or more seasons of the year. The manifestation and severity of AR symptoms exhibit prominent 24-h variation; in most persons they are worse overnight or early in the morning and often comprise nighttime sleep, resulting in poor daytime quality of life, compromised school and work performance, and irritability and moodiness. BA is also an inflammatory medical condition of the lower airways characterized by hypersensitivity to specific environmental antigens, resulting in greater local inflammation as well as bronchoconstriction, vasomotor change, and mucus hypersecretion. In USA an estimated 6.5 million children and 15.7 million adults have BA. The onset and worsening of BA are signaled by chest wheeze and/or croupy cough and difficult and labored breathing. Like AR, BA is primarily a nighttime medical condition. AR is treated with H1-antagonist, decongestant, and anti-inflammatory (glucocorticoid and leukotriene receptor antagonist and modifier) medications. Only H1-antagonist AR medications have been studied for their chronopharmacology and potential chronotherapy. BA is treated with some of the same medications and also theophylline and beta2-agonists. The chronopharmacology and chronotherapy of many classes of BA medications have been explored. This article reviews the rather extensive knowledge of the chronobiology of AR and BA and the chronopharmacology and chronotherapy of the various medications used in their treatment.

The concept of homeostasis (i.e., constancy of the milieu interne) has long dominated the teaching and practice of medicine. Concepts and findings from chronobiology, the scientific study of biological rhythms, challenge this construct. Biological processes and functions are not at all constant; rather, they are organized in time as rhythms with period lengths that range in duration from as short as a second or less to as long as a year. It is the body's circadian (24 h) rhythms that have been researched most intensely. The peak and trough of these rhythms are ordered rather precisely in time to support the biological requirements of activity during the day and sleep at night. The timing of the peak and trough plus the magnitude of variation (amplitude) of physiological and biochemical functions during the 24 h give rise to predictable-in-time, day-night patterns in the manifestation and exacerbation of many common medical conditions. Circadian rhythms also can influence the response of patients to diagnostic tests and therapeutic interventions according to their timing with reference to body rhythms. Rhythms in the pathophysiology of medical conditions and patient tolerance to medications constitute the basis for chronotherapeutics, the timing of treatment in relation to biological rhythm determinants as a means of optimizing beneficial effects and safety. The article discusses recent advances in medical chronobiology and chronotherapeutics and their relevance to clinical medicine in general and the management of asthma in particular. Indeed, since asthma is a disease that exhibits rather profound circadian rhythmicity, investigation of its pathophysiology and therapy necessitates a chronobiologic approach.

Published asthma consensus reports now acknowledge that asthma is a nocturnal disease in as many as 75% of those afflicted by this medical condition. Nonetheless, the treatment of this chronic obstructive pulmonary disease in the clinic continues to be based primarily on homeostatic considerations in that it relies on long-acting bronchodilator and other therapies formulated and scheduled to ensure constant or near-constant levels of medication during the 24h. The need of asthma patients prone to nighttime attacks is not the same during the day and night; the therapeutic requirements of patients who experience nocturnal asthma, especially ones with the more severe forms of the disease, are often not satisfied by conventional medications. The therapeutic response and patient tolerance to bronchodilator medications can be improved markedly when the medications are proportioned during the 24h as a chronotherapy, that is, when more medication is delivered during nighttime sleep than daytime activity, as verified by numerous studies. This article reviews how the body's circadian rhythms influence the pharmacokinetics and effects of commonly prescribed asthma therapies and addresses why and how they must be taken into consideration to increase the effectiveness of asthma treatment.

Once-daily morning (7 AM) vs evening (10 PM) administration of the terbutaline prodrug bambuterol (20-mg tablet dose) was investigated in a double-blind, cross-over, randomized, and placebo-controlled study involving 29 diurnally active patients with asthma. Terbutaline plasma concentration, spirometry, and drug tolerance were assessed during 39-h inpatient studies. A 7-day washout period separated each treatment. Mean 24-h plasma concentration was comparable for morning and evening bambuterol (13.2 vs 14.0 nmol/L). The Cmax for evening vs morning dosing was 17.2 vs 15.5 nmol/L (p < 0.02). The 24-h mean FEV1 was greater (p < 0.001) for bambuterol (morning: 3.2 L; evening: 3.4 L) vs placebo (2.9 L) as it was for FVC, FEF25-75%, and peak expiratory flow rate (PEFR), with the maximum effect at 4 AM independent of medication time. Evening dosing, however, resulted in greatest 7 AM (awakening) FEV1, FEV25-75, and PEFR (p < 0.03). With reference to corresponding-in-time placebo values, improvement in FEV1 at the end of the 24-h dosing intervals amounted to 0.34 L (13.5%) (p < 0.0004) and 0.35 L (15.9%) (p < 0.0012) with evening and morning bambuterol dosing, respectively. Side effects were greater for bambuterol than placebo, but not significantly so. Once-daily bambuterol therapy proved to be an effective treatment for asthma, whether administered in the evening or morning. Evening dosing seems best for nocturnal asthma since airway patency overnight and on awakening at 7 AM is most improved.

Eleven diurnally active asthma patients having a history of nocturnal asthma and treated regularly with albuterol or metaproterenol alone or with twice-daily sustained-release theophylline were evaluated for day-night pattern in peak expiratory flow (PEF) and use of supplemental beta-agonist aerosol for relief of acute asthma. Overall, significant day-night variation was observed in the supplemental use of beta-agonist medication and in airway patency. The patients managed by albuterol or metaproterenol alone used supplemental beta-agonist medication significantly more between 4 AM and 8 AM and also 8 PM and midnight in comparison to 4 PM to 8 PM; this was not true for those treated with both theophylline and beta-agonist aerosol. In patients taking a beta-agonist bronchodilator, the 24-hour mean PEF was greater than in those who also took theophylline, but the day-night variation in PEF was comparable. Supplemental isoproterenol use was significantly correlated with circadian amplitude of the PEF rhythm, but not with the 24-hour mean PEF. The greater the day-night variation in PEF, the greater the reliance on a supplemental beta-agonist bronchodilator.

In this study we examined the efficacy and pharmacokinetics of a new chrono-optimized theophylline sustained release preparation for once-daily dosing in the evening for treating bronchial asthma. In a randomized, open crossover study, Euphylong (administered once daily at 2000 hours) was compared with the same dose of a reference preparation (subdivided into two equal doses taken at 800 and 2000 hours). Administration and dosage were in accordance with prior determination of clearance. The patients were outpatients during the first six days of every phase, whereas for the following 24-hour measurement period they were admitted as inpatients for measuring the requisite pharmacokinetic and pharmacodynamic data (PEF, FEV1, PEF 25 = 75, FVC). The theophylline levels remained practically constant for 24 hours under conventional theophylline treatment with twice-daily administration. In contrast, the variations of the theophylline serum levels and the night levels were higher after once-daily dosage of Euphylong, and the daytime levels and especially at the end of the dosage interval were lower. Compared with the standard profile without medication, both sustained release preparations improved the airway obstruction significantly and comparably during a 24-hour period. However, in the early morning hours between 200 and 600 both PEF and FEV1 were significantly higher under Euphylong. Between the improvement of PEF and FEV1 and the theophylline serum concentrations there was a significant correlation between 200 and 600 under Euphylong only. It is concluded that the treatment of asthma with the chrono-optimized once-daily theophylline preparation Euphylong over night is more effective than treatment with a conventional preparation in twice-daily dosage.

Many patients with asthma experience a worsening of symptoms at night and in the early morning, resulting in sleep disruption and possibly altered daily performance. A bronchodilator agent that exerts its maximal effect overnight to control nocturnal symptoms, without a worsening of the disease during the daytime, should improve the treatment of asthma. This investigation examined the efficacy and kinetics of a new chronotherapeutically optimized, sustained-release theophylline formulation administered once daily (OD) in the evening at 8:00 P.M. in comparison with a conventional sustained-release theophylline administered twice daily (TD) at 8:00 A.M. and at 8:00 P.M. in the same dose. After a theophylline clearance study to substantiate normal or slow metabolism of the drug, a dose-titration period, and a 24-h baseline spirometric study of patients not receiving any medication, participants were randomized to 7-day treatment phases with either OD or TD. Each outpatient segment of 6 days of OD and TD was followed by a 24-h inpatient study on Day 7 when serum drug level and spirometric (PEF, FEV1, and FEF25-75) parameters were obtained every 2 h. The conventional TD treatment was associated with a constant serum theophylline level over the 24 h. In contrast, the OD treatment was associated with larger peak-to-trough drug level fluctuation, with higher levels produced overnight and lower ones in the evening at the end of the dosing interval. Compared with the baseline references, both OD and TD significantly improved airflow over the entire 24 h and to a comparable extent. However, between 2:00 and 6:00 A.M., PEF and FEV1 were significantly greater with OD than with TD. The improvement in PEF and FEV1 at this time, because of OD, was correlated with the serum theophylline level. This was not the case for TD. The improvement in airflow over baseline values between 2:00 and 6:00 P.M. was not correlated with theophylline level with either treatment regime. Overall, the chronotherapeutically conceptualized OD treatment administered in the evening resulted in better airflow levels overnight than did the TD regime without loss of airflow in the afternoon.

Many chronobiologic and cyclic environmental factors are implicated in the pathophysiology of nocturnal asthma. A better understanding of these interrelating processes is essential for an optimization of medications for asthma. A reasonable therapeutic approach for the management of nocturnal asthma is the use of inhaled beta-agonists routinely, on a daily basis, and if symptoms persist, the use of an appropriate SR theophylline scheduled once-daily in the evening. Inhaled cromolyn sodium and corticosteroid therapy, properly timed to rhythms, may be warranted to control inflammation and stabilize the airways.

The symptoms of allergic asthmatic patients typically worsen during the night, especially during the early morning hours. Although 24-hour variations in the environment contribute to the intensification of the asthmatic condition nocturnally, environmental changes themselves do not fully explain the temporal aspects of this disease. Circadian (about 24-hour) rhythms in critical bioprocesses constitute significant contributory factors. The exacerbation of asthma during the night represents the changing status of biological functioning due to circadian rhythms in bronchial patency; airways hyperreactivity to acetylcholine, histamine, and house dust; and plasma cortisol, epinephrine, histamine, and cyclic AMP, among others.

Synthetic corticosteroids are frequently used to manage asthma and other inflammatory diseases. The timing of such drugs (whether ingested, inhaled, or infused) in relation to body rhythms influences the magnitude of both desired and undesired effects. It is crucial that corticotherapy be correctly scheduled to the circadian system of the hypothalamic-pituitary-adrenocortical (HPA) system. The secretion of cortisol from the adrenal cortex is not constant during each 24-hour period. Instead, production of this hormone varies as a high-amplitude circadian rhythm, with most of the secretion taking place during the initial hours of the activity span and very little late in the evening and during the first half of the sleep span. Results of laboratory and human studies indicate that the timing of exogenous corticosteroids, in relation to the circadian rhythm in HPA activity, is a critical factor. For example, the optimization of corticosteroid therapy for asthmatics entails daily (or alternate-day) administrations in the morning and, if necessary, early afternoon. By timing exogenous corticosteroids early during the activity span, the risk of adrenal suppression is minimized or avoided while bronchial patency is optimally enhanced, i.e., increasing the 24-hour average forced expiratory volume in 1 second (FEV1) and reducing its nocturnal dip. Clinical findings indicate that these results are obtainable with both acute and chronic corticosteroid therapies. In contrast, splitting the daily dose of corticosteroids into several small administrations, such as at mealtimes and before bedtime, markedly increases the likelihood of adrenal suppression without achieving the desired therapeutic effect. The dosing of synthetic corticosteroids late in the afternoon or evening, whatever the route of delivery, suppresses pituitary adrenocorticotropic hormone (ACTH) production during subsequent 24-hour spans, resulting in adrenocortical inhibition. Also, morning dosing of corticosteroids over many years seems to induce less--if any--osteopenia compared to dosing at other times. The adrenal response to exogenous administration of ACTH also is circadian-rhythmic. ACTH dosing in the morning results in greatest adrenal response in terms of cortisol secretion, while dosing in the evening results in least response. Knowledge of the circadian organization of the HPA axis is necessary to optimize the effect of synthetic corticosteroids, whether they be used to treat asthma, rheumatoid arthritis or other cortico-dependent diseases, or as a substitution therapy for Addison's disease.

We examined the relationship over 24 hours between percent-predicted values (PPV) of peak expiratory flow (PEF) and forced expiratory volume in one second (FEV1) in a group of 23 stable untreated asthmatic children 6 to 17 years of age by means of regression analysis as well as the percentage difference between the PPV of these two measurements. Although the Pearson correlation coefficient between the PPV was consistently high, ranging between 0.854 and 0.892, the assumption that such a finding substantiates the substitution of PEF for FEV1 is called into question. Over 50 percent of the subjects displayed a 10 percent or greater difference in the PPV between the two measurements, regardless of the time of day the two respiratory variable were determined, while over one-third of all subjects evidenced a 20 percent or greater discrepancy between the PPV of the two measures. While, on a group basis, there was no statistically significant difference in the mean percentage difference over 24 hours between the PPV of FEV1, when compared with the corresponding measurement of PEF, reliance on PEF alone in individual subjects may result in a false impression of the patency of the airways in comparison to the FEV1.

Potential day-night differences of theophylline absorption and disposition were examined in day-active asthmatic children. Theophylline was given orally as TheoDur tablets and Somophyllin-CRT capsules (random crossover) every 12 hr (0700 and 1900), and patients were studied during two consecutive dosing intervals. In addition, patients were studied during the last 24 hr of a 48-hr continuous, intravenous aminophylline infusion. Serum theophylline concentrations were essentially constant during the intravenous infusion for the day and night periods. Thus, day and night clearances were nearly identical. Following oral administration of Somophyllin-CRT or TheoDur, areas under the serum concentration-time curves were greater during the day than the night, with Somophyllin-CRT yielding greater areas than TheoDur for both dosing intervals. Theophylline was absorbed more rapidly during the day than the night, as evidenced by a time to maximum concentration that occurred earlier in the daytime dosing interval. We conclude that theophylline clearance is not characterized by a circadian rhythm and that absorption of theophylline from Somophyllin-CRT and TheoDur is more rapid and complete during the day than the night.

The effects of differently timed, but equivalent TheoDur (Key Pharmaceutical Co.) dosage schedules--twice-daily equally divided 12 hr (BID), once-daily evening (OD-PM) and once-daily morning (OD-AM)--were compared under steady-state conditions in 10 adult asthmatics with a documented history of nocturnal dyspnea. Assessments of airways function by spirometry were done every 3-hr over one complete 24-hr dosing interval for each dosage schedule under carefully controlled conditions. The different TheoDur regimens did not affect the 24-hr group average FEV1.0, PEF, MMEF or FVC. However, statistically significant circadian variation in airways function existed irrespective of the drug dosing schedule. Airways patency and FVC were least overnight (0200-0500 hr) and best during the morning or afternoon. With regard to FEV1.0 and PEF, which evidenced group circadian change for BID and OD-PM regimen by Cosinor analysis, the peak-to-trough (double amplitude) difference expressed as a percentage of the 24-hr average was rather large, being greatest for the OD-PM schedule (20.5% for FEV1.0 and 24.3% for PEF). The data for the 10 participants revealed individual differences in the effectiveness of the 3 studied theophylline dosing regimens when assessed in terms of the mean level and stability of airways function over the 24 hr. Based on the findings, neither the BID, OD-PM nor the OD-AM regimen effectively moderated the nocturnal deterioration of pulmonary function suggesting theophylline as dosed and timed may not be as efficacious as desired for patients with a history of strictly nighttime dyspnea. Thus, the schedule and prescription of TheoDur must take into account differences between patients, including the time when asthma symptoms are most likely to be experienced by each.

Medical practice and research in the United States and other countries are pervaded by the traditional concepts of homeostasis. As a result, the time of day or year when a diagnostic or therapeutic procedure is performed or a drug is administered is not considered important. However, during the last three decades, the science of chronobiology has revealed the importance to medicine of the rhythms that exist in the biologic functions and processes of humans. This article reviews the basic concepts of human chronobiology and discusses the rhythm dependence of certain disease states and the pharmacodynamics of medications frequently prescribed for their treatment. Special reference is made to the nocturnal exacerbation of asthma and the use of chronobiologic principles in its treatment.

Twenty-two British electronics workers suffering from occupationally-induced asthma due to their exposure to colophony fumes self-recorded their peak expiratory flow (PEF) every 1-2 hr throughout the waking span for at least two weeks, both during work and vacation periods. Data were analyzed by a two-step procedure using the statistical techniques of Single and Population Mean Cosinor analyses. The objective endpoints of mesor (24-hr mean), amplitude (measure of 24-hr rhythmic variation) and acrophase (peak time along the scale of 24 hr) for the time-spans of the work-week (Monday-Friday), weekend after work (Saturday-Sunday) and vacation weekdays and vacation weekends were compared. The PEF data of four workers who participated in the study for nearly one year also were evaluated for seasonal variation. A statistically significant difference (P less than 0.04) was detected in the PEF amplitude between work and vacation weeks; the difference in the PEF mesor and acrophase between work-weekdays and work-weekends achieved near or statistical significance (P = 0.07 and 0.05, respectively). The at-work amplitude was higher and the acrophase earlier timed. There was no statistically significant difference between work-week and weekend-after-work PEF mesors. Winter PEF mesors were significantly lower than summer ones in the four subjects self-measuring their bronchial patency over the year. Overall, the findings indicate that data obtained through employee surveys, using lightweight portable and inexpensive PEF Wright meters and analyzed by statistical analyses used in the field of biological rhythm research, yield objective evidence of occupationally associated decrements in pulmonary function resulting from colophony fume exposure.

Many asthmatic patients experience aggravation of symptoms overnight resulting in disruption of their sleep. Sustained-release theophylline represents at this time a major bronchodilator medication which possesses a sufficient duration of activity to avert the nocturnal breathing distress of asthma. Circadian rhythm-adapted theophylline schedules consisting of unequal dosing--more or all the drug taken in the evening--have proven efficacious in clinical investigations for certain patients. Although the kinetic behavior of some formulations is affected by food, the circadian rhythm-adapted schedules represent a significant step forward toward the goal of optimizating sustained-release theophyllines for patients who experience nighttime symptoms.

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.

In two studies, 25 diurnally active patients (6-17 years of age) were evaluated for day-night differences in serum theophylline concentration (STC) by frequent blood sampling over two consecutive 12-hr dosing intervals while being treated with Theo-Dur. In both studies, findings were similar; Cmax was greater and Tmax shorter following dosing at 0700 or 0800 vs. 1900 or 2000 with Cmax -Cmin approximately 7 micrograms/ml over the 24 hr. After the morning dosing, 22 of 25 patients exhibited Cmax within 4 hr; 23 of 25 exhibited Cmin 12 hr after this dosing. After the evening ingestion, the situation was very different: Cmin occurred within the initial 4 hr in 21 of 25 patients, whereas Cmax occurred in 22 of 25 patients just prior to the next (morning) dose. The findings indicate the most appropriate time to estimate Cmax in Theo-Dur-treated children is within the 4 hr after the morning ingestion. The best time to estimate Cmin is a few hours after the evening ingestion. Sampling at these times is likely to represent within 10-20% the actual Cmax or Cmin.

Several bronchodilator medications exhibit body-time (i.e., biological rhythm)-dependent changes in their pharmacokinetics and effects. Epinephrine (Adrenalin), metaproterenol (orciprenaline), aminophylline, and ipratropium bromide all have a better effect on the tone of the airways during the night and/or morning, when bronchial patency is low, than during the day, when it is high. The pharmacokinetics of sustained-release theophyllines (SRTs) exhibit administration-time differences. Day-night dosing-time differences in the kinetics of theophylline are especially prominent in children. Generally, in day-active asthmatic children the absorption of SRT is more rapid after a morning than an evening dosing. The administration-time effect on the kinetics of SRTs also is apparent in adult patients, but the magnitude of difference between the day versus evening administrations apparently is more moderate. Initial findings from studies of unequal (morning versus evening) BID dosing schedules--more theophylline or terbutaline before bed-time than arising--reveal a better therapeutic advantage relative to equal BID dosing schedules for those patients with predominantly nocturnal symptoms. Once-daily (OD) SRTs intended for delivery of the entire daily dose at a single time also differ quantitatively in their chronokinetics. Since asthma is mainly a nocturnal disease in many patients, it has been recommended by many that ODSRTs be taken in the evening. If taken in the morning, as is the current practice in the United States, they may not ensure therapeutic theophylline blood levels during the night when most needed. Moreover, not all ODSRTs appear suitable for once-nightly administration because of unacceptable kinetics.

Asthma typically worsens overnight. Although 24-hr variation in environmental conditions may contribute to the worsening of dyspnea at night, this does not fully explain day-night patterns of this disease. Circadian (about 24-hr) rhythms in bioprocesses which influence airways patency constitute major contributory factors. The nighttime exacerbation of asthma may represent the influence of circadian bioperiodicities in bronchial patency, airways hyperreactivity to acetylcholine, histamine and house dust, and altered levels of several plasma constituents such as cortisol, epinephrine, histamine and cyclic AMP.

Using a double-blind, placebo-control, crossover study design, 8 asthmatic children (8-15 years) were evaluated for temporal patterns in airways function throughout separate study periods when treatment was placebo or Theo-24 once-daily on separate occasions at 0600, 1500 or 2100 hr. During 39-hr in-hospital observations, pulmonary function and serum theophylline concentrations (STC) were assessed every 3 hr under all treatments. The pharmacokinetics of Theo-24 varied greatly depending on the dosing time. For the afternoon and evening dosings, the Cmax, Tmax, AUC, % swing, % fluctuation, % AUC fluctuation, % nocturnal excess and Cav(2-6 hr) were all statistically significantly greater than for the morning dosing. Compared with the placebo regimen, dosing patients with Theo-24 at 1500 hr disrupted circadian patterns of airways function, especially airways patency, while dosing at 2100 hr, reduced the amplitude and shifted the acrophase of several spirometric measures to a slightly earlier time. Theo-24 treatment irrespective of dosing time resulted in comparable enhancement of the group 24-hr mean, minimum and maximum values of airways patency with reference to placebo baselines. Theo-24 dosing at 1500 or 2100 hr, however, resulted in the best effect on the airways as assessed by the 24-hr mean FEV 1.0 level in 7 of the 8 asthmatic children. When the drug was given at 1500 hr, the time of lowest FEV 1.0 was shifted from the nighttime hours in 5 of 8 patients. These findings suggest that clinicians need to individualize the theophylline dosing schedule of patients to best control the symptoms of asthma.