Day-night patterns in bronchial patency and dyspnea: basis for once-daily and unequally divided twice-daily theophylline dosing schedules

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.     

Inflammatory and mechanical factors of allergen-induced bronchoconstriction in mild asthma and rhinitis.

We studied whether different bronchial responses to allergen in asthma and rhinitis are associated with different bronchial inflammation and remodeling or airway mechanics. Nine subjects with mild asthma and eight with rhinitis alone underwent methacholine and allergen inhalation challenges. The latter was preceded and followed by bronchoalveolar lavage and bronchial biopsy. The response to methacholine was positive in all asthmatic but in only two rhinitic subjects. The response to allergen was positive in all asthmatic and most, i.e., five, rhinitic subjects. No significant differences between groups were found in airway inflammatory cells or basement membrane thickness either at baseline or after allergen. The ability of deep inhalation to dilate methacholine-constricted airways was greater in rhinitis than in asthma, but it was progressively reduced in rhinitis during allergen challenge. We conclude that 1) rhinitic subjects may develop similar airway inflammation and remodeling as the asthmatic subjects do and 2) the difference in bronchial response to allergen between asthma and rhinitis is associated with different airway mechanics.     

Clinical Chronobiology and Chronotherapeutics with Applications to Asthma

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 (24h) 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 24h 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.     

Clinical Chronobiology and Chronotherapeutics with Applications to Asthma

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 (24h) 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 24h 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.     

The early snail acquires the learning. Comparison of scores for conditioned taste aversion between morning and afternoon

The pond snail Lymnaea stagnalis acquires conditioned taste aversion (CTA) and maintains its memory for more than a month. Snails in our laboratory were cultured at 20 degrees C on a 12:12 light-dark cycle (light from 7 am to 7 pm). To examine the hours during which snails acquire CTA effectively, we trained some snails in the morning and others in the afternoon, and then compared their scores. CTA developed in both cases, but scores were significantly better in the morning than in the afternoon. To elucidate the cause of this difference in scores, we observed the voluntary activity of snails and found the circadian rhythm reflected in the snails' free-movement distances; distances at the circadian time 0-12 (daytime) were significantly longer than those at the circadian time 12-24 (nighttime). This rhythm was kept up for at least 3 days, even in constant darkness. In conclusion, L. stagnalis should be trained in the morning to acquire associative learning, possibly because of its greater propensity to roam about at that time as opposed to the afternoon.     

High prevalence of asthma in cross country skiers.

OBJECTIVES--To study the prevalence of asthma (asthma symptoms and bronchial hyperresponsiveness) in Swedish cross country skiers compared with non-skiers and monitor changes in symptoms and bronchial hyperresponsiveness during the year. DESIGN--Cross sectional study during the winter ski season and in the summer. SETTING--Six ski clubs for élite skiers (total 47) in two different areas of Sweden. SUBJECTS--42 élite cross country skiers and 29 non-skiing referents. MAIN OUTCOME MEASURES--Bronchial responsiveness, asthma symptoms, and lung function. RESULTS--Bronchial responsiveness was significantly greater and asthma symptoms more prevalent in the skiers than in the referents. There was no difference in bronchial responsiveness within either group between winter and summer. 15 of the 42 skiers used antiasthmatic drugs regularly and 23 had a combination of asthma symptoms and hyperresponsive airways or physician diagnosed asthma, or both. Altogether 33 skiers had symptoms of asthma or bronchial hyperresponsiveness. One of the referents had symptoms of asthma and bronchial hyperresponsiveness, and none used antiasthmatic drugs regularly. CONCLUSIONS--Asthma, asthma-like symptoms, and bronchial hyperresponsiveness are much more common in cross country skiers than in the general population and non-skiers. Strenuous exercise at low temperatures entailing breathing large volumes of cold air is the most probable explanation of persistent asthma in skiers.     

Circadian Rhythms in Stomatal Responsiveness to Red and Blue Light

Stomata of many plants have circadian rhythms in responsiveness to environmental cues as well as circadian rhythms in aperture. Stomatal responses to red light and blue light are mediated by photosynthetic photoreceptors; responses to blue light are additionally controlled by a specific blue-light photoreceptor. This paper describes circadian rhythmic aspects of stomatal responsiveness to red and blue light in Vicia faba. Plants were exposed to a repeated light:dark regime of 1.5:2.5 h for a total of 48 h, and because the plants could not entrain to this short light:dark cycle, circadian rhythms were able to "free run" as if in continuous light. The rhythm in the stomatal conductance established during the 1.5-h light periods was caused both by a rhythm in sensitivity to light and by a rhythm in the stomatal conductance established during the preceding 2.5-h dark periods. Both rhythms peaked during the middle of the subjective day. Although the stomatal response to blue light is greater than the response to red light at all times of day, there was no discernible difference in period, phase, or amplitude of the rhythm in sensitivity to the two light qualities. We observed no circadian rhythmicity in net carbon assimilation with the 1.5:2.5 h light regime for either red or blue light. In continuous white light, small rhythmic changes in photosynthetic assimilation were observed, but at relatively high light levels, and these appeared to be attributable largely to changes in internal CO2 availability governed by stomatal conductance.     

Circadian rhythm in peak expiratory flow: alteration with nocturnal asthma and theophylline chronotherapy

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513-519, 2000)     

Alteration of the circadian rhythm in peak expiratory flow of nocturnal asthma following nighttime transdermal beta2-adrenoceptor agonist tulobuterol chronotherapy

We investigated the efficacy of nighttime transdermal tulobuterol (beta2-adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group-mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276 +/- 45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p < 0.001) the 03:00 h group average PEF to 363 +/- 67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p < 0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.     

CIRCADIAN RHYTHM IN PEAK EXPIRATORY FLOW: ALTERATION WITH NOCTURNAL ASTHMA AND THEOPHYLLINE CHRONOTHERAPY*

We investigated changes in the circadian rhythm of peak expiratory flow (PEF) in seven persons with nocturnal asthma for a 24h span when (1) they were symptom free and their disease was stable, (2) their asthma deteriorated and nocturnal symptoms were frequent, and (3) they were treated with theophylline chronotherapy. Subjects recorded their PEF every 4h between 07:00 and 23:00 one day each period. Circadian rhythms in PEF were assessed using the group-mean cosinor method. The circadian rhythm in PEF varied according to asthma severity. Significant circadian rhythms in PEF were detected during the period when asthma was stable and when it was unstable and nocturnal symptoms were frequent. When nocturnal symptoms were present, the bathyphase (trough time) of the PEF rhythm narrowed to around 04:00; during this time of unstable asthma, the amplitude of the PEF pattern increased 3.9-fold compared to the symptom-free period. No significant group circadian rhythm was detected during theophylline chronotherapy. Evening theophylline chronotherapy proved to be prophylactic for persons whose symptoms before treatment had occurred between midnight and early morning. Changes in the characteristics of the circadian rhythm of PEF, particularly amplitude and time of bathyphase, proved useful in determining when to institute theophylline chronotherapy to avert nocturnal asthma symptoms. (Chronobiology International, 17(4), 513–519, 2000)     

Postembryonic changes in circadian photo-responsiveness rhythms of optic lobe interneurons in the cricket Gryllus bimaculatus

The photo-responsiveness of 2 groups of interneurons responding to light in the protocerebrum was investigated at 2 developmental stages, the last instar nymphs and adults, in the cricket Gryllus bimaculatus. The cricket is diurnally active during the nymphal stage but becomes nocturnal as an adult. In both adults and nymphs, light-induced responses of optic lobe light-responding interneurons that conduct light information from the optic medulla to the lobula and the cerebral lobe showed a circadian rhythm peaking during the subjective night. Amplitudes of the rhythms were not significantly different between adults and nymphs, but adults showed more stable day and night states than did nymphs. The medulla bilateral neurons that interconnect the bilateral medulla areas of the optic lobe also showed circadian rhythms in their light-induced responses in both adults and nymphs. The rhythm had a clear peak and a trough in adults, and its amplitude was significantly greater than that of nymphs. These results suggest that the 2 classes of interneurons are differentially controlled by the circadian clock. The difference might be related to their functional roles in the animal's circadian behavioral organization.     

Circadian rhythm of circulating corticosterone and prolactin levels in spontaneously hypertensive rats

Circulating levels of corticosterone and prolactin were measured by radioimmunoassay at hourly intervals during a 24 h period to establish the diurnal rhythm of these hormones in spontaneously hypertensive rats (SHR). Corticosterone levels exhibited a distinct circadian variation with concentrations reaching a zenith at 2000 h and a nadir at 1200 h in male and female SHR. Corticosterone levels in females were consistently greater than males. Circulating prolactin levels were greater during the light h than dark in the female; the opposite occurred in males. Measurement of pituitary prolactin content tended to be low when serum prolactin levels were high and vice versa. The circadian rhythm of circulating corticosterone and prolactin in the hypertensive SHR was found to be similar to the day-night patterns established for normotensive rats. However, these measurements were made under quiescent conditions. It is suggested that because SHR are hyper-responsive to stress and because corticosterone and prolactin have synchronous effects on stress-induced adrenal steroidogenesis, further investigation of prolactin and corticosterone may reveal a participatory role of these hormones in the pathogenesis of the genetically-programmed hypertension of SHR.     

2007～2011年鄂州市气传致敏真菌调查及其与支气管哮喘的相关性

目的 探讨2007年5月～ 2011年4月鄂州市气传致敏真菌和支气管哮喘关系,以了解该地区支气管哮喘情况.方法 运用暴片调查法和暴皿调查法统计和记录鄂州市气传致敏真菌的种类及数量.选择该时期内鄂州市100例支气管哮喘患者采用真菌变应原浸液作过敏原皮试发现有35例患者皮内试验阳性,将35例发作期患者和40例稳定期支气管哮喘患者行曲霉特异性IgE测定.结果 100例支气管哮喘患者皮内实验组阳性35例,阳性率为35％,而在35例患者中IgE阳性有31例,检测符合率为88.58％,稳定期患者中阳性反应例数2例,阳性率为5％,两组阳性率比较差异具有显著性（P＜0.05）.结论 鄂州市气传致敏真菌和支气管哮喘密切相关,主要致病菌为曲霉,是支气管哮喘的致敏原之一,需要注意环境卫生以减少气传致敏真菌的数量.     

Airways responsiveness determined by consecutive histamine challenges in asymptomatic asthmatics

The effect of two consecutive histamine inhalation challenges on airways responsiveness was assessed in a group of eight nonsmoking nonmedicated asthmatics aged 19-27 yr. All subjects had a base-line forced expiratory volume in 1 s (FEV1) of greater than 80% of their predicted normal value before the initial challenge and were allowed to recover to greater than 95% of the initial base-line FEV1 value before the second challenge was initiated. The average airways recovery time after the first challenge was 44 min but ranged between 30 and 90 min. The mean +/- SD values of cumulative histamine dose units provoking a 20% decrease of the FEV1 from the buffer control value (PD20FEV1) were 10.79 +/- 5.95 determined with the first and 30.50 +/- 46.36 with the second challenge (P greater than 0.05). We conclude that sequential histamine challenges performed in mild asthmatics with closely controlled prechallenge airways function are well tolerated. Although some variance does exist in intersubject airways recovery time and in intra-subject histamine airways responsiveness determined by sequential challenges, our data do not support recent observations (J. Appl. Physiol. 63: 1572-1577, 1987) that histamine tolerance is a characteristic finding associated with bronchial asthma.     

Alteration of the Circadian Rhythm in Peak Expiratory Flow of Nocturnal Asthma Following Nighttime Transdermal β2‐adrenoceptor Agonist Tulobuterol Chronotherapy

We investigated the efficacy of nighttime transdermal tulobuterol (β₂‐adrenoceptor agonist) chronotherapy for nocturnal asthma by assessing changes both in the frequency of symptoms and features of the circadian rhythm in peak expiratory flow (PEF), a measure of airway caliber. Thirteen patients with nocturnal asthma were evaluated before and during tulobuterol patch chronotherapy, applied once daily in the evening for 6 consecutive days. Patients were asked to record their PEF every 4 h between 03:00 and 23:00 h for one day. Circadian rhythms in PEF were examined by group‐mean cosinor analysis. The group average PEF at 03:00 h, the time during the 24 h when PEF is generally the poorest, before the application of the chronotherapy, when asthma was unstable and nocturnal symptoms frequent, was 276±45 L/min. Application of the tulobuterol patch at nighttime significantly increased (p<0.001) the 03:00 h group average PEF to 363±67 L/min. Significant circadian rhythms in PEF were observed during the span of study when nocturnal symptoms were frequent as well as with the use of the tulobuterol patch. Before the initiation of tulobuterol chronotherapy, the bathyphase (trough time of the circadian rhythm) in PEF narrowed to around 04:00 h, and the group circadian amplitude was 28.8 L/min. In contrast, the group circadian amplitude significantly (p<0.01) decreased to 10.4 L/min, and the 24 h mean PEF increased significantly with tulobuterol patch chronotherapy. These changes indicate that tulobuterol chronotherapy significantly increased both the level and stability of airway function over the 24 h. The circadian rhythm in PEF varied with the severity and frequency of asthmatic symptoms with and without the nighttime application of the tulobuterol patch medication. We conclude that the parameters of the circadian rhythm of PEF proved useful both in determining the need for and effectiveness of tulobuterol chronotherapy for nocturnal asthma.     

Optic lobe circadian pacemaker sends its information to the contralateral optic lobe in the cricket Gryllus bimaculatus

The bilaterally paired optic lobe pacemakers of the cricket Gryllus bimaculatus are mutually coupled. In the present study we recorded the neural activity conveyed from the brain toward the optic lobe with a suction electrode to examine the coupling signals. The results demonstrated that the brain efferents to the optic lobe encode the circadian information: Both in constant light (LL) and constant darkness (DD), the neural activity of brain efferents showed a clear circadian rhythm with a nocturnal peak. Since the rhythm survived the severance of the contralateral optic nerve but disappeared when the contralateral optic lobe was removed, it is apparent that the rhythm originates from the contralateral optic lobe. The amplitude of the rhythm was greater in LL than in DD, suggesting that light affects the amplitude of the rhythm. This was confirmed by the fact that the light-induced response was under circadian control, being greater during the subjective night. These data suggest that the bilaterally paired optic lobe pacemakers exchange circadian information as well as light information. The data are also consistent with the results of previous behavioral experiment.Abbreviations DD constant darkness - LD light dark cycle - LL constant light     

Inconsistency in the expression of locomotor and ERG circadian rhythms in the German cockroach, Blattella germanica (L.).

ERG recordings from German cockroaches showed that the amplitude of light-evoked responses have a circadian rhythmicity in adult males that coincided with the locomotor circadian rhythm. The peak of the response occurred during the subjective night, and the circadian period was less than 24 h under DD condition. In contrast, although the locomotor circadian rhythm was masked by the development of ovaries and pregnancy in females, their visual responses displayed circadian rhythmicity. This inconsistency in expression of locomotor and visual sensitivity circadian rhythms in females implied separate pacemakers for these two overt rhythms. After severing the optic nerves, changes in ERG amplitude of the operated cockroaches still displayed a circadian rhythm under DD condition, demonstrating that the visual sensitive pacemaker was located in the eye and independent from the locomotor pacemaker.     

Light activates the adrenal gland: timing of gene expression and glucocorticoid release

Light is a powerful synchronizer of the circadian rhythms, and bright light therapy is known to improve metabolic and hormonal status of circadian rhythm sleep disorders, although its mechanism is poorly understood. In the present study, we revealed that light induces gene expression in the adrenal gland via the suprachiasmatic nucleus (SCN)-sympathetic nervous system. Moreover, this gene expression accompanies the surge of plasma and brain corticosterone levels without accompanying activation of the hypothalamo-adenohypophysial axis. The abolishment after SCN lesioning, and the day-night difference of light-induced adrenal gene expression and corticosterone release, clearly indicate that this phenomenon is closely linked to the circadian clock. The magnitude of corticostereone response is dose dependently correlated with the light intensity. The light-induced clock-dependent secretion of glucocorticoids adjusts cellular metabolisms to the new light-on environment.     

Administration-time-dependency of the pharmacokinetic behavior and therapeutic effect of a once-a-day theophylline in asthmatic children

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.