[Circadian rhythms in the toxic effects of the histamine antagonist cetirizine in mice]. / Rythmes circadiens des effets toxiques d'un antihistaminique H1: la cétirizine chez la souris.

UNLABELLED: Cetirizine is a second generation histamine H(1) receptor antagonist used to provide symptomatic relief of allergic signs caused by histamine release. The aim of the study was to learn whether the survival and the motor incoordination (ataxia) side effect of cetirizine administration is dosing time-dependent. MATERIALS AND METHODS: A total of 240 male Swiss mice, 10 weeks of age were synchronized for 3 weeks by 12 h light (rest span)/12 h dark (activity span). Different doses of cetirizine were administered orally at fixed times during the day to determine both the sublethal (TD(50)) and lethal (LD(50)) doses, which were, respectively, 55 +/- 0.35 and 750 +/- 0.40 mg/kg. In the chronotoxicologic study a single dose of cetirizine (DL(50)) was administered to comparable groups of animals at six different circadian stages [1, 5, 9, 13, 17, 21 h after light onset (HALO)]. RESULTS: The survival was statistically significant dosing time-dependent (chi(2) = 16.73; P < 0.001). Drug dosing at 17 HALO resulted in 83.3% survival rate whereas drug dosing at 5 HALO was only 23.25%. Cosinor analysis revealed a statistically significant circadian (period approximately 24 h) rhythmic component in survival. Lowest (20%) and highest (88%) ataxia occurred when cetirizine was administered, respectively, at 17 and 5 HALO. Cosinor analysis revealed a statistically significant circadian (period approximately 24 h) rhythmic component in ataxia. CONCLUSION: Our results reveal that the best safety is shown when cetirizine is administered in the middle of the dark (activity) span of the mice, since it produces some side effects: ataxia and hyperthermia. Taking into account of the hour administration of cetirizine, improves treatment efficacy and permit the best control of allergic diseases.

Analysis of circadian and ultradian rhythms of skin surface properties of face and forearm of healthy women.

Biologic rhythms of cells and organisms are well documented and have been extensively studied at the physiologic and molecular levels. For the skin, many circadian changes have been investigated but few systematic studies comparing skin at different body sites have been reported. In this study we investigated facial and forearm skin circadian rhythms in eight healthy Caucasian women. Noninvasive methods were used to assess skin capacitance, sebum excretion, skin temperature, transepidermal water loss, and skin surface pH on fixed sites of the face and the volar forearm during a 48 h span under standardized environmental conditions. Using the cosinor or ANOVA methods, circadian rhythms could be detected for sebum excretion (face), transepidermal water loss (face and forearm), skin temperature (forearm), pH (face), and capacitance (forearm). No circadian rhythmicity was found for the other biophysical parameters. In addition to the 24 h rhythm component, rhythms with periods of 8 h were found for sebum excretion, of 8 and 12 h for transepidermal water loss (face and forearm), and of 12 h for skin temperature (forearm). Our study confirms that rhythms of skin surface parameters are readily measurable and that these rhythms differ between different sites. Furthermore, we demonstrate for the first time that, for transepidermal water loss (face and forearm), sebum excretion, and skin temperature (forearm), in addition to circadian rhythms, ultradian and/or component rhythms can be detected.

The birth of chronobiology: Julien Joseph Virey 1814.

Julien-Joseph Virey (1775-1846) held the position of pharmacist-in-chief at the Val-de-Grâce, a military hospital. He was an innovative pharmacist, naturalist, anthropologist, and philosopher and a prolific author. His writings encompassed a wide range of topics, although many of his ideas were sometimes harshly questioned. Interest in Virey's work today stems from renewed appreciation of his doctoral thesis in medicine, which was completed in 1814 in Paris and was the first devoted to biological rhythms. Virey envisioned biological rhythms to be innate in origin and controlled by living clocks entrained by periodic environmental changes, such as the day-night alternation in light and darkness. He also reported that the effects of drugs vary according to their administration time. But, above all, he collected and published quantified time series that demonstrated human circadian and annual mortality rhythms. Statistical analysis of Virey's data using modern time series methods confirms his deduction that human mortality exhibits rhythmicity. Comparison of his findings with those derived from analyses of more recent human mortality time series shows the characteristics of these rhythms have changed little since 1807 despite differences in environmental conditions. Virey deserves credit for establishing the field of chronobiology based on his insights and writings.

Role of school schedule, age, and parental socioeconomic status on sleep duration and sleepiness of Parisian children.

The aim of the study was to assess the duration and quality of sleep of prepubertal (Tanner Scale level 1) physically and mentally healthy children as a function of school schedule (4 versus 4.5 days per week), age and grade (median age of 9.5 years for 4th grade versus median age of 10.5 years for 5th grade), school district (wealthy versus nonwealthy) in Paris, France, and parental socioeconomic status (high, medium, or low). We studied 51 girl and 44 boy volunteer pupils with written parental consent. The study lasted 2 weeks during the month of March. During the first study week, the children attended school 4.5 days, and during the second week, they attended school only 4 days without difference in the length of the school day. A sleep log was used to ascertain time of lights off for sleep and lights on at awakening, nighttime sleep duration, and self-rated sleep quality. A visual analog scale (VAS) was also used by pupils to self-rate the level of perceived sleepiness at four specific times of the school day. Conventional statistical methods (e.g., t and chi2 tests) were used to examine differences in mean values. Sleep duration, self-rated sleepiness, and subjective sleep quality were comparable (P > .05) by gender, school schedule, school district, and parental socioeconomic status. Overall, the sleep of this sample of Parisian children around 10 years of age was rather stable in its duration and timing, suggesting flexibility to adjust to the different school schedules.

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 (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.

[Utilization of a self-contained psychometry-oriented device, for study of affective and cognitive function of a subject]. / Utilisation d'un appareil autonome de psychométrie pour l'étude des fonctions affectives et cognitives d'un sujet.

We appraised the possibility to use the Psycho-Log 24, an ambulatory, adapted to chronopsychometry device, which realizes simplified questionnaires and performance test adaptable to each subject; this device has dimensions like a pocketbook; its storage capacity is compatible with a long time use. 9 adult volunteers (8 healthy subjects and 1 depressive patient) participated to this study. All of them effected reaction times (TRS) during 3 to 31 days at the rate of at least 4 sessions/day; some of them completed mental calculations (CM), letters cancellations (BRL) and auto-estimation scales (from 1 to 9 items, also measured by a classic method). For TRS and all the subjects, the frequencies histograms calculated by hour and on a 24 h scale, showed a bimodal variation, with a major peak suggesting a circadian rhythm. 5 subjects had different time for the daily best performances of each hand (shifted from 5 to 12 h). In the healthy adults, for BRL and CM, the best performances in speed and precision are shifted and could be related to the "fatigue" auto-estimated peaks. There is a significant correlation between auto-estimations by Psycho-Log and the classic method. The coherence between the auto-estimations of the depressive subject is strong during the remission stage, and lower during the relapse stage. The used method seems an effective mean to know the temporal structure of the cognitive and affective functions of a subject, and to estimate the preserving of this structure; the method first could constitute an exploratory mean for an objective evaluation of the drugs effects and patients quality of life, secondly could be implicated in researches with diagnosis target.

Morning versus afternoon gymnastic time and diurnal and seasonal changes in psychophysiological variables of school children.

The aims of this study were to document time-related (morning versus afternoon) effects of physical activities (gymnastics) on a set of physiological and psychological variables in school children, including diurnal changes. For the study, 61 boys and 69 girls, 6 to 11 years of age, volunteered. They were considered healthy according to routine clinical criteria. They were synchronized with diurnal activity from around 07:00 to 21:00 and nocturnal rest, time of year being taken into account. Tests were performed at school during 4 weeks of 4.5 days of school at fixed clock hours: 09:00, 11:00, 14:00, and 16:00. Gym time was randomized with regard to week order and season. Four different classes (39 boys and 38 girls) were involved in psychophysiological tests, and two different classes (22 boys and 31 girls) collected saliva samples for morning free cortisol determination. Both t-test and three-factor analysis of variance (ANOVA) were used for statistical analyses. Better performances were obtained in June than in mid-winter with reference to letter cancellation and random number addition tests. As a group phenomenon, morning (09:00 to 10:00) versus afternoon (14:00 to 15:00) gym was not an influential condition with regard to sleep duration, oral temperature, self-rated fatigue and drowsiness, letter cancellation, addition tests, or salivary cortisol. However, gym-time-related differences were observed in classes of younger subjects (e.g., 6-7 years) with regard to self-rated fatigue and the letter cancellation test. Such variability among subgroups suggests that interindividual differences are likely to exist in younger children with regard to manipulation of environmental factors. In addition, gym itself (without gym time consideration) may be an influential factor with regard to diurnal patterns of some variables (e.g., the letter cancellation test).

Variability in the period of the blood pressure circadian rhythm in human beings.

In studies and assessments of human beings done in natural settings, it is assumed that the period tau of circadian rhythms, including ones of systolic (SBP) and diastolic (DBP) blood pressure, is equal to 24 hours. To test this hypothesis, SBP and DBP rhythms were studied in 112 medication-free, non-hospitalized subjects (62 males, 47.1 + 2.0 years [x +/- SEM], and 50 females, 54.5 +/- 2.1 years) by 48 h ambulatory blood pressure monitoring (ABPM). Of these, 26 were hypertensive (diurnal SBP > 140 mmHg and diurnal DBP > 90 mmHg) and 86 normotensive. All subjects were synchronized by their habitual daytime activities from approximately 08:00 h to approximately 23:00 h +/- 1 h and by sleep at night. The BP was assessed at 15-minute intervals during a continuous 48h span using a Spacelabs model #90207 ABPM. The time series data of each subject were individually evaluated by power spectra analysis for the prominent tau of the SBP and DBP rhythms. The prominent tau differed from 24 hours in 22/112 subjects for SBP and in 16/112 subjects for DBP. Generally, in these individuals the tau was less than 24 hours. The occurrence of non-24 h tau's was more frequent in hypertensive than normotensive subjects; the difference between the groups in the distribution of the prominent tau's by class (tau = 24 h, tau = 12, 12 h > tau < 24 h, etc.) was statistically significant (chi 2 test = 19.1; p < 0.001). No difference in the distribution of tau's of blood pressure was detected according to the subject's age and gender. These findings suggest that ABPM done only for a duration of 24 h may be too short to characterize accurately the features of the day-night variation in human BP, including the precise period of its rhythm.

Interindividual differences in the flexibility of human temporal organization: pertinence to jet lag and shiftwork.

Interindividual variability in the human temporal structure is seldom taken into account, especially in studies devoted to the effects of shiftwork and jet lag. The understated postulate is that humans can be treated as a pure strain species. This paper reviews some facts and concepts with special reference to interindividual changes in the rhythm period tau and the resulting dyschronism. The following points are addressed. (1) Subjects and methods (importance of longitudinal field studies on shift workers). (2) Criteria for tolerance to shiftwork and jet lag. (3) Interindividual differences and shiftwork problems (subject type; the association between good shiftwork tolerance and stable temporal structure; dychronism with tau s differing from 24h and from variable to variable. (4) The genetic background of circadian dyschronism. The Dian-circadian genetic model of biological rhythms. It allows understanding of one's susceptibility to dyschronism, which was actually observed in approximately equal to 30% of subjects studied longitudinally. (5) Practical implications of interindividual differences (dissociate problems of passengers after a transmeridian flight-who have to adjust their temporal structure to local time-from problems of shiftworkers-who need to prevent alteration of their temporal structure; the advantage for the latter of participating in a rapid rotation system rather than a weekly rotation; emphasis that the suitability of a given subject for a given shiftworking condition is likely to be estimated only after a trial span of time including longitudinal study of a set of rhythms.

Circadian rhythm period in reaction time to light signals: difference between right- and left-hand side.

The study was designed to test the hypothesis that the prominent rhythm period tau of simple reaction time (SRT) and three-choice reaction time (CRT) to light signals may vary between the dominant (DH) and non-dominant (NDH) hand. Eleven healthy subjects, 8 males (16-74 years, including two left-handed) and 3 females (18-43 years), synchronized with a diurnal activity (approximately 07.00 h to approximately 23.00 h) and a nocturnal rest, volunteered for the study. A battery-powered ambulatory device was used to self-record SRT to a yellow light signal and CRT to yellow, green and red signals. Tests were performed 4-7 times/24 h during a 12- to 15-day span. Power spectra, ANOVA, cosinor, chi2 and correlation tests were used to individually analyze time series. Tau = 24 h in SRT rhythms of DH (8/11 cases) and NDH (6/11 cases) with chi2 = 3.5 and p > 0.05. In CRT rhythms, tau = 24 h for DH (8/11 cases) while tau = 8 h for NDH (7/11 cases), a difference which was statistically significant (chi2 = 9.4 with p < 0.02). Concordant results were obtained with other statistical tests leading to the conclusion that the rather complex cognitive task (CRT) and, to a certain extent, SRT of certain individuals, were associated with tau = 24 h for DH and tau = 8 h for NDH. These findings are in favor of the hypothesis that functional clocks are present in the human brain cortex, associated with the possible expression of rhythms with a prominent period differing from the right- and left-hand side.

Differences between left- and right-hand reaction time rhythms: indications of shifts in strategies of human brain activity.

Reaction time (RT) measurements serve as quantitative indices for pilots' cognitive processes of the brain. To examine if laterality exists in the brain hemispheres we measured, by the use of a Pilot Evaluation System (PES), right- and left-hand performance rhythms as indicative of RT to audible and visual stimuli. The tests included sets of simple tasks and complex ones to which a secondary task composed of audio signals was added. The accuracy of recorded reaction time was 27 ms. Seven right-handed males, 27-42 years of age, experienced with the PES flight simulator, were tested every 2 h, nine times daily (starting at 08:00 h) during 3 consecutive days. The results indicated that for simple tasks, the 24 h period of RT rhythm is either exclusive or prominent for both hands. For complex tasks the prominent period of RT is 24 h for the right (dominant) hand and 8 h for the left (non-dominant) hand (right-hand 24 h period Fstat = 140, r2 = 0.62 and 8 h period Fstat = 25, r2 = 0.22; left-hand 24 h period Fstat = 44, r2 = 0.34 and 8 h period Fstat = 100, r2 = 0.54). The findings suggest that a laterality exists in the brain hemispheres with regard to differences in rhythm periodicities. The expression of this laterality is dependent on the task-load level and points to a strategy of linkage and integrity in brain activity.

[Annual endocrine rhythms in man]. / Les rythmes annuels endocriniens chez l'homme.

Biological rhythms spread over a wide range of frequencies: circadian, ultradian and infradian. Circannual rhythms belong to this latter domain as their period average one year +/- 2 months. The seasonal rhythms in man of melatonin, prolactin, hormones of bone metabolism, ACTH and HCG are here reviewed and the questions raised by their characterization - including methodological problems - their origin and their incidence on health and diseases.

Oral contraceptives alter circadian rhythm parameters of cortisol, melatonin, blood pressure, heart rate, skin blood flow, transepidermal water loss, and skin amino acids of healthy young women.

Sixteen healthy women users and nonusers of oral contraceptives (OC) volunteered to document a set of circadian rhythms. Nine were taking OC providing ethynyl estradiol (0.03-0.05 mg/24h, 21 days/month) combined with DL- or L-norgestrel or norethisterone. There was no group difference (p > 0.05) in median age (22 years), weight (57 kg), and height (162) cm). Data were obtained at fixed hours, 5 times/24h, during a 48-h span, in November. (Day activity from approximately 08:00 to approximately 23:00 h and night rest). Environmental conditions were controlled, using air-conditioned rooms of constant temperature (26 degrees +/- 0.5) and relative humidity 45% +/- 1. Both cosinor and ANOVA were used for statistical analyses. All circadian rhythms were validated with one exception: that of salivary melatonin was not detected in OC users. The 24h mean (M) exhibited group differences for certain variables: M was greater in OC than non-OC users for systolic blood pressure (p < 0.0001), heart rate (p < 0.01), skin blood flow (p < 0.04), and transepidermal water loss (p < 0.02). M was lower in OC than non-OC users in salivary cortisol (p < 0.04) and skin amino acids (p < 0.003). No group difference was detected in any other documented rhythms: diastolic blood pressure, grip strength of both hands, oral temperature, self-rated fatigue, and the skin variables of urea, lactate, triglycerides, and acid phosphatase activity.

PIP: In November in France, researchers compared data on 8 healthy women using combined oral contraceptives (OCs) containing ethinyl estradiol (0.03-0.05 mg/24 h, 21 days/month) and DL-norgestrel, L-norgestrel , or norethisterone with data on 8 healthy women not using OCs to assess circadian changes in a set of various variables. They obtained data from all subjects in the sitting position, both forearms lying horizontally on armchair supports, flexor surfaces up, at fixed clock hours (04:00, 09:00, 14:00, 19:00, 23:00 h) during a 48 hour span, beginning on Friday at 18:00 h and ending Sunday at 15:00 h. The data were obtained during the follicular/luteal phases only, and not during menses. The women maintained a social synchronization with a nonstrenuous diurnal activity from 07:00 to 23:00 h and a nocturnal rest. Environmental conditions were controlled (26 degrees Celsius and relative humidity of 45%). The 2 groups were similar in median age (22 years), weight (57 kg), and height (162 cm). The 24 hour mean was greater in OC users than nonusers for systolic blood pressure (104.4 vs. 101.1 mmHg; p 0.0001), heart rate (73 vs. 69.3 count/min; p 0.01), skin blood flow (295 vs. 271 arbitrary units; p 0.04), and transepidermal water loss (317 vs. 287 arbitrary units; p 0.02). It was lower in OC users than nonusers for salivary cortisol (30.7 vs. 39.3 mcg/dl; p 0.04) and skin amino acids (0.9 vs. 7.6 nmoles/sq cm; p 0.003). Even though the 24 hour mean for salivary melatonin and the peak time were similar for both groups, the peak time was only significant in nonusers (p 0.02), suggesting that OCs obliterated the circadian rhythm of melatonin. It has been suggested that OCs alter an individual's sensitivity to light and consequently the circadian rhythm of melatonin. Other documented rhythms (diastolic blood pressure, grip strength of both hands, oral temperature, self-rated fatigue, and the skin variables of urea, lactate, triglycerides, and acid phosphatase activity) were similar in both groups.

[Synchronization and dyschronism of human circadian rhythms]. / Synchronisation et dyschronisme des rythmes circadiens humains.

Properties of biological rhythms are presented briefly as well as the conventional model dealing with the synchronizing effects of the day/night (or Light/Dark) alternation on the suprachiasmatic nuclei (SCN) the master-clock, which is supposed to control all our rhythms. However, apart from the SCN role, a set of experimental arguments supports the existence of biological clocks in the brain cortex. The synchronization of the latter (resetting them and making their period = 24 h) may be achieved not only by the periodicity of physical Light/Dark signals but also by the periodicity of social signals involving perceptions with eyes, ears, nose and skin. Distribution of peaks and troughs of biological rhythms in the 24h scale reveals the organism's temporal order. Its alteration (dyschronism) results from a phase shift and/or a change in the period length of a rhythm with regard to the others. In human beings, dyschronism is a trivial phenomenon. It appears even if synchronizers are present, with interindividual differences. It is likely that dyschronism induces a set of symptoms in sensitive subjects, prone to react to it.

Temperature rhythm of patients with major affective disorders: reduced circadian period length.

The aim of the study was to explore circadian alterations of the temperature rhythm in adults with Major Affective Disorders (DSM III-R:296.xx). The axillary temperature of 56 inpatients was recorded (6-min intervals for at least a 48-h span) when major clinical symptoms occurred and thereafter during the remission. Periods (tau s) of the temperature rhythm were accurately quantified from individual time series by power spectra analyses. Twenty-seven subjects with no affective disorders served as controls. Histograms of the frequency distribution of tau s, chi square, and so forth were used as statistical methods. In both patients and controls a multimodal distribution of prominent tau s was observed. However, in controls this distribution showed the highest frequency (88.9%) with tau s = 24h, and seldom tau s < 24h or tau s > 24h, while in patients with major affective disorders, tau s exhibited a statistically significant (x2 = 10.84; p < 0.004) different distribution with the highest frequency for tau s < 24h in 50% of the patients. Subjects diagnosed as suffering from Major Affective Disorders commonly exhibit a period shorter than 24h in the axillary temperature circadian rhythm suggestive of a desynchronized time structure.

[Circadian rhythm in the sensitivity of target systems to drugs: an underestimated phenomenon]. / Rythmes circadiens de la sensibilité des systèmes cibles aux médicaments: un phénomène sous-estimé.

The chronokinetics of a drug corresponds to dosing time-dependent and predictable (rhythmic) changes in parameters used to characterize its pharmacokinetics e.g. Cmax, t(max), t1/2, AUC, etc.) The chronesthesy or chronopharmacodynamics corresponds to circadian changes in susceptibility of target biosystems to this drug. The target system can be an organ or a tissue (skin, bronchial tree, etc.) as well as a receptor, a membrane, an enzymatic process. Both theoretical and practical implications of chronesthesy have been underestimated and even ignored. It is usually assumed that the constant level over time of a drug in the plasma should result in constant effects. Much experimental evidence have shown that this hypothesis must be rejected.

Twenty-four hour pattern in symptom intensity of viral and allergic rhinitis: treatment implications.

The symptoms of rhinorrhea secondary to influenza and cold virus or seasonal and perennial allergic rhinitis are circadian rhythmic. Cough frequency and handkerchief use by persons suffering from virus-induced rhinorrhea are more prominent during the daytime, especially during the initial hours after awakening from nocturnal sleep. The elevation in sublingual temperature as well as the decrement in mental alertness associated with influenza in particular are more profound at this time. Sneezing, blocked nose, and runny nose secondary to allergic rhinitis are also greater in intensity during the morning in approximately 70% of sufferers. The day-night variation in symptom intensity amounts to approximately 20% of the 24-hour mean level. The treatment of these diseases and their symptoms has traditionally involved equal-interval, equal-dose (homeostatic) medication schedules. The effects of antihistamine and antiinflammatory medicines may be enhanced by timing them to the day-night temporal pattern in symptom manifestation and intensity to achieve an optimization of their beneficial effects with control of toxicity, that is, as a chronotherapy.

Biological rhythms in the inflammatory response and in the effects of non-steroidal anti-inflammatory drugs.

It is well known that some signs and symptoms of rheumatoid arthritis (RA) vary within a day and between days, and the morning stiffness observed in RA patients has become one of the diagnostic criteria of the disease. Research carried out in the last 10 years confirmed these clinical observations, and circadian, circaseptan or circannual variations were detected in experimental inflammation and in patients with arthritis diseases. The human data showed also that large interindividual differences can be found in the symptoms of RA. The chronopharmacological studies carried out with the non-steroidal anti-inflammatory drugs (NSAID) revealed circadian and circannual variations in the effectiveness, toxicity and pharmacokinetics of NSAID. A review of the available data suggests that peak and trough values found in different arthritic diseases do not occur at the same hour of the day and that the side effects produced by NSAID are more important after the morning than the evening administration. This information should be used by clinicians to determine when to administer drugs to arthritic patients, to optimize the effectiveness of NSAID and/or to reduce the side effects of these drugs. These new data could also be useful to physicians who would like to individualize NSAID use in patients with different arthritic diseases.