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.

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.

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.

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.

[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.

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.

Preservation of the functional advantage of human time structure.

Upon exposure to sustained and synchronized diurnal activity, most human variables exhibit rhythms with a 24 h period. The best-fitting cosine curve to the data with a selected period (24 h) may yield parameters like acrophase (estimated peak time), amplitude, and mesor (rhythm adjusted mean). The sequential array of the rhythms' acrophases constructs the temporal order. Analyzing 168 different human rhythms revealed a time-dependent distribution with regard to the number of acrophases/h and to the clustering of variables according to function. Rhythms' amplitude/mesor ratios yielded a five modal distribution. The modes occurred at those clock times where repetitive habitual signals are anticipated. It is assumed that these specific features evolved to optimize the adaptive value of the temporal order.

Circadian dosing time dependency in the forearm skin penetration of methyl and hexyl nicotinate.

The forearm skin penetration of hydrophilic methyl nicotinate (MN) and lipophilic hexyl nicotinate (HN) was assessed around the clock. The sixteen healthy women (median age: 22 years, weight: 57 kg and height: 162 cm) who volunteered for the study were synchronized with a diurnal activity from 07.00h (+/- 1h) to 23.00h (+/- 1h.30min) and a nocturnal rest before and during the 48h sojourn in air-conditioned rooms (26 degrees C +/- 0.5 degrees C). Both HN (0.5% ethanol solution) and MN (5% ethanol solution) have a vasodilative effect on dermal vessels. The lag time (LT) between the delivery of a fixed volume (10 microliters) of the agent at the skin surface and the beginning of the vasodilatation, detected with a laser-Doppler method, was used to quantify the penetration kinetics. Tests were performed every 4h, at fixed clock hours, over a span of a 40h. Two types of tests were done with each of the agents: fixed site (one site only) and shifted sites (10 different places). Both cosinor and ANOVA have been used for statistical analyses. The shortest LT (fastest penetration) was located around 04.00h. The longest LT (slowest penetration) occurred during the day with a single peak around 13.00h in three of the situations, or two peaks (HN with fixed site). A rather large rhythm amplitude (peak-to-trough difference larger than 50% of the 24h mean LT) was validated.

Placebo effect on the circadian rhythm period tau of temperature and hand-grip strength rhythms: interindividual and gender-related difference.

Two different medications, one assumed to be a tranquilizer and the other an antifatigue agent, were tested. Both were found to be ineffective and thus were viewed as placebos and named P1 and P2. The effect of P1 and P2 on the circadian rhythms of a set of variables (e.g., sleep/wake, oral temperature and grip strength of both hands) were monitored by five to 10 measurements per day over three consecutive 8- to 10-day spans. The first documented span was a control (no medication), and the second and third spans (in randomized order) were under P1 and P2. Healthy subjects volunteered for the studies: nine men and seven women (median age 28 years) in study 1 and 12 men and 12 women (median age 36 years) in study 2. They were synchronized with diurnal activity from 07:00 h (+/- 30 min) to 00:00 h (+/- 1 h) and nocturnal rest. De Prins' method was used to obtain the prominent period tau in each (control, P1, and P2) individual time series. The chi 2 test was used to test group and subgroup differences. All 40 subjects exhibited a significant sleep/wake rhythm with a tau = 24 h in control, P1, and P2 series. During the control span a gender-related statistically significant difference was observed: fewer men than women exhibited a temperature rhythm desynchronized from 24 h. In addition, more women than men had a tau < 24 h during control. The gender-related difference was obliterated by placebos. Similarly desynchronized circadian rhythms of left and right hand-grip strength were observed in both men and women during the control span, which were all obliterated by placebo but only in men. Results are discussed with regard to a genetic model of human dyschronism as proposed by the authors.

Interindividual differences in chronopharmacologic effects of drugs: a background for individualization of chronotherapy.

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffectiveness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by "conventional" zeitgebers (e.g., bright light, physical activity).

Concepts in chronopharmacology.

Circadian and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical and chemical agents including medications and foods are rather common phenomena. Time-related differences in drug effects depend upon endogenous circadian rhythms, which include metabolic pathways. In addition, chronopharmacology investigates drug effects on parameters (e.g. circadian period, peak time, amplitude, and adjusted mean) used to characterize biological rhythms. A better understanding of periodic and thus predictable changes in drug effects can be attained by consideration of complementary concepts: (a) The chronokinetics for a drug, i.e. dosing time-dependent and predictable (rhythmic) changes in parameters used to characterize the pharmacokinetics (or the bioavailability) of a drug, e.g. Cmax, tmax, AUC, and t1/2; (b) the chronesthesy, i.e. rhythmic changes in susceptibility of the target biosystem to this drug, including CR in pharmacodynamic processes; and (c) the chronergy, i.e. the drug-integrated overall effect. One of the aims of chronopharmacology refers to the use of a chronopharmacological approach to clinical treatment so as to enhance both effectiveness and tolerance of a drug by determining the best biological time for its administration.

Concepts of circadian chronopharmacology.

Circadian and other rhythmic changes in biological susceptibility and response of organisms to a large variety of physical as well as chemical agents including medications and foods are rather common phenomena. Modern chronopharmacology investigates drug effects (a) as a function of biological timing and (b) upon parameters characterizing the endogenous bioperiodicities. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of complementary concepts: (1) the chronokinetics of a drug--dosing time-dependent and predictable (rhythmic) changes in parameters used to characterize the pharmacokinetics (or the bioavailability) of a drug, e.g., maximum concentration (Cmax), span of time to reach Cmax (tmax), area under the concentration-time curve (AUC), half-life (t1/2), etc.; (2) the chronesthesy (rhythmic changes in susceptibility of a target biosystem to this drug); and (3) the chronergy (the drug-integrated overall effects). One of the aims of chronopharmacology is solving problems of drug optimization. Chronotherapy refers to the use of a chronopharmacologic approach to clinical treatment so as to enhance both effectiveness and tolerance of a drug by determining the best biological time for its dosing.

Circadian rhythms in plasma levels of cortisol, dehydroepiandrosterone, delta 4-androstenedione, testosterone and dihydrotestosterone of healthy young men.

Three healthy males (18, 22 and 30 years of age; 85 kg/177 cm, 82 kg/181 cm and 75 kg/168 cm, respectively), synchronized with a diurnal activity (06.00 to 23.00 h) and nocturnal rest, volunteered for this study. Blood was sampled (venous catheter) hourly during a 24 h span. A radiocompetition method was used for cortisol determinations. Other steroids were first extracted (ethyl-ether) from each plasma sample, then chromatographed on a celite column to isolate 3 fractions: 1) delta 4-androstenedione (delta-4); 2) dihydrotestosterone (DHT) and dehydroepiandrosterone (DHA); 3) testosterone (T). A radioimmunological assay was used thereafter for the determination of androgenic steroids. Statistically significant (both conventional and cosinor methods) circadian rhythms were detected (P > 0.005). Acrophases (peak times) occurred in the following order: cortisol (07.28), DHA (08.43), delta-4 (09.54), T (11.15) and DHT (16.37). The respective circadian amplitudes of DHA and delta-4 were smaller than those of cortisol while the amplitudes T and DHT did not show differences statistically significant from each other.