Chronobiology and biometeorology.
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Chronobiology Phenomena↗
Biomedical subjects
A Reinberg
Publications and source records attributed to A Reinberg.
[Aspects of chronopharmacology in pediatrics].
Pediatric chronopharmacological findings until now have been limited to circadian changes in children 6 to 15 years old. This means that (a) data in neonates and even in infants of one year is not available and (b) other bioperiodicities with periods of several hours (ultradian rhythms) as well as several months and about one year (infradian rhythms) have not been explored in older children. Biologic time-related changes have been documented for phenytoin and theophylline with regards to pharmacokinetics and for orciprenaline and methylprednisolone with regards to effectiveness (bronchodilatation). Despite the limited number of experiments performed to date, it is already possible to admit that, (a) a chronopharmacological approach provides better precision of pharmacologic study than the conventional approach not using time-related data; (b) better therapeutics can be achieved with the help of chronopharmacological facts since an appropriate timing in administration of a medicine usually enhances its desired effects and/or reduces its undesired effects.
Adolescent↗
Circadian and/or circahemidian rhythms in nine lymphocyte-related variables from peripheral blood of healthy subjects.
Circadian variations were investigated for nine lymphocyte-related variables in the peripheral blood of healthy subjects. Monoclonal antibodies targeted at membrane immunoglobulins (anti-Ig, anti-kappa, anti-lambda) or differentiation antigens (anti-IA and OKT3) were used to characterize respectively mature B cells (SIg+, kappa +, lambda +), cells expressing HLA-DR antigen (IA+), and T cells (OKT3+). Blood (33 ml) was drawn every 4 hr for 24 hr starting at 8.30 hr, on seven occasions in five apparently healthy male volunteers, recumbent from 23.00 hr to 07.00 hr. Leukocyte and differential counts were measured. Mononuclear cells were isolated on Ficoll-Hypaque before being incubated with monoclonal antibodies. The proportion of fluorescent cells per 100 microscopically determined cells was multiplied by the number of circulating lymphocytes per milliliter of venous blood. Temporal variations were validated by both paired t-test and cosinor. Rhythms with a period (tau) identical to 24 hr were validated with statistical significance (p less than 0.05) for total lymphocytes, OKT3+ cells and OKT3+:SIg+ ratio, and suggested (0.05 less than or equal to p less than or equal to 0.10) for lambda + and (kappa + + lambda +) cells. Rhythms with tau identical to 12 hr were also found (p less than 0.05) for OKT3+, SIg+, kappa +, and IA+ cells as well as for the OKT3+:SIg+ and the kappa +:lambda + ratios. Validated rhythms exhibited a large amplitude, e.g., peak-through differences were 40% of the 24-hr mean. This circadian and circahemidian temporal structure of immunologic variables constitutes a time-qualified reference system for investigating immune regulations and a tool for optimizing both diagnostic criteria and effectiveness of immunotherapeutic attempts.
Adult↗
[Nycthemeral change in the anticoagulant effect of heparin given at a constant rate by the intravenous route].
Six subjects with venous thromboembolism volunteered for this prospective study. Heparin was administrated intravenously at a constant rate with an infusion pump. The activated partial thromboplastin time (A.P.T.T.) and thrombin time (T.T.) were measured every 4 hrs. for 48 hrs. These coagulation tests exhibited a nycthemeral variation with a large amplitude which was reproducible from one day to the next and statistically validated by the cosinor method (p less than 0.001). All patients had a nocturnal peak of A.P.T.T. and T.T. on both days. In four patients this peak for A.P.T.T. exceeded the upper desired limit.
Aged↗
Circadian rhythm in tolerance of mice for etoposide.
Etoposide (40 mg/kg/day X 3 days and 60 mg/kg/day X 3 days) was best tolerated by male B6D2F1 mice when given in the second half of the rest span of their sleep-wake circadian cycle. Such a time-qualified treatment resulted in increased long-term survival rate, highest peripheral leukocyte count at nadir, and lowest body weight loss, as compared to results from drug dosing in the activity span. Assuming that such results may be extrapolated to human beings, the treatment time of etoposide associated with an optimal tolerance would be located in the second half of the sleeping span (usually near 5.00 hrs).
Animals↗
Patterns of plasma melatonin with ageing and mental condition: stability of nyctohemeral rhythms and differences in seasonal variations.
Effects of ageing and mental condition on the nyctohemeral and seasonal rhythms of plasma melatonin in human subjects were investigated. Four groups of subjects were formed for a transverse study: 7 healthy young men (24 years), 6 elderly women, 6 elderly men and 6 elderly patients (2 men and 4 women) suffering from senile dementia (70-80 years). The subjects were synchronized. Blood samples were taken every 4 h during 24 h in January, March, June and October. In comparison to young men, the plasma levels of melatonin were markedly decreased (by about one half) in elderly subjects without any difference according to sex or mental condition. Nyctohemeral rhythms of the hormone were validated in all groups and at all sampling sessions. The nyctohemeral acrophases were remarkably stable (around 03.00 h) whatever the season, age or sex. A seasonal variation was found in all groups (except elderly women) with differences between young and elderly subjects: plasma melatonin levels were significantly lower in January than in June in young men, whereas in elderly subjects they were significantly lower in October than in January/March. No significant difference was observed in mesor, amplitude or acrophase of nyctohemeral and seasonal rhythms of plasma melatonin in patients with senile dementia when compared with healthy elderly subjects. The stability of the nyctohemeral peak time whatever the age group or season as opposed to the differences in the seasonal pattern of plasma melatonin according to the age groups raises the problems of both outdoor photoperiod and ageing in ruling the secretion of melatonin in man.
Adult↗
Interindividual differences in a set of biological rhythms documented during the high arctic summer (79 degrees N) in three healthy subjects.
The High Arctic summer with its permanent sunlight provides a situation in which one of the natural synchronizers, the light-dark alternation, is minimal. During the summers of 1981 and 1982 three healthy right-handed geographers who were performing field studies in Svalbard as part of their own research volunteered to document, 4-6 times per 24 hr for respectively 63, 141 and 147 days, a set of circadian rhythms: self-rated fatigue, oral temperature, grip strength of both hands, heart rate and times of awakening and retiring. Tests were performed before departure from France, in Svalbard (79 degrees N latitude) where their daily activities were often strenuous, and after returning to France. Time series were treated individually according to three methods: display of data as a function of time, cosinor analyses to quantify rhythm parameters, and spectral analyses to estimate component periods of rhythms. Circadian parameters such as period and acrophase of activity-rest, oral temperature and fatigue rhythms were not altered. On the other hand, the circadian rhythm in grip strength was altered: the period differed from 24 hr in one subject, while grip strength acrophase of the left, but not the right, hand of the other two subjects was phase shifted during the sojourn in Svalbard. A prominent circahemidian (about 12 hr) rhythm was observed in two subjects for their heart rate in Svalbard, while a prominent circadian rhythm (differing from exactly 24 hr) was observed in France associated with a small circahemidian component.
Activity Cycles↗
[Clinical chronopharmacokinetics].
Circadian (approximately or equal to 24 hours) and other endogenous biological rhythms, detectable at all levels of organisation, constitute a temporal structure in all species, including man. Circadian, circannual, 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. A better understanding of periodic and thus predictable changes in drug effects can be attained through consideration of three complementary concepts: the chronopharmacokinetics of a drug (rhythmic changes in its pharmacokinetics), the chronesthesy (rhythmic changes in susceptibility of target biosystems to the drug), and the chronergy (the drug-integrated overall effects). The chronopharmacokinetics of many drugs have been evaluated in man (tables I-IV) including sodium salicylate, aspirin, indomethacin (fig. 1), sustained-release indomethacin, paracetamol (acetaminophen), phenacetin, amidopyrine, theophylline sustained-release theophylline (fig. 2), aminophylline, sustained-release aminophylline, digitalis, propranolol, clorazepate, hexobarbitone (hexobarbital), diazepam, midazolam, lithium, phenytoin (diphenylhydantoin), nortriptyline, ethanol, erythromycine , ampicillin, sulfasymazine , sulphanilamide, cis-diammine-dichloroplatinum (fig. 3), mequitazine (fig. 4), d-xylose, ferrous sulphate, potassium chloride, hydrocortisone and prednisolone, among others. The roles presumably played by circadium rhythms in drug metabolizing liver enzymes (fig. 5), and kidney function are summarized, and the practical implications of chronopharmacokinetics, aiming both to improve in a quantitative manner the metabolic fate of a drug and its effectiveness, are discussed.
Anesthesia↗
[Circadian rhythm of the grip strength of the right and left hands: desynchronization in some shift workers].
38 male shift workers and former shift workers volunteered to self-measure 4 to 8 times/24 hrs. their oral temperature (OT) as well as right and left hand grip strength (HGS) best performance during a 16 to 30 day span. Time series were analyzed individually according to two methods: day by day circadian acrophase drift and power spectrum. Mainly, but not exclusively, subjects with poor tolerance to shift work exhibited an internal desynchronization with a circadian period tau different from 24 hrs. which was the case for OT as well as right and left HGS; each could be different in tau between one another and from 24 hrs. These results suggest that oscillatory systems may be influenced by the neocortex apparently with difference between right and left side.
Adult↗
A four-day subrenal capsule assay for testing the effectiveness of anticancer drugs against human tumors.
The subrenal capsule assay may predict to which anticancer drug a given patient's tumor is sensitive and may also be used to screen new anticancer drugs. The present study documents that the use of this model requires a histological assessment of both the exploitability of a subrenal capsule assay and the extent of drug-induced antitumor lesions. Thirty-five tumors from 34 patients with solid tumor were submitted to a subrenal capsule assay in a total of 1130 male B6D2F1 mice. After being biopsied, each tumor was dissected by a pathologist and cut into 50 pieces (1.5 X 1.5 X 1.5 cu mm), and one piece was implanted under the renal capsule of 35 mice; the mean tumor diameter was measured on Day 0. Mice were randomized into groups of 6 to 10 animals each. On Days 1, 2, and 3, mice were treated either with placebo (control group) or with various anticancer agents. On Days 4 or 6, mice were sacrificed, the mean tumor diameter measured, and the tumor-bearing kidney fixed in Bouin's picroformol solution and processed for histological analysis after staining with hematein -eosin. Seven histological parameters were blindly rated in a semiquantitative fashion yielding a compound score ( PAPAN ) which estimated the overall quality of each xenograft between -3 and +11. On Day 4, as opposed to Day 6, mean lymphocytic infiltration was 3-fold lower (p less than 0.01), and the rate of xenografts containing well-preserved cancer cells was 2-fold larger (p less than 0.01) in three different tumor specimens. Twenty-two of 31 (71%) assays were evaluable, as defined by a histological quality control test. In those, drug effects were demonstrable by statistically significant differences among groups in 2 assays (9%) by using the relative variation in tumor size as an index of drug effectiveness and in 12 assays (54%) by PAPAN histological score. This suggests the higher sensitivity of histological scoring over tumor size measurements. Moreover, no correlation between relative variation in tumor size and PAPAN was demonstrable with statistical significance indicating the poor reliability of tumor size measurements as an index of the antitumor effectiveness of cytostatic drugs.
Adenocarcinoma↗
Large-amplitude circadian rhythm in helper:suppressor ratio of peripheral blood lymphocytes.
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Circadian Rhythm↗
Circadian variations in beta-endorphin concentrations in pituitary and in some brain nuclei of the adult male rat.
Using both the 'punch' microdissection and a radioimmunological technique, circadian variations in beta-endorphin concentrations can be observed in the pituitary and in some discrete brain regions of the male rat (Wistar CFY). Animals were synchronized with light from 06.00 to 18.00 h, then darkness. Water and food were available ad libitum. Very well marked circadian rhythms were in evidence in the anterior lobe of the pituitary, the septum, the pons, the medulla oblongata and the cerebellum. There crest time locations were situated between 20.00 and 24.00 h. No significant circadian rhythms but biphasic variations were observed in the intermediate lobe of the pituitary, the POA, the thalamus, the central gray and the caudatus. There crest time locations were synchronized around 08.00 and 20.00 h. The most striking finding was that, regardless of the brain area investigated so far, maximal values were observed a short time after the beginning of the activity period of rats. This fact is identical with the one which has been observed for substance P and LH-RH contents in brain areas where these peptides are mostly present in nerve terminals in high concentrations.
Animals↗
Circadian and seasonal changes in ACTH-induced effects in healthy young men.
The effects of the ACTH 1-17 analogue (100 micrograms i.m.) as a function both of time of day (7.00, 14.00 and 21.00 h) and season (winter versus summer) were determined on a set of physiological variables: urinary 17-hydroxycorticosteroids, oral temperature, grip strength (right and left hands), peak expiratory flow and self - rated fatigue. Six young healthy males took part in the study in January-February 1980 and June-July 1981. They were synchronized with a diurnal activity from 7.00 to midnight and a nocturnal rest. Urine was collected every 3 to 4 hours, at fixed clock hours over 72 h (winter) and 48 h (summer). There was a one week interval between each ACTH test or placebo control. Variables were measured according to the same schedule. 24 h urinary 17-OHCS excretion was maximum for ACTH injected at 7.00 in winter and 14.00 in summer, and the minimum occurred after ACTH given at 21.00. The highest peak of urinary 17-OHCS was found after ACTH at 7.00 both in winter and in summer. It is likely that the maximal stimulation of glucocorticoid secretion occurs when ACTH is administered around the beginning of the activity span. Both in winter and summer the injection of ACTH at 7.00 was followed by the greatest decrease in self-rated fatigue (24 h mean) and the largest increase (24 h mean) both in grip strength and peak expiratory flow (bronchial patency) in comparison with other times of ACTH administration (14.00 and 21.00 h).
17-Hydroxycorticosteroids↗
Circadian changes in effectiveness of corticosteroids in eight patients with allergic asthma.
A double-blind, crossover, randomized, placebo-controlled chronotherapeutic study was designed in which eight patients (two men, 20 and 48 yr old, and six women, 22 to 58 yr old) suffering from corticosteroid-dependent allergic asthma were socially synchronized, with a diurnal activity from about 7:30 A.M. to about 11 P.M. and a nocturnal rest. During an 8 day span they were treated on a Dutimelan 8-15 regimen, labeled DTM 8-15: at 8 A.M. a pill containing 7 mg of prednisolone acetate and 4 mg of prednisolone alcohol, at 3 P.M. a pill with 15 mg of cortisone acetate and 3 mg of prednisolone alcohol, and a placebo at 8 P.M. During another 8 day span they were given a placebo at 8 A.M. and at 3 P.M. a pill with 15 mg of cortisone acetate and 3 mg of prednisolone alcohol and at 8 P.M. another pill with 7 mg of prednisolone acetate and 4 mg of prednisolone alcohol, a regimen labeled Rx 15-20. During wakefulness (between 7 A.M. and 11 P.M.), every 2 hr at eight fixed clock hours, peak expiratory flow (PEF), grip strength, and oral temperature were self-measured and dyspnea, cough, and fatigue were self-rated. The PEF 24 hr mean as well as the nocturnal dip were lower (p less than 0.05 to p less than 0.0005) with Rx 15-20 than with DTM 8-15, while the nocturnal increase of dyspnea was greater with Rx 15-20 than with DTM 8-15. Long-term administration of corticosteroids at 8 A.M. and 3 P.M. was more effective to control asthma and enhance PEF values than the same agents and dose given at 3 and 8 P.M.
Adult↗
Chronobiology and thermoregulation.
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Adrenal Cortex Hormones↗
Aspects of clinical chronopharmacology.
Circadian (congruent to 24 h), circannual (congruent to 1 year) and other biological rhythms of endogenous origin, detectable at all levels of organization, constitute a temporal structure in all animal species, including man. Circadian, circannual 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 three complementary concepts: the chronokinetics of a drug (rhythmic changes in its pharmacokinetics); the chronesthesy (rhythmic changes in susceptibility of target biosystems to this drug), and the chronergy (the drug integrated overall effects). One of the aims of chronopharmacology is solving problems of drug optimization. Knowledge of those administration times coinciding with best effectiveness or tolerance is required to optimize both timing(s) and dosage(s) of a medication. Illustrative examples of both experimental and clinical investigative chronopharmacology are corticosteroids and anticancerous agents.
Adult↗
Seasonal rhythms of plasma gonadotrophins: their persistence in elderly men and women.
Circannual changes of immunoreactive LH and FSH were documented on a circadian basis in January, March, June and October in four groups of subjects: seven young men, six elderly men, six elderly women and six men and women suffering from senile dementia. The sampling was serially dependent only for the young men and the core subgroups of elderly men and elderly women. A circadian rhythm for FSH was not detected in any group of subjects during any of the sampling sessions, whereas a circadian rhythm for LH was detected twice (June and October) in young men, once (October) in elderly demented patients, and not at all in the groups of elderly men and women. Both 24-h and yearly mean levels of gonadotrophins were higher in elderly subjects (two-to 25-fold according to the hormone, sex and season) than in young men. Circannual rhythms of plasma LH with large amplitudes were validated by the cosinor method, with an acrophase located in April or May. A circannual rhythm of plasma FSH was validated only in young men, with an acrophase in October. The persistence of a circannual rhythm of plasma LH with large amplitude in elderly subjects, associated with high mean levels of the hormone, especially in elderly women, suggests that this bioperiodicity of the pituitary gland is independent of gonadal function.
Adult↗
Adrenocortical hormones, ageing and mental condition: seasonal and circadian rhythms of plasma 18-hydroxy-11-deoxycorticosterone, total and free cortisol and urinary corticosteroids.
The circannual rhythms of plasma 18-hydroxy-11-deoxycorticosterone (18-OH-DOC), total and free cortisol have been documented on a circadian basis in January, March, June and October in seven young men (24 years old), six elderly men, six elderly women and six elderly demented subjects, both men and women, in their eighties. Blood samples were drawn every 4 h over a 24-h period at each sampling session and urine samples were collected at 4-h intervals only from the young men. A circadian rhythm of 17-hydroxy-corticosteroids (17-OH-CS), 17-ketosteroids (17-KS), urinary free cortisol and 18-OH-DOC was defined for each of the four seasons with stable acrophases throughout the year and the same excretory profiles. A circannual rhythm was validated in young men for 17-OH-CS, urinary free cortisol and 18-OH-DOC but not for 17-KS. A circadian rhythm of plasma free cortisol, the active form of the hormone, plasma total cortisol and plasma 18-OH-DOC was validated in all groups and at all the seasons at which samples were taken. The secretory profiles of 18-OH-DOC, free and total cortisol were very similar, with no differences attributable to age, sex or mental condition except for the levels of plasma free cortisol and 18-OH-DOC which were higher and lower respectively in the elderly subjects. Whereas a circannual rhythm of plasma 18-OH-DOC was validated for all groups, a circannual rhythm of both free and total cortisol in the plasma was validated in young men but not in any group of elderly subjects. This loss of the circannual rhythmicity of cortisol in the elderly may reflect the decrease with age of the capacity to adapt to seasonal external factors.
17-Hydroxycorticosteroids↗