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.

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.

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).

[Chronotherapy of tenoxicam]. / Chronothérapie du ténoxicam.

A study was carried out in order to investigate the chronotherapy (dosing time dependency) of an NSAID, the tenoxicam administered in ankylosing spondylitis, rheumatoid arthritis and osteoarthritis of the hip. These variations in efficacy exist as much for pain as for stiffness and maximum efficacy is obtained with administration at 8 am or 12 pm. Since the tolerance was good, we recommend midday as an optimal once-a-day dosing time.

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.

Aspects of chronopharmacology and chronotherapy in children.

Pediatric studies involving chronopharmacology until now have been limited mainly to investigation of circadian patterns in children of 6 to 15 years. This means that: a. data on newborns and even on infants of one year or younger are not available, and b. other bioperiodicities, such as those of one year (infradian rhythms), have not yet been explored in older children. Biological time-related changes have been documented for phenytoin and theophylline with regard to their pharmacokinetics and for orciprenaline, ipratropium bromide, corticosteroids and anticancerous agents with regard to their effectiveness. Despite the small number of investigations performed to date, results indicate that: a. more comprehensive and precise characterization of pharmacokinetic and pharmacodynamic phenomena can be achieved by a chronopharmacological approach than the conventional one and, b. better therapeutics can be achieved using chronopharmacological facts since an appropriate timing of medicines with regard to biological rhythms is likely to enhance desired and/or reduce undesired effects.

[Chronotherapy and allergic diseases]. / Chronothérapie des maladies allergiques.

The author presents a study synthesizing chronobiological data on allergic diseases and their treatment. It is referred to circannual and circadian chronobiological progress in the field of neurovegetative and immunological respiratory functions. Optimization of treatment is described for inhaled medication, adrenergic and anticholinergic bronchodilators, anti-inflammatory corticoids and cromoglycate derivatives. Importance of ingestion of corticoids at the beginning of activity and of long acting theophylline when diurnal activity ceases is described at endocrinian and pharmacodynamic level. It is finally followed by a presentation of optimization of rhinitis treatment with non sedative antihistaminics, mequitazine, terfenadine, which when taken in the evening are more efficient and better tolerated.

Aspects of chronopharmacology and chronotherapy in pediatrics.

Pediatric chronopharmacological findings until now have been limited to circadian changes in children from ages 6 to 15 years. This means that data in newborns and even in infants of 1 year are not available and other bioperiodicities with periods of about-1-year (infradian rhythms) have not been explored in older children. Biologic time-related changes have been documented for phenytoin and theophylline with regard to pharmacokinetics, for orciprenaline with regard to bronchodilation, and for corticosteroids as well as anticancer agents with regard to their effectiveness. Despite the limited number of experiments performed to date, it is already possible to state that a chronopharmacological approach provides better precision in pharmacologic study than the conventional approach not using time-related data and better therapeutics can be achieved with the help of chronopharmacological facts since appropriate timing in administration of medicine usually enhances its desired and/or reduces its undesired effects.

Hypothalamo-pituitary regulation of thyrotrophin secretion in chronically catheterized Brattleboro rats.

Plasma TSH rhythms were measured in Brattleboro (DI) and control Long-Evans (LE) rats with an intracardiac catheter allowing repeated sampling in conscious unstressed animals. The TSH response to thyrotrophin-releasing hormone (TRH; 500 ng/100 g body weight) was also determined. Finally, hypothalamic and pancreatic TRH concentrations and TRH-degrading activity (TRH-DA) were measured by specific radioimmunoassay. Long-Evans rats had a 24-h rhythm with a major modulatory 8-h component. In DI rats, only the 24-h rhythm was detected. The mean 24-h rhythm-adjusted mean TSH level was higher in DI than in LE rats (1.38 +/- 0.05 and 1.14 +/- 0.06 micrograms/l respectively, P less than 0.01). The peak TSH response to TRH was significantly increased in DI rats while the pituitary concentration of TSH was also higher (0.93 +/- 0.09 vs 0.39 +/- 0.06 micrograms/mg wet weight in LE, P less than 0.001). Hypothalamic TRH and TRH-DA were similar in both strains. The response to propylthiouracil-induced hypothyroidism was identical in both strains. We conclude that DI rats have a normal pituitary sensitivity to tri-iodothyronine but a central dysfunction in the pituitary environment leading to some alterations of TSH secretion.

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.

[Clinical chronopharmacokinetics]. / Chronopharmacocinétique clinique.

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.

Circadian changes of drug disposition in man.

Circadian (approximately equal to 24 hours) and other endogenous biological rhythms, detectable at all levels of organisation, 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 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 including sodium salicylate, aspirin, indomethacin, paracetamol (acetaminophen), phenacetin, amidopyrine, theophylline, digitalis, propranolol, clorazepate, hexobarbitone (hexobarbital), lithium, phenytoin (diphenylhydantoin), nortriptyline, ethanol, erythromycin, ampicillin, sulfasymazine, sulphanilamide, cisplatin (cis-diammine dichloroplatinum), d-xylose, ferrous sulphate, potassium chloride, hydrocortisone and prednisolone, among others. The roles presumably played by circadian rhythms in drug metabolising liver enzymes 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.

The chronotherapy of corticosteroids: practical application of chronobiologic findings to nursing.

In this paper evidence is presented pointing to the significance of when to treat along with why, what, and how much. Because of the circadian organization of the pituitary-adrenal axis, the long-term management of steroid-dependent patients must recognize and take into consideration the advantages of chronotherapy with corticosteroids. Thus, when corticosteroids are administered either daily or on alternate days, adrenal suppression and possibly growth disturbance can be minimized by timing to the circadian crest in adrenocortical function. As more findings are accumulated from ongoing and planned investigations, it can be expected that in the near future chronotherapeutics will become established in the practice of clinical and hospital nursing.