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Biomedical subjects

Y Touitou

Publications and source records attributed to Y Touitou.

At least 73 records · Page 4Linked to original sources
PubMed1996

[Synchronization and dyschronism of human circadian rhythms].

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.

Animals↗
PubMed1996

[Chronobiological approach of aging].

Ageing is a complex, multifactorial phenomenon. The existence of biologic rhythms as well as the study of their modifications or their alteration in the aged are useful and pertinent to understand the biologic age. These modifications, if any, may be interpreted as a change in the adaptability of aged subjects to environmental factors. The loss or decrease of adaptation capacity with ageing is worth quantifying. This paper rounds up the question.

Aged↗
PubMed1996

[Annual endocrine rhythms in man].

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.

Adrenocorticotropic Hormone↗
PubMed1996

[Melatonin and biological rhythms: various aspects in human physiopathology].

Melatonin (N-Acetyl-5-methoxytryptamine) is a hormone secreted mainly by the pineal gland or epiphyse and in smaller amounts by the retina. It is biosynthesized from tryptophan, the two critical enzymatic steps depend upon N-Acetyl-transferase (NAT) and 5-hydroxyindole-O-methyltransferase (5-HIOMT). The circadian rhythm of melatonin is the same in man and all the laboratory animals studied until now with noctural plasma concentrations 3-10 times greater than during daytime. The secretion and release of melatonin depend upon a large number of exogenous and endogenous factors as e.g. sex, age, pubertal stage, menstrual cycle, drugs, season... Light is the major regulating factor which acts through the retino-hypothalamic tract. Melatonin is considered as a transducer of the light signal forwarding to the organism the information about day length (relative length of day and night). It is a time-clue provider used by the organism to adapt itself to its environment.

Aging↗
PubMed1995

Beta-adrenoceptor agonists do not stimulate daytime melatonin secretion in healthy subjects. A double blind placebo controlled study.

Noradrenergic stimulation of pineal beta-adrenoceptors results in melatonin secretion. To investigate beta-adrenoceptor mediated plasma melatonin responses in humans, ritodrine, salbutamol (beta 2-adrenoceptor agonists) and dobutamine (beta 1-adrenoceptor agonist) were infused from 0900 to 1200 h to 8 healthy subjects (four men and four women) in a double blind, crossover, placebo controlled study. Ritodrine and salbutamol significantly increased plasma cyclic AMP and decreased serum potassium concentrations indicating the presence of beta 2-adrenoceptor stimulation. Dobutamine substantially increased systolic blood pressure corresponding to its beta 1-adrenoceptor agonist propriety. However, neither beta 2- nor beta 1-adrenoceptor stimulation modified plasma melatonin concentration. These results show that beta-adrenoceptor agonists do not increase daytime plasma melatonin concentration.

Adrenergic beta-Agonists↗
PubMed1995

Rhythm alteration in patients with metastatic breast cancer and poor prognostic factors.

Circulating blood cell counts, serum cortisol, proteins, alkaline phosphatase, carcinoembryonic antigen and CA15.3 displayed significant circadian rhythms in a group of 13 women with metastatic breast cancer. Statistical significance (P < 0.05) was assessed with both analysis of variance and cosinor analysis. All patients had been previously treated with chemo-and/or radiotherapy and/or antiestrogens. All patients had been treatment-free for 1 month prior to the study. Each patient had blood drawn every 4 h for 48 h. Circadian rhythms were examined as a function of performance status, graded according to the World Health Organization, liver involvement and number of metastatic sites. Group circadian rhythms in serum cortisol or proteins were abolished in patients with liver metastases, and were altered in cases of poor performance status. Circulating leukocytes, neutrophils or platelets did not exhibit synchronized circadian rhythmicity in patients with poor performance status or liver metastases. The number of metastatic organs had a minor influence on circadian rhythmicity. These results suggest that rhythm alteration may be associated with both poor performance status and liver metastases in patients with advanced breast cancer. Such alteration of the normal circadian time structure may favor and/or result from cancer spread.

Adult↗
PubMed1995

Sinusoidal 50-Hz magnetic fields depress rat pineal NAT activity and serum melatonin. Role of duration and intensity of exposure.

The purpose of this study was to determine whether the exposure to a 50-Hz sinusoidal magnetic field could influence serum melatonin concentration and pineal enzymes activities in rats. The effects of both duration and intensity of exposure were also looked at. Two groups of Wistar male rats were exposed to 50-Hz magnetic fields of either 1, 10 or 100 microT. The first group was exposed for 12 hours and the second for 30 days (18 hours per day). During this time the animals were kept under a standard 12:12 light: dark cycle with a temperature of 25 degrees C and a relative humidity of 45 to 50%. Control (Sham-exposed) animals were kept in a similar environment but without exposure to a magnetic field. The animals were sacrificed under red dim light. Serum melatonin concentration and pineal N-acetyltransferase (NAT) and hydroxyindole-O-methyltransferase (HIOMT) activities were studied. Long-term exposure to a magnetic field (10 and 100 microT) significantly depressed the nocturne peak of serum melatonin concentration and pineal NAT activity whereas no effect was observed on HIOMT activity. Short-term exposure depressed both pineal NAT activity and nocturnal serum melatonin concentration but only with the highest intensity used (100 microT). Our results suggest that sinusoidal magnetic fields alter the production of melatonin through an inhibition of pineal NAT activity. Both duration and intensity of exposure play an important role in this effect. This work shows that, 1) sinusoidal magnetic field depresses NAT activity as static magnetic field does whereas HIOMT activity remains unaltered whatever the type of experiment and the intensity used, 2) the effect observed is related to both the duration of exposure and the intensity of magnetic fields, 3) the sensitivity threshold to magnetic fields vary with the duration of exposure which strongly suggests a cumulative effect of sinusoidal magnetic fields on pineal function.

Acetylserotonin O-Methyltransferase↗
PubMed1995

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.

Adult↗
PubMed1995

Light-induced suppression of the rat circadian system.

In a constant environment, circadian rhythms persist with slightly altered period lengths. Results of studies with continuous light exposure are less clear, because of short exposure durations and single-variable monitoring. This study sought to characterize properties of the oscillator(s) controlling the rat's circadian system by monitoring both body temperature and locomotor activity. We observed that prolonged exposure of male Sprague-Dawley rats to continuous light (LL) systematically induced complete suppression of body temperature and locomotor activity circadian rhythms and their replacement by ultradian rhythms. This was preceded by a transient loss of coupling between both functions. Continuous darkness (DD) restored circadian synchronization of temperature and activity circadian rhythms within 1 wk. The absence of circadian rhythms in LL coincided with a mean sixfold decrease in plasma melatonin and a marked dampening but no abolition of its circadian rhythmicity. Restoration of temperature and activity circadian rhythms in DD was associated with normalization of melatonin rhythm. These results demonstrated a transient internal desynchronization of two simultaneously monitored functions in the rat and suggested the existence of two or more circadian oscillators. Such a hypothesis was further strengthened by the observation of a circadian rhythm in melatonin, despite complete suppression of body temperature and locomotor activity rhythms. This rat model should be useful for investigating the physiology of the circadian timing system as well as to identify agents and schedules having specific pharmacological actions on this system.

Animals↗
PubMed1995

Effects of ageing on endocrine and neuroendocrine rhythms in humans.

Biological rhythms in blood variables are now fairly well documented in young healthy adults whereas reports in elderly subjects are few for obvious reasons including the difficulty of setting up a group of elderly subjects comparable in age and social background and moreover free of major liver, heart, kidney, bone or any other degenerative disease and consequently not requiring medication. We have observed that the parameters characteristic of the biological rhythm may be modified with ageing. However, the modifications are different from one function or variable to the next. Differences in acrophases, mesors and amplitudes could be demonstrated. For instance the acrophase may be phase-advanced in the elderly for plasma cortisol, DHEA-S, 18-OHDOC, the amplitude may be modified for testosterone, 18-OHDOC, proteins, melatonin, gonadotrophins. The administration as a function of time of drugs or agents used as a diagnostic tool made it possible to ascertain the importance of the time structure in this field. Both validity and interpretation of such administration depend upon the timing of the agent administration in the 24-hour scale. Therefore, the temporal organization of the subjects undergoing such treatments should be taken into account. In the near future this kind of investigation on various biological variables may lead to an improvement of the desired drug effects in elderly patients.

Aging↗
PubMed1995

An alternate pathway to androstenedione synthesis by human adrenals: evidence of a balance in 11 beta-hydroxylase and 17,20-lyase activities leading to androstenedione.

Until now, dehydroepiandrosterone and 17-hydroxyprogesterone were thought to be the main precursors for the synthesis of androstenedione by the human adrenal cortex. However, secretion of androstenedione and 11-deoxycortisol are increased when 11 beta-hydroxylase activity is impaired, e.g. by metyrapone test or by congenital adrenal hyperplasia resulting from 11 beta-hydroxylase deficiency. The present study with human adrenals shows that 11-deoxycortisol, the precursor of cortisol synthesis, is also a precursor of androstenedione in humans. Our data show that androstenedione synthesis is inversely related to the synthesis of cortisol and cortisone. This new pathway is thus triggered by a lower activity of 11 beta-hydroxylase that is responsible for the last step of cortisol. Indeed, when the activity of this enzyme is impaired, 11-deoxycortisol follows the pathway that leads to androstenedione synthesis in the adrenals. These data, together with the increase in ACTH secretion, may explain the increased androstenedione plasma levels observed in patients with congenital adrenal hyperplasia caused by 11 beta-hydroxylase deficiency and in patients given inhibitors of 11 beta-hydroxylase for therapeutic purposes.

Adenoma↗
PubMed1994

Differences in isoproterenol-stimulated melatonin production by perifused rat pineal glands: time dependent effects and role of enantiomeric forms.

The perifusion of rat pineal glands removed at different times of the light-dark cycle showed a greater beta adrenergic-stimulated production of melatonin in glands obtained at the beginning of either the light or the dark stage. The effect of isoproterenol was found dependent upon its enantiomeric forms (-, +/-, +). The relative order of potency was (-) > (+/-) > (+) enantiomer. These results show that the response of pineal beta-adrenergic receptors to isoproterenol is stereospecific and circadian stage dependent.

Analysis of Variance↗
PubMed1994

Pineal perfusion with calcium channel blockers inhibits differently daytime and nighttime melatonin production in rat.

In a previous study we have shown that the response of perifused pineal glands to calcium was different according to the circadian stage at which the glands were removed. This difference may be explained by circadian changes in calcium channel function. Therefore in the present study we documented the effects of calcium channel blockers in perifused rat pineal glands removed in the middle of the light and dark spans (7 and 19 HALO (hours after light onset), in a L/D 12:12 regimen). Moreover, we have studied the effect of calcium channel blockers on adrenergically stimulated pineal glands removed 7 HALO. Inorganic (Co2+ and Cd2+) and organic (nifedipine and diltiazem) calcium channel blockers at 10(-4) mol/l all significantly reduced melatonin production and this inhibition was more effective with the glands removed 7 HALO. In a concentration of 10(-)5 mol/l, only Cd2+ and diltiazem reduced melatonin production significantly in pineal glands removed 7 HALO. Verapamil at 10(-4) and 10(-5) mol/l showed no significant effect on melatonin production in glands removed both during the light and dark spans. Mn2+ at 10(-4) mol/l (but not at 10[-5] mol/l) appeared to stimulate melatonin production in glands removed both during the light and the dark (significant increase only with glands removed during the dark). Cobalt showed an immediate short inhibitory effect on both isoproterenol and norepinephrine-stimulated melatonin release, whereas nifedipine showed a significant inhibition only on isoproterenol-stimulated melatonin release. These results strongly suggest a circadian stage dependence of the pineal gland response to some calcium channel blockers and the involvement of calcium in the release of melatonin from pinealocytes.

Animals↗
PubMed1994

Spontaneous or imposed circadian changes in plasma concentrations of 5-fluorouracil coadministered with folinic acid and oxaliplatin: relationship with mucosal toxicity in patients with cancer.

Pharmacokinetics of total platinum, 5-fluorouracil, l-folinic and d-folinic acid, and 5-methyltetrahydrofolate were studied in plasma from nine patients with advanced colorectal cancer treated with oxaliplatin (20 mg/m2/day), 5-fluorouracil (600 mg/m2/day), and folinic acid (300 mg/m2/day). Drugs were administered with a programmable-in-time pump by continuous infusion for 5 days. We compared two drug delivery schedules: constant rate versus chronomodulated rate with peak of oxaliplatin at 4 pm and peak of 5-fluorouracil and folinic acid at 4 am. In the chronomodulated schedule, plasma concentrations of the drugs paralleled the pump functioning: maximum platinum concentration near 4 pm, and maximum 5-fluorouracil and folate concentrations near 4 am. When drugs were administered at a constant rate, mean plasma concentration of 5-fluorouracil varied in a circadian manner each treatment day, that is, a peak at 4 am (approximately 800 ng/ml) and a trough at 1 pm (approximately 100 ng/ml). Mean plasma levels of total platinum and folate compounds increased over the first 24 hours. Total platinum mean level and that of the inactive d-folinic acid isomer reached a constant plasma concentration, whereas biologically active folates exhibited circadian variation in their plasma concentrations (peak around 7 am, trough near 6 pm, and amplitude approximately 10%). Severe mucositis was exhibited by all four patients on the flat schedule, but only by one on the chronomodulated schedule (p < 0.008). Individual pharmacokinetic and toxicity data showed that patients with circadian rhythms in 5-fluorouracil concentrations were least sensitive to 5-fluorouracil-related toxicity. Thus amplification or induction of such rhythm in 5-fluorouracil exposure may permit dose escalation.

Adult↗
PubMed1994

Effects of bright light on circadian patterns of cyclic adenosine monophosphate, melatonin and cortisol in healthy subjects.

Bright light is known as a strong zeitgeber on human circadian rhythms and influences several endocrine and neuroendocrine functions. In the present study we examined the influence of a 3-h bright light stimulus, given at different times during the day (morning or evening), on circadian patterns of cyclic adenosine monophosphate (cAMP), melatonin and cortisol. Two groups of synchronized healthy volunteers (lights on: 05.00-23.00 h) were exposed to bright light (2500 lux) for 3 h over 6 days either in the morning (05.00-08.00 h) or in the evening (18.00-21.00 h). The results showed a significant phase advance in the circadian rhythms of melatonin and cortisol when bright light was given in the morning but not when given in the evening. Rhythm in plasma cAMP basically was not affected by either light treatment.

Adult↗
PubMed1993

Effect of morning bright light on body temperature, plasma cortisol and wrist motility measured during 24 hour of constant conditions.

Using 24 h constant conditions, time course of body temperature, plasma cortisol and wrist motility was measured in response to a 3 day morning 2 h bright light pulse. This protocol demonstrated that a 2000 lux illumination was sufficient to elicit a shift of about 2 h of temperature minimum and cortisol peak. In reference session, actimetric recordings showed a circadian time course, closely in relation with core temperature. Bright light pulse resulted in a decrease of amplitude and a disappearance of circadian pattern of actimetry.

Adult↗