[Circadian variations in bronchial sensitivity to house dust in four allergic asthma cases (Proceedings)].
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Biomedical subjects
Publications and source records attributed to A Reinberg.
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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.
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In eight apparently healthy young men a circadian rhythm (P less than 0,05) in urinary 17-hydroxycorticosteroids (17 OHCS) and tetrahydro-11-deoxycortisol (THS) has been demonstrated before (A), during (B) and after (C) a 36 h sustained oral administration of metyrapone (7.50 g in ten doses of 0.75 g every 4 h). Subjects synchronization: light-on 0715; light-off 2300. 17 OHCS have the acrophase phi located at 1430 (2:30 p.m.) in the three circumstances. Only traces of THS are excreted during A. During B and C when THS is excreted, a circadian rhythm is validated (p less than 0.05) with a phi at 1430.
Six healthy adults volunteered to ingest a 1 g solution/24 h of sodium salicylate in a study consisting of 4 standardized tests. The difference between tests was the timing of drug absorption: 07(00), 11(00), 19(00) and 23(00) respectively. The 4 separate tests were performed at least 1 week apart. Subjects; synchronization : diurnal routine activity with light-on at 07(00) and light-off at 23(00) Urine was collected at four-hour intervals, for 48 hours following drug ingestion. By the mean cosinor summary of least squares fits of a 24-hour cosine curve, or by other testing, a within-day difference is established for several chronopharmacokinetic parameters characterizing urinary salicylate excretion. By criteria including the height of the peak excretion, the span necessary to reach the peak, etc., it is shown that, as compared to drug administration at other times, salicylate is excreted faster into the urine, reaches higher values sooner and falls off faster when the drug is ingested between 19(00) and 23(00).
Circadian rhythms in lung resistance (R1) and dynamic compliance (C1dyn) of 7 healthy children (6 to 10 years) were validated (p less than .05) and then quantified (cosinor method); subjects' synchronization: light on at 0700; light off at 2100. Measurements were performed at fixed per hours (0730, 1130, 1630 and 2230) before and after the inhalation of a beta sympathomimetic bronchodilatator: minus 2mg orciprenaline. The measurements carried out after orciprenaline inhalation show a flattening of the curves, both circadian rhythms in R1 and C1 dyn are not detected (p greater than .05).
Every other month, during the course of 14 months, the circadian rhythm in plasma testosterone (among others variables) of 5 healthy males (26 to 32 years) was documented. Subjects' synchronization: light-on at 7 +/- 1 h; light-off at 23 +/- 1.5 h during the whole year. Blood sampling 4-hourly, at fixed times during 28 h, for radioimmunological testosterone determinations. The cosinor method was used for statistical analyses. An annual rhythm in the testosterone 24-h mean is detected (P less than 0.025) with a peak in October (from 16 July to 26 December, with 95% confidence limits). Annual mean (+/-1 se)= 759 (+/- 26) ng/100 ml. Peaktrough difference=197 ng/100 ml (from 106 to 290 with 95% confidence limits). The timing of the testosterone circadian peak, in the 24-h-scales also varies during the course of the year. The peak is found around 8 h in May and around 14 h in November, this phase-shift being statistically significant (P less than 0.05).
Temperature in man measured or recorded by different means, is not constant but varies in a predictable and rhythmic fashion. Circadian (about 24-hour) rhythms have been demonstrated and studied in healthy men and women as well as in patients under a wide variety of experimental conditions and diseases. With the help of special computer programs (Halberg's cosinor) inferential statistical analyses can be performed. There validate and characterize a biological rhythm (i.e., core temperature) by several parameters: the period (tau) the acrophase (phi) (timing of the peak), the amplitude (A) and the rhythm-adjusted mean (M). Each one of these parameters is given with its confidence limits when the studied rhythm is detectable (p less than 0.05). The human temperature (oral, rectal and skin) circadian rhythm has been validated and quantified in healthy newborns, in healthy adults on various diets (including near-fasting conditions: 220 cal/24h, casein) and various type of activities. Food intake does not appear to influence the temperature circadian rhythm. The rhythm persists with a change of period and/or acrophase during isolation underground, without time dues or clues. Its acrophase can be shifted by manipulating synchronizing factors (i.e., shift-working, transmeridian flight). Alteration of circadian temperature rhythm may result from the timed administration of certain drugs (i.e. reserpine) and from certain chronic diseases (without overt fever). A first attempt to use both thermography and chronobiological method has been made independantly by Gautherie et al [40] and Smolensky [41] in the prediction of therapeutic value of a given modality during the course of breast cancer treatment.
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Six healthy young men (22 to 26 years) who had fasted for 12 hours volunteered for this study (subject synchronization: diurnal activity from 07(00) to midnight and nocturnal rest). A set dose of ethanol (0.67 g/kg body weight) was ingested at the fixed (and random) hours of 07(00), 11(00), 19(00) and 23(00), with a week between tests. A set of physiological variables: psychological tests (selft-rating of mood, of physical vigor and of ebriety, tempo, random number addition test); physical variables (heart rate, systolic and diastolic blood pressure, peak expiratory flow, oral temperature and grip strength); blood variables (plasma ethanol, cortisol, lactic acid, pyruvic acid, glucose and erythrocyte K+) and urinary variables (volume, epinephrine, nor-epinephrine and 5-HIAA) were documented at least at 4 hourly intervals and set times. The cosinor method was used for chronobiological statistical analyses. The parameters characterizing the ethanol pharmacokinetics (chronopharmacokinetics) demonstrated a circadian rhythm (p less than 0.05): e. g. the peak height of ethanolemia is greater when ethanol is ingested at 07(00) than at other times. Also a circadian rhythm in biosystems susceptibility can be demonstrated (p less than 0.05) (chronesthesy) with a peak time not necessarily corresponding either to that of ethanolemia or to that of other variables. The overall circadian changes in ethanol effects (chronergy) can be viewed as a combination of both ethanol chronesthesy and chronokinetics.
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Intake of total calories, proteins, lipids and carbohydrates was measured individually in four separate groups each of 26 to 29 children studied during different seasons of the year and an additional group of eight children investigated during all seasons. The subjects came from broken homes, had been abandoned or were orphans; 60% were males, 4 +/- 1.5 years of age (mean and standard error) and were of similar body weight and height. They were residents in one of two separate institutions in Nancy, France, living on similar, rigorously enforced schedules unchanged throughout the year. Socio-ecologic synchronization involved "lights-on" at 0700 "lights-out" at 1830, meals at 0800, 100, 1400 and 1800 with food of similar origin and kind, and similar timing of mental and physical activities. Each child was asked at fixed meal times to select spontaneously the kind and amount of food desired, uninfluenced as far as possible by choices of others, and to consume the food in any order. During seven days of adherence to this request, the amounts of protein, lipid, carbohydrate and total calories consumed at each meal were carefully determined for each individual. Time series thus obtained were analyzed according to the mean cosinor method for detecting and characterizing bioperiodic phenomena. A statistically significant circadian rhythm was detected in each of the 4 variables for each day of the best fitting sine function used to approximate the rhythm occurred around noon in almost all the studied circumstances. In other words the spontaneously larger meals were usually taken at 0800 (breakfast) and 1800 (supper). The trough of both lipid and protein spontaneous intake was clustered around 1800 only on Sunday. Cosinor analysis of individual seven-day time series (of each variable of each season) indicated a statistically significant circaseptan (approximately equal to 7-days) rhythm, with a peak occuring on Saturday, Sunday or Monday, but never on Wednesday. Changes in the weekly mean adjusted levels obtained by this method (as well as changes in mean values resulting from other statistical methods) demonstrate: 1) a circannual variation in spontaneous intake of lipids, carbohydrates and calories (protein changes are not statistically significant): 2) a peak of lipid intake, occuring in spring time, and a peak of carbohydrate and calorie intake, occuring in summer time. The probability of both exogenous and endogenous components of these rhythms is suggested.
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