Significant Circadian Variation Research Articles

There are days ... and moons; Self‐poisoning is not lunacy

To determine whether there are significant circadian, weekly or lunar variations in self-poisoning presentations and whether patients' names or dates of birth have an influence on the likelihood of self-poisoning by analysing biorhythms, numerology and star sign. Hunter Valley, Australia. Consecutive adult patients admitted with self-poisoning between January 1987 and June 1993. There were 2215 patients admitted. There was a marked circadian variation. Over 6% of all admissions occurred in each of the hours between 6 p.m. and 1 a.m. compared with less than 2% per hour between 5 a.m. and 9 a.m. This pattern was not different for patients with a diagnosis of depression. Numerology, biorhythms and star signs had no significant correlations with self-poisoning, nor was there a significant weekly or yearly variation in presentations. There was a small but statistically significant sex difference in presentations analysed by lunar phases. At the new moon 60% of self-poisonings were in women, compared with 45% when the moon was full. The odds ratios (OR) for women to be admitted at full moon and at new moon were 1.27 (95% confidence interval [CI], 0.92-1.66; P value not significant) and 0.73 (95% CI, 0.57-0.92; P = 0.009) respectively. The mean illumination of the moon at the time of overdose was 50.63% +/- 0.91% for men, compared with 47.45% +/- 0.85% for women (P = 0.014). The circadian cycle (but not weekly, yearly or mystical cycles) should be taken into account when determining staffing levels for poison information and casualty services. The full moon is protective for women.

Circadian variation in peripheral blood flow in relation to core temperature at rest.

The aim of the present study was to examine the circadian variation in skin blood flow and its relationship to the rhythm of rectal temperature. Eight young men were confined to continuous bed rest for 24 h in a thermoneutral environment. Rectal temperature, oxygen consumption, and peripheral blood flow (laser-Doppler flowmetry and plethysmography) were measured at intervals of 2 h, except at 2400 hours and 0600 hours. According to the cosinor-method, the mean rectal temperature displayed a statistically significant circadian variation with a minimum at 0400 hours. A significant circadian rhythm was also observed in total finger blood flow, finger laser-Doppler flow, and forearm laser-Doppler flow, but not in total forearm blood flow and forehead laser-Doppler flow. The rhythms of rectal temperature and extremity skin blood flow were phased differently, i.e. the decrease in rectal temperature was preceded by an increase in extremity skin blood flow with an average of 4-h time difference. The results would support the idea that circadian rhythm of core temperature is, at least in part, regulated by variation in extremity skin blood flow.

Correlation between reproductive photoresponsiveness and photoregulated locomotor activity in meadow voles

Some rodent populations contain individuals that undergo complete gonadal regression under short day lengths, other individuals whose gonads are little affected by such treatment, and still others that are intermediate in their response. Meadow voles exhibiting this variation were used to explore the relationship between reproductive photoresponsiveness and photoregulated locomotor activity. The activity patterns of the two extreme phenotypes—reproductively photoresponsive vs. nonresponsive—were compared, first under short day lengths and then under long day lengths. The primary component of the daily running wheel activity pattern for both phenotypes under both conditions was ultradian. Within that framework, reproductively photoresponsive voles were predominantly nocturnal in their locomotor activity under both day lengths. In contrast, the nonresponsive individuals showed no significant circadian variation in their activity under either day length. These results suggest that reproductively photoresponsive and nonresponsive individuals may have fundamentally different patterns of activity throughout the year in the wild. Furthermore, the data suggest that the inability of some voles to respond reproductively to variations in photoperiod may be caused by a decoupling of the circadian system from the entraining effects of day length.

Heterogeneity in the mouse epidermal cell cycle analysed by computer simulations.

Different sets of cell kinetic data obtained over many years from hairless mouse epidermis have been simulated by a mathematical model including circadian variations. Simulating several independent sets of data with the same mathematical model strengthens the validity of the results obtained. The data simulated in this investigation were all obtained with the experimental system in a state of natural synchrony. The data include cell cycle phase distributions measured by DNA flow cytometry of isolated epidermal basal cells, fractions of tritiated thymidine ([3H]TdR) labelled cells within the cell cycle phases measured by cell sorting at intervals after [3H]TdR pulse labelling, bivariate bromodeoxyuridine (BrdUrd)/DNA data from epidermal basal cells isolated at intervals after pulse labelling with BrdUrd, mitotic rate and per cent labelled mitosis (PLM) data from histologic sections. The following main new findings were made from the simulations: the second PLM peak observed at about 35 h after pulse labelling is hardly influenced by circadian variations; the peak is mainly determined by persisting synchrony of a rapidly cycling population with a G1-duration (TG1) of 20 h to 30 h; and there is a highly significant population of slowly cycling G1-cells (G1 sigma). However, no significant circadian variations were found in the number of these cells.

Circadian variation of cardiac autonomic regulation during 24‐h bed rest

We examined the effect of circadian variation on cardiac autonomic regulation in 11 young and middle-aged, healthy men during 24-h bed rest. Cardiac parasympathetic regulation expressed significant circadian variation: sensitivity of baroreceptor reflex, standard deviation of R-R intervals and the power of high frequency component of R-R interval variability (HFP) increased during the evening (2000-2100 h), were highest during the night (0200-0300 h), and gradually decreased again towards afternoon (1400-1500 h). Cardiac sympathetic regulation, the power of medium frequency component of R-R interval variability (MFP), did not show any significant circadian variation. The autonomic response to orthostatic stress changed after the 24-h bed rest; the sympathetic dominance in response to assuming upright position was before bed rest principally attributable to increased sympathetic activity (MFP increase), whereas after bed rest this was due to withdrawal of parasympathetic activity (HFP decrease). We conclude that the effect of circadian variation must be taken into account, while assessing cardiac autonomic regulation in patients with acute cardiovascular disorders.

Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischaemic heart disease.

To determine whether plasma concentrations of tissue plasminogen activator antigen, von Willebrand factor antigen, and prostacyclin stimulating factor and plasminogen activator inhibitor activity show circadian variation in men with ischaemic heart disease. Blood samples were obtained every four hours for 24 hours from 10 men with ischaemic heart disease. The men were ambulant from 08:10 until 00:00 when they went to bed and they remained in bed until 08:00 the following morning. Ten men with positive diagnostic exercise tolerance tests with no significant past history, who were not regularly taking any medical treatment except for glyceryl trinitrate. There was significant circadian variation in plasminogen activator inhibitor activity (p = 0.001) (peak value 04:00 and trough value 20:00), but not in plasma concentrations of tissue plasminogen activator antigen, von Willebrand factor, or prostacyclin stimulating factor. Men with ischaemic heart disease showed a significant circadian variation in fibrinolysis. The combination of peak values of plasminogen activator inhibitor activity and failure of plasma concentrations of tissue plasminogen activator antigen to increase in the early morning must predispose to thrombosis at this time. The circadian variation in fibrinolysis may contribute to the increased incidence of myocardial infarction in the morning.

Diurnal changes of GABA turnover rate in brain and pineal gland of Syrian hamsters

Circadian rhythms of GABA turnover rate in cerebral cortex, preoptic area-medial basal hypothalamus (PMBH), cerebellum, and pineal gland were examined in Syrian hamsters kept for 3 months under either long (14 h of light/day) or short days (10 h of light/day). In vivo GABA turnover rate was measured by the increase of GABA levels following inhibition of GABA-transaminase by gamma-acetylenic GABA. Under long photoperiods, a significant rhythm of GABA turnover was detected in the four areas studied (cerebral cortex, PMBH, cerebellum, and pineal gland), with maxima at night. A Cosinor analysis indicated acrophases which varied from 2300 to 0400 h (3rd to 8th h of darkness). Under short photoperiods, there were no significant circadian variations in GABA turnover in the cerebral cortex, and the synchronization in turnover rate among the remaining regions was lost, with acrophases being detectable either during the light phase of daily photoperiod (PMBH) or at night (cerebellum, pineal gland). Steady state levels of GABA also changed periodically in the same brain regions under both lighting environments, although phase relationships of circadian rhythms in GABA content and turnover rate varied significantly among tissues, as well as on photoperiodic conditions.

Circadian variation of white blood cell aggregation and free radical indices in men with ischaemic heart disease.

The fibrinolytic activity of blood has a circadian variation with increased thrombotic tendency in the morning. This may be a contributory factor to the circadian variation in the time of onset of thrombotic events. However, there has recently been increasing interest to the role of the white blood cells (WBC) and free radicals (FRs) in thrombosis. We have previously reported a circadian variation in WBC aggregation and FR status in normal volunteers. No one has yet studied possible circadian variations in these parameters in patients with stable ischaemic heart disease (IHD). Ten men with stable IHD had blood samples collected at four-hourly intervals from midday until midday the following day. The patients were ambulant until midnight at which time they went to bed and remained in bed until 0800 h. The following were measured on each sample: WBC aggregation, malondialdehyde (MDA) which is a product of lipid peroxidation by FRs; the FR scavengers, plasma thiol (PSH), red cell glutathione (GSH) and superoxide dismutase (SOD) which are all altered in the presence of increased FR activity. WBC aggregation and PSH had significant circadian variations, P < 0.015 and P < 0.001 respectively. The WBC aggregation peak was at 1200 h and trough at 1600 h, the PSH peak was at midnight and the trough at 0400 h. WBC behaviour and FR status influence the flow properties of blood. The largest rise in WBC aggregation occurred from 0800 h to 1200 h; such an increase in aggregation could predispose to microcirculatory occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Caries susceptibility and renal excretion of calcium.

Clearance studies were performed for 2 days in two groups of age-matched young female volunteers: those with low caries prevalence and those with high caries prevalence. Both groups were kept on a low-calcium diet for 1 week and received 0.5 g calcium at the beginning of the second day. In both groups, glomerular filtration rate, urinary flow rate and renal excretions of sodium, calcium, and phosphate were subject to significant circadian variations. In both groups the administration of calcium led to a significant increase in renal excretion of sodium and calcium and a significant decrease in that of phosphate. On the first day, calcium excretion was significantly greater in those with low caries prevalence than in those with high caries prevalence, pointing to altered calcium homeostasis in this group.

Circadian variation of ventricular tachycardia in patients with coronary arterial disease

Sudden cardiac death and ischaemic cardiac events occur in a circadian pattern. Because ventricular tachycardia is thought to play an important role in sudden cardiac death, the episodes of spontaneous ventricular tachycardias (≥ 3 consecutive beats) ( n = 1314) were analysed from 24-hour long term electrocardiographic recordings in 34 patients with coronary arterial disease to determine whether circadian rhythm exists in spontaneous ventricular tachycardia. Twelve patients had suffered cardiac arrest, four patients had a history of syncope, and palpitation was the indication for electrocardiographic recordings in eighteen patients. Analysis using chronobiologic single cosinor method showed a significant circadian variation in the occurrence of ventricular tachycardia episodes with the peak occurring at 6 a.m. Similar circadian rhythm was also observed in the occurrence of the longest episode of ventricular tachycardia. Ischaemic ST-segment depression preceded the longest ventricular tachycardia episode only in one patient. Thus, a circadian rhythm occurs also in spontaneous episodes of ventricular tachycardia, a finding which is similar to that in sudden cardiac death.

Osteocalcin 24-hour profiles during normal pregnancy.

The interpretation of previous data on osteocalcin during pregnancy has been complicated by the fact that serum levels, at least in nonpregnant women, display a significant circadian variation. In the present study, serum concentrations of osteocalcin were recorded for 24 h in 12 individual women. In 4 nonpregnant women, there were striking diurnal fluctuations during the sampling period, with values ranging from 0.5 to 4.0 ng/ml. One woman who was investigated in the 11th week of pregnancy showed similar fluctuations in osteocalcin concentrations whereas in the 15th and 17th week values were much lower with minor fluctuations. In 4 women investigated during late pregnancy (weeks 34-38), osteocalcin serum levels were extremely low (range 0.2-0.4 ng/ml), often below the detection limit of the assay, and there was no diurnal variation. Also, in 1 lactating woman, osteocalcin serum levels were low (0.3-0.8 ng/ml) and stable. Low osteocalcin values during pregnancy may indicate a reduced bone turnover possibly mediated via an altered estrogen and growth hormone secretion.

Rat circadian rhythms entrain to a descending saw-tooth light intensity cycle

We reexamined whether rat circadian rhythms entrained to the light intensity cycle of a descending saw-tooth (ST-d) form, in which illuminance decreased rectilinearly from 300 lx to 0 lx in 24 h, and abruptly returned to 300 lx (lights-on time). Ambulation, drinking and subcutaneous body temperature were simultaneously monitored in 5 intact, 5 pinealectomized and 5 orchiectomized rats. Additionally, sleep was monitored in the intact rats. In all the rats, entrainment was confirmed during 65 days' exposure to the ST-d cycle. The waveforms of the entrained rhythms were much modified compared with those during LD 12:12. The estimated activity periods of the entrained rhythms straddled the lights-on time of the ST-d cycle. In all the groups of rats, administration of a single ST-d cycle in constant dim red light produced only delay shifts irrespective of its circadian phase, and there was no significant circadian variation in the magnitude of phase shifts. The results indicate that rat circadian rhythms entrain to the ST-d cycle with an unexpected phase position, which cannot be explained by the phase-response curve.

Circadian phase-dependent protein and tissular binding of three local anesthetics (bupivacaine, etidocaine, and mepivacaine) in mice: a possible mechanism of their chronotoxicokinetics?

The aim of this study was to investigate the possible influence of the time of administration on bupivacaine (B), etidocaine (E), and mepivacaine (M) protein and tissue (brain and heart) binding. For each anesthetic agent, a single dose of B (20 mg/kg), E (40 mg/kg), or M (60 mg/kg) was administered intraperitoneally at 10:00, 16:00, 22:00, and 04:00 h. Blood and tissue samples were collected 15 min after drug administration. This study documents significant circadian variations in protein and tissue binding of the three local anesthetic agents. We did not demonstrate a temporal relationship between the respective free and tissue levels. Thus, the temporal variations of free plasma, brain, and heart levels do not seem to be involved in the temporal changes of induced mortality.

Circadian rhythm of plasma testosterone in men with idiopathic hypogonadotrophic hypogonadism before and during pulsatile administration of gonadotrophin-releasing hormone.

The aim was to investigate whether a pulsatile discharge of LH from the pituitary is necessary to achieve the circadian secretion of testosterone. The daily rhythm of the androgen has been studied in patients with idiopathic hypogonadotrophic hypogonadism (IHH) both in the absence of therapy and during pulsatile administration of gonadotrophin releasing hormone (GnRH). Six patients with IHH and ten normal subjects were analysed. Blood sampling was performed at 2-hourly intervals, for 24 hours. The IHH patients then received synthetic GnRH i.v. at the rate of one pulse every 2 hours (10 micrograms/pulse). On day 11 of treatment, blood samples were taken for the rhythm analysis every 2 hours, for 24 hours. Plasma testosterone and LH were measured in the individual samples by radioimmunoassay. Evaluation of the rhythm was performed by cosinor analysis. A significant circadian rhythm of plasma testosterone was statistically validated in the normal subjects, whereas no rhythm was detected in the IHH patients in the absence of therapy. On day 11 of GnRH pulsatile administration the IHH patients showed normal testosterone levels and a statistically significant circadian rhythm of the androgen was evident, with acrophase between 0700 and 0800 h. Moreover, the amplitude, acrophase and mesor of testosterone rhythm in IHH patients in the course of treatment were statistically indistinguishable from the corresponding values in the normal subjects. Plasma LH did not show statistically significant circadian variations, either in the control group or in the IHH patients before or during therapy. We conclude that a physiological circadian rhythm of plasma testosterone can be obtained, in IHH men, by treatment with GnRH. Since the pulsatile administration of exogenous GnRH at constant doses induced a circadian rhythm in testosterone and no daily variations in LH were evident, we suggest that, although a pulsatile secretion of LH is probably necessary for the synchronization of the circadian rhythm with acrophase in the morning, the testosterone variations might be the results of a local testicular modulation of LH action.

Loss of nocturnal increase in plasma concentration of atrial natriuretic peptide in hypertensive chronic renal failure.

Diurnal change of plasma atrial natriuretic peptide (ANP) concentration was investigated in 12 patients with hypertension due to chronic renal failure (CRF) and in 12 patients with essential hypertension (EH) of comparable degree. Blood pressure (BP) monitoring was performed at 15-min intervals, while peripheral blood samples were obtained at 4-hour intervals starting from 8.00 h. The mean 24-hour plasma levels (+/- SEM) of ANP were 24.3 +/- 1.8 pmol/l in EH and 23.4 +/- 1.2 pmol/l in CRF. In EH, plasma ANP concentration was highest at 4.00 h (33.5 +/- 0.8 pmol/l) and lowest at 16.00 h (15.5 +/- 0.6 pmol/l). In CRF, no significant circadian change was present (22.2 +/- 3.1 and 20.4 +/- 3.6 pmol/l, respectively), and the nocturnal fall in BP was lost. Our data demonstrate that in CRF the loss and possible reversal of the nocturnal decline in BP is associated with the disappearance of any significant circadian variation in the circulating concentrations of ANP. These findings suggest a role for ANP in the alteration of BP variability of CRF, possibly mediated by autonomic dysfunction, and are further evidence for the existence of a relation between the circadian rhythms of ANP and BP.

Nocturnal Asthma: β2-Adrenoceptors on Peripheral Mononuclear Leukocytes, cAMP- and Cortisol-Plasma Concentrations

To evaluate pathophysiologic mechanisms of the predominantly nocturnal complaints in atopic bronchial asthma, the expression and function of beta 2-adrenoceptors on peripheral mononuclear leukocytes (pMNL), the cAMP--as well as the cortisol--plasma concentrations were studied in eight healthy men and ten so far untreated male asthmatic patients at 4-h intervals for 24 h. No difference was seen in the beta 2-adrenoceptor density (Bmax) on pMNL between healthy and asthmatic men (24-h means +/- SE: 908 +/- 59 sites per cell and 821 +/- 54 sites per cell, respectively). The equilibrium dissociation constant (Kd), however, was significantly higher in the asthmatic patients (24-h mean +/- SE: 8.8 +/- 1.2 pmol/L vs 3.0 +/- 0.2 pmol/L in healthy men, p less than 0.0001), which is equivalent to a lower affinity of the beta 2-adrenoceptors for the radioligand 125iodocyanopindolol. Bmax showed a statistically significant circadian variation, but Kd did not. The circadian variation in Bmax was reflected in the basal intracellular cyclic adenosine-monophosphate (cAMP) content of the cells investigated. High Kd values (equivalent to low receptor affinities) tended to be associated with small increases of the intracellular cAMP content after in vitro stimulation by 10(-7) mol/L isoprenaline (isoproterenol) (24-h mean +/- SE: 1.4 +/- 0.2 pmol/10(6) cells; r = -0.529, p = 0.05 at r = -0.549, n = 10). Plasma cAMP concentrations were found to be significantly lower in the asthmatic patients (24-h means +/- SE: 22.9 +/- 1.3 nmol/L vs 29.1 +/- 1.1 nmol/L, p less than 0.0001). Plasma cortisol concentrations were significantly higher in the asthmatic patients (24-h means +/- SE: 0.500 +/- 0.084 mumol/L vs 0.319 +/- 0.063 mumol/L). The results support the hypothesis that a lesion of the beta-adrenergic system contributes to the pathophysiology of atopic bronchial asthma. In the patients investigated in this study, such a lesion could be demonstrated in the affinity rather than in the number of beta 2-adrenoceptors expressed on peripheral cells of the immune system (pMNL). According to present-day knowledge of adrenergic effects on pMNL, such an affinity decrease of beta 2-adrenoceptors could account for overshooting immune responses. In association with other factors influencing respiratory function, it could be responsible for the predominantly nocturnal complaints in atopic bronchial asthma. Plasma cortisol concentrations did not appear to be related to the principal cause of "nocturnal asthma;" they rather reflected an endogenous defense mechanism to the disease.

Effect of propranolol (long-acting) on the circadian fluctuation of tissue-plasminogen activator and plasminogen activator inhibitor-1

The incidence of myocardial infarction and sudden cardiac death is highest in the morning. Inhibition of fibrinolytic activity in blood also peaks in the morning and this inhibition may favor the development of arterial thrombosis. It has been reported that patients treated with β blockers do not show the typical circadian pattern of onset of myocardial infarction and sudden cardiac death. This study was undertaken to investigate whether β blockade alters the circadian rhythm of 2 major fibrinolytic factors, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Repeated blood samples were taken over a 24-hour period in 13 healthy volunteers: 7 taking 160 mg/day of long-acting propranolol orally for 14 days, and the other 6 taking no medications. Blood samples were analyzed for the plasma levels of t-PA activity, t-PA antigen, PAI activity and PAI-1 antigen. A significant circadian variation of all 4 parameters was present in both groups. No significant differences in peak and nadir values, 24-hour mean, amplitude of fluctuation, and time of peak and nadir were found between the treated and untreated subjects. The data therefore suggest that propranolol treatment does not affect the plasma concentrations at rest or the endogenous circadian rhythm of t-PA and PAI-1 in healthy volunteers. The reported alteration in the circadian pattern of onset of myocardial infarction and sudden cardiac death by β blockers does not appear to be mediated by effects on the fibrinolytic system.

Circadian rhythm in airway responsiveness and airway tone in patients with mild asthma

To determine the characteristics and reproducibility of circadian rhythms of airway responsiveness to histamine and methacholine and their relationship to airway tone in patients with mild asthma, we studied nine subjects with complaints of nighttime awakening due to dyspnea and/or cough at least once a week. Their mean age was 31.4 yr (range 17-65) and their mean daytime FEV1 was 99 +/- 14 (SD) % predicted. Forced expiratory volume in 1 s (FEV1) and the provocative concentrations of histamine and methacholine necessary to decrease FEV1 by 20% (PC20FEV1) were determined every 4 h for 13 consecutive measurements. Three subjects were measured with histamine, three with methacholine, and three with both histamine and methacholine. Data were evaluated on an individual basis. PC20FEV1 to histamine and methacholine showed significant and reproducible circadian variations in all cases (P less than 0.01 each) with a mean amplitude of 1.00 +/- 0.17 (SD) doubling concentrations for histamine and 1.35 +/- 0.29 doubling concentrations for methacholine. The amplitude of PC20FEV1 was significantly larger (P less than 0.05) and the time of maximum responsiveness was significantly earlier (P less than 0.05) with methacholine compared with histamine. FEV1 showed significant (P less than 0.05) circadian variations in three of nine subjects, and peak expiratory flow rate showed variations in two subjects. Correlation between the variations of FEV1 and PC20FEV1 was significant (P less than 0.05) in 5 of 12 cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Feeding, Fasting, and Caerulein Treatment on Ornithine Decarboxylase in Rat Pancreas

Ornithine decarboxylase (ODC) is the rate-limiting enzyme in polyamine biosynthesis. We examined circadian variations in pancreatic ODC activity and time-course effects of caerulein in fed and fasted rats. Significant circadian variations in amount of ODC activity were observed. The highest values were obtained during the dark period (1855 +/- 406 pmoles CO2/h), and the lowest during the light period (359 +/- 84 pmoles CO2/h). Caerulein treatment induced hypertrophy and hyperplasia of the pancreas in fed rats; increases in pancreatic ODC activity preceded the rise in protein and DNA contents (447 +/- 44 pmoles CO2/h and 5573 +/- 893 pmoles CO2/h, 6 and 12 h after the first injection of caerulein, respectively). In fasted rats, pancreatic ODC activity was very low (149 +/- 37 pmoles CO2/h) and caerulein treatment induced a transient increase in this activity 12 h after the first injection; hypertrophy but not hyperplasia of the pancreas was observed. In caerulein-treated fasted rats, refeeding during the night following a 48 h fasting period was not enough to increase either ODC activity or DNA content. These findings demonstrate that nutritional status is an important factor in the regulation of ODC activity and, thereby, in caerulein-induced pancreatic growth.

The influence of dosage time of midazolam on its pharmacokinetics and effects in humans

The influence of dosage time of midazolam on its pharmacokinetics and effects on the central nervous system were investigated in six healthy volunteers, with pharmacokinetic-pharmacodynamic modeling. Each volunteer received single oral doses of 15 mg midazolam on four separate occasions: 8 AM, 2 PM, 8 PM, and 2 AM. An almost significant circadian variation was found in elimination half-life, shortest at 2 PM (1.26 +/- 0.47 hours, mean +/- SD) and longest at 2 AM (1.57 +/- 0.44 hours) (p = 0.05). Drug effects measured were alpha activity of the electroencepalograph and P100 latency of the visual-evoked response. The maximum drug effect (Emax) model described the concentration-effect relationship, extended with either a threshold drug concentration or a sigmoidicity parameter. A significant circadian variation was found in baseline alpha activity: highest at 8 AM (109% +/- 19% of the 24-hour mean) and lowest at 2 AM (80% +/- 12%). For alpha activity the drug concentration at half-maximum effect of both threshold Emax model and sigmoid Emax model showed lower values at 8 AM and 2 AM and higher values at 2 PM and 8 PM. However, these differences were either not significant (p = 0.10, threshold model) or on the verge of statistical significance (p = 0.05, sigmoid model). No circadian variation was found in the parameters describing the effect on the visual-evoked response. We conclude that the sensitivity of the central nervous system to midazolam, as reflected in alpha activity, possibly shows a circadian variation.