Chronopharmacokinetics of Imipramine and Desipramine in Rat Forebrain and Plasma After Single and Chronic Treatment with Imipramine

Daily variations in the pharmacokinetics of imipramine (IMI) could contribute to circadian phase-dependent effects of the drug. Therefore, the chronopharmacokinetics of IMI and its metabolite, desipramine (DMI), were studied after single and chronic application. Male rats were synchronized to a 12:12 hour lightdark (L:D) regimen with lights on from 07:00 to 19:00 (dark, 19:00-07:00). In single-dose experiments rats were injected with IMI (10 mg/kg) i.p. or i.v. at 07:30 or 19:30 and groups of rats were killed 0-22 hours thereafter. After chronic application of IMI in drinking water (≈ 15 mg/kg/d) groups of rats were killed during the 14th day of treatment at 02:00, 08:00, 14:00, and 20:00, respectively. Brain and plasma concentrations of IMI and DMI were determined by reversed-phase high-performance liquid chromatography with ultraviolet detection. After single i.p. application of IMI, maximal brain concentrations (C_max) of IMI and DMI were nearly twofold higher in darkness (IMI, 4.8 μg/g; DMI, 1.8 μg/g) than in light (IMI, 2.85 Mg/g; DMI, 0.85 Mg/g). Also, the area under the curve (AUC) (0-22 hours) was about 1.6-fold greater in darkness than in light for IMI and DMI; half-lives were not circadian phase dependent. After i.v. injection of IMI, the AUC in brain was also about 30% greater in darkness than in light. After chronic application of IMI in drinking water, brain concentrations of IMI and DMI varied more than threefold within 24 hours. The data demonstrate that the pharmacokinetics of IMI and DMI are circadian phase dependent. It is assumed that circadian variations in drug distribution are more likely to contribute to the drug's chronopharmacokinetics than variations in the drug's metabolism. The 24-hour variations in the drug's concentrations after chronic IMI application in drinking water can be explained by the drinking behavior of the rats, which by itself is altered by IMI.     

Pharmacokinetics of imipramine are affected by age and sex in rats

Chronic treatment with the antidepressant imipramine (IMI) leads to accumulation of imipramine's major metabolite desmethylimipramine (DMI) in the brain. Juvenile, young and middle-aged female rats, as well as juvenile and young male rats were treated chronically with imipramine (14 days) and analyzed 24 hours later for levels of IMI and DMI in the hypothalamus-preoptic area (HPA) and serum. Older animals of both sexes showed higher levels of DMI than juvenile animals, in both the HPA and serum. Females also had higher DMI levels than males at comparable ages. Analysis of IMI and DMI levels at intervals after a single imipramine injection suggested that the initial metabolism of imipramine is slower in older animals and in females (compared to males). The results indicate that age and gender alter the initial metabolism of imipramine, leading to enhanced accumulation of metabolites during chronic treatment in older animals and in female rats, compared to younger rats and males, respectively.     

Effect of photoperiod, injection of pentobarbitone sodium or lesion of the suprachiasmatic nucleus on pre-partum decrease of blood progesterone concentrations or time of birth in the rat

In Sprague-Dawley rats kept under 14L:10D (lights on 05:00-19:00 h), parturition occurred during the light phase on Day 23, and the pre-partum decrease in progesterone concentrations was observed between 07:00 and 15:00 h during the light period on Day 22. When the rats were transferred to reversed light-dark regimen (lights on 17:00-07:00 h) on Day 7, the progesterone decrease and parturition still occurred during the light period on Day 21 and 22-23, respectively. However, when rats were kept in constant darkness from Day 7, parturition occurred independently of the time of day between Day 22 and 24. A gradual decline of progesterone concentrations was randomly observed in individual rats. In Wistar rats kept under the usual light-dark regimen, parturitions were biphasic, occurring during the light periods on Day 22 and 23. The progesterone decrease occurred at the usual time even when the lighting regimen was changed only on the day of the expected progesterone decrease. However, treatment with pentobarbitone sodium at 15:00, 19:00 or 21:00 h, but not at 12:00 or 23:00 h, on Day 21 resulted in a delay of progesterone decrease and of parturition. Complete lesion of the suprachiasmatic nucleus on Day 13 or 14 led to advancement and random distribution of the time of birth. These results suggest that the time of parturition and of pre-partum progesterone decrease may be closely associated with an endogenous circadian system, and a luteolytic factor involving the nervous system may be present during a limited period before parturition.     

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure, Heart Rate, and Motility: A Telemetric Study in Rats

In male Wistar rats [light (L): 07:00-19:00 h, dark (D): 19:00-07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED₅₀ values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.     

Circadian variations of the effects of ethanol and of blood ethanol values in the healthy adult man. Chronopharmacological study]

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.     

Effects of Amlodipine on Orcadian Rhythms in Blood Pressure,Heart Rate,and Motility: A Telemetric Study in Rats

In male Wistar rats [light (L): 07:00–19:00 h, dark (D): 19:00–07:00 h], the effects of the calcium channel blocker amlodipine (1, 3, 10 mg/kg i.p.) on blood pressure, heart rate, and motor activity were studied by telemetric monitoring. Amlodipine was injected either at 07:00 h or at 19:00 h. Systolic and diastolic blood pressure were dose-dependently decreased with more pronounced effects in the dark span, ED₅₀ values in D were about seven times lower than in L. In contrast, the dose-dependent increase in heart rate was more pronounced in L than in D. No significant effects of amlodipine were found on motor activity. The study gives evidence for a circadian phase-dependency in the cardiovascular effects amlodipine in rats.     

Prenatal and Neonatal Diazepam Administration Synchronizes Testicular Malate Dehydrogenase Circadian Rhythms in Young Rats

Rat or hamster pups exposed to constant light or darkness since birth exhibit many circadian rhythms synchronized with those of the mother. During early development, a number of cues derived from the maternal circadian system synchronize the fetal and neonatal circadian clock. Maternal pineal sympathetic denervation during early pregnancy disrupts maternal synchronization of parotid α-amylase and testicular malate dehydrogenase circadian rhythms in rat pups. Maternal pineal sympathetic denervation was used to study potential agents able to synchronize the fetal or neonatal circadian clock. Melatonin injection to denervated pregnant mothers prevents the pineal sympathetic denervation effect on those circadian rhythms. We now studied the synchronizing effect of a benzodiazepine compound, diazepam. This GABA_A agonist synchronized testicular malate dehydrogenase (MDH) activity of pups when it was injected to sympathetic denervated pregnant dams (a daily dose at 07:00 or 19:00 h from the 14 th to the 20 th day of gestation) or orally administered to the pups (a daily dose at 19:00 h from the 10 th to 24 th day of life). Co-injection of diazepam and GABA_A antagonist, flumazenil, blocked the synchronizing effect of diazepam. The results demonstrate that diazepam has a synchronizing effect on the development of the circadian clock in rats and suggest that modulation of maternal GABA_A could participate in mammalian maternal synchronization.     

AII amacrine neurons of the rat retina show diurnal and circadian rhythms of parvalbumin immunoreactivity

We investigated parvalbumin immunoreactivity (PA-IR) in the retinas of rats maintained on a 12:12 h light:dark cycle, or after being placed in constant darkness for 24–72 h. Retinas were harvested at zeitgeber and circadian times 02:00, 06:00, 10:00, 14:00, 18:00 and 22:00 h. PA-IR was found primarily in retinal amacrine cells of the AII subtype. In a light/dark cycle, PA-IR showed a clear rhythm, with a low near zeitgeber time (ZT) 10:00 h and a peak near ZT 18:00 h. The ratio of immunofluorescence intensities at these timepoints was >15-fold. When animals were kept in complete darkness for 1–3 days, the rhythm of PA-IR was still preserved, but was progressively reduced in amplitude. The rhythm of PA-IR inferred from immunohistochemical data was confirmed by Western blots. We conclude that PA-IR in the rat retina shows an underlying circadian rhythm that is enhanced by cyclic light. The regulation may involve translocation of the protein between cell compartments and/or new protein synthesis.This study was supported by an OTKA grant (T 34160), NIH grants NS 37919 (R.S.) and ET 03570, NSF grant IBN-96418886 (R.S.), and grants from the Helen Hoffritz Charitable Trust and Research to Prevent Blindness, Inc. R.G. was also in receipt of a János Bolyai fellowship     

Gastric Potential Difference in Fasted Rats: Circadian Studies

The pathophysiology of gastroduodenal ulcer disease remains the subject of intense research and controversy. One model of gastric ulcerogenesis implicates a disruption of complementary circadian rhythms between protective and destructive factors. Parallel circadian rhythms have been reported between acid secretion and gastric potential difference (PD) in in vitro models. The purpose of this study was to investigate the circadian measurements of PD, a parameter of intact gastric mucosal function and thus a putative parameter of gastric protection, in intact, fasted, anesthetized rats. Sixty-four male Sprague-Dawley rats were acclimatized in sound-attenuating, lightproof chambers for 3 weeks on a 12:12-h light-dark schedule. Eight rats were fasted 18 h before being sampled at each of eight times on the circadian clock (01:00, 04:00, 07:00, 10:00, 13:00, 16:00, 19:00. and 22:00 hours after lights on) (HALO). In each rat, after anesthesia (ketamine/ acepromazine) and laparotomy, the tip of a catheter (pre-filled with KC1 agar) was passed into the gastric corpus through the duodenum. The tip of a second KC1-agar catheter was placed within the peritoneal cavity. The position of the intragas-tric catheter was gently adjusted for obtaining the highest stable PD reading. The data showed significantly higher values at 07:00 and 10:00 HALO. The lowest value was at 13:00 HALO. The difference between high (10:00 HALO) and low (13:00 HALO) values was 4.5 mV or 13% of the mean. This difference was highly significant (p = 0.003) Analysis of variance showed that the values at 07:00 and 10:00 HALO were significantly higher than the values at 01:00, 13:00, and 16:00 HALO. Thus, the existence of a circadian rhythm in gastric PD is supported.     

Treatment-time-dependent difference of ketamine pharmacological response and toxicity in rats

Circadian rhythms impact many physiological functions that may affect drug pharmacological response. Ketamine is a dissociative agent commonly used for surgical anesthesia in rats. The aim of the present study was to analyze the central nervous system (CNS) depression and lethality of ketamine injected intraperitoneally at different times during the 24 h. The study was conducted in October 2001, spring in the Southern hemisphere. Female prepuberal Sprague-Dawley rats synchronized to a 12h light:12h dark cycle (light, 07:00h-19:00h) were studied. Ketamine (40 mg/kg) was administered to one of six different clock-time treatment groups (n=6-7 rats each). Duration of latency period, ataxia, loss of righting reflex (LRR), post-LRR ataxia, and total pharmacological response were determined by visual assessment. To investigate acute toxicity, ketamine lethal dose 50 (148.0 mg/kg) was also administered as a single injection to six different treatment-time groups of rats. Significant temporal differences and circadian rhythms were detected in drug-induced post-LRR ataxia and total pharmacological response duration. The longest pharmacological response occurred in rats injected during the light (rest) phase and the shortest response in the dark (activity) phase. No circadian rhythm was detected in acute toxicity. The study findings indicate that the duration of CNS depression of ketamine in rats exhibits circadian rhythmic variation.     

Diurnal rhythm of drinking activity in the house musk shrew]

A diurnal rhythm of drinking activity in 7 male and 6 female house musk shrews (Jic: SUN) aged about one year was observed over a period of 10 days under a schedule of 12 hr light and 12 hr darkness (light on at 07:00). In general, the pattern of drinking activity was similar among both sexes, with around 24-hr diurnal rhythm. A few typical drinking patterns of these animals were represented as follows: 1) Drinking interval was very close in the dark phase, while it was a little too sparse in the light phase (n = 4). 2) Its interval remains stationary through a whole day (n = 5). 3) Drinking was performed between the latter half of light and the first half of dark phases (n = 4).     

Timing Light Treatment for Eastward and Westward Travel Preparation

Jet lag degrades performance and operational readiness of recently deployed military personnel and other travelers. The objective of the studies reported here was to determine, using a narrow bandwidth light tower (500 nm), the optimum timing of light treatment to hasten adaptive circadian phase advance and delay. Three counterbalanced treatment order, repeated measures studies were conducted to compare melatonin suppression and phase shift across multiple light treatment timings. In Experiment 1, 14 normal healthy volunteers (8 men/6 women) aged 34.9±8.2 yrs (mean±SD) underwent light treatment at the following times: A) 06:00 to 07:00 h, B) 05:30 to 07:30 h, and C) 09:00 to 10:00 h (active control). In Experiment 2, 13 normal healthy subjects (7 men/6 women) aged 35.6±6.9 yrs, underwent light treatment at each of the following times: A) 06:00 to 07:00 h, B) 07:00 to 08:00 h, C) 08:00 to 09:00 h, and a no-light control session (D) from 07:00 to 08:00 h. In Experiment 3, 10 normal healthy subjects (6 men/4 women) aged 37.0±7.7 yrs underwent light treatment at the following times: A) 02:00 to 03:00 h, B) 02:30 to 03:30 h, and C) 03:00 to 04:00 h, with a no-light control (D) from 02:30 to 03:30 h. Dim light melatonin onset (DLMO) was established by two methods: when salivary melatonin levels exceeded a 1.0 pg/ml threshold, and when salivary melatonin levels exceeded three times the 0.9 pg/ml sensitivity of the radioimmunoasssy. Using the 1.0 pg/ml DLMO, significant phase advances were found in Experiment 1 for conditions A (p?<?.028) and B (p?<?0.004). Experiment 2 showed significant phase advances in conditions A (p?<?0.018) and B (p?<?0.003) but not C (p?<?0.23), relative to condition D. In Experiment 3, only condition B (p?<?0.035) provided a significant phase delay relative to condition D. Similar but generally smaller phase shifts were found with the 2.7 pg/ml DLMO method. This threshold was used to analyze phase shifts against circadian time of the start of light treatment for all three experiments. The best fit curve applied to these data (R²?=?0.94) provided a partial phase-response curve with maximum advance at approximately 9–11 h and maximum delay at approximately 5–6 h following DLMO. These data suggest largest phase advances will result when light treatment is started between 06:00 and 08:00 h, and greatest phase delays will result from light treatment started between 02:00 to 03:00 h in entrained subjects with a regular sleep wake cycle (23:00 to 07:00 h).     

Twenty-Four-Hour Variations in the Sensitivity of Rat Aorta to Vasoactive Agents

The presence of time-dependent variations in the in vitro sensitivity of aorta preparations to either vasoconstricting or relaxing agents was investigated in rats maintained in light from 08: 00 to 20: 00 and in darkness from 20: 00 to 08: 00. Rat thoracic aorta rings were obtained from animals sacrificed at four different times of the day. The rat aorta was found to be more sensitive to the constricting effect of phenylephrine at 15: 00, and of 5-hydroxytryptamine at 21: 00. On the other hand, both endothelium-dependent and -independent relaxations were more remarkable at 03: 00 than at other times of the day. These variations represented significant circadian rhythms when analyzed by analysis of variance. Different in vitro responsiveness to these agents might reflect changes in the sensitivity and/or number of related receptors in vascular preparations. In conclusion, the circadian time of animal sacrifice to obtain vascular preparations constitutes an important aspect of the research method and a key determinant of findings. (Chronobiology International, 13(6), 465-475, 1996)     

Adrenergic response patterns in vas deferens isolated from rats under diurnal rhythms. Influence of stress

The aim of this study was to verify, by means of functional methods, whether the circadian rhythm changes adrenergic response patterns in the epididymal half of the vas deferens isolated from control rats as well as from rats submitted to acute stress. The experiments were performed at 9:00 a.m., 3:00 p.m., 9:00 p.m., and 3:00 a.m. The results showed a light-dark dependent variation of the adrenergic response pattern on organs isolated from control as well as from stressed rats. In the control group, only the phenylephrine sensitivity was changed throughout the circadian rhythm. Under the stress condition, both norepinephrine and phenylephrine response patterns were changed, mainly during darkness. The maximal contractile response to both alpha- and beta-agonist and alpha1-agonist was increased in the dark phase, corresponding to high plasmatic concentrations of endogenous melatonin. The vas deferens isolated from stressed rats during the light phase simultaneously incubated with exogenous melatonin showed the same pattern of response obtained in the dark phase, thus indicating a peripheric action of melatonin on this organ. Therefore, the circadian rhythms are important to the adrenergic response pattern in rat vas deferens from both control and stressed rats. In conclusion, we suggest a melatonin modulation on alpha1-postsynaptic adrenergic response in the rat vas deferens.     

Circadian rhythmicity of vasopressin levels in the cerebrospinal fluid of suprachiasmatic nucleus-lesioned and -grafted rats

Transplantation of the fetal suprachiasmatic nucleus (SCN) in arrhythmic SCN-lesioned rats can reinstate circadian drinking rhythms in 40% to 50% of the cases. In the current article, it was investigated whether the failure in the other rats could be due to the absence of a circadian rhythm in the grafted SCN, using a circadian vasopressin (VP) rhythm in the cerebrospinal fluid (CSF) as the indicator for a rhythmic SCN. CSF was sampled in continuous darkness from-intact control rats and SCN-lesioned and -grafted rats. VP could be detected in all samples, with concentrations of 15 to 30 pg/ml in the control rats and 5 to 15 pg/ml in the grafted rats. A circadian VP rhythm with a two- to threefold difference between peak and nadir values was found in all 7 control rats but in only 4 of 13 experimental rats, despite the presence of a VP-positive SCN in all grafts. A circadian VP rhythm was present in 2 drinking rhythm-recovered rats (6 of 13) and in 2 nonrecovery rats. Apparently, in these latter rats, the failure of the grafted SCN to restore a circadian drinking rhythm cannot be attributed to a lack of rhythmicity in the SCN itself. Thus, the presence of a rhythmic grafted SCN, as is deduced from a circadian CSF VP rhythm, appears not to be sufficient for restoration of a circadian drinking rhythm in SCN-lesioned arrhythmic rats.     

Interruption of the rat circadian clock by short light-dark cycles

Ninety male Sprague-Dawley rats were exposed to 1:1-h light-dark (LD1:1) cycles for 50-90 days, and then they were released into constant darkness (DD). During LD1:1 cycles, behavioral rhythms were gradually disintegrated, and circadian rhythms of locomotor activity, drinking, and urine 6-sulfatoxymelatonin excretion were eventually abolished. After release into DD, 44 (49%) rats showed arrhythmic behavior for >10 days. Seven (8%) animals that remained arrhythmic for >50 days in DD were exposed to brief light pulses or 12:12-h light-dark cycles, and then they restored their circadian rhythms. These results indicate that the circadian clock was stopped, at least functionally, by LD1:1 cycles and was restarted by subsequent light stimulation.     

Perspectives in chronobiology of air pollution

In a series of experiments, male and female Sprague Dawley rats, kept in light (L) from 06(00) to 18(00) alternating with darkness (LD 12:12) inhaled different concentrations of carbon monoxide (50-1,700 ppm) at each of two test times, 12 h apart. A decrease in flow of CO2 (VCO2) resulting from CO inhalation was greater in the active dark (D) than resting light (L) span. Experimental hypoxic mortality of male and female mice also shows circadian variations, being greater in the D than in the L span. Moreover, a difference of mortality was observed betwen hypoxic exposures performed at 12(00) (in LD or DL) and hypoxic exposures performed at 00(00) (in LD or DL). Such results await tests of any extent to which they model responses of human beings to air pollution. In human beings any external environmental circadian, circaseptan and circannual variations in air pollution as such may serve to variable extent as socioeconomic synchronizers of innate rhythms with a corresponding frequency, rather than as solely generators of time patterns in any physiopathologic response to air pollution.     

Day-night variation in the in vitro contractility of aorta and mesenteric and renal arteries in transgenic hypertensive rats

TGR(mREN2)27 (TGR) rats develop severe hypertension and an inverted circadian blood pressure profile with peak blood pressure in the daytime rest phase. The present study investigated the in vitro responsiveness of different arteries of TGR rats during day and night. Twelve-week-old TGR rats and normotensive Sprague-Dawley (SPRD) controls, synchronized to 12h light, 12h dark (LD 12:12) (light 07:00 19:00), were killed at 09:00 (during rest) and 21:00 (during activity), and endothelium-dependent relaxation by acetylcholine and vascular contraction by angiotensin II were studied by measuring isometric force in ring segments of abdominal aorta and mesenteric and renal arteries. In SPRD rats, consistent day-night variation was found, with greater responses to angiotensin II during the daytime rest span. In TGR rats, biological time-dependent differences were found in the renal vasculature, but not in the aorta and mesenteric artery. Relaxation of SPRD rat aorta and mesenteric artery by acetylcholine was greater at 09:00, whereas in TGR rats, day-night variation was absent (mesenteric artery) or inverted (aorta). In conclusion, based on the study of two time points, daynight variation in vascular contractility of aorta and mesenteric artery is blunted in TGR rats, whereas renal artery segments showed an unchanged daynight pattern compared to SPRD controls. (Chronobiology International, 18(4), 665 681, 2001)     

Differences in sleep, light, and circadian phase in offshore 18:00-06:00 h and 19:00-07:00 h shift workers

Complaints concerning sleep are high among those who work night shifts; this is in part due to the disturbed relationship between circadian phase and the timing of the sleep-wake cycle. Shift schedule, light exposure, and age are all known to affect adaptation to the night shift. This study investigated circadian phase, sleep, and light exposure in subjects working 18:00-06:00 h and 19:00-07:00 h schedules during summer (May-August). Ten men, aged 46+/-10 yrs (mean+/-SD), worked the 19:00-07:00 h shift schedule for two or three weeks offshore (58 degrees N). Seven men, mean age 41+/-12 yrs, worked the 18:00-06:00 h shift schedule for two weeks offshore (61 degrees N). Circadian phase was assessed by calculating the peak (acrophase) of the 6-sulphatoxymelatonin rhythm measured by radioimmunoassay of sequential urine samples collected for 72 h at the end of the night shift. Objective sleep and light exposure were assessed by actigraphy and subjective sleep diaries. Subjects working 18:00-06:00 h had a 6-sulphatoxymelatonin acrophase of 11.7+/-0.77 h (mean+/-SEM, decimal hours), whereas it was significantly later, 14.6+/-0.55 h (p=0.01), for adapted subjects working 19:00-07:00 h. Two subjects did not adapt to the 19:00-07:00 h night shift (6-sulphatoxymelatonin acrophases being 4.3+/-0.22 and 5.3+/-0.29 h). Actigraphy analysis of sleep duration showed significant differences (p=0.03), with a mean sleep duration for those working 19:00-07:00 h of 5.71+/-0.31 h compared to those working 18:00-06:00 h whose mean sleep duration was 6.64+/-0.33 h. There was a trend to higher morning light exposure (p=0.07) in the 19:00-07:00 h group. Circadian phase was later (delayed on average by 3 h) and objective sleep was shorter with the 19:00-07:00 h than the 18:00-06:00 h shift schedule. In these offshore conditions in summer, the earlier shift start and end time appears to favor daytime sleep.