Diurnal Profiles of Blood Glucose in Relation to Time of Administration of Melatonin in Male Spotted Munia (Lonchura punctulata)

The study was aimed at demonstration of the effect of a single acute dose of melatonin (0.5 mg/ 100 g body wt.) on the diurnal profile of blood glucose in male spotted munia in relation to the administration of hormone at the onset of light (i.e., at 06.00 h) or at the onset of darkness (i.e., at 18.00 h) under natural photoperiodic (~12L : 12D) conditions. Blood samples from all birds belonging to the control, sham-control (administered only with the vehicle of hormone, i.e., ethanol-saline 1:9 v/v), and melatonin treated groups were collected at four time points, i.e. 06.00 h, 12.00 h, 18.00 h, and 24.00 h, in a 24 hour cycle. The blood glucose levels in control and sham-control birds showed marked variation with regard to the time of sampling, with a mid-day peak and morning nadir. Exogenous melatonin induced a significant alteration in this diurnal pattern of blood glucose with a marked variation in relation to the time of administration of melatonin. While morning administration of melatonin resulted in hypoglycemia at 12.00 h and 24.00 h and hyperglycemia at 18.00 h, the response to evening injection of melatonin was only hypoglycemic at 24.00 h leaving the glycemic values at other time-points almost unaltered compared to the blood glucose levels in control and sham-control munias. The results of this investigation demonstrate for the first time that a schedule of morning administration of melatonin induces a more broad range of variations in the blood glucose levels than a schedule of evening administration does.     

Diurnal Profiles of Blood Glucose in Relation to Time of Administration of Melatonin in Male Spotted Munia (Lonchura punctulata)

The study was aimed at demonstration of the effect of a single acute dose of melatonin (0.5 mg/ 100 g body wt.) on the diurnal profile of blood glucose in male spotted munia in relation to the administration of hormone at the onset of light (i.e., at 06.00 h) or at the onset of darkness (i.e., at 18.00 h) under natural photoperiodic (~12L : 12D) conditions. Blood samples from all birds belonging to the control, sham-control (administered only with the vehicle of hormone, i.e., ethanol-saline 1:9 v/v), and melatonin treated groups were collected at four time points, i.e. 06.00 h, 12.00 h, 18.00 h, and 24.00 h, in a 24 hour cycle. The blood glucose levels in control and sham-control birds showed marked variation with regard to the time of sampling, with a mid-day peak and morning nadir. Exogenous melatonin induced a significant alteration in this diurnal pattern of blood glucose with a marked variation in relation to the time of administration of melatonin. While morning administration of melatonin resulted in hypoglycemia at 12.00 h and 24.00 h and hyperglycemia at 18.00 h, the response to evening injection of melatonin was only hypoglycemic at 24.00 h leaving the glycemic values at other time-points almost unaltered compared to the blood glucose levels in control and sham-control munias. The results of this investigation demonstrate for the first time that a schedule of morning administration of melatonin induces a more broad range of variations in the blood glucose levels than a schedule of evening administration does.     

Does melatonin have a time-dependent effect on brain and gill ionic metabolism in a teleost, Anabas testudineus (Bloch)?

Exogenous administration of 0.20, 0.40 and 0.60 microg/g body weight melatonin over a 24 hr cycle caused an inhibition of Na+, K+ ATPase activity in both brain and gills of A. testudineus. However, Ca2+ ATPase activity in the brain was significantly inhibited by the highest dose, and that in the gill at all the doses of melatonin. Evening injection of melatonin had an inhibitory effect on both brain and gill Na+ K+ and Ca2+ ATPase activity. Melatonin treatment in the morning for 12 hrs did not have an effect on brain Na+, K+ ATPase, while Ca2+ ATPase was inhibited. Similar treatment stimulated Na+, K+ and Ca2+ ATPase activity in the gills. Sodium, potassium and calcium ions in the gill were significantly reduced in the evening treated group while no change was observed in the morning melatonin injected group. The results suggest that melatonin elicits a time-dependent effect on the enzymes and ionic content in the brain and gills of A. testudineus.     

Different mechanisms of phase delays and phase advances of the circadian rhythm in rat pineal N-acetyltransferase activity

The circadian rhythm in rat pineal N-acetyltransferase (NAT) activity, which drives the rhythm in melatonin production, is controlled by a pacemaker located in the suprachiasmatic nucleus of the hypothalamus. As the NAT rhythm has two well-defined phase markers--namely, the time of the evening activity rise and of the morning decline--it is suitable for studies of the entrainment of the pacemaker by environmental light. Phase delays of the NAT rhythm proceed more rapidly than phase advances. One day after a brief light pulse applied before midnight, or after a delay in evening lights-off, or a delay of a light-dark (LD) cycle, phase delays of the evening NAT rise result in almost corresponding delays of the morning NAT decline. Consequently, the NAT rhythm is phase-shifted, but its pattern does not change. One day after a brief light pulse applied past midnight, or after bringing forward morning lights-on, or after an advance of an LD cycle, the morning NAT decline is phase-advanced, but the evening rise is not phase-advanced at all or may even by phase-delayed. Consequently, the phase relationship between the evening NAT activity onset and the morning offset may be compressed considerably, and it may take several transient cycles before phase advances of the morning NAT decline are followed by corresponding advances of the evening NAT rise. Due to the phase-delaying effect of evening light on the NAT rise and to the phase-advancing effect of morning light on the NAT decline, the phase relationship between the NAT rise and the decline is compressed on long days and decompressed on short days. Different phase shifts of the evening NAT rise and of the morning decline, even in opposite directions, are consistent with the hypothesis of a complex, two-component (evening-morning, or E-M) pacemaker controlling the NAT rhythm. As the E-M phase relationship determines duration of the high night melatonin production, and the duration of the nocturnal melatonin pulse may convey information on daylength, the data are consistent with the internal coincidence model for photoperiodic time measurement.     

Melatonin reverses pinealectomy-induced decrease of benzodiazepine binding in rat cerebral cortex

Pinealectomy of rats resulted in significant depression of benzodiazepine receptors (assessed by [³H]flunitrazepam binding) in cerebral cortex 3–14 days after surgery without affecting their affinity significantly. A single s.c. injection of melatonin (800 μg/kg body wt) restored the depressed brain benzodiazepine receptor sites. Single melatonin injections (up to 1600 μg/kg) to intact rats did not affect brain benzodiazepine binding when injected at either morning or evening hours. Daily melatonin treatment to intact rats for 5 days augmented benzodiazepine receptor density in brain (morning injections) or its dissociation constant (evening injections). Melatonin added in vitro to rat cerebral cortex membranes only slightly depressed [³H]flunitrazepam binding at 100 μM concentrations. These results point out a link between pineal activity and benzodiazepine receptor function in rats. They also indicate that pharmacological doses of melatonin affect benzodiazepine binding sites in rat cerebral cortex.     

Reduced phase-advance of plasma melatonin after bright morning light in the luteal, but not follicular, menstrual cycle phase in premenstrual dysphoric disorder: an extended study

The authors previously observed blunted phase-shift responses to morning bright light in women with premenstrual dysphoric disorder (PMDD). The aim of this study was to determine if these findings could be replicated using a higher-intensity, shorter-duration light pulse and to compare these results with the effects of an evening bright-light pulse. In 17 PMDD patients and 14 normal control (NC) subjects, the authors measured plasma melatonin at 30-min intervals from 18:00 to 10:00 h in dim (<30 lux) or dark conditions the night before (Night 1) and after (Night 3) a bright-light pulse (administered on Night 2) in both follicular and luteal menstrual cycle phases. The bright light (either 3000 lux for 6 h or 6000 lux for 3 h) was given either in the morning (AM light), 7 h after the dim light melatonin onset (DLMO) measured the previous month, or in the evening (PM light), 3 h after the DLMO. In the luteal, but not in the follicular, phase, AM light advanced melatonin offset between Night 1 and Night 3 significantly less in PMDD than in NC subjects. The effects of PM light were not significant, nor were there significant effects of the light pulse on melatonin measures of onset, duration, peak, or area under the curve. These findings replicated the authors' previous finding of a blunted phase-shift response to morning bright light in the luteal, but not the follicular, menstrual cycle phase in PMDD compared with NC women, using a brighter (6000 vs. 3000 lux) light pulse for a shorter duration (3 vs. 6 h). As the effect of PM bright light on melatonin phase-shift responses did not differ between groups or significantly alter other melatonin measures, these results suggest that in PMDD there is a luteal-phase subsensitivity or an increased resistance to morning bright-light cues that are critical in synchronizing human biological rhythms. The resulting circadian rhythm malsynchonization may contribute to the occurrence of luteal phase depressive symptoms in women with PMDD.     

Diurnal Profiles of Serum Triiodothyronine and Thyroxine Levels: A Study in Male Roseringed Parakeets (Psittacula krameri) Following Exogenous Administration of Melatonin

This study demonstrates that under subtropical environmental conditions the circulating levels of triiodothyronine (T 3 ) and thyroxine (T 4 ) in adult male roseringed parakeets undergo parallel changes according to a diurnal cycle with a trough in the early morning and a peak in the evening. Chronic afternoon administration of melatonin (25 µg/ 100 g body wt./ day for 30 consecutive days) abolishes time-bound changes in the concentrations of T 3 by suppressing its evening peak, but does not abolish the diurnal rhythm of T 4 . Exogenous melatonin, however, causes a significant increase in the evening value of serum T 4 and a decrease in its value at midnight resulting in phase-shifting of the diurnal fluctuations of T 4 compared to that in the control birds. It appears that exogenous melatonin can alter the diurnal profiles of serum thyroid hormones in a wild psittacine bird.     

Diurnal Profiles of Serum Triiodothyronine and Thyroxine Levels: A Study in Male Roseringed Parakeets (Psittacula krameri) Following Exogenous Administration of Melatonin

This study demonstrates that under subtropical environmental conditions the circulating levels of triiodothyronine (T 3) and thyroxine (T 4) in adult male roseringed parakeets undergo parallel changes according to a diurnal cycle with a trough in the early morning and a peak in the evening. Chronic afternoon administration of melatonin (25 µg/ 100 g body wt./ day for 30 consecutive days) abolishes time-bound changes in the concentrations of T 3 by suppressing its evening peak, but does not abolish the diurnal rhythm of T 4. Exogenous melatonin, however, causes a significant increase in the evening value of serum T 4 and a decrease in its value at midnight resulting in phase-shifting of the diurnal fluctuations of T 4 compared to that in the control birds. It appears that exogenous melatonin can alter the diurnal profiles of serum thyroid hormones in a wild psittacine bird.     

Chronopharmacology of Oral Nitrates in Healthy Subjects

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5-monitrate (IS-5-MN, 60 mg) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (t_max of 0.9 h) than in the evening (t_max of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chrono-kinetics were observed after application of the slow-release formulation of IS-5-MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.     

Reduced Phase-Advance of Plasma Melatonin After Bright Morning Light in The Luteal,But Not Follicular,Menstrual Cycle Phase in Premenstrual Dysphoric Disorder: An Extended Study

The authors previously observed blunted phase-shift responses to morning bright light in women with premenstrual dysphoric disorder (PMDD). The aim of this study was to determine if these findings could be replicated using a higher-intensity, shorter-duration light pulse and to compare these results with the effects of an evening bright-light pulse. In 17 PMDD patients and 14 normal control (NC) subjects, the authors measured plasma melatonin at 30-min intervals from 18:00 to 10:00?h in dim (<30 lux) or dark conditions the night before (Night 1) and after (Night 3) a bright-light pulse (administered on Night 2) in both follicular and luteal menstrual cycle phases. The bright light (either 3000 lux for 6?h or 6000 lux for 3?h) was given either in the morning (AM light), 7?h after the dim light melatonin onset (DLMO) measured the previous month, or in the evening (PM light), 3?h after the DLMO. In the luteal, but not in the follicular, phase, AM light advanced melatonin offset between Night 1 and Night 3 significantly less in PMDD than in NC subjects. The effects of PM light were not significant, nor were there significant effects of the light pulse on melatonin measures of onset, duration, peak, or area under the curve. These findings replicated the authors’ previous finding of a blunted phase-shift response to morning bright light in the luteal, but not the follicular, menstrual cycle phase in PMDD compared with NC women, using a brighter (6000 vs. 3000 lux) light pulse for a shorter duration (3 vs. 6?h). As the effect of PM bright light on melatonin phase-shift responses did not differ between groups or significantly alter other melatonin measures, these results suggest that in PMDD there is a luteal-phase subsensitivity or an increased resistance to morning bright-light cues that are critical in synchronizing human biological rhythms. The resulting circadian rhythm malsynchonization may contribute to the occurrence of luteal phase depressive symptoms in women with PMDD. (Author correspondence: bparry@ucsd.edu)     

Growth Hormone and Prolactin Action in a Teleost Anabas testudineus (Bloch): Effect of the Time of Administration

Circadian rhythms play a very important role on metabolic process and have considerable effects on growth, especially in ectotherms. Like variation in hormone levels, the sensitivity of target cells may show diurnal or seasonal fluctuations. The aim of this study was to compare the effects of morning versus evening injections of growth hormone and prolactin on malic enzyme, glucose-6-phosphate dehydrogenase, isocitrate dehydrogenase, aspartate aminotransferase, alanine aminotransferase and Na⁺,K⁺-ATPase in a teleost Anabas testudineus. Activities of malic enzyme, glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase of the two control groups themselves differ significantly at morning and evening. Early morning administration of growth hormone increases malic enzyme, glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase activities while evening administration of growth hormone does not effect these enzymes. Transaminase activities were stimulated by morning and evening administration of GH and PRL. Na⁺,K⁺-ATPase activity was stimulated by morning administration and inhibited by evening treatment of both hormones. The results reveal that a given hormone may provide a different message to the target tissues at different periods of the day.     

Regulation of the pineal melatonin concentration in the rat (Rattus norvegicus) and in the Djungarian hamster (Phodopus sungorus)

1. Rapid changes of melatonin concentration in pineals of rats (Rattus norvegicus) after isoproterenol administration or in the course of a day were accompanied by parallel changes of N-acetyltransferase but not of hydroxyindole-O-methyltransferase activity. 2. In pineals of Djungarian hamsters (Phodopus sungorus) the evening and morning melatonin changes were also parallel with N-acetyltransferase changes. 3. In both species, melatonin concentration during its rise had approached the maximum earlier than N-acetyltransferase reached its highest activity. 4. It is proposed that the N-acetyltransferase rhythm drives the melatonin rhythm both in rats and in Djungarian hamsters; the maximum melatonin production may, however, depend also on hydroxyindole-O-methyltransferase activity and substrate concentration.     

Chronopharmacology of Oral Nitrates in Healthy Subjects

The pharmacokinetics and the hemodynamic effects (blood pressure, heart rate) of oral organic nitrates have been investigated in healthy subjects after oral single-dose application either in the morning or in the evening. Isosorbide-5- monitrate (IS-SMN, 60 rng) was administered as an immediate-release tablet or as a slow-release formulation. Isosorbide dinitrate (ISDN, 20 mg) was ingested as an immediate-release tablet. After administration of IS-5-MN as an immediate-release tablet, the drug was more rapidly absorbed in the morning (t_max of 0.9 h) than in the evening (t_max of 2.1 h). The rapid absorption led to more pronounced effects in the morning, at which time maximum drug concentrations occurred at the same time as peak effects were observed. After evening administration, however, peak effects were in advance of the maximum drug concentrations. No chronokinetics were observed after application of the slow-release formulation of IS-5- MN. In accordance with the results of the immediate-release formulation, peak effects of the slow-release preparation occurred significantly earlier than peak drug concentrations after evening than after morning dosing. ISDN bioavailability was higher after morning than after evening administration and hemodynamic effects were more pronounced in the evening than in the morning. These results show that daily variations in pharmacokinetics and/or hemodynamic effects can be observed with oral nitrates. In addition, galenic formulation can influence the time-specified pharmacokinetics of IS-5-MN.     

Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion

To systematically determine the effects of daytime exposure to sleep in darkness on human circadian phase, four groups of subjects participated in 4-day studies involving either no nap (control), a morning nap (0900-1500), an afternoon nap (1400-2000), or an evening nap (1900-0100) in darkness. Except during the scheduled sleep/dark periods, subjects remained awake under constant conditions, i.e., constant dim light exposure (36 lx), recumbence, and caloric intake. Blood samples were collected at 20-min intervals for 64 h to determine the onsets of nocturnal melatonin and thyrotropin secretion as markers of circadian phase before and after stimulus exposure. Sleep was polygraphically recorded. Exposure to sleep and darkness in the morning resulted in phase delays, whereas exposure in the evening resulted in phase advances relative to controls. Afternoon naps did not change circadian phase. These findings indicate that human circadian phase is dependent on the timing of darkness and/or sleep exposure and that strategies to treat circadian misalignment should consider not only the timing and intensity of light, but also the timing of darkness and/or sleep.     

Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase

To examine the immediate phase-shifting effects of high-intensity exercise of a practical duration (1 h) on human circadian phase, five groups of healthy men 20-30 yr of age participated in studies involving no exercise or exposure to morning, afternoon, evening, or nocturnal exercise. Except during scheduled sleep/dark and exercise periods, subjects remained under modified constant routine conditions allowing a sleep period and including constant posture, knowledge of clock time, and exposure to dim light intensities averaging (+/-SD) 42 +/- 19 lx. The nocturnal onset of plasma melatonin secretion was used as a marker of circadian phase. A phase response curve was used to summarize the phase-shifting effects of exercise as a function of the timing of exercise. A significant effect of time of day on circadian phase shifts was observed (P < 0.004). Over the interval from the melatonin onset before exercise to the first onset after exercise, circadian phase was significantly advanced in the evening exercise group by 30 +/- 15 min (SE) compared with the phase delays observed in the no-exercise group (-25 +/- 14 min, P < 0.05). Phase shifts in response to evening exercise exposure were attenuated on the second day after exercise exposure and no longer significantly different from phase shifts observed in the absence of exercise. Unanticipated transient elevations of melatonin levels were observed in response to nocturnal exercise and in some evening exercise subjects. Taken together with the results from previous studies in humans and diurnal rodents, the current results suggest that 1) a longer duration of exercise exposure and/or repeated daily exposure to exercise may be necessary for reliable phase-shifting of the human circadian system and that 2) early evening exercise of high intensity may induce phase advances relevant for nonphotic entrainment of the human circadian system.     

CISPLATIN-INDUCED VOMITING DEPENDS ON CIRCADIAN TIMING

We examined whether the clock time of cisplatin plus antiemetic and diuretic administration affects the amount of cisplatin-associated emesis and severity of renal toxicity. We treated 22 patients with urogenital cancer with two courses of chemotherapy containing 70 mg/m² of cisplatin. Cisplatin together with furosemide was administered in the morning (05:00) or evening (17:00) during two courses 1 month apart in a crossover fashion. Ondansetron was given either before or after cisplatin to control nausea and vomiting. The number of vomiting episodes, serum creatinine, serum urea nitrogen (BUN), creatinine clearance, and urinary β-N-acetyl glucosamidase (NAG) concentration were evaluated before and after each treatment course. Regardless of the timing of ondansetron, morning compared to evening cisplatin was always associated with greater vomiting in the first treatment course. However, prophylactic administration of ondansetron markedly diminished the impact of the clock time of cisplatin administration. Serum creatinine transiently decreased rather than increased 14 days after cisplatin and furosemide administration, while NAG excretion increased 3 days after cisplatin and furosemide administration. In the first course, serum creatinine levels were similar regardless of the clock time of cisplatin and furosemide administration. However, in the second course, serum creatinine rose in patients given evening cisplatin and furosemide, while it remained unchanged in those given morning cisplatin and furosemide. Moreover, the first course morning cisplatin and furosemide treatment was associated with less change in NAG excretion (less kidney toxicity) than the first course of evening cisplatin and furosemide treatment. The second course evening cisplatin and furosemide treatment was associated with an increase in NAG excretion compared to the first course of treatment, while morning cisplatin and furosemide treatment in the second course showed less change in NAG excretion compared to the first course. The clock time of cisplatin administration had an impact on the frequency of emesis. Prophylactic ondansetron, however, diminished the time-of-day dependency of cisplatin-induced vomiting. Administration of cisplatin and furosemide in the morning rather than evening appears to cause less renal damage, and this damage may be further reduced with aggressive hydration and routine administration of furosemide. (Chronobiology International, 18(5), 851-863, 2001)     

Lack of a time-dependent effect of melatonin on radiation-induced apoptosis in cultured rat lymphocytes

Ionizing radiation is widely used for the treatment of solid tumors and it is thought to act by directly targeting tumor clonogens, also known as stem cells. Apoptosis is a genetically programmed mechanism of cell death often characterized by internucleosomal DNA cleavage. Although it has been previously shown that lymphocytes readily undergo apoptosis in patients receiving anticancer drugs or treatment with ionizing radiation, this is the first study to investigate the influence of radiotherapy and melatonin on apoptosis in rat lymphocytes at two different times of the day. Melatonin, a free radical scavenger, is an endogenous neurohormone predominantly synthesized in and secreted by the pineal gland. It has been shown that melatonin inhibits apoptosis in normal cells but it increases the rate of apoptosis in various cancer cells. Therefore, in the present study, the effect of melatonin on apoptosis in cultured lymphocytes was studied after total body irradiation (TBI) was given to rats in the morning (1 HALO) or evening (13 HALO) with morphological and DNA fragmentation analysis. Two-way analysis of variance (ANOVA) revealed that radiation increased the rate of apoptosis in rat lymphocytes after TBI, and melatonin treatment did not reduce the rate of apoptosis after TBI at either time point. We conclude that the lack of an effect of melatonin on the apoptosis rate in rat lymphocytes might be due to the dose-dependent effect of melatonin, the time course of apoptosis investigated, or the cell type in which apoptosis was examined.     

Annual testicular cycle of the lizard Anolis carolinensis: effects of pinealectomy and melatonin

The effects of pinealectomy and exogenous melatonin treatment on the reproductive system of male anoles were examined at several different times of year. In September pinealectomy of anoles exposed to either a stimulatory LD 14:10 light cycle or a nonstimulatory LD 10:14 light cycle induced significant testicular growth and development over that observed in sham-operated anoles. At a nonphotosensitive time of year (December) pinealectomy also had a significant progonadal effect but no effect of pinealectomy was seen in February-March. Daily melatonin injections given either in the morning or afternoon (or both) failed to block gonadal growth either (1) in sham-operated or pinealectomized anoles exposed to LD 14:10 in the fall or (2) in pinealectomized lizards exposed to LD 10:14 in the fall. Continuous melatonin administration via subcutaneous silastic implants blocked the progonadal effects of pinealectomy in the winter (December). The results show that pinealectomy can have significant progonadal effects; these effects are seasonal but can encompass phases of the annual testicular cycle which are either photoperiod-dependent or temperature-dependent; and melatonin may be a reproductively active factor involved.     

Alteration of internal circadian phase relationships after morning versus evening carbohydrate-rich meals in humans

The effects of a single morning and evening carbohydrate-rich meal for 3 consecutive days on circadian phase of core body temperature (CBT), heart rate, and salivary melatonin rhythms were compared under controlled constant routine conditions. In 10 healthy young men entrained to a natural light-dark cycle with regular sleep timing, CBT and heart rate were significantly elevated for approximately 8 h after the last evening carbohydrate-rich meal (EM), and nocturnal melatonin secretion (as measured by salivary melatonin and urinary 6-sulphatoxymelatonin levels) was reduced, compared to the morning carbohydrate-rich meal (MM) condition. Thus, circadian phase could not be measured until the following day due to this acute masking effect. The day after the last meal intervention, MM showed a significant advanced circadian phase position in CBT (+59+/-12 min) and heart rate (+43+/-18 min) compared to EM. However, dim-light melatonin onset was not significantly changed (+15+/-13 min). The results are discussed with respect to central (light-entrainable) and peripheral (food-entrainable) oscillators. Food may be a zeitgeber in humans for the food-entrainable peripheral oscillators, but melatonin data do not support such a conclusion for the light-entrainable oscillator in the suprachiasmatic nucleus.     

Dosing Time Optimizes Sustained-Release Ketoprofen Treatment of Osteoarthritis

A double-blind randomized parallel-group trial was undertaken to evaluate the influence of the dosing time of sustained-release ketoprofen (SRK) on its acceptability and efficacy. The SRK was prescribed for 2 weeks (200 mg once a day) to 117 outpatients with osteoarthritis of the knee and/ or hip. One group received SRK in the morning (at 8 a.m.) and the other group in the evening (at 8 p.m.). The principal aim of the trial concerned the acceptability, whereas efficacy was its secondary aim. The principal trial criterion was defined as the number of spontaneous recordings of adverse effects. Results showed clearly that the acceptability of SRK in the SRK morning group was worse than that in the evening group (39% of patients with one or more adverse effects in the SRK morning group versus 19% in the evening group; p = 0.019). It is important to stress the difference concerning the number of adverse effects (48 for SRK morning group versus 23 for SRK evening group; p = 0.0234). The analgesic efficacy seemed to be similar, but one criterion was statistically significant: The duration of analgesic efficacy was more important for the SRK evening group than for the morning group (9.37 and 5.47 h, respectively; p = 0.001). To increase its acceptability, evening administration of SRK seems to be preferred over morning administration in osteoarthritis. However, other trials of the same type, assessing other antiinflammatory agents, are necessary before a general extrapolation of such results can be undertaken.