Chronopharmacokinetics and Chronotoxicity of Lithium in Mice Eating Normal and Low-Sodium Diets

The temporal aspects of the pharmacokinetics and toxicity of lithium were studied in mice eating normal and low-sodium diets. ICR male mice, housed under a lightrdark (LD; 12:12) cycle, were injected with variable doses of lithium chloride i.p. A circadian rhythm was found in lithium clearance after a single administration in mice eating the normal diet showed the maximum value in the early dark phase and the minimum in the early light phase. The repeated administration of lithium did not affect the rhythm of the pharmacokinetics of the drug under the LD cycle. Although the low-sodium diet significantly decreased the lithium clearance, it did not influence the rhythm of the clearance. Higher toxicity was demonstrated in mice injected with the drug at the time of day with lower lithium clearance in the single-dose study but not in the repeated-doses study, regardless of the diet conditions. The low-sodium diet increased the acute and chronic toxicity of lithium. The results indicate that there is a circadian rhythm of acute toxicity and clearance of lithium after a single dose or repeated administration of the drug in mice eating normal and low-sodium diets and that the low-sodium diet increases lithium toxicity by reducing the clearance of the drug without influencing the rhythm characteristics.     

Chronotoxicity of Sodium Valproate and Its Mechanisms in Mice: Dose-Concentration-Response Relationship

A significant circadian rhythm of acute toxicity was demonstrated in mice with intraperitoneal (i.p.) injection of sodium valproate (VPA). The role of pharmacokinetics on the rhythms of the toxicity and electroshock seizure (ES) threshold was investigated. ICR male mice, housed under a light-dark (12 :12) cycle, were injected intraperitoneally 1200 mg/kg for the acute toxicity study and 300 mg/kg for the anticonvulsant effect study. In the acute toxicity, the highest mortality was found when VPA was injected at 1700 and the lowest at 0900 or 0100. The time course of mean plasma and brain VPA concentrations after an injection of VPA was not different between mice injected at 1700 and mice injected at 0100. In the anticonvulsant effect, no significant circadian rhythm was demonstrated for both the ES threshold and the plasma VPA concentrations after i.p. Injection, although a significant rhythm has been reported for them after oral administration. The results suggest that the circadian rhythm in the mortality after an i.p. Injection of VPA may be due to the rhythm in the sensitivity of the central nervous system to the drug and that the mechanism underlying the rhythm of VPA acute toxicity is different from that of the anticonvulsant action of VPA. The route and the time of drug administration are essentially important to study the anticonvulsant effect and acute toxicity of VPA in mice.     

Influence of Feeding Schedule on Chronopharmacological Aspects of Gentamicin in Mice

The effects of the time of day of drug administration on the subchronic toxicity and pharmacokinetics of gentamicin, as well as the role of feeding schedule on circadian rhythms, were investigated in mice. ICR male mice were housed in a light-dark (LD) cycle (12:12) with food and water ad libitum (ALF) or under a time-restricted feeding (TRF) schedule (feeding time: 8 h during the light phase) for 1 day or 14 days before drug administration. The animals were given a single subcutaneous dose of gentamicin 180 mg/kg for the kinetic studies and subcutaneous doses of gentamicin 180 mg/kg/day for 14 days or 220 mg/kg/day for 18 days for the subchronic toxicity studies. A significant dosing-time dependency was shown for mortality and body weight loss, with higher values at midlight and lower ones at the middark (p > 0.05). A significant circadian rhythm was also found for gentamicin kinetics in ALF mice, with the highest clearance at middark and the lowest one at midlight (p > 0.01). The kinetic rhythm of gentamicin coincided well with the toxicity rhythm of the drug. The TRF schedule had a marked influence on the rhythms of gentamicin kinetics and toxicity, showing lowest clearance and higher toxicity at middark. The rhythm of subchronic toxicity of gentamicin seems to be due, at least in part, to the rhythm in kinetics and is strongly influenced by the feeding schedule. Thus, the timing of dosing is an important factor in the kinetics and the subchronic toxicity of gentamicin administration in mice, and the manipulation of feeding schedule can modify the rhythm of the toxicity by changing the rhythm of gentamicin kinetics.     

Chronopharmacokinetics of valproic acid following constant-rate administration in mice.

This study was carried out to investigate the circadian rhythm in the pharmacokinetics of valproic acid (VPA). ICR male mice, housed under a light-dark (12 h:12 h) cycle, were used in these studies. In the constant-rate administration study (536.3 or 1,072.6 micrograms/h), osmotic minipumps were implanted subcutaneously in mice. There was a significant circadian rhythm in plasma VPA concentrations: higher values were obtained in the light phase and lower values were found during the dark phase. A significant circadian rhythm also was shown for clearance (CL) of the drug: lower values were obtained in the light phase and higher values were demonstrated in the dark phase. In the intravenous administration study, VPA (50 mg/kg) was injected into a tail vein of the mice. Mean plasma VPA concentrations were significantly higher in mice injected with the drug at 1700 h than at 0100 h. The CL was higher, the volume of distribution (V) was larger, and the area under the curve (AUC) was smaller (p less than 0.05, respectively) in mice injected with the drug at 0100 h than at 1700 h. As the values of CL and V increased similarly during the dark period, there was no effect on half-life (t 1/2) and obviously on the elimination rate constant (K). These findings indicate that the circadian rhythms of plasma VPA concentrations observed after constant-rate administration are due to those of CL and V. To keep drug concentrations constant, the drug release rate from the osmotic minipump should be controlled according to the rhythm of drug pharmacokinetics.     

Orcadian Variation in Amikacin Clearance and Its Effects on Efficacy and Toxicity in Mice with and Without Immunosuppression

A once-daily dosage regimen has been recently recommended in the use of aminoglycoside antibiotics since they induce a postantibiotic effect. In choosing this regimen, one must determine the most appropriate time of day for administration of the drug. We investigated the effects of the timing of amikacin (AMK) administration on the kinetics, the efficacy against intraperitoneal infection with Pseudomonas aeruginosa, and the toxicity of AMK in mice with and without immijnosuppression. We found circadian variations in the kinetics, efficacy, and toxicity of the drug in mice. Male and female ICR mice, which were housed under a light-dark (12:12 h) cycle with free food and water intake, were injected subcutaneously with AMK sulfate 50 mg/kg body wt. There was a circadian variation in AMK clearance for both sexes with the maximum value in the dark phase and the minimum in the light phase after a single administration. When AMK 500 mg/kg/day was repeatedly administered once daily for 30 days, higher toxicity was demonstrated in mice injected with the drug at the time of day with lower AMK clearance, although no difference was demonstrated in the toxicity between the two time points with different AMK clearance when AMK 1,500 mg/kg was administered in a single dose. The ED₅₀ of AMK to cure the infected mice in the midlight phase (13:00 h) with lower clearance was significantly lower than that in the middark phase (01:00 h) with higher clearance. In contrast, the ED₅₀ in the early light phase (09:00 h) was significantly lower than that in the early dark phase (21:00 h), although AMK clearance was not different between these two different time points. In mice premedicated with cyclophosphamide to suppress immune functions, the difference in the ED₅₀ of AMK was still demonstrated between 13:00 and 01:00 h, but not between 09:00 and 21:00 h. The present study shows not only that there were circadian variations in both AMK clearance and toxicity after repeated administration, but also that there was a circadian variation in the efficacy of AMK in mice infected with P. aeruginosa. These results suggest that the timing of drug administration should be considered in pharmacotherapy with AMK and that the most appropriate time of administration in mice and nocturnal animals may be in the midlight (resting) phase. They also suggest that the ED₅₀ of AMK. against P. aeniginosa infection may be influenced not only by the circadian variation in pharmacokinetics but also by the variations in immune systems suppressed by cyclophosphamide.     

Orcadian Variation in Amikacin Clearance and Its Effects on Efficacy and Toxicity in Mice with and Without Immunosuppression

A once-daily dosage regimen has been recently recommended in the use of aminoglycoside antibiotics since they induce a postantibiotic effect. In choosing this regimen, one must determine the most appropriate time of day for administration of the drug. We investigated the effects of the timing of amikacin (AMK) administration on the kinetics, the efficacy against intraperitoneal infection with Pseudomonas aeruginosa, and the toxicity of AMK in mice with and without immijnosuppression. We found circadian variations in the kinetics, efficacy, and toxicity of the drug in mice. Male and female ICR mice, which were housed under a light-dark (12:12 h) cycle with free food and water intake, were injected subcutaneously with AMK sulfate 50 mg/kg body wt. There was a circadian variation in AMK clearance for both sexes with the maximum value in the dark phase and the minimum in the light phase after a single administration. When AMK 500 mg/kg/day was repeatedly administered once daily for 30 days, higher toxicity was demonstrated in mice injected with the drug at the time of day with lower AMK clearance, although no difference was demonstrated in the toxicity between the two time points with different AMK clearance when AMK 1,500 mg/kg was administered in a single dose. The ED₅₀ of AMK to cure the infected mice in the midlight phase (13:00 h) with lower clearance was significantly lower than that in the middark phase (01:00 h) with higher clearance. In contrast, the ED₅₀ in the early light phase (09:00 h) was significantly lower than that in the early dark phase (21:00 h), although AMK clearance was not different between these two different time points. In mice premedicated with cyclophosphamide to suppress immune functions, the difference in the ED₅₀ of AMK was still demonstrated between 13:00 and 01:00 h, but not between 09:00 and 21:00 h. The present study shows not only that there were circadian variations in both AMK clearance and toxicity after repeated administration, but also that there was a circadian variation in the efficacy of AMK in mice infected with P. aeruginosa. These results suggest that the timing of drug administration should be considered in pharmacotherapy with AMK and that the most appropriate time of administration in mice and nocturnal animals may be in the midlight (resting) phase. They also suggest that the ED₅₀ of AMK. against P. aeniginosa infection may be influenced not only by the circadian variation in pharmacokinetics but also by the variations in immune systems suppressed by cyclophosphamide.     

Chronic Administration of Imipramine and Lithium Changes the Phase-Angle Relationship Between the Activity and Core Body Temperature Circadian Rhythms in Rats

Evidence suggests that there is an association between the pathophysiology of depression and a disturbance of circadian rhythms. Accordingly, attention has focused on the possible effects of antidepressants on circadian rhythms. In the present study, we examined the effects of chronic administration of two clinically effective antidepressant agents, imipramine and lithium, on several circadian rhythms in the rat. Activity, core body temperature, and drinking rhythms were assessed in constant darkness (DD) and light-dark (LD) conditions. In DD, lithium significantly lengthened the circadian period of the activity, temperature, and drinking rhythms, while imipramine had no effect. In LD, both drugs significantly delayed the phase of the activity rhythm, but did not change that of the other two rhythms. As a result, the phase-angle differences between the activity and temperature rhythms significantly increased. Neither lithium nor imipramine produced any effect on the resynchronization of these rhythms after an 8-h delay in the LD cycle. These results indicate that although both drugs produced different effects on the circadian period of individual rhythms, both caused a relative phase advance of the temperature rhythm as compared to the activity rhythm, and this effect may be related to the similarity in their antidepressant effects. (Chronobiology International, 13(4), 251-259, 1996)     

Circadian Disorganization Alters Intestinal Microbiota

Intestinal dysbiosis and circadian rhythm disruption are associated with similar diseases including obesity, metabolic syndrome, and inflammatory bowel disease. Despite the overlap, the potential relationship between circadian disorganization and dysbiosis is unknown; thus, in the present study, a model of chronic circadian disruption was used to determine the impact on the intestinal microbiome. Male C57BL/6J mice underwent once weekly phase reversals of the light:dark cycle (i.e., circadian rhythm disrupted mice) to determine the impact of circadian rhythm disruption on the intestinal microbiome and were fed either standard chow or a high-fat, high-sugar diet to determine how diet influences circadian disruption-induced effects on the microbiome. Weekly phase reversals of the light:dark (LD) cycle did not alter the microbiome in mice fed standard chow; however, mice fed a high-fat, high-sugar diet in conjunction with phase shifts in the light:dark cycle had significantly altered microbiota. While it is yet to be established if some of the adverse effects associated with circadian disorganization in humans (e.g., shift workers, travelers moving across time zones, and in individuals with social jet lag) are mediated by dysbiosis, the current study demonstrates that circadian disorganization can impact the intestinal microbiota which may have implications for inflammatory diseases.     

Circadian variation in methotrexate toxicity in streptozotocin-induced diabetes mellitus rats

The effects of diabetes mellitus and circadian rhythm on pharmacokinetics or pharmacodynamics of drugs have been previously separately reviewed. In our previous study, a circadian rhythm has been described in the pharmacokinetics of MTX in streptozotocin-induced diabetes mellitus (SIDM) rats. The aim of the present study was to investigate the effects of circadian rhythm on the toxicity of MTX in SIDM rats. The hematologic parameters and serum folic acid levels were measured in control and SIDM groups before and after MTX administration to evaluate its toxicity. We observed that circadian rhythm in basal peripheral WBC counts disappeared after MTX administration in the first hour and were phase shifted on the fifth day. Circadian variations were not observed in the other blood cells. One hour after MTX administration, folic acid levels were high in both groups. However, a circadian rhythm was present only in the diabetic group. The alteration in the rhythm of WBC counts in diabetic rats may originate not only from the effect of MTX but also physiological alterations due to diabetes and/or the varying cell cycle entry rates in the hematopoetic stem cells.     

Lithium Chloride SCN Injection Alters the Orcadian Rhythm of Food Intake

Effect of lithium injections through chronically implanted cannulae into the bilateral suprachiasmatic nuclei (SCN) on the circadian rhythm of food intake was investigated in the rat. It was observed that the circadian rhythm was disrupted by injections of lithium at the beginning of the light as well as the dark phase of the LD cycle. In either case the percentage of the food consumed during the 12-hr light period increased while that during the dark period decreased without any significant change in the total daily intake. Disruptions in the circadian rhythm of food intake failed to show any dose-response relation. Injections of saline into the SCN or lithium into the nearby SCN area did not produce a disruption of the circadian rhythm of food intake.     

Disruption of Daily Rhythms by High-Fat Diet Is Reversible

In mammals a network of circadian clocks coordinates behavior and physiology with 24-h environmental cycles. Consumption of high-fat diet disrupts this temporal coordination by advancing the phase of the liver molecular clock and altering daily rhythms of eating behavior and locomotor activity. In this study we sought to determine whether these effects of high-fat diet on circadian rhythms were reversible. We chronically fed mice high-fat diet and then returned them to low-fat chow diet. We found that the phase of the liver PERIOD2::LUCIFERASE rhythm was advanced (by 4h) and the daily rhythms of eating behavior and locomotor activity were altered for the duration of chronic high-fat diet feeding. Upon diet reversal, the eating behavior rhythm was rapidly reversed (within 2 days) and the phase of the liver clock was restored by 7 days of diet reversal. In contrast, the daily pattern of locomotor activity was not restored even after 2 weeks of diet reversal. Thus, while the circadian system is sensitive to changes in the macronutrient composition of food, the eating behavior rhythm and liver circadian clock are specifically tuned to respond to changes in diet.     

Pharmacological effects of vinorelbine on body temperature and locomotor activity circadian rhythms in mice

The effects of vinorelbine (VRL) on the circadian rhythms in body temperature and locomotor activity were investigated in unrestrained B6D2F₁ mice implanted with radio-telemetry transmitters. A single intravenous VRL dose (24 or 12 mg/kg) was given at 7 h after light onset (HALO), a time of high VRL toxicity, and resulted in transient suppression of temperature and activity circadian rhythms in mice kept in light-dark (LD) 12h:12h. Such suppression was dose-dependent. It occurred within 1-5 d after VRL dosing. Recovery of both rhythms was partially complete within 5 d following the high dose and within 2 or 3 d after the low dose and was not influenced by suppression of photoperiodic synchronization by housing in continuous darkness. Moreover, VRL induced a dose-dependent relative decrease in amplitude and phase shift of the temperature circadian rhythm. The mesor and amplitude of the activity rhythm were markedly reduced following the VRL administration. The relevance of VRL dosing time was studied in mice housed in LD 12h:12h. Vinorelbine was injected weekly (20 mg/kg/injection) for 3 wk at 6 or 18 HALO. Vinorelbine treatment ablated the rest-activity and temperature rhythms 3-6 d after each dose, with fewer alterations after VRL dosing at 18 HALO compared to 6 HALO, especially for the body temperature rhythm. There was at least partial recovery 1 wk after dosing, suggesting the weekly schedule of drug treatment is acceptable for therapeutic purposes. Our findings demonstrate that VRL can transiently, yet profoundly, alter circadian clock function. Vinorelbine-induced circadian dysfunction may contribute to the toxicokinetics of this and possibly other anticancer drugs.     

Chronotoxicology of florfenicol

Sixty 3-month-old homozygote male mice were studied for circadian rhythmicity in the toxicity of florfenicol overdose. Animals were kept under a regimen of 12h light, 12h darkness (12:12 LD) with food and water available ad libitum. The LD50 (median lethal) dose was determined in a preliminary experiment and was administered to groups of 10 mice at six different clock times (hours) after light onset (HALO): 0, 4, 8, 12, 16, and 20 HALO. Cosinor analysis verified a statistically significant (P < .04) circadian rhythm in the toxic effect (mortality) of florfenicol. Mortality was greatest when the drug was injected 4h after the commencement of the activity span (16 HALO) and least when injected 4h after the start of the diurnal rest span (4 HALO). Mortality was 2.5 times greater when drug injection was given at 16 HALO than at 4 HALO.     

Suppression of circadian rhythms of pineal and testicular hormones following lithium treatment in normal and reversed light-dark cycles, constant light and constant dark in rats

The aim of the current investigation was to study the effect of lithium on circadian rhythms of pineal - testicular hormones by quantitations of pineal and serum serotonin, N-acetylserotonin and melatonin, and serum testosterone at four time points (06.00, 12.00, 18.00 and 24.00) of a 24-hr period under normal photoperiod (L:D), reversed photoperiod (D:L), constant light (L:L) and constant dark phase (D:D) in rats. Circadian rhythms were observed in pineal hormones in all the combinations of photoperiodic regimens, except in constant light, and in testosterone levels in all the photoperiodic combinations. Pineal and serum N-acetylserotonin and melatonin levels were higher than serotonin at night (24.00 hr), in natural L:D cycle, in reversed L:D cycle or similar to normal L:D cycle in constant dark phase, without any change in constant light. In contrast, testosterone level was higher in light phase (12.00 hr through 18.00 hr) than in the dark phase (24.00 hr through 06.00 hr) in normal L:D cycle, in reversed L:D cycle, similar to normal L:D cycle in constant dark (D:D), and reversed to that of the normal L:D cycle in constant light (L:L). Lithium treatment (2 mEq/kg body weight daily for 15 days) suppressed the magnitude of circadian rhythms of pineal and serum serotonin, N-acetylserotonin and melatonin, and testosterone levels by decreasing their levels at four time points of a 24-hr period in natural L:D or reversed D:L cycle and in constant dark (D:D). Pineal indoleamine levels were reduced after lithium treatment even in constant light (L:L). Moreover, lithium abolished the melatonin rhythms in rats exposed to normal (L:D) and reversed L:D (D:L) cycles, and sustained the rhythms in constant dark. But testosterone rhythm was abolished after lithium treatment in normal (L:D)/reversed L:D (D:L) cycle or even in constant light/dark. The findings indicate that the circadian rhythm exists in pineal hormones in alternate light - dark cycle (L:D/D:L) and in constant dark (D:D), but was absent in constant light phase (L:L) in rats. Lithium not only suppresses the circadian rhythms of pineal hormones, but abolishes the pineal melatonin rhythm only in alternate light - dark cycles, but sustains it in constant dark. The testosterone rhythm is abolished after lithium treatment in alternate light - dark cycle and constant light/dark. It is suggested that (a) normal circadian rhythms of pineal hormones are regulated by pulse dark phase in normal rats, (b) lithium abolishes pineal hormonal rhythm only in pulse light but sustains it in constant dark phase, and (c) circadian testosterone rhythm occurs in both pulse light or pulse dark phase in normal rats, and lithium abolishes the rhythm in all the combinations of the photoperiod. The differential responses of circadian rhythms of pineal and testicular hormones to pulse light or pulse dark in normal and lithium recipients are discussed.     

Behavioral characterization and modulation of circadian rhythms by light and melatonin in C3H/HeN mice homozygous for the RORbeta knockout

This study reports for the first time the effects of retinoid-related orphan receptors [RORbeta; receptor gene deletion RORbeta(C3H)(-/-)] in C3H/HeN mice on behavioral and circadian phenotypes. Pineal melatonin levels showed a robust diurnal rhythm with high levels at night in wild-type (+/+), heterozygous (+/-), and knockout (-/-) mice. The RORbeta(C3H)(-/-) mice displayed motor ("duck gait," hind paw clasping reflex) and olfactory deficits, and reduced anxiety and learned helplessness-related behaviors. Circadian rhythms of wheel-running activity in all genotypes showed entrainment to the light-dark (LD) cycle, and free running in constant dark, with RORbeta(C3H)(-/-) mice showing a significant increase in circadian period (tau). Melatonin administration (90 microg/mouse sc for 3 days) at circadian time (CT) 10 induced phase advances, while exposure to a light pulse (300 lux) at CT 14 induced phase delays of circadian activity rhythms of the same magnitude in all genotypes. In RORbeta(C3H)(-/-) mice a light pulse at CT 22 elicited a larger phase advance in activity rhythms and a slower rate of reentrainment after a 6-h advance in the LD cycle compared with (+/+) mice. Yet, the rate of reentrainment was significantly advanced by melatonin administration at the new dark onset in both (+/+) and (-/-) mice. We conclude that the RORbeta nuclear receptor is not involved in either the rhythmic production of pineal melatonin or in mediating phase shifts of circadian rhythms by melatonin, but it may regulate clock responses to photic stimuli at certain time domains.     

Regulation of Circadian and Acute Activity Levels by the Murine Suprachiasmatic Nuclei

The suprachiasmatic nuclei (SCN) coordinate the daily sleep-wake cycle by generating a circadian rhythm in electrical impulse frequency. While period and phase of the SCN rhythm have been considered as major output parameters, we propose that the waveform of the rhythm of the SCN also has significance. Using implanted micro-electrodes, we recorded SCN impulse frequency in freely moving mice and manipulated its circadian waveform by exposing mice to light-dark (LD) cycle durations ranging from 22 hours (LD 11∶11) to 26 hours (LD 13∶13). Adaptation to long T-cycles (>24 h) resulted in a trough in electrical activity at the beginning of the night while in short T-cycles (<24 h), SCN activity reached a trough at the end of night. In all T-cycle durations, the intensity of behavioral activity was maximal during the trough of SCN electrical activity and correlated negatively with increasing levels of SCN activity. Interestingly, small changes in T-cycle duration could induce large changes in waveform and in the time of trough (about 3.5 h), and accordingly in the timing of behavioral activity. At a smaller timescale (minutes to hours), we observed a negative correlation between SCN activity and behavioral activity, and acute silencing of SCN neurons by tetrodotoxin (TTX) during the inactive phase of the animal triggered behavioral activity. Thus, the SCN electrical activity levels appear crucially involved in determining the temporal profile of behavioral activity and controls behavior beyond the circadian time domain.     

Circadian Rhythm of Blood Ethanol Clearance Rates in Rats: Response to Reversal of the L/D Regimen and to Continuous Darkness and Continuous Illumination

Phase relationships of the circadian rhythms of blood ethanol clearance (metabolic) rates and body temperature were studied in rats successively exposed to 4 illumination regimens: LD (light from 0800-2000 hr), DL (light from 2000-0800 hr), constant darkness (DD) and, lastly, constant light (LL). After a 4-wk standardization to each regimen, body temperatures were taken at 9 × 4-hr intervals to establish baseline circadian profiles. One week later, groups (N = 8) received 1.5 g/kg ethanol (i.p.) at 6 equally spaced timepoints during a 24-hr span, when temperatures were again measured. Ethanol clearance rates were estimated from decreasing blood ethanol levels sampled every 20 min from 60-200 min after dosing, and the resultant elimination curves were subjected to cosinor analysis. These studies show for the first time that the high amplitude circadian rhythm in ethanol metabolism persists under constant conditions of illumination (DD and LL), demonstrating that it may well be a truly internal circadian rhythm and not a response to exogenous cues of the light/dark cycle. During both LD and DL, maximal and minimal ethanol clearance rates fell near the end of the dark and light phases, respectively, and followed circadian peak and trough control temperatures by approximately 6 hr. A fixed internal phase relationship between the core body temperature and the circadian rhythm in ethanol metabolism is demonstrated, thus establishing the rhythm in body temperature as a suitable and convenient internal marker rhythm for studies of the metabolism of low-to-moderate ethanol doses. These studies demonstrate that the phase relationships of blood ethanol clearance rate and body temperature can be manipulated by the illumination regimen selected, an observation of both basic and practical importance.     

Circadian locomotory rhythm and the influence of moulting in Australian field cricket nymphs

ABSTRACT. Evidence is presented for a circadian control of locomotory activity in the larval stadia of the cricket, Teleogryllus commodus Walker. Under light—dark cycles (LD), maximal activity occurs around the L/D transition and/or in the hours preceding it. Free-running rhythm patterns longer than 24 h are observed in constant light. Re-entrainment to phase advances in the LD cycle is also accompanied by several transient cycles. However, free-running rhythms under constant darkness or transients when exposed to LD cycle delays were not found. LD cycles during the eighth stadium set the phase of a free-running rhythm in the adult, even if the nymph does not show a rhythm. Nymphal activity is often erratic and is disrupted periodically by the moulting cycle, but moulting does not interrupt the operation of the circadian system. The daily timing of the moult itself is not under circadian control.     

Chronopharmacological Study of an Antimicrobial Agent,Norfloxacin, in the Rat

Circadian rhythms in physiological processes may affect pharmacological actions of drugs. The purpose of this study was to determine whether pharmacokinetics or acute lethality (LD 50) of norfloxacin, exhibited circadian rhythmicity. Female Sprague- Dawley prepuberal rats (weight 115.8 ± 10.2 g) synchronized with a 12-h-light/ 12-h-dark cycle (lights on 7:00h) were used throughout the study. Norfloxacin pharmacokinetics after intraperitoneal administration at 4:00, 10:00, 16:00 and 22:00h was characterized. Intraperitoneal norfloxacin LD 50 was administered at 2:00, 6:00, 10:00, 14:00, 18:00 and 22:00 h. Pharmacokinetic parameters and lethality percentages were analyzed by the cosinor method for the presence of circadian rhythmicity. The results showed evidence of circadian rhythmicity for norfloxacin k abs, t ½abs, t max, MRT abs, Cl t /f and AUC. Absorption was higher when the drug was administered during the rest (16:00 h) period, meanwhile elimination was higher when administered during the activity (22:00 h) period. No rhythmicity was determined for norfloxacin lethality. It is concluded that, in this study, time of administration modifies the pharmacokinetics of norfloxacin.