Chronopharmacokinetics of imipenem in the rat

There are no studies indicating a possible modification of imipenem pharmacokinetics related to the hour (i.e., circadian time) of its administration. The aim of this study was to evaluate the influence of different times of intramuscular imipenem administration on its disposition in Wistar AF EOPS rats. Four groups of eight animals were given a single intramuscular injection of 140 mg/kg of imipenem either at 10:00, 16:00, 22:00, or 04:00 h. Blood samples were collected 0.5, 1, 2, 3, 4, 6, and 8 h after drug injection, and the main pharmacokinetic parameters determined were C_max, T_max, elimination half-life (t_1/2), area under the concentration-versus-time curve (AUC), total serum clearance (CL/F), and volume of distribution (V/F). Circadian variation of C_max (49%), T_max (92%), and AUC (19%) was observed leading to variability of imipenem exposure. Clearance and volume of distribution were modified according to the circadian time of drug injection but did not reach statistical significance. The results suggest that varying the time of administration induces intra-individual variability.     

Clinical chronopharmacology in the elderly

The behavior and effects of medications may be modified in the elderly. Factors contributing to such alterations may involve differences in drug pharmacokinetics and response and/or social and economic factors that affect nutrition and compliance to medications. Many studies have been devoted to such factors, but most of them have not taken into account chronopharmacologic data. Indeed, drug-administration time constitutes an additional factor of variability in drug response in the elderly. Biological rhythm-dependent differences in the kinetics and dynamics of medications seem to be diminished or altered with aging. Chronopathological (rhythmic aspects of disease) data in the elderly are of particular importance, taking into account frequently associated diseases, such as chronic obstructive pulmonary disease, cancer, diabetes, glaucoma, hypertension, and inflammatory conditions, among others. Although some chronobiological data are available, chronopharmacologic phenomena have yet to be extensively investigated in the elderly. Most of the sparse studies concern drug chronokinetics, but the data found in the literature do not reveal a clear trend in the age-related changes. Chronokinetic variations in the elderly, compared to young adults, suggest an amplification of the administration-time effects, as demonstrated for digoxin; dampening, as demonstrated for indomethacin; or detection of administration-time effects only in aged but not in young subjects, as found for others medications. Additional studies are needed to better understand the influence of age on the chronokinetics of medications. Moreover, the literature on possible administration-time differences in drug dynamics in the elderly is also very sparse. Altered receptor and/or post-receptor properties and impaired sensitivity of homeostatic mechanisms have yet to be studied from a chronopharmacological point of view. Thus, additional studies are needed to properly understand how drug responses in the elderly may vary in relation to the circadian timing of medications.     

Chronopharmacological Study of Cephalexin in Dogs

Recent studies have identified a 24 h rhythm in the expression and function of PEPT1 in rats, with significantly higher levels during the nighttime than daytime. Similarly, temporal variations have been described in glomerular filtration rate and renal blood flow, both being maximal during the activity phase and minimal during the rest phase in laboratory rodents. The aim of this study was to assess the hypothesis that the absorption of the first‐generation cephalosporin antibiotic cephalexin by dogs would be less and the elimination would be slower after evening (rest span) compared to morning (activity span) administration, and whether such administration‐time changes could impair the medication's predicted clinical efficacy. Six (3 male, 3 female; age 4.83±3.12 years) healthy beagle dogs were studied. Each dog received a single dose of 25 mg/kg of cephalexin monohydrate per os at 10∶00 and 22∶00 h, with a two‐week interval of time between the two clock‐time experiments. Plasma cephalexin concentrations were determined by microbiological assay. Cephalexin peak plasma concentration was significantly reduced to almost 77% of its value after the evening compared to morning (14.52±2.7 vs. 18.77±2.8 µg/mL) administration. The elimination half‐life was prolonged 1.5‐fold after the 22∶00 h compared to the 10∶00 h administration (2.69±0.9 vs. 1.79±0.2 h). The area under the curve and time to reach peak plasma concentration did not show significant administration‐time differences. The duration of time that cephalexin concentrations remained above the minimal inhibitory concentrations (MIC) for staphylococci susceptiblity (MIC=0.5 µg/mL) was>70% of each of the 12 h dosing intervals (i.e., 10∶00 and 22∶00 h). It can be concluded that cephalexin pharmacokinetics vary with time of day administration. The findings of this acute single‐dose study require confirmation by future steady‐state, multiple‐dose studies. If such studies are confirmatory, no administration‐time dose adjustment is required to ensure drug efficacy in dogs receiving an oral suspension of cephalexin in a dosage of 25 mg/kg at 12 h intervals.     

MORNING-EVENING ADMINISTRATION TIME DIFFERENCES IN DIGOXIN KINETICS IN HEALTHY YOUNG SUBJECTS

Digoxin, frequently used in the treatment of congestive heart failure, has a very narrow therapeutic index. We studied the differences in digoxin pharmacokinetics when ingested in the morning versus evening. A single digoxin (0.25 mg) dose was given orally to the same group of 10 diurnally active healthy (6 male and 4 female) volunteers in the morning at 08:00 and evening at 20:00 in separate experiments scheduled 2 weeks apart. Blood samples were collected at specific times for 48h after each timed dose; digoxin was determined by radioimmunoassay (RIA). Maximum plasma concentration C_max; T_max, the time to reach C_max; area under plasma concentration curve AUC; and elimination half-time T_1/2 of digoxin were determined. T_max was statistically significantly shorter (54 min) following 08:00 dosing compared to 20:00 dosing (96 min). Although the C_max was higher after morning than evening dosing, it was not significantly so. No other parameter of digoxin pharmacokinetics except T_max exhibited administration time dependency. (Chronobiology International, 18(5), 841-849, 2001)     

MORNING-EVENING ADMINISTRATION TIME DIFFERENCES IN DIGOXIN KINETICS IN HEALTHY YOUNG SUBJECTS

Digoxin, frequently used in the treatment of congestive heart failure, has a very narrow therapeutic index. We studied the differences in digoxin pharmacokinetics when ingested in the morning versus evening. A single digoxin (0.25 mg) dose was given orally to the same group of 10 diurnally active healthy (6 male and 4 female) volunteers in the morning at 08:00 and evening at 20:00 in separate experiments scheduled 2 weeks apart. Blood samples were collected at specific times for 48h after each timed dose; digoxin was determined by radioimmunoassay (RIA). Maximum plasma concentration C_max; T_max, the time to reach C_max; area under plasma concentration curve AUC; and elimination half-time T_1/2 of digoxin were determined. T_max was statistically significantly shorter (54 min) following 08:00 dosing compared to 20:00 dosing (96 min). Although the C_max was higher after morning than evening dosing, it was not significantly so. No other parameter of digoxin pharmacokinetics except T_max exhibited administration time dependency. (Chronobiology International, 18(5), 841–849, 2001)     

Chronopharmacokinetics and Cardiovascular Effects of Nifedipine

Orcadian phase dependency in pharmacokinetics and hemodynamic effects on blood pressure and heart rate of different galenic formulations of nifedipine (immediate-release, sustained-release, and i.v. solution) were studied in healthy subjects or in hypertensive patients. Pharmacokinetics of immediate-release but not sustained-release and i.v. nifedipine were dependent on time of day: immediate-release nifedipine had higher C_max (peak concentration) and shorter t_max (time-to-peak concentration) after morning than evening application, and bioavailibility in the evening was reduced by about 40%. Orcadian rhythm in estimated hepatic blood flow as determined by indocyanine green kinetics may contribute to these chronokinetics. A circadian time dependency was also found in nifedipine-induced effects on blood pressure and heart rate as monitored by 24-h ambulatory blood pressure measurements. In conclusion, the dose response relationship of oral nifedipine is influenced by the circadian organization of the cardiovascular system as well as by the galenic drug formulation.     

Chronopharmacokinetics and Cardiovascular Effects of Nifedipine

Orcadian phase dependency in pharmacokinetics and hemodynamic effects on blood pressure and heart rate of different galenic formulations of nifedipine (immediate-release, sustained-release, and i.v. solution) were studied in healthy subjects or in hypertensive patients. Pharmacokinetics of immediate-release but not sustained-release and i.v. nifedipine were dependent on time of day: immediate-release nifedipine had higher C_max (peak concentration) and shorter t_max (time-to-peak concentration) after morning than evening application, and bioavailibility in the evening was reduced by about 40%. Orcadian rhythm in estimated hepatic blood flow as determined by indocyanine green kinetics may contribute to these chronokinetics. A circadian time dependency was also found in nifedipine-induced effects on blood pressure and heart rate as monitored by 24-h ambulatory blood pressure measurements. In conclusion, the dose response relationship of oral nifedipine is influenced by the circadian organization of the cardiovascular system as well as by the galenic drug formulation.     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

Interindividual Differences in Chronopharmacologic Effects of Drugs: A Background for Individualization of Chronotherapy

In order to optimize chronotherapeutic schedules (designs), we examined the interindividual differences in chronopharmacologic effects of drugs with consideration of the following three factors: (a) inherited factors of direct relevance to chronopharmacology (genetic variability, gender-related differences) as well as age-related differences; (b) interindividual difference in chronoeffective-ness related to disease (e.g., various types and stages of cancer, affective disorders, etc.) as well as to drug-dependent alteration (phase shifts, distortion) of biological rhythms; and (c) means to solve problems resulting from the need of individualization in chronotherapy. These involve the use of circadian marker rhythms (MR) whose characteristics (peak or trough time, amplitude, etc.) can be precisely quantified and thus are applicable as a reference system for physiologic, pathologic, pharmacologic, and therapeutic uses. The MR has to be specific and pertinent and must be easily monitored and documented. This approach can be further advanced by the use of a battery of MRs rather than a single MR. Other suggested means relate to the fact that chronobiotics (agents capable of influencing parameters of a set of biological rhythms) should be considered (e.g., corticoids and adrenocorticotropic hormone) and/or to the subject's synchronization should be enforced by “conventional” zeitgebers (e.g., bright light, physical activity).     

CHRONOKINETICS OF CEFTAZIDIME AFTER INTRAMUSCULAR ADMINISTRATION TO DOGS

Ceftazidime, a third-generation cephalosporin, is widely used for the treatment of Pseudomonas aeruginosa infections. The aims of the present study were to characterize the pharmacokinetics of ceftazidime and to estimate the T?>?MIC against P. aeruginosa, after its intramuscular (im) administration at two different dosing times (08:30?h and 20:30?h) to dogs, in order to determine whether time-of-day administration modifies ceftazidime pharmacokinetics and/or predicted clinical antipseudomonal efficacy. Six female healthy beagle dogs were administered ceftazidime pentahydrate by the intramuscular route in a single dose of 25?mg/kg at both 08:30 and 20:30?h, two weeks apart. Plasma ceftazidime concentrations were determined by microbiological assay. Pharmacokinetic parameters and time above the minimum inhibitory concentration (T?>?MIC) and 4xMIC for Pseudomonas aeruginosa were calculated from the disposition curve of each dog. No differences between the daytime and nighttime administrations were found for the main pharmacokinetic parameters, including C_max, t_max, t_{½ λ}, AUC, and MRT; however, the high interindividual variability shown by these values and the small number of individuals may account for this lack of difference. Rate of absorption (k_a) was significantly higher after the 20:30?h than 08:30?h administration. No significant differences between T?>?MIC were found when comparing the 08:30?h and 20:30?h administrations. Mean T?>?MIC values predicted a favorable bacteriostatic effect for all susceptible strains of P. aeruginosa for the 12?h dosing interval at both dosing times. Our results suggest that similar antipseudomonal activity may be expected when ceftazidime is administered at 8:30 and 20:30?h; however, as only two timepoints of drug administration were explored, we are unable to draw any conclusions for other treatment times during the 24?h. (Author correspondence: rebuelto@fvet.uba.ar).     

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.     

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.     

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.     

Circadian Rhythm of Irinotecan Tolerability in Mice

The toxicity of irinotecan (CPT-11), a topoisomerase-I inhibitor largely used in cancer patients, was investigated as a function of the circadian time of its administration in mice, with mortality, body weight loss, leukopenia, neutropenia, intestinal lesions, and bone marrow cell cycle phase distribution as end points. Four experiments were performed on a total of 773 male mice standardized with 12 h light/12 h darkness. Irinotecan was administered daily for 4 or 10 consecutive days (D1-4 and D1-10, respectively, in different experiments) at one of six circadian stages expressed in hours after light onset (HALO). The survival curves differed significantly as a function of the dosage and circadian time of drug administration by the D1-10 schedule, with 70% survival at 7 or 11 HALO and 51% at 19 or 23 HALO ( p = 0.039 from log rank test). CPT-11 administration at 19 or 23 HALO resulted in (1) greatest mean body weight loss at nadir; (2) most severe colic and bone marrow lesions and/or slowest recovery; and (3) deepest neutropenia nadir and/or slowest hematologic recovery. These circadian treatment time-related differences were statistically validated. The bone marrow cell cycle data revealed a four to eight-fold larger G2-M phase arrest following irinotecan administration at 19 or 23 HALO in comparison to the other times of drug administration, apparently representative of the repair of more extensive DNA damage ( p < 0.001 from ANOVA) when the medication was given at these circadian times. Overall, CPT-11 was better tolerated by mice treated during the light (animals’ rest) span. The results support the administration of CPT-11 to cancer patients in the second half of the night, during sleep, in order to improve drug tolerability.     

Effects of a seven-day continuous infusion of ropivacaine on circadian rhythms in the rat

The present study was conducted to evaluate the effect of a 7 d continuous infusion of ropivacaine on the 24 h rhythms of body temperature, heart rate, and locomotor activity. After an initial 7 d baseline, rats were randomly divided into two groups of 4 rats each to receive ropivacaine or saline via an osmotic pump for 7 consecutive days. The pumps were removed thereafter and observed during a 7 d recovery span. The studied circadian rhythms were measured by radiotelemetry throughout each of the 7 d periods. An additional group of 4 rats was studied under the same experimental conditions to assess the plasma levels of ropivacaine on days 3 and 8 following pump implantation. Our results indicate that ropivacaine does not induce loss of the circadian rhythms of body temperature, heart rate, or locomotor activity; a prominent period of 24 h was found for all variables in all animals, before, during, and after ropivacaine treatment. However, ropivacaine treatment did modify some characteristics of the rhythms; it increased the MESOR (24 h mean) of the heart rate and locomotor activity rhythms and advanced the acrophase (peak time) of the locomotor activity circadian rhythm. The present study indicates that the circadian rhythms of heart rate and locomotor activity are modified after continuous infusion of ropivacaine, which is of particular interest, given the potential cardiotoxicity of this local anesthetic agent.     

From circadian rhythms to cancer chronotherapeutics

Mammalian circadian rhythms result from a complex organization involving molecular clocks within nearly all “normal” cells and a dedicated neuroanatomical system, which coordinates the so-called “peripheral oscillators.” The core of the central clock system is constituted by the suprachiasmatic nuclei that are located on the floor of the hypothalamus. Our understanding of the mechanisms of circadian rhythm generation and coordination processes has grown rapidly over the past few years. In parallel, we have learnt how to use the predictable changes in cellular metabolism or proliferation along the 24h time scale in order to improve treatment outcome for a variety of diseases, including cancer. The chronotherapeutics of malignant diseases has emerged as a result of a consistent development ranging from experimental, clinical, and technological prerequisites to multicenter clinical trials of chronomodulated delivery schedules. Indeed large dosing-time dependencies characterize the tolerability of anticancer agents in mice or rats, a better efficacy usually results from treatment administration near the least toxic circadian time in rodent tumor models. Programmable in time multichannel pumps have allowed to test the chronotherapy concepts in cancer patients and to implement chronomodulated delivery schedules in current practice. Clinical phase I and II trials have established the feasibility, the safety, and the activity of the chronotherapy schedules, so that this treatment method has undergone further evaluation in international multicenter phase III trials. Overall, more than 2000 patients with metastatic disease have been registered in chronotherapy trials. Improved tolerability and/or better antitumor activity have been demonstrated in randomized multicenter studies involving large patient cohorts. The relation between circadian rhythmicity and quality of life and even survival has also been a puzzling finding over the recent years. An essential step toward further developments of circadian-timed therapy has been the recent constitution of a Chronotherapy cooperative group within the European Organization for Research and Treatment of Cancer. This group now involves over 40 institutions in 12 countries. It is conducting currently six trials and preparing four new studies. The 19 contributions in this special issue reflect the current status and perspectives of the several components of cancer chronotherapeutics.     

Time-patterned drug administration: insights from a modeling approach

The physiological effects of a drug depend not only on its molecular structure but also on the time-pattern of its administration. One of the main reasons for the importance of temporal patterns in drug action is biological rhythms—particularly those of circadian period. These rhythms affect most physiological functions as well as drug metabolism, clearance, and dynamic processes that may alter drug availability and target cell responsiveness with reference to biological time. We present an overview of the importance of time-patterned signals in physiology focused on the insights provided by a modeling approach. We first discuss examples of pulsatile intercellular communication by hormones such as gonadotropin-releasing hormone, and by cyclic adenosine monophosphate (cAMP) signals in Dictyostelium amoebae. Models based on reversible receptor desensitization account in both cases for the existence of optimal patterns of pulsatile signaling. Turning to circadian rhythms, we examine how models can be used to account for the response of 24h patterns to external stimuli such as light pulses or gene expression, and to predict how to restore the physiological characteristics of altered rhythms. Time-patterned treatments of cancer involve two distinct lines of research. The first, currently evaluated in clinical trials, relies on circadian chronomodulation of anticancer drugs, while the second, mostly based on theoretical studies, involves a resonance phenomenon with the cell-cycle length. We discuss the implications of modeling studies to improve the temporal patterning of drug administration.     

Time-patterned drug administration: insights from a modeling approach

The physiological effects of a drug depend not only on its molecular structure but also on the time-pattern of its administration. One of the main reasons for the importance of temporal patterns in drug action is biological rhythms—particularly those of circadian period. These rhythms affect most physiological functions as well as drug metabolism, clearance, and dynamic processes that may alter drug availability and target cell responsiveness with reference to biological time. We present an overview of the importance of time-patterned signals in physiology focused on the insights provided by a modeling approach. We first discuss examples of pulsatile intercellular communication by hormones such as gonadotropin-releasing hormone, and by cyclic adenosine monophosphate (cAMP) signals in Dictyostelium amoebae. Models based on reversible receptor desensitization account in both cases for the existence of optimal patterns of pulsatile signaling. Turning to circadian rhythms, we examine how models can be used to account for the response of 24h patterns to external stimuli such as light pulses or gene expression, and to predict how to restore the physiological characteristics of altered rhythms. Time-patterned treatments of cancer involve two distinct lines of research. The first, currently evaluated in clinical trials, relies on circadian chronomodulation of anticancer drugs, while the second, mostly based on theoretical studies, involves a resonance phenomenon with the cell-cycle length. We discuss the implications of modeling studies to improve the temporal patterning of drug administration.     

Effects of Pregnancy and Parturition on Free-Running Circadian Activity Rhythms in the Rat

Alterations in circadian rhythms have previously been associated with estrous and seasonal changes in reproductive state. In the present study we explored the effects of the reproductive events of pregnancy and parturition on free-running circadian activity rhythms in the rat. Free-running rhythms were monitored before mating, during pregnancy, and following parturition and removal of pups. Systematic and long-lasting alterations of the period of the free-running activity rhythm were seen following parturition. The effects of estrous, seasonal, and gestational reproductive states on circadian rhythms may be mediated by the endocrine events which accompany these states.     

Effects of Pregnancy and Parturition on Free-Running Circadian Activity Rhythms in the Rat

Alterations in circadian rhythms have previously been associated with estrous and seasonal changes in reproductive state. In the present study we explored the effects of the reproductive events of pregnancy and parturition on free-running circadian activity rhythms in the rat. Free-running rhythms were monitored before mating, during pregnancy, and following parturition and removal of pups. Systematic and long-lasting alterations of the period of the free-running activity rhythm were seen following parturition. The effects of estrous, seasonal, and gestational reproductive states on circadian rhythms may be mediated by the endocrine events which accompany these states.