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.     

Administration-time differences in the pharmacokinetics of gentamicin intravenously delivered to human beings

Administration-time differences of gentamicin pharmacokinetics were studied by crossover design after a single intravenous administration of gentamicin (80 mg) to 10 human subjects at 09:00 (morning time) and 22:00 (nighttime). The profiles of serum gentamicin concentration showed a significant statistical difference between 09:00 and 22:00, suggesting circadian variations of pharmacokinetic behaviors. A significant circadian rhythm of pharmacokinetic parameters as a function of time of day was noted in human subjects, showing lower total body clearance Clt and higher serum area under the curve (AUC) when given at nighttime. The half-life t1/2 was shorter in the morning (2.82 h +/- 0.43 h) when compared to the nighttime (2.97 h +/- 0.36 h), but the difference was not statistically significant. The AUC was significantly greater in the morning (23.4 +/- 3.84 micrograms-h/mL) than that in the nighttime (26.3 +/- 5.79 micrograms-h/mL) (p < .05), most likely because the Clt was significantly higher when gentamicin was given in the morning (3.51 +/- 0.57 L/h) versus in the nighttime (3.18 +/- 0.65 L/h). Although the volume of distribution Vd decreased when given at nighttime, it was independent of the dosing time. From this study, there was an administration-time difference of gentamicin pharmacokinetics in human beings. The optimized dosing regimen of gentamicin can be decided by considering circadian rhythm and rest-activity routine so that minimized toxicity and effective therapy are established for patients. The current findings also can be applied to other drugs with circadian rhythms of pharmacokinetics and narrow therapeutic windows in clinical chronotherapeutics.     

Diurnal Variation in Insulin-stimulated Systemic Glucose and Amino Acid Utilization in Pigs Fed with Identical Meals at 12-Hour Intervals.

The diurnal variation in insulin-stimulated systemic glucose and amino acid utilization was investigated in eleven pigs of approximately 40 kg. Pigs were fed isoenergetic/isoproteinic diets (366 kJ/kg BW (0.75) per meal) in two daily rations (06:00 and 18:00 h). After a 3-week habituation period, hyperinsulinemic euglycemic euaminoacidemic clamp studies (by intra-portal insulin, glucose and amino acids infusion and arterial blood sampling) were performed starting at 06:00 or 18:00 h (while skipping the meal), using a cross-over within-animal design. Basal (preclamp) plasma concentrations of insulin, glucose, lactate, individual amino acids and urea were similar in the morning compared to the evening. Insulin-stimulated ( approximately 4-fold increase over basal) systemic glucose utilization was similar (17.6+/-1.4 and 18.9+/-1.8 mg.kg (-1).min (-1)) but amino acid utilization was 19% greater in the morning VS. the evening (2.37+/-0.21 VS. 1.99+/-0.15 mg.kg (-1).min (-1), p<0.05), respectively. Insulin-stimulated plasma lactate concentrations remained constant in the morning (0.77+/-0.06 to 0.71+/-0.04 mmol.l (-1)) but declined in the evening (0.89+/-0.09 to 0.65+/-0.06 mmol.l (-1), p<0.05). By contrast, insulin-stimulated plasma urea concentrations declined in the morning (2.48+/-0.11 to 2.03+/-0.10 mmol.l (-1), p<0.005) but remained constant in the evening (2.18+/-0.14 to 2.12+/-0.12 mmol.l (-1)). In conclusion, pigs fed identical meals at 12-hour intervals follow a clear diurnal biorhythm in protein anabolism, with greater insulin-stimulated systemic amino acid utilization and lower plasma urea response in the morning compared to the evening.     

Morning versus evening power output and repeated-sprint ability

We investigated the effect of time-of-day on both maximal sprint power and repeated-sprint ability (RSA). Nine volunteers (22+/-4 yrs) performed a RSA test both in the morning (07:00 to 09:00 h) and evening (17:00 to 19:00 h) on different days in a random order. The RSA cycle test consisted of five, 6 sec maximal sprints interspersed by 24 sec of passive recovery. Both blood lactate concentration and heart rate were higher in the evening than morning RSA (lactate values post exercise: 13+/-3 versus 11+/-3 mmol/L(-1), p<0.05). The peak power developed during the first sprint was higher in the evening than morning (958+/-112 vs. 915+/-133 W, p<0.05), but this difference was not apparent in subsequent sprints, leading to a higher power decrement across the 5x6 sec test in the evening (11+/-2 vs. 7+/-3%, p<0.05). Both the total work during the RSA cycle test and the power developed during bouts 2 to 5 failed to be influenced by time-of-day. This suggests that the beneficial effect of time-of-day may be limited to a single expression of muscular power and fails to advantage performance during repeated sprints.     

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-to-evening differences in oxygen uptake kinetics in short-duration cycling exercise

This study analyzed diurnal variations in oxygen (O(2)) uptake kinetics and efficiency during a moderate cycle ergometer exercise. Fourteen physically active diurnally active male subjects (age 23+/-5 yrs) not specifically trained at cycling first completed a test to determine their ventilatory threshold (T(vent)) and maximal oxygen consumption (VO(2max)); one week later, they completed four bouts of testing in the morning and evening in a random order, each separated by at least 24 h. For each period of the day (07:00-08:30 h and 19:00-20:30 h), subjects performed two bouts. Each bout was composed of a 5 min cycling exercise at 45 W, followed after 5 min rest by a 10 min cycling exercise at 80% of the power output associated with T(vent). Gas exchanges were analyzed breath-by-breath and fitted using a mono-exponential function. During moderate exercise, the time constant and amplitude of VO(2) kinetics were significantly higher in the morning compared to the evening. The net efficiency increased from the morning to evening (17.3+/-4 vs. 20.5+/-2%; p<0.05), and the variability of cycling cadence was greater during the morning than evening (+34%; p<0.05). These findings suggest that VO(2) responses are affected by the time of day and could be related to variability in muscle activity pattern.     

Theophylline Dose-Concentration Relationship of a 12-Hourly Nuelin SA Regimen Supplemented with Nocturnal Nuelin Liquid in Healthy Volunteers

Twelve healthy male volunteers who were diurnally active between 05:00 and 23:00 took part in a randomized, multiple-dose, double-blind, four-way, crossover study to determine the relationship between the dose of a nonsus-tained-release theophylline (NSRT) formulation added to the evening administration of a 12-hourly sustained-release theophylline (SRT) regimen and the elevation of the early morning (between 02:00 and 05:00) steady-state plasma theophylline concentration. The four treatments were 250 mg Nuelin SA (sustained-release theophylline) every 12 h plus either placebo or Nuelin liquid (non-sustained-release theophylline) equivalent to 100 mg, 200 mg, or 300 mg of theophylline. Without evening supplementation (placebo), the early morning plasma theophylline concentrations were 13% lower than the average 24-h concentration. but with evening supplementation the early morning plasma theophylline concentration could be raised up to and above the average 24-h Concentration. A prediction equation for the early morning plasma theophylline concentration as a function of the additional evening dose of Nuelin liquid, and of the steady-state evening trough plasma theophylline concentration without evening supplementation, was established. This prediction equation can be used to determine the additional evening dose of Nuelin liquid (administered at 19:00) needed to reduce early morning bronchoconstriction in asthmatic patients who are on a 12-hourly Nuelin SA (drug administered at 07:00 and 19:00) regimen.     

Theophylline Dose-Concentration Relationship of a 12-Hourly Nuelin SA Regimen Supplemented with Nocturnal Nuelin Liquid in Healthy Volunteers

Twelve healthy male volunteers who were diurnally active between 05:00 and 23:00 took part in a randomized, multiple-dose, double-blind, four-way, crossover study to determine the relationship between the dose of a nonsus-tained-release theophylline (NSRT) formulation added to the evening administration of a 12-hourly sustained-release theophylline (SRT) regimen and the elevation of the early morning (between 02:00 and 05:00) steady-state plasma theophylline concentration. The four treatments were 250 mg Nuelin SA (sustained-release theophylline) every 12 h plus either placebo or Nuelin liquid (non-sustained-release theophylline) equivalent to 100 mg, 200 mg, or 300 mg of theophylline. Without evening supplementation (placebo), the early morning plasma theophylline concentrations were 13% lower than the average 24-h concentration. but with evening supplementation the early morning plasma theophylline concentration could be raised up to and above the average 24-h Concentration. A prediction equation for the early morning plasma theophylline concentration as a function of the additional evening dose of Nuelin liquid, and of the steady-state evening trough plasma theophylline concentration without evening supplementation, was established. This prediction equation can be used to determine the additional evening dose of Nuelin liquid (administered at 19:00) needed to reduce early morning bronchoconstriction in asthmatic patients who are on a 12-hourly Nuelin SA (drug administered at 07:00 and 19:00) regimen.     

Light exposure among adolescents with delayed sleep phase disorder: a prospective cohort study

The objective of this study was to compare light exposure and sleep parameters between adolescents with delayed sleep phase disorder (DSPD; n=16, 15.3±1.8 yrs) and unaffected controls (n=22, 13.7±2.4 yrs) using a prospective cohort design. Participants wore wrist actigraphs with photosensors for 14 days. Mean hourly lux levels from 20:00 to 05:00 h and 05:00 to 14:00 h were examined, in addition to the 9-h intervals prior to sleep onset and after sleep offset. Sleep parameters were compared separately, and were also included as covariates within models that analyzed associations with specified light intervals. Additional covariates included group and school night status. Adolescent delayed sleep phase subjects received more evening (p< .02, 22:00-02:00 h) and less morning (p .05, 08:00-09:00 h and 10:00-12:00 h) light than controls, but had less pre-sleep exposure with adjustments for the time of sleep onset (p< .03, 5-7 h prior to onset hour). No differences were identified with respect to the sleep offset interval. Increased total sleep time and later sleep offset times were associated with decreased evening (p< .001 and p= .02, respectively) and morning (p= .01 and p< .001, respectively) light exposure, and later sleep onset times were associated with increased evening exposure (p< .001). Increased total sleep time also correlated with increased exposure during the 9 h before sleep onset (p= .01), and a later sleep onset time corresponded with decreased light exposure during the same interval (p< .001). Outcomes persisted regardless of school night status. In conclusion, light exposure interpretation requires adjustments for sleep timing among adolescents with DSPD. Pre- and post-sleep light exposures do not appear to contribute directly to phase delays. Sensitivity to morning light may be reduced among adolescents with DSPD.     

Comparison of the efficacy of morning versus evening administration of olmesartan in uncomplicated essential hypertension

A total of 18 diurnally active subjects with uncomplicated, mild to moderate, essential hypertension were studied to compare the efficacy of the morning versus evening administration of an oral olmesartan medication. After a two-week, wash-out/placebo run-in period, subjects with clinic diastolic blood pressure (DBP) > or = 90 mm Hg and <110 mm Hg began 12 weeks of 20 mg olmesartan medoxomil tablet therapy at 08:00 h daily. Four of the 18 subjects required dose escalation to 40 mg at eight weeks because of clinic DBP > or = 90 mm Hg. After the 12-week period of once-a-day 08:00 h treatment, subjects were immediately switched to an evening (20:00 h) drug-ingestion schedule for another 12-week period without change in dose. Subjects underwent 24 h ambulatory blood pressure monitoring (ABPM) before the initiation of morning treatment and at the end of both the 12-week morning and evening treatment arms. Dosing time did not exert statistically significant differences on the efficacy of olmesartan: the reduction from baseline in the 24 h mean systolic (SBP) and DBP was, respectively, 18.8 and 14.6 mm Hg with morning dosing and 16.1 and 13.2 mm Hg with evening dosing (p>0.152 between groups). The amplitude of the BP 24 h pattern did not vary with dosing time, indicating full 24 h BP reduction no matter the clock hour of treatment. Although, the BP-lowering effect was somewhat better with morning dosing, the results of this study suggest that the studied olmesartan medoxomil preparation efficiently reduces BP when ingested in the morning (08:00 h) or evening (20:00 h) in equivalent manner, based on statistical testing, throughout the 24 h.     

Effect of imidapril in dipper and nondipper hypertensive patients: comparison between morning and evening administration

The purpose of the study was to identify differences in the patterns of efficacy and duration of effects of imidapril administered at different times of the day (morning versus evening) in dipper and nondipper hypertensive patients. Twenty patients with untreated hypertension were classified into two groups: dippers (n = 9) and nondippers (n = 11). Imidapril (10 mg) was given at 07:00 or 18:00 for 4 weeks in a crossover fashion. Blood pressure (BP) and heart rate (HR) were monitored before and after morning and evening treatment every 30 min for 48h by ambulatory BP monitoring (ABPM). In dipper hypertension, the mean 48h BP was reduced with both doses. The decrease in the diurnal BP was stronger when the drug was administered in the evening than morning, but without significant difference. In nondipper hypertension, the systolic BP decreased at night with both doses, but the extent of the nocturnal reduction in systolic BP was greater after morning therapy. There were no significant differences in the decrease in BP during the day or night between the morning and evening administrations. When imidapril was administered in the morning, its serum concentration reached a maximum at 16:00, and when the drug was administered in the evening, it reached a maximum at 6:00. In dipper hypertension, the time taken for the blood concentration of imidapril to reach a maximum changed depending on its time of administration, and the time when the maximum antihypertensive effect of the drug appeared was different. In nondipper hypertension, decreases in the BP were confirmed at night regardless of the time of administration; this might be caused by angiotensin converting enzyme (ACE) inhibitors effectively blocking the BP from increasing by activating the parasympathetic nervous system. Therefore, when assessing the effectiveness of antihypertensive agents, factors such as the various patterns of BP before therapy and administration time must be considered.     

Comparison of the Efficacy of Morning versus Evening Administration of Olmesartan in Uncomplicated Essential Hypertension

A total of 18 diurnally active subjects with uncomplicated, mild to moderate, essential hypertension were studied to compare the efficacy of the morning versus evening administration of an oral olmesartan medication. After a two‐week, wash‐out/placebo run‐in period, subjects with clinic diastolic blood pressure (DBP) ≥90 mm Hg and <110 mm Hg began 12 weeks of 20 mg olmesartan medoxomil tablet therapy at 08:00 h daily. Four of the 18 subjects required dose escalation to 40 mg at eight weeks because of clinic DBP≥90 mm Hg. After the 12‐week period of once‐a‐day 08:00 h treatment, subjects were immediately switched to an evening (20:00 h) drug‐ingestion schedule for another 12‐week period without change in dose. Subjects underwent 24 h ambulatory blood pressure monitoring (ABPM) before the initiation of morning treatment and at the end of both the 12‐week morning and evening treatment arms. Dosing time did not exert statistically significant differences on the efficacy of olmesartan: the reduction from baseline in the 24 h mean systolic (SBP) and DBP was, respectively, 18.8 and 14.6 mm Hg with morning dosing and 16.1 and 13.2 mm Hg with evening dosing (p>0.152 between groups). The amplitude of the BP 24 h pattern did not vary with dosing time, indicating full 24 h BP reduction no matter the clock hour of treatment. Although, the BP‐lowering effect was somewhat better with morning dosing, the results of this study suggest that the studied olmesartan medoxomil preparation efficiently reduces BP when ingested in the morning (08:00 h) or evening (20:00 h) in equivalent manner, based on statistical testing, throughout the 24 h.     

Administration-Time Differences in the Pharmacokinetics of Gentamicin Intravenously Delivered to Human Beings

Administration-time differences of gentamicin pharmacokinetics were studied by crossover design after a single intravenous administration of gentamicin (80 mg) to 10 human subjects at 09:00 (morning time) and 22:00 (nighttime). The profiles of serum gentamicin concentration showed a significant statistical difference between 09:00 and 22:00, suggesting circadian variations of pharmacokinetic behaviors. A significant circadian rhythm of pharmacokinetic parameters as a function of time of day was noted in human subjects, showing lower total body clearance Cl_t and higher serum area under the curve (AUC) when given at nighttime. The half-life t_1/2 was shorter in the morning (2.82h ± 0.43h) when compared to the nighttime (2.97h ± 0.36h), but the difference was not statistically significant. The AUC was significantly greater in the morning (23.4 ± 3.84 μg-h/mL) than that in the nighttime (26.3 ± 5.79 μg-h/mL) (p<. 05), most likely because the Cl_t, was significantly higher when gentamicin was given in the morning (3.51 ± 0.57 L/h) versus in the nighttime (3.18 ± 0.65 L/h). Although the volume of distribution V_d decreased when given at nighttime, it was independent of the dosing time. From this study, there was an administration-time difference of gentamicin pharmacokinetics in human beings. The optimized dosing regimen of gentamicin can be decided by considering circadian rhythm and rest-activity routine so that minimized toxicity and effective therapy are established for patients. The current findings also can be applied to other drugs with circadian rhythms of pharmacokinetics and narrow therapeutic windows in clinical chronotherapeutics.     

EFFECT OF IMIDAPRIL IN DIPPER AND NONDIPPER HYPERTENSIVE PATIENTS: COMPARISON BETWEEN MORNING AND EVENING ADMINISTRATION

The purpose of the study was to identify differences in the patterns of efficacy and duration of effects of imidapril administered at different times of the day (morning versus evening) in dipper and nondipper hypertensive patients. Twenty patients with untreated hypertension were classified into two groups: dippers (n = 9) and nondippers (n = 11). Imidapril (10 mg) was given at 07:00 or 18:00 for 4 weeks in a crossover fashion. Blood pressure (BP) and heart rate (HR) were monitored before and after morning and evening treatment every 30 min for 48h by ambulatory BP monitoring (ABPM). In dipper hypertension, the mean 48h BP was reduced with both doses. The decrease in the diurnal BP was stronger when the drug was administered in the evening than morning, but without significant difference. In nondipper hypertension, the systolic BP decreased at night with both doses, but the extent of the nocturnal reduction in systolic BP was greater after morning therapy. There were no significant differences in the decrease in BP during the day or night between the morning and evening administrations. When imidapril was administered in the morning, its serum concentration reached a maximum at 16:00, and when the drug was administered in the evening, it reached a maximum at 6:00. In dipper hypertension, the time taken for the blood concentration of imidapril to reach a maximum changed depending on its time of administration, and the time when the maximum antihypertensive effect of the drug appeared was different. In nondipper hypertension, decreases in the BP were confirmed at night regardless of the time of administration; this might be caused by angiotensin converting enzyme (ACE) inhibitors effectively blocking the BP from increasing by activating the parasympathetic nervous system. Therefore, when assessing the effectiveness of antihypertensive agents, factors such as the various patterns of BP before therapy and administration time must be considered. (Chronobiology International, 17(2), 209–219, 2000)     

Effect of time of day on aerobic contribution to the 30-s Wingate test performance

The purpose of this study was to evaluate the effects of time of day on aerobic contribution during high-intensity exercise. A group of 11 male physical education students performed a Wingate test against a resistance of 0.087 kg . kg(-1) body mass. Two different times of day were chosen, corresponding to the minimum (06:00 h) and the maximum (18:00 h) levels of power. Oxygen uptake (.VO(2)) was recorded breath by breath during the test (30 sec). Blood lactate concentrations were measured at rest, just after the Wingate test, and again 5 min later. Oral temperature was measured before each test and on six separate occasions at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00 h. A significant circadian rhythm was found in body temperature with a circadian acrophase at 18:16+/-00:25 h as determined by cosinor analysis. Peak power (P(peak)), mean power (P(mean)), total work done, and .VO(2) increased significantly from morning to afternoon during the Wingate Test. As a consequence, aerobic contribution recorded during the test increased from morning to afternoon. However, no difference in blood lactate concentrations was observed from morning to afternoon. Furthermore, power decrease was greater in the morning than afternoon. Altogether, these results indicate that the time-of-day effect on performances during the Wingate test is mainly due to better aerobic participation in energy production during the test in the afternoon than in the morning.     

Chronopharmacokinetic study of gentamicin in dogs

The purpose of this experiment was to determine whether the time of day of single intravenous doses of gentamicin affects the drug's pharmacokinetics in dogs maintained under a 12 h light (08:00 to 20:00 h), 12 h dark (20:00 to 08:00 h) cycle. Using a crossover design, 6 mixed-breed male dogs received a single dose of 2 mg/kg of gentamicin at 8:00 or 20:00 h. Serial blood samples were collected and pharmacokinetic parameters were calculated following each timed dose. The concentration of the antibiotic was lower following the 08:00 h compared to the 20:00 h administration. When gentamicin was administered at 20:00 h, the initial concentration, mean residence time, and area under the disposition curve were significantly higher (p < 0.05) and the apparent volume of distribution of the central compartment, apparent volume of distribution, apparent volume of distribution at steady-state, and total body clearance (1.73+/-0.55 at 20:00 h versus 3.31+/-0.67 L/min/kg at 08:00 h) were significantly lower than for the 08:00 h administration (p < 0.05). Our results show that the pharmacokinetics of gentamicin exhibits significant temporal variation when administered to dogs at different times of day.     

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)     

Responses of plasma adrenocorticotropin and cortisol to intravenous injection of synthetic ovine corticotropin releasing factor in the morning and early evening in normal human subjects

This study was designed to compare the responsiveness of adrenocorticotropin (ACTH) and cortisol secretion to corticotropin-releasing factor (CRF) in the morning and early evening in normal human subjects. Synthetic ovine CRF (1.0 micrograms/kg) or normal saline, was administered as an i.v. bolus injection to six normal males at 900 h and 1700 h. Blood samples were obtained before and 15, 30, 60, 90 and 120 min after CRF or saline injection. Significant increases in plasma ACTH and cortisol levels were observed in all subjects at the both time of testing after CRF injection. The net increments in the areas under the concentration curve (areas in the CRF experiment minus those in the saline control experiment) were not statistically different for both ACTH (mean +/- SEM: 41.0 +/- 10.6 pg/ml h in the morning: 51.1 +/- 8.9 pg/ml h in the evening) and cortisol (mean +/- SEM: 28.5 +/- 5.0 micrograms/dl h in the morning; 36.2 +/- 4.0 micrograms/dl h in the evening). Also no significant difference was observed in net increment, peak level and the ratio of peak level to the basal level of ACTH and cortisol after CRF injection. There were no appreciable changes in plasma concentrations of growth hormone, thyroid-stimulating hormone or prolactin, although slight but statistically significant rises in plasma levels of luteinizing hormone and follicle-stimulating hormone were observed. These results suggest that there is no significant difference in responsiveness of the pituitary-adrenal axis to CRF in the morning (900 h) and early evening (1700 h), and thus the time of day will not necessarily have to be considered when CRF is used between these times in a clinical test to evaluate pituitary ACTH reserve.     

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)     

Olfactory discrimination and transient mood change in young men and women: variation by season, mood state, and time of day

Odor performance varies by clinical state and gender, though little is known about its variation by season or time of day. Many odors, including lavender, induce transient mood changes. This study explored discrimination differences between various lavender oil blends and their effects on transient mood in the morning and evening in depressed and nondepressed adults. We also determined seasonal influences on these measures. A total of 169 subjects, 98 women and 71 men (mean age +/- SD, 19.3 +/- 1.6 y) participated, with different subjects studied at different times of the year. The Beck Depression Inventory (BDI) classified subjects as depressed (score > or =10; N= 57) or nondepressed (score <10; N= 112). In the discrimination test, subjects compared pairs of two different lavender oil blends or a control. Transient change in mood was assessed by the Profile of Mood States (POMS) after each trial of five lavender blends interspersed by three control odors. Tests were conducted in the morning (08:00-10:00 h) and evening (18:00-20:00h). In all subjects, discrimination was significantly better for some odor pairs than for others, thus demonstrating test specificity. Discrimination was better overall in the fall than winter/spring and better in depressed than nondepressed subjects for specific odor pairs. No significant gender or time-of-day differences in discriminability were detected. There were, however, significant group differences in transient mood profiles. Current depressed state affected mood response, with lavender increasing anger in depressed subjects only. In addition, depressed subjects and men, whether or not depressed, exhibited diurnal mood variation, with better mood in the evening; the former group also showed more evening energy. All subjects were more confused in the morning than evening. Season also affected transient mood; winter/spring-tested subjects reported more vigor than fall-tested subjects. In addition, summer-tested subjects showed more tension in the morning, whereas fall-tested subjects showed the opposite pattern in the evening. In all subjects, lavender increased fatigue, tension, confusion, and total mood disturbance, and it decreased vigor. The study showed that both chronobiological (seasonal and time-of-day) and clinical factors modify discrimination and mood response to odors. Brief lavender odor presentation may serve as a nonphotic method for altering mood in young depressed and nondepressed adults particularly during the fall, a time of heightened discriminability.